Introduction

General Information Family History as a Risk Factor for Breast Cancer Family History as a Risk Factor for Ovarian Cancer Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition Difficulties in Identifying a Family History of Breast Cancer Risk Other Risk Factors for Breast Cancer         Age         Reproductive and Menstrual History         Hormone Therapy         Radiation Exposure         Lifestyle Factors         History of Breast Disease         Other Factors Other Risk Factors for Ovarian Cancer         Age         Demographic         Reproductive         Surgical History Models for Prediction of Breast Cancer Risk

Major Genes

Introduction BRCA1 BRCA2 BRCA1 and BRCA2 Function Mutations in BRCA1 and BRCA2 Prevalence and Founder Effects Penetrance of Mutations Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation         Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation Role of BRCA1 and BRCA2 in Sporadic Cancer Molecular Correlations Pathology/Prognosis of Breast Cancer Pathology/Prognosis of Ovarian Cancer Li-Fraumeni Syndrome CHEK2 Cowden’s Syndrome Ataxia Telangiectasia Peutz-Jeghers Syndrome

Genetic Polymorphisms and Breast Cancer Risk

Background Summary of Evidence Significance         Cytochrome p450 Enzymes         N-acetyl transferase 1 and N-acetyl transferase 2         Glutathione S-transferase

Interventions

Breast Cancer         Screening         Screening Strategies Under Evaluation for Which Utility Has Not Been Established         Prevention Ovarian Cancer         Screening         Prevention

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction Anticipated and Actual Interest in Genetic Testing What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics Genetic Counseling for Hereditary Predisposition to Breast Cancer Emotional Outcomes of Individuals Family Effects Cultural/Community Effects Ethical Concerns Psychological Aspects of Medical Interventions Psychosocial Outcome Studies Interventions: Psychological Behavioral Outcomes

Disclaimer
Changes to This Summary 09/30/2004
More Information

Introduction

General Information

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and is the second leading cause of cancer deaths after lung cancer. In 2004, an estimated 217,440 new cases will be diagnosed, and 40,580 deaths from breast cancer will occur.[1] (Refer to the PDQ summary on Breast Cancer Treatment ¹ for more information on breast cancer rates, diagnosis, and management.)

A possible genetic contribution to breast cancer risk is indicated by the increased incidence of breast cancer among women with a family history of breast cancer, and by the observation of rare families in which multiple family members are affected with breast cancer, in a pattern compatible with autosomal dominant inheritance of cancer susceptibility.

Formal studies of families (linkage analysis) have subsequently proven the existence of an autosomal dominant form of breast cancer, and have led to the identification of several highly penetrant genes of major effect as the cause of inherited cancer risk in many cancer-prone families. (Refer to the PDQ summary Cancer Genetics Overview ² for more information on linkage analysis.) These mutations are rare and are estimated to account for no more than 5% to 10% of breast cancer cases overall. It is likely that other background genetic factors contribute to the etiology of breast cancer.

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree or a second-degree relative with breast cancer.[2-5] The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.[6] In a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval (CI) 2.0-2.2).[6]

Risk varies with the age at which the affected relative was diagnosed: the younger the affected relative, the greater the risk posed to relatives.[2-4,6-8] This effect was strongest for women younger than 50 years who had a first-degree relative affected before age 50 years.[6]

The number of affected relatives and the closeness of their biologic relationship are also important factors.[3,4,6] In general, the larger the number of affected relatives and the closer the biologic relationship, the greater the risk.[3,4,6] The number of female relatives in the family influences both utility and significance of the family history. In families with few women, it may be difficult to identify a genetic susceptibility to cancer. If a family has many female members, the proportion of affected relatives may be a more important indicator of risk than the number of affected relatives.

Studies of family history of ovarian cancer suggest an association with breast cancer risk. A first-degree relative with ovarian cancer confers a modest risk of breast cancer, e.g., the odds ratio (OR) derived from a case-control study based on the Utah Cancer Registry was 1.27 (95% CI 0.91-1.77),[9] and other studies have found no evidence of increased risk.[7,10] When the Utah data were analyzed according to a family history score (based on characteristics that included number of relatives with ovarian cancer, their age of diagnosis, and biologic relatedness), however, the OR for women with a score of 5 or higher (3% of the population) was 1.60 (95% CI 1.03-2.43); for women with scores of 2.0 to 4.9 (12% of the population), the OR was 1.15 (95% CI 1.01-1.36).[9] The presence of both breast and ovarian cancer in a family increases the likelihood that a cancer-predisposing mutation is present.[11,12]

In the United States the lifetime risk for developing ovarian cancer is approximately 1/70, or 1.4%. Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A population-based case-control study evaluated the degree of aggregation of epithelial ovarian cancer in families. In this study of nearly 3,000 ovarian cancer cases and controls, a familial clustering of ovarian cancer was noted. The OR for ovarian cancer in relatives of ovarian cancer cases compared with controls was 3.6 for first-degree relatives and 2.9 for second-degree relatives.[13]

Pooled estimates of relative risk from 7 case-control studies, including the Cancer and Steroid Hormone (CASH) study, were derived. The estimated OR for ovarian cancer was 3.1 (95% CI 2.1-4.5) for a woman with a single first-degree relative with ovarian cancer, and 4.6 (95% CI 1.1-18.4) for a woman with 2 or 3 relatives with ovarian cancer. This translates into lifetime probabilities of ovarian cancer of 5.0% and 7.2%, respectively.[14]

An analysis of published case-control and cohort studies in ovarian cancer that included nearly 18,000 women was performed. In this series, the relative risk of ovarian cancer for women with a first-degree family history of ovarian cancer was 3.1, which is consistent with that reported by others. In this study, the relative risk to mothers of ovarian cancer cases was substantially lower than the relative risk to sisters and daughters. The lower cancer risk to mothers observed in this study is not easily explained.[15]

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, with approximately 50% of individuals inheriting the predisposing genetic alteration. The susceptibility may be inherited through either the mother’s or the father’s side of the family.

• Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. Although the predisposition is inherited by ~50% of the offspring, it is important to remember that not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted expression.



• Both males and females can inherit and transmit an autosomal dominant cancer predisposition. Thus, the mutant gene can be passed on to either male or female children. In the case of breast cancer, the cancer risk is manifested primarily in women; males with the inherited breast cancer predisposition (especially BRCA2-related) may develop breast cancer as well, but it is still rare in this setting. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters.

Once this dominant inheritance pattern has been established through analysis of family history (pedigree analysis), the task becomes one of determining a diagnosis of a specific cancer susceptibility syndrome, since the susceptibility can be due to different genetic syndromes for any given type of cancer, such as breast cancer.

The syndromes most associated thus far with an autosomal dominant inheritance of breast cancer risk are hereditary breast and ovarian cancer due to BRCA1 or BRCA2 mutations, Li-Fraumeni syndrome ³ due to TP53 mutations, and Cowden syndrome ⁴ due to PTEN mutations.[16] Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities. The specific phenotypic characteristics are discussed later in this section.

Other genetic syndromes that may include breast cancer as an associated feature include ataxia telangiectasia ⁵ and Peutz-Jeghers syndrome ⁶. Ovarian cancer has also been associated with basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 ⁷ (MEN1), and hereditary nonpolyposis colon cancer ⁸ (HNPCC). In addition, a variety of other genes have alterations that probably produce effects that are less recognizable as autosomal dominant genetic syndromes. Some of these are discussed in the Genetic Polymorphisms and Breast Cancer Risk ⁹ section of this summary.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

• Cancers that typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).



• Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast and ovarian cancer in the same individual).



• Cases of male breast cancer.



• Possible increased risk of other selected cancers for males and females. (Refer to the Major Genes ¹⁰ section of this summary for more information.)

The accuracy and completeness of family history data must be taken into account in using family history to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. In the case of breast cancer, cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain.

A comparison of self-reported family history with data from the Utah Population Database indicates a sensitivity of 83% (95% CI 66%-93%) for reported family history of breast cancer; a measure of overall agreement between the reported family history and the database (kappa score) was 0.63 (95% CI 0.52-0.73), indicating moderate agreement.[17] Family history was less accurate for most other cancers, e.g., the sensitivity of a family history of ovarian cancer was 60% (95% CI 17%-93%), with a kappa score of 0.36 (95% CI 0.26-0.48).[17] In a Canadian study, accuracy of a reported family history of breast cancer was assessed through review of the medical records of relatives reported as affected for a consecutive series of women with breast cancer and for a population-based sample of women without breast cancer.[18] Among cases, 16% reported a first-degree relative with breast cancer; 91% of verifiable histories were confirmed. Among controls, 9% reported a first-degree relative with breast cancer; 97% of verifiable histories were confirmed.[18]

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, lifestyle factors, and history of breast disease. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to breast cancer.

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[19] In women with a genetic susceptibility, breast cancer tends to occur at an earlier age than in sporadic cases. However, the frequency of genetic mutations related to breast cancer risk is small even among women with breast cancer at an early age. For example, a population-based study in western Washington identified BRCA1 mutations in 6.2% of women diagnosed with breast cancer before age 35 years.[20] In a population-based North Carolina study, BRCA1 mutations were found in 3.3% of white women and in no black women diagnosed with breast cancer. Diagnosis at a young age did not predict carrier status in this study.[21]

In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 mutations is in the 40s.[22] Estimates of risk obtained using the Claus model, a statistical model based on data from the Cancer and Steroid Hormone Study (discussed further below), also suggest an earlier age of onset in women who have a mother or sister affected with breast cancer at an early age.[23]

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. In the Nurses’ Health Study, these factors influenced breast cancer risk only among women who did not have a mother or sister with breast cancer.[24] In women with known mutations of the BRCA1 gene, however, a protective effect has been seen with early age at first live birth, and also with parity of 3 or more.[25,26] These same studies found a higher rate of cancer and earlier age of cancer diagnosis in recent birth cohorts of women with BRCA1 mutations, compared with older relatives. This difference was only partially explained by differences in reproductive history, suggesting that other factors may also influence risk in this genetically susceptible group.[25,26] In both the general population and BRCA1 carriers, some evidence exists of a slight-to-moderate reduction in breast cancer risk with breast-feeding for at least one year.[27,28]

Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. A meta-analysis of data from 54 studies identified a relative risk (RR) of 1.24 (95% CI 1.15-1.33) for current users; 10 or more years after stopping, no difference was seen.[29] Further, the cancers diagnosed in women who had ever used hormonal contraceptives were less advanced than those in nonusers, raising the possibility that the small excess among users was due to increased detection. Breast cancer risk associated with hormonal contraceptive use did not appear to vary with family history of breast cancer.[29]

Oral contraception, sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, may increase breast cancer risk. In a small study of Jewish women with in situ or invasive breast cancer occurring before age 40 years, those with BRCA1 or BRCA2 mutations (14 of 50, or 28%) had a higher likelihood of long-term oral contraceptive use before their first pregnancy. This result was interpreted to suggest a higher risk of breast cancer with oral contraceptive use in women carrying such mutations.[30] In a case-control study of more than 1,300 pairs of women, each case was matched to a woman with a mutation in the same gene, born within 2 years of the case, and in the same country, who had not developed cancer. Oral contraceptive use was associated with a statistically significant 20% (CI 2%-40%) increase in risk of breast cancer among BRCA1 mutation carriers, particularly if use:

• Began before 1975, a period when estrogen doses were relatively high (38% increase, CI 11%-72%).
• Began before age 30 years (29% increase, CI 9%-52%).
• Lasted for 5 or more years (33% increase, CI 11%-60%).[31]

There was no increased risk associated with use among BRCA2 mutation carriers.

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal hormone replacement therapy (HRT) and breast cancer. A meta-analysis of data from 51 observational studies indicated a relative risk of breast cancer of 1.35 (95% CI 1.21-1.49) for women who had used HRT for 5 or more years after menopause.[32] Another observational study, published after the meta-analysis, also observed a significant increased risk for long-term use in a nested case-control study from Puget Sound.[33]

The Women's Health Initiative (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and 2 trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[34,35] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs 185 cases) and invasive (199 vs 150) breast cancers (RR 1.24, 95% CI 1.02-1.5, P<.001) in women randomized to receive estrogen and progestin.[35] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[35]

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[36-40,32] The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history. The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[35] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[32,41] No data exist regarding the effect of hormone replacement use on breast cancer risk among carriers of BRCA1 or BRCA2 mutations.

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear. In a case report of a family with multiple cases of breast cancer in a single generation, the cancers were associated with repeated fluoroscopic exposure in childhood.[42] Lymphocytes from affected family members demonstrated reduced efficiency of repair of x-ray-induced DNA breaks, suggesting that the breast cancers could have resulted from a genetic susceptibility to the mutagenic effect of radiation exposure.[42] A small follow-up study found evidence of suboptimal repair of x-ray-induced DNA breaks in 12 of 17 women at increased breast cancer risk due to a positive family history, compared with 6 of 19 controls subjects (OR 5.2, 95% CI 1.04-28.57).[43]

In vitro studies of BRCA1 and BRCA2 function suggest a possible role for these genes in x-ray-induced DNA repair. Mouse cells lacking the BRCA1 protein have been shown to be deficient in repair of oxidative DNA damage (the kind of damage caused by ionizing radiation), and to have reduced survival after exposure to x-rays.[44] While human tumor cells deficient in the BRCA2 protein also demonstrate deficiencies in the repair of radiation-induced DNA breaks, cells that carry a mutated copy of BRCA2 and a normal copy have normal repair.[45] These preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations. Since mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation damaged the normal copy of the gene.

Increased sensitivity to radiation has also been postulated as a source of increased breast cancer risk among carriers of mutations in the ataxia telangiectasia gene.[46,47]

Radiation sensitivity has also been reported in Li-Fraumeni syndrome (LFS) and is associated with a greatly increased rate of multiple primary malignancies in persons with this disorder (57% cumulative probability of second malignancy 30 years after diagnosis of a first cancer).[48] Breast cancer is the most common tumor in LFS families, occurring at an average age of 37 years.[49]

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers.[50] Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Empiric data are needed to address these questions.

Several lifestyle factors are associated with breast cancer risk. These lifestyle factors include weight gain, obesity, fat intake, and level of physical activity. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.)

Weight gain and being overweight are commonly recognized risk factors for breast cancer, with overweight women most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations. Similarly, alcohol consumption and a high-fat diet may be associated with an increased risk.

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer).[51] The risk of developing breast cancer varies by the result of the breast biopsy (i.e., type of benign breast disease). The risk among women with atypical hyperplasia is 2.5 to 5.3 times that among women with nonproliferative BBD. Women who have proliferative disease without atypia are at a 1.6-fold to 1.9-fold risk.[52-54] Even among women with fibroadenomas who have no evidence of proliferative disease, breast cancer risk is increased 40% to 90% over an average of 22 years of follow-up.[55]

In several studies, the association between types of BBD and breast cancer differed in certain subgroups. For example, a study found that the association between atypical hyperplasia and breast cancer was stronger among premenopausal women (OR = 5.9) than among postmenopausal women (OR = 2.3).[54] In this study, the association of proliferative BBD (with or without atypia) with breast cancer was stronger among women who reported a positive family history of breast cancer (mother or sister) than among women who reported no such history, confirming the stronger relationship that was reported in another study between atypical hyperplasia and breast cancer among women with a positive family history of breast cancer.[52]

A meta-analysis of 6 studies found evidence for a cumulative risk of breast cancer of 19% by age 50 years for women with both a positive family history (mother or sister with breast cancer) and a previous breast biopsy showing atypical hyperplasia.[56] No studies have assessed the predictive value of atypical hyperplasia in women carrying autosomal dominant cancer-predisposing mutations.

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram.[57,58] This increased risk occurs in both premenopausal and postmenopausal women.[58] Compared with women with no visible breast density, a breast density of 75% or greater is associated with an approximately 5-fold increase in risk (95% CI 3.6-7.1).[58] Some observational studies suggest the possibility of a genetic contribution to breast density.[59-61]

Women with a previous primary breast cancer have a 3-fold to 4-fold increase in risk of a second breast cancer in the contralateral breast.[62] Most studies report an annual risk of development of a second breast cancer of 0.5% to 0.7%.[63] While the risk of contralateral breast cancer persists for up to 30 years after the original diagnosis, the median interval between primary breast cancer and contralateral disease is approximately 4 years.[64]

Although risk is similar following invasive and in situ ductal cancer, it is higher for women with a family history of breast cancer, and for those with a lobular histology in the original cancer.[65] Lobular carcinoma in situ (LCIS), which is often an incidental finding in breast biopsies, is associated with an increased risk of subsequent invasive cancer. Long-term follow-up studies of women diagnosed with LCIS report relative risks of developing breast cancer ranging from 7 to 12. Risks are higher for women diagnosed at a younger age, and for those with a family history of breast cancer. Subsequent breast cancers are most often of ductal histology, and occur equally in either breast, suggesting that LCIS is a marker of risk rather than a precancerous lesion itself.[66]

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in subgroups of women defined according to genotype. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer.[67] This possible gene-environment interaction has varied in some reported studies according to whether the breast cancers occurred premenopausally or postmenopausally. The clinical significance of these emerging findings remains to be defined.

Ethnicity has been inconsistently associated with breast cancer in earlier studies that did not examine associations with genetic mutations or polymorphisms. Even when associations with ethnic factors have been identified, the magnitude of the associations has often been modest. Such inconsistently identified, weak associations with ethnicity may well have been due to uncontrolled confounding by reproductive factors and other established risk factors for breast cancer, rather than to genetic factors such as specific mutations of BRCA1 and BRCA2 breast cancer genes that are now known to occur with increased frequency in certain populations due to founder effects. Nevertheless, the use of genetic markers in epidemiologic studies may help to clarify associations with purported risk factors for breast cancer where the causality of the associations or biologic mechanisms are uncertain.

Other risk factors for ovarian cancer include age, demographics, and reproductive and surgical history. (Refer to the PDQ summary on Prevention of Ovarian Cancer ¹² for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer.

Risk for ovarian cancer increases as a woman gets older. Before age 30 years, the risk of developing ovarian cancer is remote; even in hereditary cancer families, epithelial ovarian cancer is virtually nonexistent before age 20 years. Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, although at a slower rate, thereafter. The highest incidence is found in the eighth decade of life, with a rate of 57 cases per 100,000 women aged 75 to 79 years, compared with 16 cases per 100,000 women aged 40 to 44 years.[68]

Ovarian cancer incidence varies significantly depending on country of birth, and ranges from a high of 14.9 cases per 100,000 women in Sweden to a low of 2.7 cases per 100,000 women in Japan.[69] Incidence in the United States is 13.3 cases per 100,000 women. Immigration appears to alter the risk to match that of the host country. Offspring of Japanese immigrants to the United States have an increased risk of developing ovarian cancer that approaches the rate among women born in the United States, indicating a possible role for dietary and environmental factors.

Nulliparity is associated with an increased risk of ovarian cancer. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[70] A small subset from a large retrospective cohort study did not confirm a strong link between infertility drugs and ovarian cancer risk.[71] Evidence is growing that the use of menopausal hormone replacement therapy is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[72,73] In a prospective study of 329 incident ovarian cancer cases in the Breast Cancer Detection Demonstration Project, use of estrogen only was associated with a significant 60% increased risk of ovarian cancer, and the risk increased with increasing duration of use.[74] In the WHI, 38 incident ovarian cancers were identified, and the hazard ratio for those taking estrogen plus progestin was 1.6 (95% CI 0.8-3.2) compared with the placebo group.[75] No data exist regarding risk either in those with a family history of breast or ovarian cancer or in BRCA1/2 mutation carriers. Data on the role of age at menarche and age at menopause are inconsistent.

Bilateral tubal ligation and hysterectomy have also been reported to be associated with reduced ovarian cancer risk.[70,76,77] A retrospective study and a prospective study have reported a >90% reduction in risk of ovarian cancer in women with documented BRCA1 or BRCA2 mutations who chose prophylactic oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[78,79] For further information on these studies refer to the Ovarian Ablation ¹³ section of this summary.

Models to predict an individual’s lifetime risk for developing breast cancer are available. In addition, models ¹⁴ exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to the study population on which the model was based. The table, Characteristics of the Gail and Claus Models ¹⁵, summarizes the salient aspects of the risk assessment models and is designed to aid in choosing the one that best applies to a particular individual.

Two models for predicting breast cancer risk, the Claus model [23] and the Gail model,[51] are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the 2 models may differ for an individual patient. These models, however, represent the best methods currently available for individual risk assessment.

It is important to note that these models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. In those cases, Mendelian risks would apply. A 3-generation cancer family history is taken before applying any model. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling ¹⁶ for more information on Taking a Family History ¹⁷.) Generally, the Claus or Gail models should not be used for families with 1 of the following characteristics:

• Three individuals with breast or ovarian cancer (especially when 1 or more breast cancers are diagnosed before age 50 years).
• A woman who has both breast and ovarian cancer.
• Ashkenazi Jewish ancestry with at least 1 case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography.[83-87] While the model is reliable in predicting the number of breast cancer cases expected in a group of women from the same age-risk strata, it is less reliable in predicting risk for individual patients. Risk can be overestimated in:

• Noncompliant women (i.e., not compliant with screening).[83,84]
• Women in the highest risk strata.[86]

Risk could be underestimated in the lowest risk strata.[86] Earlier studies [83,84] suggested risk was overpredicted in younger women and underpredicted in older women. More recent studies [85,86] using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations.[87]

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model and the Claus model in predicting breast cancer risk.[88] The 2 models were positively correlated ®=.55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.

The Gail model is the basis for the Breast Cancer Risk Assessment Tool ¹⁸, a computer program that is available from the NCI by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237, or TTY at 1-800-332-8615). This version of the Gail Model estimates only the risk of invasive breast cancer.

References

1. American Cancer Society.: Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society, 2004. Also available online. ¹⁹ Last accessed September 27, 2004. 
   
   
2. Yang Q, Khoury MJ, Rodriguez C, et al.: Family history score as a predictor of breast cancer mortality: prospective data from the Cancer Prevention Study II, United States, 1982-1991. Am J Epidemiol 147 (7): 652-9, 1998.  [PUBMED Abstract]
   
   
3. Colditz GA, Willett WC, Hunter DJ, et al.: Family history, age, and risk of breast cancer. Prospective data from the Nurses' Health Study. JAMA 270 (3): 338-43, 1993.  [PUBMED Abstract]
   
   
4. Slattery ML, Kerber RA: A comprehensive evaluation of family history and breast cancer risk. The Utah Population Database. JAMA 270 (13): 1563-8, 1993.  [PUBMED Abstract]
   
   
5. Johnson N, Lancaster T, Fuller A, et al.: The prevalence of a family history of cancer in general practice. Fam Pract 12 (3): 287-9, 1995.  [PUBMED Abstract]
   
   
6. Pharoah PD, Day NE, Duffy S, et al.: Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer 71 (5): 800-9, 1997.  [PUBMED Abstract]
   
   
7. Negri E, Braga C, La Vecchia C, et al.: Family history of cancer and risk of breast cancer. Int J Cancer 72 (5): 735-8, 1997.  [PUBMED Abstract]
   
   
8. Hemminki K, Vaittinen P: Familial breast cancer in the family-cancer database. Int J Cancer 77 (3): 386-91, 1998.  [PUBMED Abstract]
   
   
9. Kerber RA, Slattery ML: The impact of family history on ovarian cancer risk. The Utah Population Database. Arch Intern Med 155 (9): 905-12, 1995.  [PUBMED Abstract]
   
   
10. Auranen A, Pukkala E, Mäkinen J, et al.: Cancer incidence in the first-degree relatives of ovarian cancer patients. Br J Cancer 74 (2): 280-4, 1996.  [PUBMED Abstract]
    
    
11. Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997.  [PUBMED Abstract]
    
    
12. Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997.  [PUBMED Abstract]
    
    
13. Schildkraut JM, Thompson WD: Familial ovarian cancer: a population-based case-control study. Am J Epidemiol 128 (3): 456-66, 1988.  [PUBMED Abstract]
    
    
14. Kerlikowske K, Brown JS, Grady DG: Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstet Gynecol 80 (4): 700-7, 1992.  [PUBMED Abstract]
    
    
15. Stratton JF, Pharoah P, Smith SK, et al.: A systematic review and meta-analysis of family history and risk of ovarian cancer. Br J Obstet Gynaecol 105 (5): 493-9, 1998.  [PUBMED Abstract]
    
    
16. Lindor NM, Greene MH: The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst 90 (14): 1039-71, 1998.  [PUBMED Abstract]
    
    
17. Kerber RA, Slattery ML: Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146 (3): 244-8, 1997.  [PUBMED Abstract]
    
    
18. Parent ME, Ghadirian P, Lacroix A, et al.: The reliability of recollections of family history: implications for the medical provider. J Cancer Educ 12 (2): 114-20, 1997 Summer.  [PUBMED Abstract]
    
    
19. Feuer EJ, Wun LM, Boring CC, et al.: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85 (11): 892-7, 1993.  [PUBMED Abstract]
    
    
20. Malone KE, Daling JR, Thompson JD, et al.: BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 279 (12): 922-9, 1998.  [PUBMED Abstract]
    
    
21. Newman B, Mu H, Butler LM, et al.: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279 (12): 915-21, 1998.  [PUBMED Abstract]
    
    
22. Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.  [PUBMED Abstract]
    
    
23. Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.  [PUBMED Abstract]
    
    
24. Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.  [PUBMED Abstract]
    
    
25. Narod S, Lynch H, Conway T, et al.: Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341 (8852): 1101-2, 1993.  [PUBMED Abstract]
    
    
26. Narod SA, Goldgar D, Cannon-Albright L, et al.: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64 (6): 394-8, 1995.  [PUBMED Abstract]
    
    
27. Collaborative Group on Hormonal Factors in Breast Cancer.: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002.  [PUBMED Abstract]
    
    
28. Jernström H, Lubinski J, Lynch HT, et al.: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96 (14): 1094-8, 2004.  [PUBMED Abstract]
    
    
29. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996.  [PUBMED Abstract]
    
    
30. Ursin G, Henderson BE, Haile RW, et al.: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57 (17): 3678-81, 1997.  [PUBMED Abstract]
    
    
31. Narod SA, Dubé MP, Klijn J, et al.: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94 (23): 1773-9, 2002.  [PUBMED Abstract]
    
    
32. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350 (9084): 1047-59, 1997.  [PUBMED Abstract]
    
    
33. Chen CL, Weiss NS, Newcomb P, et al.: Hormone replacement therapy in relation to breast cancer. JAMA 287 (6): 734-41, 2002.  [PUBMED Abstract]
    
    
34. Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.  [PUBMED Abstract]
    
    
35. Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.  [PUBMED Abstract]
    
    
36. Schuurman AG, van den Brandt PA, Goldbohm RA: Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control 6 (5): 416-24, 1995.  [PUBMED Abstract]
    
    
37. Steinberg KK, Thacker SB, Smith SJ, et al.: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265 (15): 1985-90, 1991.  [PUBMED Abstract]
    
    
38. Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997.  [PUBMED Abstract]
    
    
39. Stanford JL, Weiss NS, Voigt LF, et al.: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274 (2): 137-42, 1995.  [PUBMED Abstract]
    
    
40. Colditz GA, Egan KM, Stampfer MJ: Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 168 (5): 1473-80, 1993.  [PUBMED Abstract]
    
    
41. Gorsky RD, Koplan JP, Peterson HB, et al.: Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 83 (2): 161-6, 1994.  [PUBMED Abstract]
    
    
42. Helzlsouer KJ, Harris EL, Parshad R, et al.: Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the development of breast cancer. Int J Cancer 64 (1): 14-7, 1995.  [PUBMED Abstract]
    
    
43. Helzlsouer KJ, Harris EL, Parshad R, et al.: DNA repair proficiency: potential susceptiblity factor for breast cancer. J Natl Cancer Inst 88 (11): 754-5, 1996.  [PUBMED Abstract]
    
    
44. Gowen LC, Avrutskaya AV, Latour AM, et al.: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281 (5379): 1009-12, 1998.  [PUBMED Abstract]
    
    
45. Abbott DW, Freeman ML, Holt JT: Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90 (13): 978-85, 1998.  [PUBMED Abstract]
    
    
46. Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66 (6 Suppl): S177-82, 1994.  [PUBMED Abstract]
    
    
47. Kastan M: Ataxia-telangiectasia--broad implications for a rare disorder. N Engl J Med 333 (10): 662-3, 1995.  [PUBMED Abstract]
    
    
48. Hisada M, Garber JE, Fung CY, et al.: Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 90 (8): 606-11, 1998.  [PUBMED Abstract]
    
    
49. Kleihues P, Schäuble B, zur Hausen A, et al.: Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150 (1): 1-13, 1997.  [PUBMED Abstract]
    
    
50. Pierce LJ, Strawderman M, Narod SA, et al.: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18 (19): 3360-9, 2000.  [PUBMED Abstract]
    
    
51. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.  [PUBMED Abstract]
    
    
52. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312 (3): 146-51, 1985.  [PUBMED Abstract]
    
    
53. Carter CL, Corle DK, Micozzi MS, et al.: A prospective study of the development of breast cancer in 16,692 women with benign breast disease. Am J Epidemiol 128 (3): 467-77, 1988.  [PUBMED Abstract]
    
    
54. London SJ, Connolly JL, Schnitt SJ, et al.: A prospective study of benign breast disease and the risk of breast cancer. JAMA 267 (7): 941-4, 1992.  [PUBMED Abstract]
    
    
55. Dupont WD, Page DL, Parl FF, et al.: Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 331 (1): 10-5, 1994.  [PUBMED Abstract]
    
    
56. Unic I, Stalmeier PF, Peer PG, et al.: A review on family history of breast cancer: screening and counseling proposals for women with familial (non-hereditary) breast cancer. Patient Educ Couns 32 (1-2): 117-27, 1997 Sep-Oct.  [PUBMED Abstract]
    
    
57. Boyd NF, Byng JW, Jong RA, et al.: Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87 (9): 670-5, 1995.  [PUBMED Abstract]
    
    
58. Byrne C, Schairer C, Wolfe J, et al.: Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87 (21): 1622-9, 1995.  [PUBMED Abstract]
    
    
59. Pankow JS, Vachon CM, Kuni CC, et al.: Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 89 (8): 549-56, 1997.  [PUBMED Abstract]
    
    
60. Boyd NF, Lockwood GA, Martin LJ, et al.: Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst 91 (16): 1404-8, 1999.  [PUBMED Abstract]
    
    
61. Vachon CM, King RA, Atwood LD, et al.: Preliminary sibpair linkage analysis of percent mammographic density. J Natl Cancer Inst 91 (20): 1778-9, 1999.  [PUBMED Abstract]
    
    
62. Kelsey JL, Gammon MD: The epidemiology of breast cancer. CA Cancer J Clin 41 (3): 146-65, 1991 May-Jun.  [PUBMED Abstract]
    
    
63. Singletary SE, Taylor SH, Guinee VF, et al.: Occurrence and prognosis of contralateral carcinoma of the breast. J Am Coll Surg 178 (4): 390-6, 1994.  [PUBMED Abstract]
    
    
64. Cook LS, White E, Schwartz SM, et al.: A population-based study of contralateral breast cancer following a first primary breast cancer (Washington, United States) Cancer Causes Control 7 (3): 382-90, 1996.  [PUBMED Abstract]
    
    
65. Habel LA, Moe RE, Daling JR, et al.: Risk of contralateral breast cancer among women with carcinoma in situ of the breast. Ann Surg 225 (1): 69-75, 1997.  [PUBMED Abstract]
    
    
66. Bodian CA, Perzin KH, Lattes R: Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer 78 (5): 1024-34, 1996.  [PUBMED Abstract]
    
    
67. Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.  [PUBMED Abstract]
    
    
68. Amos CI, Struewing JP: Genetic epidemiology of epithelial ovarian cancer. Cancer 71 (2 Suppl): 566-72, 1993.  [PUBMED Abstract]
    
    
69. Heintz AP, Hacker NF, Lagasse LD: Epidemiology and etiology of ovarian cancer: a review. Obstet Gynecol 66 (1): 127-35, 1985.  [PUBMED Abstract]
    
    
70. Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 136 (10): 1184-203, 1992.  [PUBMED Abstract]
    
    
71. Brinton LA, Lamb EJ, Moghissi KS, et al.: Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 103 (6): 1194-203, 2004.  [PUBMED Abstract]
    
    
72. Rodriguez C, Patel AV, Calle EE, et al.: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 285 (11): 1460-5, 2001.  [PUBMED Abstract]
    
    
73. Riman T, Dickman PW, Nilsson S, et al.: Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 94 (7): 497-504, 2002.  [PUBMED Abstract]
    
    
74. Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.  [PUBMED Abstract]
    
    
75. Anderson GL, Judd HL, Kaunitz AM, et al.: Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 290 (13): 1739-48, 2003.  [PUBMED Abstract]
    
    
76. Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.  [PUBMED Abstract]
    
    
77. Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA 270 (23): 2813-8, 1993.  [PUBMED Abstract]
    
    
78. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.  [PUBMED Abstract]
    
    
79. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.  [PUBMED Abstract]
    
    
80. Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003.  [PUBMED Abstract]
    
    
81. Rubinstein WS, O'Neill SM, Peters JA, et al.: Mathematical modeling for breast cancer risk assessment. State of the art and role in medicine. Oncology (Huntingt) 16 (8): 1082-94; discussion 1094, 1097-9, 2002.  [PUBMED Abstract]
    
    
82. Rhodes DJ: Identifying and counseling women at increased risk for breast cancer. Mayo Clin Proc 77 (4): 355-60; quiz 360-1, 2002.  [PUBMED Abstract]
    
    
83. Bondy ML, Lustbader ED, Halabi S, et al.: Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst 86 (8): 620-5, 1994.  [PUBMED Abstract]
    
    
84. Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.  [PUBMED Abstract]
    
    
85. Rockhill B, Spiegelman D, Byrne C, et al.: Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93 (5): 358-66, 2001.  [PUBMED Abstract]
    
    
86. Costantino JP, Gail MH, Pee D, et al.: Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst 91 (18): 1541-8, 1999.  [PUBMED Abstract]
    
    
87. Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.  [PUBMED Abstract]
    
    
88. McTiernan A, Kuniyuki A, Yasui Y, et al.: Comparisons of two breast cancer risk estimates in women with a family history of breast cancer. Cancer Epidemiol Biomarkers Prev 10 (4): 333-8, 2001.  [PUBMED Abstract]
    
    

Major Genes

Introduction

Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. In most cases an extensive family history (more than 4 relatives in the same biologic line affected) is not present. In some families, however, inherited factors are clearly the major component of an individual’s cancer risk. We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The recent isolation of several of these genes associated with a significantly increased risk of breast/ovarian cancer make it possible to identify families who carry mutations in these genes. Mutation carriers who have a risk of developing breast cancer that may exceed 50% comprise no more than 5% to 10% of all breast cancer cases.

Hereditary breast cancer is characterized by early age at onset (on average 5-15 years earlier than sporadic cases), bilaterality, vertical transmission through both maternal and paternal lines, and familial association with tumors of other organs, particularly the ovary and prostate gland.[1-3]

The clinical evidence of an autosomal dominant inherited predisposition to breast cancer has been supported by segregation analysis, a statistical genetics method to determine if a particular trait follows a Mendelian pattern of inheritance. (For more information on criteria of autosomal dominant inheritance, refer to the Introduction ²⁰ section of this summary.)

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[4] When segregation analysis was applied to the Cancer and Steroid Hormone (CASH) data set, goodness-of-fit tests of genetic models provided additional evidence for the existence of a rare autosomal dominant allele associated with increased susceptibility to breast cancer.[5]

The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by the study of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, and PTEN/MMAC1.

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21.[6] The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed.[1] The BRCA1 gene was subsequently identified by positional cloning methods, and has been found to contain 24 exons that encode a protein of 1,863 amino acids. BRCA1 appears to be responsible for disease in 45% of families with multiple cases of breast cancer only, and in up to 90% of families with both breast and ovarian cancer.[7]

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 are thought to account for approximately 35% of multiple case breast cancer families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.[8,9] BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[10] While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene, with loss of the unmutated allele found in tumor specimens.

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on 1 copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. However, in most breast and ovarian cancers that have been studied from mutation carriers, the normal allele is deleted, resulting in loss of all function. This finding strongly suggests that BRCA1 and BRCA2 are in the class of tumor suppressor genes, i.e., genes whose loss of function can result in neoplastic growth.[11,12]

Additional evidence that BRCA1 is a tumor suppressor gene is that overexpression of the BRCA1 protein leads to tumor growth suppression in vitro and in a mouse model, in a fashion similar to the tumor suppressor gene TP53 and the retinoblastoma (RB) gene.[13] While this provides a conceptual framework for understanding the role of mutations in cancer progression, it does little to indicate how these genes normally function to prevent cancer.

However, a variety of evidence now points to BRCA1 and BRCA2 being directly involved in the DNA repair process. Several strategies are used to evaluate gene function. These include comparing the sequence and structure of the protein product to other known genes; determining the tissues, cell types, and stages of the cell cycle in which the protein is expressed; and identifying other proteins with which the protein interacts. Animal models also provide an important tool; in particular, knockout mice provide a way to study the effects of different gene mutations. In this approach, the normal mouse gene coding for the analogous function has been removed, and normal or mutated human genes are then inserted to assess their biological effects. Epidemiological studies can provide important evidence for other factors, both genetic and nongenetic, that modify the effect of BRCA1 and BRCA2 gene mutations. New technical tools for study of gene function are now being developed; for example, microarray techniques that permit the assessment of gene variants or gene expression at multiple gene sites may allow the identification of other gene proteins that interact with or modify the effect of the BRCA1 and BRCA2 protein products.

Taken together, current data suggest that the BRCA1 and BRCA2 protein products interact with each other and with RAD51 and other proteins known to be involved in DNA repair. Loss of DNA repair function is assumed to lead to the accumulation of additional mutations and ultimately to carcinogenesis. Several review articles are available in the literature on BRCA1 and BRCA2 gene function.[14,15]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[16] The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-strand conformational polymorphism (SSCP) analysis and conformation sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.[17] In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing, currently used for clinical testing. Such rearrangements are believed to be responsible for 10% to 15% of BRCA1 inactivating mutations.[18]

Approximately 1 in 800 individuals in the general population may carry a pathogenic mutation in BRCA1. The frequency of carriers in selected groups has been measured. Among cases identified from the Cancer Surveillance System of Western Washington, the frequency of BRCA1 mutations was highest in cases diagnosed before age 30 years (23% carriers, 95% confidence interval (CI) 5.0-53.8), and in those with more than 3 relatives with breast cancer (20%, 95% CI 6%-44%). A family history of ovarian cancer in a first-degree relative was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI 3.2%-65.1%).[19] In a second study, 263 women with familial breast cancer were analyzed.[20] BRCA1 mutations were found in 7% (95% CI 0.3%-39%) of families with site-specific breast cancer, 18% of families with bilateral breast cancer, and 40% (95% CI 1.7%-80.0%) of families with both breast and ovarian cancer. In a population-based series of incident cases of ovarian cancer in Canada, the overall prevalence of BRCA1/2 mutations was 11.7%; among women with a first-degree relative with breast or ovarian cancer, it was 19%. Of note, 6.5% of women with no affected first-degree relative carried a mutation, suggesting a higher overall prevalence of mutations in women with a diagnosis of ovarian cancer than in those with breast cancer.[21]

In some cases the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a “founder effect.” This occurs when a contemporary population can be traced back to a small, isolated group of founders. Most notably, 2 specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews (those tracing their roots to Central and Eastern Europe). Carrier frequencies for these mutations have been determined in the general Jewish population: 0.9% (95% CI 0.7%-1.1%) for the 185delAG mutation, 0.3% (95% CI 0.2%-0.4%) for the 5382insC mutation, and 1.3% (95% CI 1.0%-1.5%) for the BRCA2 6174delT mutation.[22-25] Altogether, the frequency of these 3 mutations approximates 1 in 40 among Ashkenazi Jews; they account for 25% of early-onset breast cancer, and up to 90% of families with multiple cases of both breast and ovarian cancer in this population.[26,27] Additional founder mutations have been described in the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 995del5), and Sweden (BRCA1, 3171ins5).[28-31]

The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for “ethnic-specific” alleles. This greatly simplifies the technical aspects of the test but is not without pitfalls. It is estimated that 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[32]

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. For adult onset diseases, penetrance is usually dependent upon the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/2 mutation carriers is often quoted by age 50 years (generally premenopausal) and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Estimates of penetrance by age 70 years for BRCA1 and BRCA2 mutations show a large range, from 14% to 87% for breast cancer and 10% to 68% for ovarian cancer.[7,21,24,33-49] Initial penetrance estimates for BRCA1 and BRCA2 mutations were derived from multiple-case families from the Breast Cancer Linkage Consortium (BCLC), families studied to localize and clone the genes.[7,33,34] For breast cancer, the estimates ranged from 50% to 73% by age 50 years and 65% to 87% by age 70 years for BRCA1, and 59% and 82% at ages 50 years and 70 years, respectively, for BRCA2. For ovarian cancer, the estimates were as high as 29% by age 50 years and 63% by age 70 years.[33,34] For many patients currently seeking genetic testing for BRCA1 and BRCA2, the family history will not be as strong as this study by the BCLC (e.g., more than 4 affected relatives in the same biologic lineage). Thus, the penetrance figures derived from the BCLC may not provide a high level of accuracy for individual patients seeking genetic counseling and testing.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[7,33,34,36,38,42,49,50] at least 13 studies have estimated penetrance by studying the families of mutation carriers who were not specifically recruited and studied because of a positive family history.[24,37,39,40,21,41-48] Often these studies have concentrated on founder populations in which testing of larger, more population-based subjects are possible owing to a reduced number of mutations that require testing,[24,35,37,40,43,44,46] compared with complete sequencing of the 2 genes required in most populations. The first study of a community-based series was carried out in the Washington, DC, area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.[24] Study participants were tested for 3 founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. The prevalence of breast cancer in the relatives of carriers was compared with that reported by mutation-negative individuals. The risk of breast cancer in carriers of these mutations was estimated to be 56% (95% CI 40%-73%) by age 70 years. Ovarian cancer risk was estimated to be 16% (95% CI 6%-28%). These values were lower than most prior risk estimates. Men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately 2-fold increased risk of prostate cancer in BRCA2 mutation carriers.[40,51,52] .

Many subsequent studies, whether in founder or predominantly outbred populations, have estimated breast cancer risks by age 70 years of ~60% or lower and ovarian cancer risks of ~40% or lower, although often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. Most studies have done molecular testing on the proband only and have done no,[21,24,35,37,40-44,46,47] or limited,[39,49] testing among relatives. Instead, the mutation status of relatives is modeled on simple Mendelian principles that on average, one half of first-degree relatives of mutation carriers will themselves be carriers. Such modeling may lead to imprecision in the penetrance estimates; by chance, more than or less than half the relatives of some families will be carriers. In the New York Breast Cancer Study of 104 mutation-positive Ashkenazi Jews with breast cancer, penetrance estimates were based only on relatives whose mutation status was known.[48] These estimates were 69% and 74% for breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively, and 46% and 12% for ovarian cancer for BRCA1 and BRCA2, respectively.

The largest study to date to estimate penetrance involved a pooled analysis of 22 studies of over 8,000 breast and ovarian cancer cases unselected for family history.[47] Subjects were from 12 different countries and had a broad spectrum of mutations. Using modified segregation analysis on the families of the nearly 500 cases found to carry a BRCA1/2 mutation, the cumulative risk of breast cancer by age 70 years was 65% (95% CI 44%-78%) for BRCA1 and 45% (95% CI 31%-56%) for BRCA2. The penetrances for ovarian cancer are somewhat higher for BRCA1 mutation carriers, especially for ovarian cancer and early-onset breast cancer. These estimates are "average" risks of cancer among mutation carriers, assuming there is at least one family member with breast cancer or ovarian cancer (since all probands had these cancers), the situation likely to be encountered in clinical genetics situations.

The continuing uncertainty as to the exact penetrance for breast and ovarian cancer among BRCA1/2 mutation carriers may be due to several factors, including differences owing to study design, allelic heterogeneity (differing risks for different mutations within either of the genes), and to modifying genetic and/or environmental factors.[47,48,53-55] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are very high, both in relative and absolute terms, and additional studies will be required to further characterize potential modifying factors in order to arrive at more precise individual risk projections. Precise penetrance estimates for less frequent cancers, such as pancreatic cancer, are lacking.

The tables titled “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer ²¹” and “Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer ²²” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. These studies have used populations derived from clinical referral centers.[20,56-61] Personal characteristics associated with an increased likelihood of a BRCA1 or BRCA2 mutation include the following:

• Breast cancer diagnosed at an early age.
• Bilateral breast cancer.
• A history of both breast and ovarian cancer.
• The presence of breast cancer in 1 or more male family members.[20,56-58,61]

Family history characteristics associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation include the following:

• Multiple cases of breast cancer in the family.
• Both breast and ovarian cancer in the family.
• One or more family members with 2 primary cancers.
• Ashkenazi Jewish background.[20,56-58]

The likelihood of having a BRCA mutation can vary from one individual to the next based on their country of origin, ethnicity, and family history of cancer. The models outlined in the table titled Characteristics of Common Models for Estimating the Likelihood of a BRCA Mutation take these factors into account and assist in providing tailored risk assessments.

Statistics regarding the percentage of women found to be BRCA mutation carriers among samples of women with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing, but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

• General non-Ashkenazi Jewish population: 1 in 500 (.002%).[63]
• Women with breast cancer (all ages): 1 in 50 (2%).[64]
• Women with breast cancer (younger than 40 years): 1 in 11 (9%).[65]
• Men with breast cancer (regardless of age): 1 in 20 (5%).[66]
• Women with ovarian cancer (all ages): 1 in 10 (10%).[21,67]

Among Ashkenazi Jewish individuals (likelihood of having one of 3 founder mutations):

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[24]
• Women with breast cancer (all ages): 1 in 10 (10%).[48]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).[48,68,69]
• Men with breast cancer (regardless of age): 1 in 5 (19%).[70]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).[43,71,72]

Genetic testing for BRCA1 and BRCA2 has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This in turn gives providers better data with which to estimate an individual patient’s risk of carrying a mutation. There remains an art to risk assessment in practitioners’ selection of the best model to fit their individual patient’s circumstances and consideration of factors that might limit the ability to provide an accurate risk assessment (i.e., small family size or paucity of women).

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. To date, only weak connections have been made between these genes and sporadic breast and ovarian cancer. Studies of tumor tissue from sporadic breast cancers have detected no somatic BRCA1 mutations and a very low frequency of BRCA2 mutations.[73-77] In ovarian cancer tumor tissue, however, BRCA1 mutations appear to occur with some frequency. In an unselected series of 103 ovarian cancers, 7 disease-causing mutations in BRCA1 were found that were not present in normal tissue of these patients.[78] Another series of 221 ovarian cancers analyzed for mutations in BRCA1 identified 15 somatic mutations and 18 tumors with evidence of BRCA1 dysfunction due to hypermethylation.[79]

Since few somatic BRCA1 and BRCA2 mutations are seen in sporadic breast tumors, other mechanisms for the inactivation of these tumor suppressor genes have been investigated. In particular, decreased expression of wild-type BRCA1 may occur on an epigenetic basis, i.e., as a result of DNA methylation or other physiological change that results in loss of gene expression, an event that in turn leads to cancer. In support of this hypothesis, artificially decreasing expression of BRCA1 using antisense oligonucleotides resulted in accelerated growth of mammary epithelial cells in culture.[80] Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[80-84] Similar findings have not been reported for BRCA2, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[85,86]

Taken together, current pathologic, cytogenetic, and gene expression data suggest not only that inactivation of BRCA1 and BRCA2 plays a role in sporadic cancer, but also that there are biologic differences between BRCA1-related, BRCA2-related, and sporadic breast cancers. A clear understanding of these differences (and similarities) has not yet been reached.[87-91]

Mutations in BRCA1 and BRCA2 confer a highly increased susceptibility to breast and ovarian cancer, but these mutations do not lead to cancer by themselves. The current consensus is that these are “gatekeeper” genes that, when removed, allow other genetic defects to accumulate. The nature of these other molecular events may define the pathway through which BRCA1 and BRCA2 function.

A number of studies have looked at steroid hormone receptor levels in tumors containing BRCA1 and BRCA2 mutations. In most of these studies, BRCA1 cancers were shown to be more often estrogen receptor negative than nonhereditary cancers.[92-96] Some discrepancies exist in these studies that may be attributable to the relatively small sample sizes and the geographically or ethnically defined populations that may all carry the same mutation. This raises the issue of whether specific founder mutations in BRCA1 or BRCA2 such as the Ashkenazi or Icelandic mutations have specifically associated phenotypes.

One such genotype-phenotype correlation that appears significant is with families carrying BRCA2 mutations in a specific region of the gene. From 25 families with BRCA2 mutations, an “ovarian cancer cluster region” was identified in exon 11 bordered by nucleotide 3,035 and 6,629.[9,36] This is the region of the gene containing the “BRC” repeats, which have been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region.[45] In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401-4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191.[97] These observations have generally been confirmed in subsequent studies;[47,49,98] however, none of the studies has had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management.

Additional evidence exists that this region of BRCA2 contains a specific functional domain. Of the 5 different homozygous BRCA2 knockout mice constructed by independent laboratories, 3 lead to embryonic lethality during the first 10 days of gestation.[99-101] The other 2 knockouts yield viable full-term mice that can survive to adulthood.[102,103] The dramatic difference in phenotype correlates with the position of the BRCA2 mutation. The mice that die in utero contain a truncation in the BRCA2 gene before a series of repeated sequences in the large exon 11, while in those mice that can come to term, some copies of these repeats are retained. The repeats themselves have been shown to be the site of interaction of the Rad51 protein, suggesting that Rad51 binding is critical in determining the function of BRCA2 both during development and neoplasia.[104]

Genetic changes associated with BRCA1- and BRCA2-related cancers are just beginning to be examined. Mutations in TP53 seem to be much more frequent in BRCA1 breast cancers (20/26) and somewhat more frequent in BRCA2-associated breast cancers (10/22) than in grade-matched sporadic cancers (7/20).[105] BRCA mutation-associated cancers contain TP53 mutations not typically found in sporadic breast cancer, and 12 individual hereditary breast cancers were shown to contain more than a single TP53 mutation. This raised the issue that mutations of BRCA1 and BRCA2 may confer a “mutator” phenotype allowing the general accumulation of a high rate of genetic abnormalities. Analysis of the coding sequence from the I-ran and Pancho oncogenes and the a-globin gene revealed no increase in mutations in BRCA mutation-associated breast cancers. In addition, no evidence was seen of the microsatellite instability characteristic of HNPCC associated cancers. Therefore, TP53 inactivation (or perhaps gain of function mutations) may be specifically selected for during BRCA1 and BRCA2 tumor progression.

A genome-wide screening for chromosomal gains or losses was performed on BRCA1 and BRCA2 breast cancers to determine the presence of other associated genetic “hot-spots.”[88] On the whole, BRCA-associated cancers had more regions that were amplified or deleted compared with controls (not stage matched and grade matched), suggesting a generalized increase in large-scale genomic instability. Specifically, chromosomes 5q, 4q, and 4p had very frequent LOH in BRCA1 tumors, while BRCA2 tumors were characterized by losses at 13q (near the BRCA2 locus itself) and 6q and chromosomal gains at 17q (outside of the HER2/neu locus) and 20q. LOH of both chromosomes 13 and 17 have been found simultaneously in a series of sporadic ovarian cancers, suggesting a synergistic mechanism.[106] In addition, the oncogene MYC on chromosome 8q24 was found to be amplified in 48% of 60 BRCA1-related breast cancers versus 14% of non-BRCA1 tumors.[107]

The identification of a histologic pattern characterizing hereditary breast cancer has been elusive, although historically, medullary, tubular, and lobular histologies and improved survival have been associated with familial breast cancer.[108] Others have noted an excess of medullary histology in multicase families.[109,110] Medullary histology was significantly more common (19% versus 0%) in a series of BRCA1-associated breast cancers compared with sporadic cases in a study from France,[111] in carriers from the Breast Cancer Linkage Consortium,[112] and among women with early-onset breast cancer in a population-based study,[113] suggesting that medullary histology itself is an indication for BRCA1 testing.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well characterized than that of BRCA1 to date.[114] A report from Iceland, where a founder effect has been observed in the BRCA2 999del5 mutation, found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls.[115] Other reports suggest that BRCA2-related tumors may include an excess of lobular and tubulolobular histology.[113,116] To date, studies of the prognosis of BRCA2-associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[117]

The mutation's phenotypic expression of BRCA1-related breast cancer indicates distinctive prognostic features. The Breast Cancer Linkage Consortium examined histopathologic features of breast cancer in women with BRCA1 mutations and, when compared with controls, showed an excess of high-grade tumors in BRCA1 carriers, and a relative lack of in situ component adjacent to invasive lesions. High mitotic rates and high total grade, as well as higher rates of aneuploidy and high proliferative fractions, were also reported for BRCA1 carriers in kindreds being followed. Also noted were higher rates of medullary histology.[118] A Norwegian study also reported that breast cancers occurring in BRCA1 mutation carriers were phenotypically distinct, with invasive, high-grade, estrogen receptor-negative breast cancers.[119] The Breast Cancer Linkage Consortium also found an increased frequency of high-intensity immunostaining for p53 in tumors among BRCA1 mutation carriers.[120] In a separate study, immunohistochemical analysis of BRCA1 and BRCA2 tumors (all Ashkenazi Jewish individuals with one of the 3 founder mutations) demonstrated a relatively low rate of HER2/neu positivity and no differences in p53, epidermal growth factor receptor, cathepsin D, bcl-2, or cyclin D staining compared with a control group of cancers.[93] Another study used tissue microarray technology to compare BRCA1, BRCA2, and sporadic breast tumors. In addition to the above findings, BRCA1 tumors were more likely to be BCL2 negative and express high levels of P-cadherin. BRCA2 tumors were intermediate between BRCA1 and sporadic tumors.[96]

Another case-control study among women of Jewish descent found that BRCA1-associated tumors were significantly more likely to be grade III and estrogen receptor negative.[121] A population-based study confirmed an excess of high-grade tumors with high mitotic rates in BRCA1 carriers, but did not find a relative absence of in situ cancers in this group.[113] A study of 76 ER-negative/erbB-2 negative breast cancers found that those occurring in BRCA1 mutation carriers were significantly more likely to have a basal epithelial phenotype as determined by cytokeratin 5/6 expression.[122] Breast cancers derived from the basal epithelial layer of cells characteristically exhibit higher grade features and frequent TP53 mutations. In accordance with the poor prognostic features noted histologically for BRCA1-related breast cancer, 2 European studies reported survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer.[95,123,124] Encouraging, however, was a report that failed to find a higher rate of local, regional, or distant failure among young women treated with breast-conserving surgery and radiation therapy whose family history was suggestive of hereditary breast cancer compared with a group without a significant family history.[125] On the other hand, a case series report found higher rates of both ipsilateral and contralateral breast cancers among BRCA1/2 mutation carriers compared with mutation negative cases.[126]

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS), in which germline mutations of the TP53 gene on chromosome 17p have been documented.[127] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[128,129] Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset.[130] Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age of onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.

Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. In response to DNA damage, p53 protein arrests cells in the G1 phase of the cell cycle, allowing DNA repair mechanisms to proceed before DNA synthesis. The p53 protein is also an active component of programmed cell death.[131] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[129] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy.

Mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.[132] Because many of the cancers associated with germline TP53 mutations do not lend themselves to early detection, predictive testing of LFS family members has so far been limited and primarily confined to the research setting.

Based on numerous studies, a mutation in the CHEK2 gene appears to be a rare low-penetrance susceptibility allele. The 1100delC mutation was initially identified in a patient with LFS.[133] While other mutations in CHEK2 have been identified in LFS patients, the 1100delC mutation does not appear to be a common cause of this syndrome.[134-140] The deletion was present in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases. In both Europe and the United States (where the mutation appears to be slightly less common), additional studies have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 2-fold increased risk of female breast cancer.[141-144] Because of its low frequency, however, no single study has had sufficient power to detect a statistically significant risk among unselected breast cancer cases. A multicenter combined analysis/reanalysis of nearly 20,000 subjects from 10 case-control studies, however, has verified a significant, 2.3-fold excess of breast cancer among mutation carriers.[145] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[142] Although the initial report suggested that male mutation carriers were at a significantly increased risk of breast cancer,[140] several follow-up studies have failed to confirm the association.[146-149] Additional, larger studies will be required to more precisely define the absolute risk of female breast and other cancers in individuals who carry germline CHEK2 variants.

One of the more than 50 cancer-related genodermatoses, Cowden’s syndrome is characterized by an excess of breast cancer, gastrointestinal malignancies, and thyroid disease, both benign and malignant.[148] Lifetime estimates for breast cancer among women with Cowden’s syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at young ages and may be bilateral.[149] Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden’s syndrome. Germline mutations in PTEN, a protein tyrosine phosphatase with homology to tensin, located on chromosome 10q23, are responsible for this syndrome. Loss of heterozygosity at the PTEN locus observed in a high proportion of related cancers suggests that PTEN functions as a tumor suppressor gene. Its defined enzymatic function indicates a role in maintenance of the control of cell proliferation.[150] Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN accounts for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[151]

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of the ATM gene, which has been localized to chromosome 11q22-23.[152] More than 200 mutations in the gene have been identified to date, most of which are truncating mutations.[153] ATM proteins have been shown to play a role in cell cycle control.[154] In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[155]

It is well known that individuals homozygous for ATM are at increased risk of malignancies, especially hematologic. A number of epidemiologic studies have also suggested a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of 3.9 to 6.4.[156-158] Studies searching for an excess of ATM mutations among breast cancer patients have provided conflicting results.[159-166] If an association between the heterozygous carrier status and breast cancer is established, it could account for a significant proportion of hereditary breast cancer, given the high heterozygote carrier rate in the population, and could pose a potential risk related to screening-related radiation exposure in these individuals.

Peutz-Jeghers syndrome (PJS) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, perioral, and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[167-169] Mutations in the STK11 gene at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[170] have been identified as one cause of PJS.[171,172] Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.[171-176] A meta-analysis performed on available reports from the literature concluded that patients with this syndrome have a very high risk of developing breast, gastrointestinal, and other malignancies. Of 210 patients with PJS in this overview, it was estimated that the risk of developing noncutaneous cancer between the ages of 15 years and 64 years is 93%. The highest cumulative risk in these patients was for breast (54%), colon (39%), pancreatic (36%), stomach (29%), and ovarian (21%) cancer. The risk estimates for breast and ovarian cancer are similar to those observed in women carrying BRCA1 or BRCA2 mutations.[177] Multiple case reports have suggested most ovarian cancer cases associated with this syndrome are sex cord stromal tumors, which have a variable behavior, ranging from benign to highly malignant.[178-181]

The identification and location of breast cancer genes permit further investigation of the precise role they play in cancer progression, and will allow us to determine the percentage of total breast cancer caused by the inheritance of mutant genes. This in turn will ultimately enrich our understanding of all breast cancer, sporadic as well as hereditary, and will facilitate the identification of high-risk individuals.

References

1. Narod SA, Feunteun J, Lynch HT, et al.: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338 (8759): 82-3, 1991.  [PUBMED Abstract]
   
   
2. Phipps RF, Perry PM: Familial breast cancer. Postgrad Med J 64 (757): 847-9, 1988.  [PUBMED Abstract]
   
   
3. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994.  [PUBMED Abstract]
   
   
4. Newman B, Austin MA, Lee M, et al.: Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proceedings of the National Academy of Sciences 85(9): 3044-3048, 1988. 
   
   
5. Claus EB, Risch N, Thompson WD: Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 48 (2): 232-42, 1991.  [PUBMED Abstract]
   
   
6. Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.  [PUBMED Abstract]
   
   
7. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.  [PUBMED Abstract]
   
   
8. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.  [PUBMED Abstract]
   
   
9. Gayther SA, Mangion J, Russell P, et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15 (1): 103-5, 1997.  [PUBMED Abstract]
   
   
10. Tonin P, Weber B, Offit K, et al.: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 (11): 1179-83, 1996.  [PUBMED Abstract]
    
    
11. Smith SA, Easton DF, Evans DG, et al.: Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet 2 (2): 128-31, 1992.  [PUBMED Abstract]
    
    
12. Collins N, McManus R, Wooster R, et al.: Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene 10 (8): 1673-5, 1995.  [PUBMED Abstract]
    
    
13. Holt JT, Thompson ME, Szabo C, et al.: Growth retardation and tumour inhibition by BRCA1. Nat Genet 12 (3): 298-302, 1996.  [PUBMED Abstract]
    
    
14. Jasin M: Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21 (58): 8981-93, 2002.  [PUBMED Abstract]
    
    
15. Liu Y, West SC: Distinct functions of BRCA1 and BRCA2 in double-strand break repair. Breast Cancer Res 4 (1): 9-13, 2002.  [PUBMED Abstract]
    
    
16. An Open Access On-Line Breast Cancer Mutation Data Base. Bethesda, Md: National Human Genome Research Institute, 2002. Available online. ²⁴ Last accessed September 27, 2004. 
    
    
17. Eng C, Brody LC, Wagner TM, et al.: Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet 38 (12): 824-33, 2001.  [PUBMED Abstract]
    
    
18. Unger MA, Nathanson KL, Calzone K, et al.: Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67 (4): 841-50, 2000.  [PUBMED Abstract]
    
    
19. Malone KE, Daling JR, Thompson JD, et al.: BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 279 (12): 922-9, 1998.  [PUBMED Abstract]
    
    
20. Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997.  [PUBMED Abstract]
    
    
21. Risch HA, McLaughlin JR, Cole DE, et al.: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68 (3): 700-10, 2001.  [PUBMED Abstract]
    
    
22. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.  [PUBMED Abstract]
    
    
23. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.  [PUBMED Abstract]
    
    
24. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.  [PUBMED Abstract]
    
    
25. Roa BB, Boyd AA, Volcik K, et al.: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14 (2): 185-7, 1996.  [PUBMED Abstract]
    
    
26. Ellisen LW, Haber DA: Hereditary breast cancer. Annu Rev Med 49: 425-36, 1998.  [PUBMED Abstract]
    
    
27. Brody LC, Biesecker BB: Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine (Baltimore) 77 (3): 208-26, 1998.  [PUBMED Abstract]
    
    
28. Peelen T, van Vliet M, Petrij-Bosch A, et al.: A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 60 (5): 1041-9, 1997.  [PUBMED Abstract]
    
    
29. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al.: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13 (1): 117-9, 1996.  [PUBMED Abstract]
    
    
30. Arason A, Jonasdottir A, Barkardottir RB, et al.: A population study of mutations and LOH at breast cancer gene loci in tumours from sister pairs: two recurrent mutations seem to account for all BRCA1/BRCA2 linked breast cancer in Iceland. J Med Genet 35 (6): 446-9, 1998.  [PUBMED Abstract]
    
    
31. Einbeigi Z, Bergman A, Kindblom LG, et al.: A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer 37 (15): 1904-9, 2001.  [PUBMED Abstract]
    
    
32. Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002.  [PUBMED Abstract]
    
    
33. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.  [PUBMED Abstract]
    
    
34. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.  [PUBMED Abstract]
    
    
35. Levy-Lahad E, Catane R, Eisenberg S, et al.: Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 60 (5): 1059-67, 1997.  [PUBMED Abstract]
    
    
36. Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.  [PUBMED Abstract]
    
    
37. Thorlacius S, Struewing JP, Hartge P, et al.: Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352 (9137): 1337-9, 1998.  [PUBMED Abstract]
    
    
38. Cancer risks in BRCA2 mutation carriers.The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.  [PUBMED Abstract]
    
    
39. Hopper JL, Southey MC, Dite GS, et al.: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev 8 (9): 741-7, 1999.  [PUBMED Abstract]
    
    
40. Warner E, Foulkes W, Goodwin P, et al.: Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91 (14): 1241-7, 1999.  [PUBMED Abstract]
    
    
41. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer 83 (10): 1301-8, 2000.  [PUBMED Abstract]
    
    
42. Antoniou AC, Gayther SA, Stratton JF, et al.: Risk models for familial ovarian and breast cancer. Genet Epidemiol 18 (2): 173-90, 2000.  [PUBMED Abstract]
    
    
43. Moslehi R, Chu W, Karlan B, et al.: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66 (4): 1259-72, 2000.  [PUBMED Abstract]
    
    
44. Satagopan JM, Offit K, Foulkes W, et al.: The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 10 (5): 467-73, 2001.  [PUBMED Abstract]
    
    
45. Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001.  [PUBMED Abstract]
    
    
46. Satagopan JM, Boyd J, Kauff ND, et al.: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8 (12): 3776-81, 2002.  [PUBMED Abstract]
    
    
47. Antoniou A, Pharoah PD, Narod S, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 (5): 1117-30, 2003.  [PUBMED Abstract]
    
    
48. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.  [PUBMED Abstract]
    
    
49. Scott CL, Jenkins MA, Southey MC, et al.: Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 112 (5-6): 542-51, 2003.  [PUBMED Abstract]
    
    
50. Thompson D, Szabo CI, Mangion J, et al.: Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci U S A 99 (2): 827-31, 2002.  [PUBMED Abstract]
    
    
51. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.  [PUBMED Abstract]
    
    
52. Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.  [PUBMED Abstract]
    
    
53. Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001.  [PUBMED Abstract]
    
    
54. Levy-Lahad E, Lahad A, Eisenberg S, et al.: A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A 98 (6): 3232-6, 2001.  [PUBMED Abstract]
    
    
55. Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2 (2): 113-23, 2002.  [PUBMED Abstract]
    
    
56. Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997.  [PUBMED Abstract]
    
    
57. Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.  [PUBMED Abstract]
    
    
58. Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.  [PUBMED Abstract]
    
    
59. Chang-Claude J, Dong J, Schmidt S, et al.: Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes. J Med Genet 35 (2): 116-21, 1998.  [PUBMED Abstract]
    
    
60. Couch FJ, Hartmann LC: BRCA1 testing--advances and retreats. JAMA 279 (12): 955-7, 1998.  [PUBMED Abstract]
    
    
61. Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62 (1): 145-58, 1998.  [PUBMED Abstract]
    
    
62. Berry DA, Iversen ES Jr, Gudbjartsson DF, et al.: BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20 (11): 2701-12, 2002.  [PUBMED Abstract]
    
    
63. Szabo CI, King MC: Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60 (5): 1013-20, 1997.  [PUBMED Abstract]
    
    
64. Papelard H, de Bock GH, van Eijk R, et al.: Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients. Br J Cancer 83 (6): 719-24, 2000.  [PUBMED Abstract]
    
    
65. Loman N, Johannsson O, Kristoffersson U, et al.: Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93 (16): 1215-23, 2001.  [PUBMED Abstract]
    
    
66. Basham VM, Lipscombe JM, Ward JM, et al.: BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4 (1): R2, 2002.  [PUBMED Abstract]
    
    
67. Rubin SC, Blackwood MA, Bandera C, et al.: BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol 178 (4): 670-7, 1998.  [PUBMED Abstract]
    
    
68. Gershoni-Baruch R, Dagan E, Fried G, et al.: Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36 (8): 983-6, 2000.  [PUBMED Abstract]
    
    
69. Hodgson SV, Heap E, Cameron J, et al.: Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 36 (5): 369-73, 1999.  [PUBMED Abstract]
    
    
70. Struewing JP, Coriaty ZM, Ron E, et al.: Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 65 (6): 1800-2, 1999.  [PUBMED Abstract]
    
    
71. Hirsh-Yechezkel G, Chetrit A, Lubin F, et al.: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89 (3): 494-8, 2003.  [PUBMED Abstract]
    
    
72. Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003.  [PUBMED Abstract]
    
    
73. Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994.  [PUBMED Abstract]
    
    
74. Lancaster JM, Wooster R, Mangion J, et al.: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13 (2): 238-40, 1996.  [PUBMED Abstract]
    
    
75. Weber BH, Brohm M, Stec I, et al.: A somatic truncating mutation in BRCA2 in a sporadic breast tumor. Am J Hum Genet 59 (4): 962-4, 1996.  [PUBMED Abstract]
    
    
76. Miki Y, Katagiri T, Kasumi F, et al.: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13 (2): 245-7, 1996.  [PUBMED Abstract]
    
    
77. Teng DH, Bogden R, Mitchell J, et al.: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13 (2): 241-4, 1996.  [PUBMED Abstract]
    
    
78. Berchuck A, Heron KA, Carney ME, et al.: Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 4 (10): 2433-7, 1998.  [PUBMED Abstract]
    
    
79. Geisler JP, Hatterman-Zogg MA, Rathe JA, et al.: Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94 (1): 61-7, 2002.  [PUBMED Abstract]
    
    
80. Thompson ME, Jensen RA, Obermiller PS, et al.: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9 (4): 444-50, 1995.  [PUBMED Abstract]
    
    
81. Sourvinos G, Spandidos DA: Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun 245 (1): 75-80, 1998.  [PUBMED Abstract]
    
    
82. Ozçelik H, To MD, Couture J, et al.: Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers. Int J Cancer 77 (1): 1-6, 1998.  [PUBMED Abstract]
    
    
83. Dobrovic A, Simpfendorfer D: Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57 (16): 3347-50, 1997.  [PUBMED Abstract]
    
    
84. Mancini DN, Rodenhiser DI, Ainsworth PJ, et al.: CpG methylation within the 5' regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16 (9): 1161-9, 1998.  [PUBMED Abstract]
    
    
85. Cleton-Jansen AM, Collins N, Lakhani SR, et al.: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72 (5): 1241-4, 1995.  [PUBMED Abstract]
    
    
86. Hamann U, Herbold C, Costa S, et al.: Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer. Cancer Res 56 (9): 1988-90, 1996.  [PUBMED Abstract]
    
    
87. van 't Veer LJ, Dai H, van de Vijver MJ, et al.: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415 (6871): 530-6, 2002.  [PUBMED Abstract]
    
    
88. Kallioniemi OP, Kallioniemi A, Sudar D, et al.: Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors. Semin Cancer Biol 4 (1): 41-6, 1993.  [PUBMED Abstract]
    
    
89. Kallioniemi OP: Linking chromosomal clues. Nat Genet 15 (1): 5-6, 1997.  [PUBMED Abstract]
    
    
90. Tirkkonen M, Johannsson O, Agnarsson BA, et al.: Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 57 (7): 1222-7, 1997.  [PUBMED Abstract]
    
    
91. Tirkkonen M, Kainu T, Loman N, et al.: Somatic genetic alterations in BRCA2-associated and sporadic male breast cancer. Genes Chromosomes Cancer 24 (1): 56-61, 1999.  [PUBMED Abstract]
    
    
92. Karp SE, Tonin PN, Bégin LR, et al.: Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer 80 (3): 435-41, 1997.  [PUBMED Abstract]
    
    
93. Robson M, Rajan P, Rosen PP, et al.: BRCA-associated breast cancer: absence of a characteristic immunophenotype. Cancer Res 58 (9): 1839-42, 1998.  [PUBMED Abstract]
    
    
94. Loman N, Johannsson O, Bendahl PO, et al.: Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations or unknown susceptibility genes. Cancer 83 (2): 310-9, 1998.  [PUBMED Abstract]
    
    
95. Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351 (9099): 316-21, 1998.  [PUBMED Abstract]
    
    
96. Palacios J, Honrado E, Osorio A, et al.: Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9 (10 Pt 1): 3606-14, 2003.  [PUBMED Abstract]
    
    
97. Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11 (4): 329-36, 2002.  [PUBMED Abstract]
    
    
98. Lubinski J, Phelan CM, Ghadirian P, et al.: Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 3 (1): 1-10, 2004.  [PUBMED Abstract]
    
    
99. Sharan SK, Morimatsu M, Albrecht U, et al.: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 (6627): 804-10, 1997.  [PUBMED Abstract]
    
    
100. Ludwig T, Chapman DL, Papaioannou VE, et al.: Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev 11 (10): 1226-41, 1997.  [PUBMED Abstract]
     
     
101. Suzuki A, de la Pompa JL, Hakem R, et al.: Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev 11 (10): 1242-52, 1997.  [PUBMED Abstract]
     
     
102. Connor F, Bertwistle D, Mee PJ, et al.: Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet 17 (4): 423-30, 1997.  [PUBMED Abstract]
     
     
103. Patel KJ, Yu VP, Lee H, et al.: Involvement of Brca2 in DNA repair. Mol Cell 1 (3): 347-57, 1998.  [PUBMED Abstract]
     
     
104. Chen PL, Chen CF, Chen Y, et al.: The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A 95 (9): 5287-92, 1998.  [PUBMED Abstract]
     
     
105. Crook T, Brooks LA, Crossland S, et al.: p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene 17 (13): 1681-9, 1998.  [PUBMED Abstract]
     
     
106. Gras E, Cortes J, Diez O, et al.: Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors. Cancer 92 (4): 787-95, 2001.  [PUBMED Abstract]
     
     
107. Grushko TA, Dignam JJ, Das S, et al.: MYC is amplified in BRCA1-associated breast cancers. Clin Cancer Res 10 (2): 499-507, 2004.  [PUBMED Abstract]
     
     
108. Malone KE, Daling JR, Weiss NS, et al.: Family history and survival of young women with invasive breast carcinoma. Cancer 78 (7): 1417-25, 1996.  [PUBMED Abstract]
     
     
109. Claus EB, Risch N, Thompson WD, et al.: Relationship between breast histopathology and family history of breast cancer. Cancer 71 (1): 147-53, 1993.  [PUBMED Abstract]
     
     
110. Rosen PP, Lesser ML, Senie RT, et al.: Epidemiology of breast carcinoma III: relationship of family history to tumor type. Cancer 50 (1): 171-9, 1982.  [PUBMED Abstract]
     
     
111. Eisinger F, Jacquemier J, Charpin C, et al.: Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 58 (8): 1588-92, 1998.  [PUBMED Abstract]
     
     
112. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349 (9064): 1505-10, 1997.  [PUBMED Abstract]
     
     
113. Armes JE, Egan AJ, Southey MC, et al.: The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 83 (11): 2335-45, 1998.  [PUBMED Abstract]
     
     
114. Phillips KA: Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol 18 (21 Suppl): 107S-12S, 2000.  [PUBMED Abstract]
     
     
115. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al.: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 47 (2): 121-7, 1998.  [PUBMED Abstract]
     
     
116. Marcus JN, Watson P, Page DL, et al.: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77 (4): 697-709, 1996.  [PUBMED Abstract]
     
     
117. Verhoog LC, Berns EM, Brekelmans CT, et al.: Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 18 (21 Suppl): 119S-24S, 2000.  [PUBMED Abstract]
     
     
118. Marcus JN, Page DL, Watson P, et al.: BRCA1 and BRCA2 hereditary breast carcinoma phenotypes. Cancer 80(3 suppl): 543-556, 1997. 
     
     
119. Møller P, Borg A, Heimdal K, et al.: The BRCA1 syndrome and other inherited breast or breast-ovarian cancers in a Norwegian prospective series. Eur J Cancer 37 (8): 1027-32, 2001.  [PUBMED Abstract]
     
     
120. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al.: The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20 (9): 2310-8, 2002.  [PUBMED Abstract]
     
     
121. Robson M, Gilewski T, Haas B, et al.: BRCA-associated breast cancer in young women. J Clin Oncol 16 (5): 1642-9, 1998.  [PUBMED Abstract]
     
     
122. Foulkes WD, Stefansson IM, Chappuis PO, et al.: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95 (19): 1482-5, 2003.  [PUBMED Abstract]
     
     
123. Jóhannsson OT, Ranstam J, Borg A, et al.: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16 (2): 397-404, 1998.  [PUBMED Abstract]
     
     
124. Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al.: Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 18 (24): 4053-9, 2000.  [PUBMED Abstract]
     
     
125. Chabner E, Nixon A, Gelman R, et al.: Family history and treatment outcome in young women after breast-conserving surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 16 (6): 2045-51, 1998.  [PUBMED Abstract]
     
     
126. Haffty BG, Harrold E, Khan AJ, et al.: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet 359 (9316): 1471-7, 2002.  [PUBMED Abstract]
     
     
127. Garber JE, Goldstein AM, Kantor AF, et al.: Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51 (22): 6094-7, 1991.  [PUBMED Abstract]
     
     
128. Bottomley RH, Condit PT: Cancer families. Cancer Bull 20: 22-24, 1968. 
     
     
129. Malkin D: The Li-Fraumeni syndrome. Cancer: Principles and Practice of Oncology Updates 7(7): 1-14, 1993. 
     
     
130. Olivier M, Goldgar DE, Sodha N, et al.: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63 (20): 6643-50, 2003.  [PUBMED Abstract]
     
     
131. Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993.  [PUBMED Abstract]
     
     
132. Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992.  [PUBMED Abstract]
     
     
133. Lee SB, Kim SH, Bell DW, et al.: Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res 61 (22): 8062-7, 2001.  [PUBMED Abstract]
     
     
134. Sodha N, Houlston RS, Bullock S, et al.: Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum Mutat 20 (6): 460-2, 2002.  [PUBMED Abstract]
     
     
135. Kuschel B, Auranen A, Gregory CS, et al.: Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 12 (8): 809-12, 2003.  [PUBMED Abstract]
     
     
136. Sodha N, Bullock S, Taylor R, et al.: CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87 (12): 1445-8, 2002.  [PUBMED Abstract]
     
     
137. Ingvarsson S, Sigbjornsdottir BI, Huiping C, et al.: Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res 4 (3): R4, 2002.  [PUBMED Abstract]
     
     
138. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31 (1): 55-9, 2002.  [PUBMED Abstract]
     
     
139. Vahteristo P, Bartkova J, Eerola H, et al.: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71 (2): 432-8, 2002.  [PUBMED Abstract]
     
     
140. Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003.  [PUBMED Abstract]
     
     
141. Offit K, Pierce H, Kirchhoff T, et al.: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4 (1): 1, 2003.  [PUBMED Abstract]
     
     
142. Oldenburg RA, Kroeze-Jansema K, Kraan J, et al.: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63 (23): 8153-7, 2003.  [PUBMED Abstract]
     
     
143. Neuhausen S, Dunning A, Steele L, et al.: Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108 (3): 477-8, 2004.  [PUBMED Abstract]
     
     
144. Ohayon T, Gal I, Baruch RG, et al.: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108 (3): 479-80, 2004.  [PUBMED Abstract]
     
     
145. CHEK2 Breast Cancer Case-Control Consortium.: CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74 (6): 1175-82, 2004.  [PUBMED Abstract]
     
     
146. Osorio A, Rodríguez-López R, Díez O, et al.: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108 (1): 54-6, 2004.  [PUBMED Abstract]
     
     
147. Syrjäkoski K, Kuukasjärvi T, Auvinen A, et al.: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108 (3): 475-6, 2004.  [PUBMED Abstract]
     
     
148. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
     
     
149. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
     
     
150. Lynch ED, Ostermeyer EA, Lee MK, et al.: Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 61 (6): 1254-60, 1997.  [PUBMED Abstract]
     
     
151. Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997.  [PUBMED Abstract]
     
     
152. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.  [PUBMED Abstract]
     
     
153. Telatar M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62 (1): 86-97, 1998.  [PUBMED Abstract]
     
     
154. Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.  [PUBMED Abstract]
     
     
155. Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.  [PUBMED Abstract]
     
     
156. Swift M, Reitnauer PJ, Morrell D, et al.: Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316 (21): 1289-94, 1987.  [PUBMED Abstract]
     
     
157. Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66 (6 Suppl): S177-82, 1994.  [PUBMED Abstract]
     
     
158. Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst 93 (2): 121-7, 2001.  [PUBMED Abstract]
     
     
159. FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997.  [PUBMED Abstract]
     
     
160. Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.  [PUBMED Abstract]
     
     
161. Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998.  [PUBMED Abstract]
     
     
162. Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.  [PUBMED Abstract]
     
     
163. Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001.  [PUBMED Abstract]
     
     
164. Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001.  [PUBMED Abstract]
     
     
165. Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002.  [PUBMED Abstract]
     
     
166. Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.  [PUBMED Abstract]
     
     
167. Peutz JL: On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921. 
     
     
168. Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 241(25): 993-1005, 1949. 
     
     
169. Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989.  [PUBMED Abstract]
     
     
170. Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998.  [PUBMED Abstract]
     
     
171. Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.  [PUBMED Abstract]
     
     
172. Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.  [PUBMED Abstract]
     
     
173. Ylikorkala A, Avizienyte E, Tomlinson IP, et al.: Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet 8 (1): 45-51, 1999.  [PUBMED Abstract]
     
     
174. Yoon KA, Ku JL, Choi HS, et al.: Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients. Br J Cancer 82 (8): 1403-6, 2000.  [PUBMED Abstract]
     
     
175. Westerman AM, Entius MM, Boor PP, et al.: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13 (6): 476-81, 1999.  [PUBMED Abstract]
     
     
176. Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003.  [PUBMED Abstract]
     
     
177. Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000.  [PUBMED Abstract]
     
     
178. Humphries AL Jr, Shepherd MH, Peters HJ: Peutz-Jeghers syndrome with colonic adenocarcinoma and ovarian tumor. JAMA 197(4): 138-140, 1966. 
     
     
179. Christian CD, McLoughlin TG, Cathcart ER, et al.: Peutz-Jeghers syndrome associated with functioning ovarian tumor. JAMA 190(10):157-160, 1964. 
     
     
180. Solh HM, Azoury RS, Najjar SS: Peutz-Jeghers syndrome associated with precocious puberty. J Pediatr 103 (4): 593-5, 1983.  [PUBMED Abstract]
     
     
181. Scully RE: Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25 (5): 1107-21, 1970.  [PUBMED Abstract]
     
     

Genetic Polymorphisms and Breast Cancer Risk

Background

The search for genetic markers for breast cancer susceptibility has led to an increasing number of epidemiologic studies of relatively common genetic markers referred to as genetic polymorphisms.[1] These polymorphically expressed genes code for enzymes that may have a role in the metabolism of estrogens or detoxification of drugs and environmental carcinogens. Although the clinical significance and causality of associations with breast cancer reported to date is unclear, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens such as replacement estrogens or cigarette smoke.

Evidence of associations between genetic polymorphisms and breast cancer risk in women has been obtained from case-control or cohort (nested case-control) analytic studies, usually with just a single center or research group (level of evidence: 3). The endpoint in these studies has sometimes been prevalent breast cancer rather than the more satisfactory endpoint of incident breast cancer. In several studies of genetic polymorphisms and breast cancer, convenience samples of cases and controls have been used. However, some studies have been population based, with incident cases of breast cancer and with adequate control of confounding factors. Results to date have largely been inconsistent, and none of the markers so far has clinical applications.

Cytochrome p450 enzymes are members of a multiple gene “superfamily” that play an important role in steroidogenesis and detoxification of xenobiotics such as polycyclic aromatic hydrocarbons, benzo(a)pyrene, arylamines, and heterocyclic amines.[2] The p450 cytochromes provide a line of defense against exposure to environmental chemicals. However, carcinogens may be activated by p450 metabolism. Cytochrome p450 enzymes are expressed primarily in the liver and in other tissues.

Molecular epidemiology studies of cancer of the breast (as well as lung, bladder, colon, and other sites) have examined associations with p450 cytochrome genotypes such as CYP1A1, CYP2D6, and CYP17. Earlier studies, carried out before the availability of DNA tests for CYP1A1 and CYP2D6, examined the activity of the corresponding polymorphically expressed enzyme.

The CYP1A1 gene, located on chromosome 15q, codes for aryl hydrocarbon hydroxylase (AHH). AHH, which catabolizes polycyclic aromatic hydrocarbons and arylamines, has been found in breast tumor tissue. AHH is strongly inducible, i.e., greater enzymatic activity is seen with greater exposure to substrates. AHH catalyzes the mono-oxygenation of polycyclic aromatic hydrocarbons to phenolic products and epoxides that may be carcinogenic. AHH is also involved in the conversion of estrogen to hydroxylated conjugated estrogens such as 2-hydroxyestradiol.

Three polymorphisms of this p450 gene that code for AHH have been identified so far: an MspI RFLP of the 3’ end of the gene (MspI); an adenine-to-guanine mutation in exon 7 of this gene, which causes an isoleucine to valine substitution (Ile-Val); and a polymorphism of the CYP1A1 gene identified among African Americans (AA). The frequencies of the MspI and Ile-Val polymorphisms vary considerably by race; the frequencies are higher among Japanese and Hawaiian populations as compared with Caucasians and African Americans.

The CYP2D6 gene is located on chromosome 22q and codes for debrisoquine hydroxylase, which metabolizes a variety of drugs and other xenobiotics. Like other polymorphically expressed p450 enzymes, debrisoquine hydroxylase may activate procarcinogens or, conversely, detoxify carcinogens. A number of alleles have been characterized at the CYP2D6 locus. The “poor metabolizer” phenotype (CYP2D6 mutant/mutant genotype), which is rare in Asians, occurs in about 5% to 10% of Caucasians and in 2% of African Americans.

Relatively few molecular epidemiology studies of the CYP2D6 genotype and breast cancer risk have been reported. Based upon genotype assays in breast cancer cases and controls, negative results have been reported in Great Britain [3,4] and in the United States.[5]

The N-acetyl transferase-1 (NAT1) and N-acetyl transferase-2 (NAT2) genes are located on chromosome 8q. Both are polymorphically expressed in a variety of tissues. NAT2 detoxifies or, conversely, activates aromatic amines such as 4-aminobiphenyl found in tobacco smoke.[5] Both phenotypic assays and genotypic assays for NAT2 can be used to classify individuals as rapid or slow acetylators. Genetic variants of the NAT2 gene have been cloned, and 6 alleles at this locus have been identified; the F1 allele confers the fast acetylator phenotype. The distribution of NAT1 and NAT2 alleles differs widely between racial and ethnic groups. Studies of the NAT2 genotype and breast cancer susceptibility have reported inconsistent results.[6-9]

The glutathione S-transferase-M1(GSTM1) gene is located on chromosome 1, and the gene for glutathione S-transferase-T1 (GSTT1) is located on chromosome 11q. A glutathione S-transferase-P1 (GSTP1) gene has also been identified. The glutathione S-transferase genes may play a role in susceptibility to cancer. Glutathione S-transferases detoxify a variety of carcinogens and cytotoxic drugs (for example, benzo(a)pyrene, monohalomethanes such as methyl chloride, ethylene oxide, pesticides, and solvents used in industry) by catalyzing the conjugation of a glutathione moiety to the substrate. Individuals who are homozygous carriers of deletions in the GSTM1, GSTT1, or GSTP1 genes may have a higher risk of cancer of the breast and other sites because of their impaired ability to metabolize and eliminate carcinogens.[10-12]

GSTM1 is polymorphically expressed and 3 alleles at the GSTM1 locus have been identified: GSTM1-0 (homozygous deletion genotype), GSTM1a, and GSTM1b. The null allele (GSTM1-0) is present in about 38% to 67% of Caucasians and 22% to 35% of African Americans. GSTM is not expressed in breast tissue at high levels. Two functionally different genotypes at the GSTT1 locus have been described: GSTT1-0 (homozygous deletion genotype) and GSTT1-1 (genotypes with 1 or 2 undeleted alleles).[9] A polymorphism of the GSTP1 gene, A313G (changing codon 105 from Ile to Val), has been identified.

Glutathione S-transferase genotypes have also been examined in relation to age at breast cancer diagnosis in women with a positive family history. One study examined 185 breast cancer cases ascertained through hereditary breast cancer clinics in the United States and found no association between GSTM1 genotypes and breast cancer penetrance. However, the GSTT1-0 allele was associated with accelerated age of first breast cancer diagnosis as compared with the GSTT1-1 allele. Approximately 40% of the subjects were diagnosed before age 40 years.[9]

References

1. Nathanson KL, Weber BL: "Other" breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet 10 (7): 715-20, 2001.  [PUBMED Abstract]
   
   
2. Strong LC, Amos CI: Inherited susceptibility. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 2nd ed. New York, NY: Oxford University Press, 1996, pp 559-583. 
   
   
3. Wolf CR, Smith CA, Gough AC, et al.: Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility. Carcinogenesis 13 (6): 1035-8, 1992.  [PUBMED Abstract]
   
   
4. Smith CA, Moss JE, Gough AC, et al.: Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. Environ Health Perspect 98: 107-12, 1992.  [PUBMED Abstract]
   
   
5. Buchert ET, Woosley RL, Swain SM, et al.: Relationship of CYP2D6 (debrisoquine hydroxylase) genotype to breast cancer susceptibility. Pharmacogenetics 3 (6): 322-7, 1993.  [PUBMED Abstract]
   
   
6. Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.  [PUBMED Abstract]
   
   
7. Agúndez JA, Ladero JM, Olivera M, et al.: Genetic analysis of the arylamine N-acetyltransferase polymorphism in breast cancer patients. Oncology 52 (1): 7-11, 1995 Jan-Feb.  [PUBMED Abstract]
   
   
8. Millikan RC, Pittman GS, Newman B, et al.: Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 7 (5): 371-8, 1998.  [PUBMED Abstract]
   
   
9. Morabia A, Bernstein M, Heritier S, et al.: NAT2-smoking interaction with respect to breast cancer in menopausal women. Am J Epidemiol 147: A179, S45, 1998. 
   
   
10. Rebbeck TR: Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6 (9): 733-43, 1997.  [PUBMED Abstract]
    
    
11. Maugard CM, Charrier J, Pitard A, et al.: Genetic polymorphism at the glutathione S-transferase (GST) P1 locus is a breast cancer risk modifier. Int J Cancer 91 (3): 334-9, 2001.  [PUBMED Abstract]
    
    
12. Mitrunen K, Jourenkova N, Kataja V, et al.: Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer. Cancer Epidemiol Biomarkers Prev 10 (3): 229-36, 2001.  [PUBMED Abstract]
    
    

Interventions

Few data exist on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast or ovarian cancer. As a result, recommendations for management are primarily based on expert opinion. In addition, as outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

Refer to the PDQ summary on Screening for Breast Cancer ²⁵ for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

In the general population, evidence for the value of breast self-examination (BSE) is limited. Preliminary results have been reported from a randomized study of BSE being conducted in Shanghai, China.[1] At 5 years, no reduction in breast cancer mortality was seen in the BSE group compared with the control group of women, nor was a substantive stage shift seen in breast cancers that were diagnosed. (Refer to the PDQ summary on Screening for Breast Cancer ²⁵ for more information.)

Little direct prospective evidence exists regarding BSE among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer. In the Canadian National Breast Screening Study, women with first-degree relatives with breast cancer had statistically significantly higher BSE competency scores than those without a family history. In a study of 251 high-risk women at a referral center, 5 breast cancers were detected by self-examination less than a year after a previous screen (as compared with 1 cancer detected by clinician exam and 11 cancers detected as a result of mammography). Women in the cohort were instructed in self-examination, but it is not stated whether the interval cancers were detected as a result of planned self-examination or incidental discovery of breast masses.[2] In another series of BRCA1/2 mutation carriers, 4 of 9 incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting potential value of self-examination.[3] A task force convened by the Cancer Genetics Studies Consortium has recommended “monthly self-examination beginning early in adult life (e.g., by age 18-21) to establish a regular habit and allow familiarity with the normal characteristics of breast tissue. Education and instruction in self-examination are recommended.”[4]

Level of evidence: 5

Few prospective data exist regarding clinical breast examination (CBE) among female carriers of a BRCA1 or BRCA2 high-risk mutation, male carriers of a BRCA2 mutation, or women at inherited risk of breast cancer.

The Cancer Genetics Studies Consortium task force concluded, “as with self-examination, the contribution of clinical examination may be particularly important for women at inherited risk of early breast cancer.” They recommended that female carriers of a BRCA1 or BRCA2 high-risk mutation undergo annual or semiannual clinical examinations beginning at age 25 to 35 years.[4]

Level of evidence: 5

In the general population, strong evidence suggests that regular mammography screening of women aged 50 to 59 years leads to a 25% to 30% reduction in breast cancer mortality. (Refer to the PDQ summary on Screening for Breast Cancer ²⁵ for more information.) For women who begin mammographic screening at age 40 to 49 years, a 17% reduction in breast cancer mortality is seen, which occurs 15 years after the start of screening.[5] Observational data from a cohort study of more than 28,000 women suggest that the sensitivity of mammography is lower for young women. In this study, the sensitivity was lowest for younger women (aged 30-49 years) who had a first-degree relative with breast cancer. For these women, mammography detected 69% of breast cancers diagnosed within 13 months of the first screening mammography. By contrast, sensitivity for women younger than 50 years without a family history was 88% (P=.08). For women aged 50 years and older, sensitivity was 93% at 13 months and did not vary by family history.[6] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[3] Subsequent observational studies have found that the positive- predictive value of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[7] Higher positive-predictive values may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[8] One study found an association between the presence of pushing margins, a histopathologic description of a pattern of invasion, and false-negative mammograms in 28 women, 26 of whom had a BRCA1 mutation and 2 of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.[9]

The randomized Canadian National Breast Screening Study-2 (NBSS2) compared annual CBE plus mammography to CBE alone in women aged 50 to 59 years from the general population. Both groups were given instruction in BSE.[10] Although mammography detected smaller primary invasive tumors and more invasive as well as ductal carcinomas in situ (DCIS) than CBE, the breast cancer mortality rates in the CBE plus mammography group and the CBE alone group were nearly identical, and compared favorably with other breast cancer screening trials. After a mean follow-up of 13 years (range 11.3-16.0 years), the cumulative breast cancer mortality ratio was 1.02 (95% confidence interval (CI) = 0.78 to 1.33). One possible explanation of this finding was the careful training and supervision of the health professionals performing CBE.

In a prospective study of 251 individuals with BRCA mutations who received uniform recommendations regarding screening and risk-reducing, or prophylactic, surgery, annual mammography detected breast cancer in 6 women at a mean of 20.2 months after receipt of BRCA results.[2] The Cancer Genetics Studies Consortium task force has recommended for female carriers of a BRCA1 or BRCA2 high-risk mutation, “annual mammography, beginning at age 25 to 35 years. Mammograms should be done at a consistent location when possible, with prior films available for comparison.”[4] Data from prospective studies on the relative benefits and risks of screening with an ionizing radiation tool versus CBE or other nonionizing radiation tools would be useful, given accumulating evidence that the BRCA1 and BRCA2 gene products are involved in repair of DNA damage from radiation.[11-13]

Level of evidence: 5

The limited sensitivity of mammography and an interest in methods of screening that do not involve ionizing radiation has led to evaluation of other screening techniques, including magnetic resonance imaging, breast ultrasound, breast ductal lavage, and digital mammography. Studies of these screening techniques are ongoing. There is insufficient evidence regarding screening outcomes to determine their utility in routine practice. A brief review of current evidence is provided here.

All studies to date indicate that screening magnetic resonance imaging (MRI) has higher sensitivity than mammography; specificity is generally lower.[14-18] Positive-predictive value has been estimated in the range of 26% to 33% and negative-predictive value in the range of 97% to 100%.[14-16,19] Uncertainties about MRI screening include the effect of screening on mortality; the rate and outcome of false-positive results; cost; and access to screening and MRI-guided biopsy.

Several studies have reported instances of breast cancer detected by ultrasound (US) that were missed by mammography, as discussed in 1 review.[20] In a pilot study of US as an adjunct to mammography in 149 women with moderately increased risk based on family history, 1 cancer was detected, based on US findings. Nine other biopsies of benign lesions were performed, one based on abnormalities on both mammography and US, the remaining 8 based on abnormalities on US alone.[20] Uncertainties about US include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

All ductal and lobular breast cancers originate in the epithelial cells that line the breast milk ducts. Breast ductal lavage (BDL) involves the insertion of a catheter into the milk ducts under local anesthesia through breast duct openings on the surface of the nipple, followed by a saline infusion to wash out cells for cytological examination. The technique has been shown to be a feasible method for collecting adequate samples of cells for examination, and cytological atypia can be detected.[21] The finding of atypia on BDL may provide risk information beyond that provided by the Gail risk model.[22] A study involving 426 high-risk women reported on the diagnosis of 2 cases of DCIS following BDL.[21] The risk implications of atypia found on BDL, as compared with atypia found on breast biopsy, are not known; neither is the sensitivity or specificity of BDL as a predictor of early breast cancer known. There are no current data that BDL is an effective screening strategy.

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,[23] and has been proposed as a potential strategy for improving the sensitivity of mammography. A screening study comparing digital with routine mammography in 6,736 examinations of women aged 40 years and older found no difference in cancer detection rates;[24] however, digital mammography resulted in fewer recalls.

Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

In the general population, breast cancer risk increases with early menarche and late menopause, and is reduced at early first full-term pregnancy. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.) In the Nurses’ Health Study, these were risk factors among women who did not have a mother or sister with breast cancer.[25] Among women with a family history of breast cancer, pregnancy at any age appeared to be associated with an increase in risk of breast cancer, persisting to age 70 years.

One study evaluated risk modifiers among 333 female carriers of a BRCA1 high-risk mutation. In women with known mutations of the BRCA1 gene, early age at first live birth and parity of 3 or more have been associated with a lowered risk of breast cancer.[26,27] A relative risk (RR) of 0.85 was estimated for each additional birth, up to 5 or more. As noted in the Ovarian Cancer Prevention ²⁶ section of this summary, however, increasing parity appeared to be associated with an increased risk of ovarian cancer. In a case-control study from New Zealand, investigators noted no difference in the impact of parity upon the risk of breast cancer between women with a family history of breast cancer and those without a family history.[28]

Level of evidence: 3

Among the general population, oral contraceptives may produce a slight, short-term increase in breast cancer risk. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.) In a meta-analysis of data from 54 studies, family history of breast cancer was not associated with any variation in risk associated with oral contraceptive use.[29] In a study of 50 Jewish women younger than 40 years with breast cancer, those with a BRCA1 or BRCA2 high-risk mutation had a higher likelihood of long-term oral contraceptive use (>48 months) before their first pregnancy.[30] The authors concluded that oral contraceptive use might increase the risk of breast cancer among carriers of a BRCA1 or BRCA2 mutation more than in noncarriers. In a case-control study of more than 1,300 pairs of women, each case was matched to a woman with a mutation in the same gene, born within 2 years of the case, and in the same country, who had not developed cancer. Oral contraceptive use was associated with a statistically significant 20% (CI 2%-40%) increase in risk of breast cancer among BRCA1 mutation carriers, particularly if use:

• Began before 1975, a period when estrogen doses were relatively high (38% increase, CI 11%-72%).
• Began before age 30 years (29% increase, CI 9%-52%).
• Lasted for 5 or more years (33% increase, CI 11%-60%).[31]

There was no increased risk associated with use among BRCA2 mutation carriers.

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.[32] The study found a substantially higher cellular proliferation rate among women who used oral contraceptives before their first full-term pregnancy. In addition, among women currently on oral contraceptives, women with a family history of breast cancer had much higher cellular proliferation rates than those women without a family history. These findings are consistent with increased breast cancer risk among women with a family history of breast cancer who use oral contraceptives.

In considering contraceptive options and preventive actions, the potential impact of oral contraceptive use upon the risk of both breast and ovarian cancer, as well as other health-related effects of oral contraceptives, needs to be considered.

Levels of evidence for oral contraceptive studies: 3B, 3

In the general population, removal of both ovaries has been associated with a reduction in breast cancer risk of up to 75%, depending on parity, weight, and age at time of artificial menopause. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.) Ovarian ablation, however, is associated with important side effects such as hot flashes, impaired sleep habits, vaginal dryness, dyspareunia, and increased risk of osteoporosis and heart disease. A variety of strategies may be necessary to counteract the adverse effects of ovarian ablation.

In support of early small studies,[33,34] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (hazard ratio (HR) 0.47, 95% CI 0.29-0.77) as well as ovarian cancer (HR 0.04, 95% CI 0.01-0.16) after bilateral oophorectomy.[35] A prospective single-institution study of 272 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, the HR was 0.15 (95% CI 0.02-1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI 0.08-1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI 0.08-0.74).[36]

Levels of evidence: 3, 4

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.[37-40] The Women’s Health Initiative (WHI) is a randomized controlled trial of ~160,000 postmenopausal women investigating the risks and benefits of strategies that may reduce the incidence of heart disease, breast and colorectal cancer, and fractures, including dietary interventions and 2 trials of hormone therapy. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined hormone therapy or placebo, was halted early because health risks exceeded benefits.[39,40] One of the adverse outcomes prompting closure was a significant increase in both total (245 vs 185 cases) and invasive (199 vs 150) breast cancers (RR 1.24, 95% CI 1.02-1.50, P<.001) in women randomized to receive estrogen and progestin.[40] HRT-related breast cancers had adverse prognostic characteristics (more advanced stages and larger tumors) compared with cancers occurring in the placebo group, and HRT was also associated with a substantial increase in abnormal mammograms.[40]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [41-43] or unaffected by a family history of breast cancer;[26,44,45] risk did not vary by family history in the meta-analysis.[29] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[40] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[46]

No data exist on the effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 high-risk mutation.

Level of evidence: 4B

Tamoxifen (a synthetic “antiestrogen“) increases breast-cell growth inhibitory factors and concomitantly reduces breast-cell growth stimulatory factors. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (NSABP-P1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) to placebo for 5 years. Tamoxifen was shown to reduce the risk of invasive breast cancer by 49%. The protective effect was largely confined to estrogen receptor-positive breast cancer, which was reduced by 69%. The incidence of estrogen receptor-negative cancer was not reduced with statistical significance.[47] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted among women with a family history of breast cancer and those without a family history. These benefits were associated with an increased incidence, among women older than 50 years, of endometrial cancers and thrombotic events. Interim data from 2 European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [48] and 70 months,[49] respectively. In 1 trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.[48] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for more information.)

A substudy of the NSABP-P1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/2 mutation-negative participants; however, tamoxifen use among healthy women with BRCA1 mutations did not appear to reduce breast cancer incidence. These data must be viewed with caution in view of the small number of mutation carriers in the sample (8 BRCA1 carriers and 11 BRCA2 carriers).[50]

Level of evidence: 1

In the general population, both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy.[51] In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared with subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures. The risk of breast cancer following either of these procedures has not been well established.

The effectiveness of risk-reducing mastectomy in women with BRCA1 or BRCA2 mutations has been evaluated in several studies. In one retrospective cohort study of 214 women considered to be at hereditary risk by virtue of a family history suggesting an autosomal dominant predisposition, 3 women were diagnosed with breast cancer after bilateral risk-reducing mastectomy, with a median follow-up of 14 years.[52] As 37.4 cancers were expected, the calculated risk reduction was 92.0% (95% CI 76.6-98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutational analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, 8 variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.[53] Two of the 3 women diagnosed with breast cancer after risk-reducing mastectomy were tested, and neither carried a mutation. The calculated risk reduction among mutation carriers was 89.5% to 100% (95% CI 41.4%-100%), depending on the assumptions made about the expected numbers of cancers among mutation carriers and the status of the untested woman who developed cancer despite mastectomy. The result of this retrospective cohort study has been supported by a prospective analysis of 76 mutation carriers undergoing risk-reducing mastectomy and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas 8 were identified in women undergoing regular surveillance (HR for breast cancer after risk-reducing mastectomy = 0 [95% CI 0-0.36]).[54]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after risk-reducing mastectomy in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral risk-reducing mastectomy was compared with that in 378 mutation carriers who did not choose surgery. Bilateral mastectomy reduced the risk of breast cancer after a mean follow-up of 6.4 years by approximately 90%.[55]

Studies describing histopathologic findings in risk-reducing mastectomy specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In 2 series, proliferative lesions associated with an increased risk of breast cancer (lobular carcinoma in situ, atypical lobular hyperplasia, atypical ductal hyperplasia, DCIS) were noted in 43% to 46% of women with mutations undergoing either unilateral or bilateral risk-reducing mastectomy.[56,57] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of prophylactic bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, 3 (6%) cancers were detected at surgery.[58]

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in 0 of 11 bilateral mastectomies from patients with deleterious mutations and in only 2 of 7 contralateral unilateral risk-reducing mastectomies in affected mutation carriers.[59]

Although data are sparse, the evidence to date indicates that while a substantial proportion of women with a strong family history of breast cancer are interested in discussing risk-reducing mastectomy as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in 1 setting where the providers made 1 to 2 field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained risk-reducing mastectomy within 1 year of follow-up.[60] Among women at increased risk of breast cancer due to family history, less than 10% opted for mastectomy.[61] Selection of this option was related to breast cancer-related worry as opposed to objective risk parameters (e.g., number of relatives with breast cancer). In addition, self-perceived risk has been closely linked to interest in risk-reducing mastectomy.[61]

Assuming risk reduction in the range of 90%, a theoretical model suggests that for a group of 30-year-old women with BRCA1 or BRCA2 mutations, risk-reducing mastectomy would result in an average increased life expectancy of 2.9 to 5.3 years.[62] While these data are useful for public policy decisions, they cannot be individualized for clinical care as they include assumptions that cannot be fully tested. Another study of at-risk women showed a 70% time-tradeoff value, indicating that the women were willing to sacrifice 30% of life expectancy in order to avoid risk-reducing mastectomy.[63] A cost-effectiveness analysis study estimated that risk-reducing surgery (mastectomy and oophorectomy) is cost-effective compared with surveillance with regard to years of life saved, but not for improved quality of life.[64]

In contrast, in a Dutch study of highly motivated women being followed every 6 months at a high-risk center, more than half (51%) of unaffected carriers opted for risk-reducing mastectomy. Almost 90% of the risk-reducing mastectomy surgeries were performed within 1 year of DNA testing. In this study, those most likely to have risk-reducing mastectomy were women younger than 55 years and with children.[65]

Individual psychological factors have an important role in decision-making about risk-reducing mastectomy by unaffected women. Research is emerging about psychosocial outcomes of risk-reducing mastectomy. (Refer to the Psychological Aspects of Medical Interventions ²⁷ section of this summary.)

Level of evidence: 3B

No data exist regarding the impact of abortion, diet, or alcohol on the risk of breast cancer among women at inherited risk of breast cancer. (Refer to the PDQ summary on Prevention of Breast Cancer ¹¹ for information relevant to the general population.) In a retrospective analysis of 104 BRCA1/2 mutation-positive families, physical exercise as a teenager was associated with a delayed onset of breast cancer.[66]

Refer to the PDQ summary on Screening for Ovarian Cancer ²⁸ for information on screening in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

In the general population, clinical examination of the ovaries has neither the specificity nor the sensitivity to reliably identify early ovarian cancer. No data exist regarding the benefit of clinical examination of the ovaries (bimanual pelvic examination) in women at inherited risk of ovarian cancer.

Level of evidence: none

Limited data are available on the potential benefit of screening with serum CA 125 in women at inherited risk of ovarian cancer. When 180 women considered at high risk of ovarian cancer based on family history were screened for ovarian cancer by gynecologic examination, transvaginal ultrasound (TVUS), and serum CA 125, 1 granulosa cell tumor, 3 tumors of low malignant potential, and 5 epithelial ovarian tumors (1 stage II and 4 stage III) were detected. CA 125 levels were elevated in 1 of the tumors of low malignant potential and 3 of the 4 stage III ovarian carcinomas.[67]

One study examined the role of screening with serum CA 125 among 1,502 women with first-degree or second-degree relatives with ovarian cancer. Of these women, 147 (10%) appeared to have a pedigree consistent with site-specific ovarian cancer susceptibility, and 271 (18%) a pedigree consistent with hereditary nonpolyposis colon cancer (HNPCC). Using an elevated CA 125 threshold value of 35 U/mL, compared with 2 U/mL, increased the positive-predictive value of TVUS from 12.7% to 42.9%. The detection rate, however, dropped from 100% to 43%. Elevated CA 125 levels were noted in 2 of the 4 identified ovarian cancer patients. Among these 4 patients, normal CA 125 levels were noted in 1 patient with stage I disease and 1 patient with stage II disease, while elevated levels of CA 125 were noted in 1 patient with stage I disease and 1 patient with stage III disease.[68]

One study found elevated CA 125 levels in 68 of 597 (11.4%) women screened for ovarian cancer. Most of these women had a first-degree or second-degree relative with ovarian cancer, although 51 had a pedigree consistent with inherited susceptibility to breast or ovarian cancer, and 7 had a pedigree consistent with HNPCC. Among the premenopausal patients, the elevations in CA 125 were associated with ultrasonographic evidence of endometriosis, adenomyosis, or leiomyomas. Among the 8 postmenopausal patients, all had normal ovarian architecture on ultrasound.[69,70] No data are available to address the effectiveness of ovarian cancer screening in preventing deaths from ovarian cancer.

In 1994, the National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo annual or semiannual screening for ovarian cancer with TVUS and serum CA 125.[71] The Cancer Genetics Studies Consortium task force recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[4]

A phase II trial evaluating annual TVUS and serial CA 125 levels in 3,000 high-risk women registered in the United Kingdom Familial Ovarian Cancer Registry is under way. In the United States, the National Cancer Institute (NCI) is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.[72]

Level of evidence: 5

In the general population, TVUS appears to be superior to transabdominal ultrasound in preoperative diagnosis of adnexal masses. Either technique has lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries that can cause difficulty in interpretation. A screening trial of TVUS in 1,300 postmenopausal, asymptomatic women detected abnormalities in 2.5%. More than 90% of the lesions found were benign. Women with a family history of ovarian cancer were more likely to be found with an ovarian malignancy (RR 4.0). No such association was noted for those with a family history of breast cancer or colon cancer.[73]

One study reported on the use of transvaginal color Doppler ultrasonography in the evaluation of 126 women with adnexal masses who subsequently underwent surgery. Twenty epithelial ovarian cancers were detected, as well as 2 dysgerminomas, 2 ovarian tumors of low malignant potential, 1 immature teratoma, and 1 Sertoli-Leydig cell tumor. It was concluded that color Doppler ultrasonography was able to increase the positive and negative-predictive value, due to increased sensitivity and specificity of ultrasound evaluation.[74]

Another study reported that the addition of color Doppler ultrasonography was able to increase the positive-predictive value of ultrasound imaging from 25% to 60% among women with a personal history of breast cancer undergoing screening for ovarian cancer.[75] As noted, however, clinical studies of color Doppler imaging have shown that normal physiologic changes in the premenopausal ovary near the time of ovulation have low impedance flow characteristics similar to those seen in malignancy.[69]

Data are limited regarding the potential benefit of pelvic ultrasound in screening women at inherited risk of ovarian cancer. One study examined 1,601 women with a family history of ovarian cancer with pelvic ultrasound. Abnormal scans were found in 3.8%. Only 3 of 61 women with abnormal results had ovarian cancer, 2 with stage I and 1 with stage III.[76,77] Another study used gynecologic examination, TVUS, and CA 125 to screen 180 women at high risk of ovarian cancer with or without breast cancer. (Refer to the Serum CA 125 ²⁹ section in this summary.) Abnormal ultrasounds were noted in all 5 women with invasive epithelial ovarian carcinomas. Of these, however, 1 had stage II disease and 4 had stage III disease.[67]

One study screened 597 women at risk of ovarian cancer with serum CA 125, TVUS, and color Doppler (described in the Serum CA 125 ²⁹ section). No epithelial ovarian cancers were found. One case of an ovarian tumor of low malignant potential, however, was identified.[69,70]

Another study reported screening 386 women with first- or second-degree relatives with ovarian cancer. The study used TVUS, color flow Doppler, and serum CA 125. Initial ultrasound was abnormal in 89 of 381 women (23%). Ovarian masses persisted in 15 patients; all of these were benign at surgery. CA 125 levels were higher than 35 U/mL in 42 of 386 women (11%). Two patients who underwent surgery for rising CA 125 levels had normal ovaries.[78]

The NIH Consensus Statement on Ovarian Cancer recommended against routine screening of the general population with TVUS and serum CA 125. The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 every 6 to 12 months, commencing at age 35 years.[71] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a BRCA1 high-risk mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[4]

In the United States, NCI is conducting a large controlled clinical trial in which 74,000 women are randomized to regular medical care or research-based screening for lung, colorectal, and ovarian cancer. The ovarian cancer screening consists of yearly serum CA 125 and TVUS.[72]

Level of evidence: 5

Refer to the PDQ summary on Prevention of Ovarian Cancer ¹² for information on prevention in the general population, and to the PDQ summary Cancer Genetics Overview ² for information on levels of evidence related to screening and prevention.

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis.[79] Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparous women. Subsequent pregnancies after the first appear to decrease ovarian cancer risk by 15%.[80] Data are limited regarding the impact of fertility on the risk of ovarian cancer in women at high risk due to genetic predisposition.

One study analyzed the reproductive histories of 333 women with a BRCA1 high-risk mutation. Among these women, the risk of ovarian cancer increased with increasing parity. Each birth was associated with an additional 40% increase in risk up to 5 births. Late birth, however, appeared to convey a protective effect. Each 5-year interval in age at last birth was associated with a risk reduction of 18%. Women who had all their children after age 30 years, or who were nulliparous, formed a low-risk group for ovarian cancer (RR 0.30).[28]

A prospective population-based study of postmenopausal women found that nulliparity slightly increased the risk of developing ovarian cancer in women without a family history of breast or ovarian cancer (RR=1.4, 95% CI 0.9-2.4). This group showed that this risk was further increased in nulliparous women with a family history compared with parous women with a similar family history (RR=2.7, 95% CI 1.1-6.6).[81]

A case-control study was conducted involving 170 women with primary ovarian carcinomas or ovarian tumors of low malignant potential and 170 population-based controls. Late age at last childbirth was protective against development of ovarian cancer among women with a family history of breast or ovarian cancer, but not those without such a family history.[82]

In a study conducted using the Utah Population Database, a genealogy of about 1 million individuals linked to cancer incidence data, parity was not related to the development of ovarian cancer in women with a strong family history of ovarian, uterine, breast, or pancreatic cancer.[83]

Level of evidence: 3

No data exist regarding the impact of lactation or hormone replacement therapy on the risk of ovarian cancer in women at inherited risk of ovarian cancer, although consistent, prolonged exposure to unopposed estrogen HRT may increase the risk of ovarian cancer in the general population.[84] A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for oral contraceptive pill use, parity, history of breast cancer, and ethnicity.[85] A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy).[86] The mechanism of protection is uncertain. (Refer to the PDQ summary on Prevention of Ovarian Cancer ¹² for information relevant to the general population.)

Data are limited and conflicting regarding the impact of oral contraceptive use on the risk of ovarian cancer among women with a BRCA1 high-risk mutation or women at inherited risk of ovarian cancer. While one study found a decreased risk among oral contraceptive pill users, another study failed to observe any protective effect.[37,85,87]

A case-control study was performed evaluating oral contraceptive use among 207 women with a BRCA1 high-risk mutation and ovarian cancer, and as controls, 161 of their sisters who had not been diagnosed with ovarian cancer. After adjustment for year of birth parity and age at delivery of first child, an association appeared to exist between oral contraceptive use and decreased risk of ovarian cancer. The association increased with duration of use. Women who took oral contraceptives for more than 6 years had a 60% reduction in risk. This reduction was similar for BRCA1 and BRCA2 high-risk mutation carriers.[37] In the Gilda Radner Familial Ovarian Cancer Registry, users of oral contraceptives had a lower incidence of ovarian cancer than nonusers.[88] Another study, however, failed to observe any protective effect. This population-based case-control study of ovarian cancer among Jewish women in Israel found the risk of ovarian cancer among BRCA1 or BRCA2 mutation carriers decreased with each birth, but not with increased use of oral contraceptives.[87]

As noted under oral contraceptives in the Breast Cancer Prevention section of this summary, however, a retrospective case-control study suggested that oral contraceptive use increases the risk of breast cancer in women at inherited risk of breast cancer.[30]

Level of evidence: 3

Several case series of women at inherited risk of ovarian cancer suggest that risk-reducing oophorectomy decreases the risk of ovarian cancer. The peritoneum, however, appears to remain at risk for the development of a Mullerian-type adenocarcinoma, even after oophorectomy.[89-93] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, 6 (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.[94]

One study analyzed the incidence of breast and ovarian cancer during 1,600 person-years of observation among 12 families with breast and ovarian cancer. They compared the observed number of cases to the number expected based on data from the Connecticut Tumor Registry, adjusted for age, race, and birth cohort. Among the women who underwent oophorectomy, 2 primary peritoneal cancers were reported during 460 person-years of observation. The ratio of observed to expected cases was 13 (95% CI 10-47). For those women who did not undergo oophorectomy, 8 cases of primary peritoneal cancer were observed during 1,665 person-years of observation. The ratio of observed to expected cases was 24 (95% CI 1-47).[33]

The NIH Consensus Statement on Ovarian Cancer recommended that women at inherited risk of ovarian cancer undergo risk-reducing oophorectomy after completion of child-bearing or at age 35 years.[71] The Cancer Genetic Studies Consortium concluded that “there was insufficient evidence to recommend for or against risk-reducing oophorectomy as a measure for reducing ovarian cancer risk.”[4]

Since these consensus statements were published, a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR 0.47, 95% CI 0.29-0.77) and ovarian cancer (HR 0.04, 95% CI 0.01-0.16) after bilateral oophorectomy.[35] A prospective single-institution study of 272 women with BRCA1 or BRCA2 mutations showed a similar trend. With oophorectomy, the HR was 0.15 (95% CI 0.02-1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI 0.08-1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI 0.08-0.74). In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (odds ratio = 0.12, 95% CI 0.06-0.24).[36]

Levels of evidence: 3, 5

Although the consensus opinion does not address removal of the uterus or the fallopian tubes at the time of risk-reducing oophorectomy, there are several case reports of fallopian tube cancer in BRCA1 and BRCA2 mutation carriers as well as a report of occult fallopian tube carcinoma diagnosed at the time of risk-reducing oophorectomy.[95]

References

1. Thomas DB, Gao DL, Self SG, et al.: Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 89 (5): 355-65, 1997.  [PUBMED Abstract]
   
   
2. Scheuer L, Kauff N, Robson M, et al.: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20 (5): 1260-8, 2002.  [PUBMED Abstract]
   
   
3. Brekelmans CT, Seynaeve C, Bartels CC, et al.: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19 (4): 924-30, 2001.  [PUBMED Abstract]
   
   
4. Burke W, Daly M, Garber J, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277 (12): 997-1003, 1997.  [PUBMED Abstract]
   
   
5. Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988. 
   
   
6. Kerlikowske K, Grady D, Barclay J, et al.: Effect of age, breast density, and family history on the sensitivity of first screening mammography. JAMA 276 (1): 33-8, 1996.  [PUBMED Abstract]
   
   
7. Kerlikowske K, Carney PA, Geller B, et al.: Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med 133 (11): 855-63, 2000.  [PUBMED Abstract]
   
   
8. Kerlikowske K, Grady D, Barclay J, et al.: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270 (20): 2444-50, 1993.  [PUBMED Abstract]
   
   
9. Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al.: A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 102 (1): 91-5, 2002.  [PUBMED Abstract]
   
   
10. Miller AB, To T, Baines CJ, et al.: Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 92 (18): 1490-9, 2000.  [PUBMED Abstract]
    
    
11. Sharan SK, Morimatsu M, Albrecht U, et al.: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 (6627): 804-10, 1997.  [PUBMED Abstract]
    
    
12. Gowen LC, Avrutskaya AV, Latour AM, et al.: BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281 (5379): 1009-12, 1998.  [PUBMED Abstract]
    
    
13. Abbott DW, Freeman ML, Holt JT: Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst 90 (13): 978-85, 1998.  [PUBMED Abstract]
    
    
14. Stoutjesdijk MJ, Boetes C, Jager GJ, et al.: Magnetic resonance imaging and mammography in women with a hereditary risk of breast cancer. J Natl Cancer Inst 93 (14): 1095-102, 2001.  [PUBMED Abstract]
    
    
15. Warner E, Plewes DB, Shumak RS, et al.: Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol 19 (15): 3524-31, 2001.  [PUBMED Abstract]
    
    
16. Kuhl CK, Schmutzler RK, Leutner CC, et al.: Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Radiology 215 (1): 267-79, 2000.  [PUBMED Abstract]
    
    
17. Tilanus-Linthorst MM, Obdeijn IM, Bartels KC, et al.: First experiences in screening women at high risk for breast cancer with MR imaging. Breast Cancer Res Treat 63 (1): 53-60, 2000.  [PUBMED Abstract]
    
    
18. Trecate G, Vergnaghi D, Bergonzi S, et al.: BMRI in early detection of breast cancer in patients with increased genetic risk: our preliminary results. J Exp Clin Cancer Res 21 (3 Suppl): 125-30, 2002.  [PUBMED Abstract]
    
    
19. Podo F, Sardanelli F, Canese R, et al.: The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk. J Exp Clin Cancer Res 21 (3 Suppl): 115-24, 2002.  [PUBMED Abstract]
    
    
20. O'Driscoll D, Warren R, MacKay J, et al.: Screening with breast ultrasound in a population at moderate risk due to family history. J Med Screen 8 (2): 106-9, 2001.  [PUBMED Abstract]
    
    
21. Dooley WC, Ljung BM, Veronesi U, et al.: Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 93 (21): 1624-32, 2001.  [PUBMED Abstract]
    
    
22. O'Shaughnessy JA, Ljung BM, Dooley WC, et al.: Ductal lavage and the clinical management of women at high risk for breast carcinoma: a commentary. Cancer 94 (2): 292-8, 2002.  [PUBMED Abstract]
    
    
23. Shtern F: Digital mammography and related technologies: a perspective from the National Cancer Institute. Radiology 183 (3): 629-30, 1992.  [PUBMED Abstract]
    
    
24. Lewin JM, D'Orsi CJ, Hendrick RE, et al.: Clinical comparison of full-field digital mammography and screen-film mammography for detection of breast cancer. AJR Am J Roentgenol 179 (3): 671-7, 2002.  [PUBMED Abstract]
    
    
25. Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.  [PUBMED Abstract]
    
    
26. Narod S, Lynch H, Conway T, et al.: Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341 (8852): 1101-2, 1993.  [PUBMED Abstract]
    
    
27. Narod SA, Goldgar D, Cannon-Albright L, et al.: Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64 (6): 394-8, 1995.  [PUBMED Abstract]
    
    
28. McCredie M, Paul C, Skegg DC, et al.: Family history and risk of breast cancer in New Zealand. Int J Cancer 73 (4): 503-7, 1997.  [PUBMED Abstract]
    
    
29. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347 (9017): 1713-27, 1996.  [PUBMED Abstract]
    
    
30. Ursin G, Henderson BE, Haile RW, et al.: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57 (17): 3678-81, 1997.  [PUBMED Abstract]
    
    
31. Narod SA, Dubé MP, Klijn J, et al.: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94 (23): 1773-9, 2002.  [PUBMED Abstract]
    
    
32. Olsson H, Jernström H, Alm P, et al.: Proliferation of the breast epithelium in relation to menstrual cycle phase, hormonal use, and reproductive factors. Breast Cancer Res Treat 40 (2): 187-96, 1996.  [PUBMED Abstract]
    
    
33. Struewing JP, Watson P, Easton DF, et al.: Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Natl Cancer Inst Monogr (17): 33-5, 1995.  [PUBMED Abstract]
    
    
34. Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999.  [PUBMED Abstract]
    
    
35. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.  [PUBMED Abstract]
    
    
36. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.  [PUBMED Abstract]
    
    
37. Narod SA, Risch H, Moslehi R, et al.: Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med 339 (7): 424-8, 1998.  [PUBMED Abstract]
    
    
38. Chen CL, Weiss NS, Newcomb P, et al.: Hormone replacement therapy in relation to breast cancer. JAMA 287 (6): 734-41, 2002.  [PUBMED Abstract]
    
    
39. Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.  [PUBMED Abstract]
    
    
40. Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.  [PUBMED Abstract]
    
    
41. Schuurman AG, van den Brandt PA, Goldbohm RA: Exogenous hormone use and the risk of postmenopausal breast cancer: results from The Netherlands Cohort Study. Cancer Causes Control 6 (5): 416-24, 1995.  [PUBMED Abstract]
    
    
42. Steinberg KK, Thacker SB, Smith SJ, et al.: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265 (15): 1985-90, 1991.  [PUBMED Abstract]
    
    
43. Colditz GA, Egan KM, Stampfer MJ: Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 168 (5): 1473-80, 1993.  [PUBMED Abstract]
    
    
44. Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997.  [PUBMED Abstract]
    
    
45. Stanford JL, Weiss NS, Voigt LF, et al.: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274 (2): 137-42, 1995.  [PUBMED Abstract]
    
    
46. Gorsky RD, Koplan JP, Peterson HB, et al.: Relative risks and benefits of long-term estrogen replacement therapy: a decision analysis. Obstet Gynecol 83 (2): 161-6, 1994.  [PUBMED Abstract]
    
    
47. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998.  [PUBMED Abstract]
    
    
48. Veronesi U, Maisonneuve P, Costa A, et al.: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352 (9122): 93-7, 1998.  [PUBMED Abstract]
    
    
49. Powles T, Eeles R, Ashley S, et al.: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352 (9122): 98-101, 1998.  [PUBMED Abstract]
    
    
50. King MC, Wieand S, Hale K, et al.: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286 (18): 2251-6, 2001.  [PUBMED Abstract]
    
    
51. Ariyan S: Prophylactic mastectomy for precancerous and high-risk lesions of the breast. Can J Surg 28 (3): 262-4, 266, 1985.  [PUBMED Abstract]
    
    
52. Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999.  [PUBMED Abstract]
    
    
53. Hartmann LC, Sellers TA, Schaid DJ, et al.: Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 93 (21): 1633-7, 2001.  [PUBMED Abstract]
    
    
54. Meijers-Heijboer H, van Geel B, van Putten WL, et al.: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345 (3): 159-64, 2001.  [PUBMED Abstract]
    
    
55. Rebbeck TR, Friebel T, Lynch HT, et al.: Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 22 (6): 1055-62, 2004.  [PUBMED Abstract]
    
    
56. Kauff ND, Brogi E, Scheuer L, et al.: Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97 (7): 1601-8, 2003.  [PUBMED Abstract]
    
    
57. Hoogerbrugge N, Bult P, de Widt-Levert LM, et al.: High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer. J Clin Oncol 21 (1): 41-5, 2003.  [PUBMED Abstract]
    
    
58. Scott CI, Iorgulescu DG, Thorne HJ, et al.: Clinical, pathological and genetic features of women at high familial risk of breast cancer undergoing prophylactic mastectomy. Clin Genet 64 (2): 111-21, 2003.  [PUBMED Abstract]
    
    
59. Adem C, Reynolds C, Soderberg CL, et al.: Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97 (1): 1-11, 2003.  [PUBMED Abstract]
    
    
60. Lerman C, Hughes C, Croyle RT, et al.: Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 31 (1): 75-80, 2000.  [PUBMED Abstract]
    
    
61. Stefanek ME, Helzlsouer KJ, Wilcox PM, et al.: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24 (4): 412-9, 1995.  [PUBMED Abstract]
    
    
62. Schrag D, Kuntz KM, Garber JE, et al.: Decision analysis--effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 336 (20): 1465-71, 1997.  [PUBMED Abstract]
    
    
63. Unic I, Stalmeier PF, Verhoef LC, et al.: Assessment of the time-tradeoff values for prophylactic mastectomy of women with a suspected genetic predisposition to breast cancer. Med Decis Making 18 (3): 268-77, 1998 Jul-Sep.  [PUBMED Abstract]
    
    
64. Grann VR, Panageas KS, Whang W, et al.: Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 16 (3): 979-85, 1998.  [PUBMED Abstract]
    
    
65. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al.: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355 (9220): 2015-20, 2000.  [PUBMED Abstract]
    
    
66. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003.  [PUBMED Abstract]
    
    
67. Dørum A, Kristensen GB, Abeler VM, et al.: Early detection of familial ovarian cancer. Eur J Cancer 32A (10): 1645-51, 1996.  [PUBMED Abstract]
    
    
68. Bourne TH, Campbell S, Reynolds K, et al.: The potential role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. Gynecol Oncol 52 (3): 379-85, 1994.  [PUBMED Abstract]
    
    
69. Karlan BY, Platt LD: Ovarian cancer screening. The role of ultrasound in early detection. Cancer 76 (10 Suppl): 2011-5, 1995.  [PUBMED Abstract]
    
    
70. Karlan BY, Raffel LJ, Crvenkovic G, et al.: A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. Am J Obstet Gynecol 169 (3): 494-501, 1993.  [PUBMED Abstract]
    
    
71. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA 273 (6): 491-7, 1995.  [PUBMED Abstract]
    
    
72. Kramer BS, Gohagan J, Prorok PC, et al.: A National Cancer Institute sponsored screening trial for prostatic, lung, colorectal, and ovarian cancers. Cancer 71 (2 Suppl): 589-93, 1993.  [PUBMED Abstract]
    
    
73. Van Nagell JR Jr, DePriest PD, Puls LE, et al.: Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography. Cancer 68 (3): 458-62, 1991.  [PUBMED Abstract]
    
    
74. Fleischer AC, Cullinan JA, Peery CV, et al.: Early detection of ovarian carcinoma with transvaginal color Doppler ultrasonography. Am J Obstet Gynecol 174 (1 Pt 1): 101-6, 1996.  [PUBMED Abstract]
    
    
75. Weiner Z, Beck D, Shteiner M, et al.: Screening for ovarian cancer in women with breast cancer with transvaginal sonography and color flow imaging. J Ultrasound Med 12 (7): 387-93, 1993.  [PUBMED Abstract]
    
    
76. Bourne TH, Whitehead MI, Campbell S, et al.: Ultrasound screening for familial ovarian cancer. Gynecol Oncol 43 (2): 92-7, 1991.  [PUBMED Abstract]
    
    
77. Bourne TH, Campbell S, Reynolds KM, et al.: Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. BMJ 306 (6884): 1025-9, 1993.  [PUBMED Abstract]
    
    
78. Muto MG, Cramer DW, Brown DL, et al.: Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecol Oncol 51 (1): 12-20, 1993.  [PUBMED Abstract]
    
    
79. Risch HA: Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 90 (23): 1774-86, 1998.  [PUBMED Abstract]
    
    
80. Hankinson SE, Colditz GA, Hunter DJ, et al.: A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer 76 (2): 284-90, 1995.  [PUBMED Abstract]
    
    
81. Vachon CM, Mink PJ, Janney CA, et al.: Association of parity and ovarian cancer risk by family history of breast or ovarian cancer in a population-based study of postmenopausal women. Epidemiology 13 (1): 66-71, 2002.  [PUBMED Abstract]
    
    
82. Godard B, Foulkes WD, Provencher D, et al.: Risk factors for familial and sporadic ovarian cancer among French Canadians: a case-control study. Am J Obstet Gynecol 179 (2): 403-10, 1998.  [PUBMED Abstract]
    
    
83. Kerber RA, Slattery ML: The impact of family history on ovarian cancer risk. The Utah Population Database. Arch Intern Med 155 (9): 905-12, 1995.  [PUBMED Abstract]
    
    
84. Lacey JV Jr, Mink PJ, Lubin JH, et al.: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 288 (3): 334-41, 2002.  [PUBMED Abstract]
    
    
85. Narod SA, Sun P, Ghadirian P, et al.: Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet 357 (9267): 1467-70, 2001.  [PUBMED Abstract]
    
    
86. Rutter JL, Wacholder S, Chetrit A, et al.: Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst 95 (14): 1072-8, 2003.  [PUBMED Abstract]
    
    
87. Modan B, Hartge P, Hirsh-Yechezkel G, et al.: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345 (4): 235-40, 2001.  [PUBMED Abstract]
    
    
88. Piver MS, Baker TR, Jishi MF, et al.: Familial ovarian cancer. A report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 71 (2 Suppl): 582-8, 1993.  [PUBMED Abstract]
    
    
89. Chen KT, Schooley JL, Flam MS: Peritoneal carcinomatosis after prophylactic oophorectomy in familial ovarian cancer syndrome. Obstet Gynecol 66 (3 Suppl): 93S-94S, 1985.  [PUBMED Abstract]
    
    
90. Lynch HT, Bewtra C, Lynch JF: Familial ovarian carcinoma. Clinical nuances. Am J Med 81 (6): 1073-6, 1986.  [PUBMED Abstract]
    
    
91. Lynch HT, Watson P, Bewtra C, et al.: Hereditary ovarian cancer. Heterogeneity in age at diagnosis. Cancer 67 (5): 1460-6, 1991.  [PUBMED Abstract]
    
    
92. Tobacman JK, Greene MH, Tucker MA, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 2 (8302): 795-7, 1982.  [PUBMED Abstract]
    
    
93. Truong LD, Maccato ML, Awalt H, et al.: Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases. Hum Pathol 21 (1): 99-110, 1990.  [PUBMED Abstract]
    
    
94. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.  [PUBMED Abstract]
    
    
95. Paley PJ, Swisher EM, Garcia RL, et al.: Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 80 (2): 176-80, 2001.  [PUBMED Abstract]
    
    

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction

Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community reactions. It also identifies behavioral factors that encourage or impede surveillance and other health behaviors. It can enhance decision-making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.

Research in these areas includes few randomized controlled trials, and many reports are based on uncontrolled studies of selected high-risk populations. Research is likely to expand considerably with access to larger populations of at-risk individuals.

There have been a number of descriptions of cancer genetics programs that provide genetic susceptibility testing.[1-9] The development of such programs was encouraged by federal funding of multidisciplinary research programs that offered intensive genetic counseling for hereditary cancer syndromes, psychological assessment and back-up, and physician involvement.[10]

Anticipated interest in breast cancer genetic testing has overestimated uptake rates for BRCA1 and BRCA2 testing. Interest ranged from 41% to 93%.[11-19] Among samples of women at higher-than-average breast cancer risk seen in clinical and research settings, uptake of testing was lower, ranging from 26% to 78%.[20-27] The discrepancy between interest and uptake on genetic testing for breast cancer is consistent with the literature on colorectal cancer and Huntington’s disease.[28-31]

The level of uptake of genetic testing in research studies is variable, ranging from 26% to 78%.[20,21,24-27] Accrual statistics in different populations are difficult to compare because there are many points in the genetic risk assessment process at which a family member can decline, and no standard method of reporting these rates has been developed.[32] With the advent of clinical testing, it is impossible to measure uptake rates because patients are self-referred. Factors that may influence uptake of testing include:

• Cost of genetic testing.
• How informative testing would be (e.g., presence of a known mutation in the family or ethnic group versus lack of an identified mutation).
• Extent to which genetic test results are likely to influence clinical decision-making.[27]

Little is known about the characteristics of at-risk individuals who decline testing. It is difficult to access samples of decliners since they are people who also may be reluctant to participate in research studies. Studies of testing are difficult to compare because people may decline at different points and with different amounts of pretest education and counseling. One study found that 43% of affected and unaffected individuals from hereditary breast/ovarian cancer families completing a baseline interview regarding testing declined. Most individuals declining testing chose not to participate in educational sessions. Decliners were more likely to be male and unmarried and had fewer relatives affected with breast cancer. Those decliners who had high levels of cancer-related stress had higher levels of depression. Decliners lost to follow-up were significantly more likely to be affected with cancer.[25] Another study looked at a small number (n=13) of women decliners who carry a 25% to 50% probability of harboring a BRCA mutation and found that these nontested women were more likely to be childless and have a higher educational level. This study showed that most women had decided not to undergo the test after serious deliberation about the risks and benefits. Satisfaction with frequent surveillance was given as 1 reason for nontesting in most of these women.[33] Other reasons for declining included having no children and becoming acquainted with breast/ovarian cancer in the family relatively early in their lives.[25,33]

Participation in breast cancer risk counseling among family relatives of breast cancer patients is positively associated with higher levels of education, income, and positive health behaviors (nonsmokers, any current alcohol use, recent clinical breast exam), and perceived and objective risk perception.[17,34] Other predictors of participation are being married, having a family history of cancer, presence of a daughter, fear of stigma, and believing there are more reasons to be tested than not to be tested.[35] Family communication of BRCA1/2 test results to relatives is another factor affecting participation in testing. For example, it has been observed that in some families in which a mutation is detected, no relatives come forward for predictive genetic testing and distant relatives pursue genetic testing less frequently. There have been more studies of communication with first-degree and second-degree relatives than with more distant family members. One study investigated the process and content of communication among sisters about BRCA1/2 test results.[36] Study results suggest that both mutation carriers and women with uninformative results communicate with sisters to provide them with genetic risk information. Among relatives with whom genetic test results were not discussed, the most important reason given was that the affected women were not close to their relatives. Other studies found that women with a BRCA mutation more often shared their results with their adult sisters and daughters than with their adult brothers and sons;[37] and another study found that disclosure was limited mainly to first-degree relatives, and dissemination of information to distant relatives was problematic.[38] Age was a significant factor in informing distant relatives with younger patients being more willing to communicate their genetic test result.[36-38]

Women recruited from high-risk clinics, i.e., women who have expressed their concern about breast cancer by seeking specialized medical attention, are more likely than women recruited from registry sources to attend counseling and educational sessions about cancer genetics and genetic testing.[39,40] Genetic testing uptake was influenced by eligibility for free testing, history of breast or ovarian cancer, and Ashkenazi Jewish heritage.[27] Interest in testing declines sharply if it is not immediately available.[39] Knowledge about the details of cancer genetic testing is not associated with the decision to be tested,[12] suggesting a need for improved education about cancer genetics. Several studies suggest that interest in cancer genetic testing is generally high despite respondents' relative lack of knowledge regarding the pros and cons of attempting to learn one's mutation status.[34] There are limited data on uptake among nonwhite populations, and further research will be needed to define factors influencing uptake in these populations.[40]

Motivations for testing include the belief that testing positive would increase one’s motivation to get regular clinical breast examinations, to do breast self-exams, and to get recommended mammograms.[41] Women known to be at increased risk do not necessarily adhere to screening recommendations at higher rates than women at population risk, nor do they necessarily pursue or complete genetic testing, although the data on this subject are contradictory.[39,42,43] An additional motivation for testing is to receive information that would benefit other family members.[26] Lastly, other motivators for testing may include recommendation by a physician. In a retrospective study of 335 women considering genetic testing, 77% reported that they wanted the opinion of the genetics physician about whether they should be tested, and 49% wanted the opinion of their primary care provider.[44]

The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision-making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/2 testing arrive with a strong belief that they have a mutation, having decided they want genetic testing, but possessing little information about the risks or limitations of testing.[45] Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits.[46] Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry. Identification of these individuals is essential to prevent adverse outcomes.

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,[47,48] in cancer patients,[19,49,48] in spouses of breast and ovarian cancer patients,[50] and among women in the general population.[51,52] This tendency may encourage a belief that BRCA1/2 genetic testing will be more informative than it is currently thought to be. There is some evidence that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable.[40] Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices.[53,54] A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.[55]

Women appear to be the prime communicators within families about the family history of breast cancer.[56] Higher numbers of maternal versus paternal transmission cases are reported, likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. Physicians and counselors taking a family history are encouraged to elicit paternal as well as maternal family histories of breast, ovarian, or other associated cancers.[56]

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,[57,58] with others finding more errors in the reporting of cancer in second-degree or more distant relatives.[59] Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history.[60] Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history.[61] Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history.[56] (Refer to the Taking a Family History ¹⁷ section of the Elements of Cancer Genetics Risk Assessment and Counseling ¹⁶ summary.)

Targeted written,[62] video, CD-ROM, interactive computer program,[63-65] and culturally targeted educational materials [66] may be an effective and efficient means of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage ineligible individuals from seeking genetic testing.[62]

Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni Syndrome, ataxia-telangiectasia, Cowden’s disease, or Peutz-Jeghers syndrome.[67] (See the Major Genes ¹⁰ section of this summary.)

Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy. The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of mutation status. (See the Interventions ³⁰ section of this summary.)

Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data are emerging that individual responses to being tested as adults are influenced by the results status of other family members.[24,68] Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information as well as adherence to screening.[42,43,69] The limited number of medical interventions with proven benefit to mutation carriers provides further basis for the expectation that mutation carriers may experience increased anxiety, depression, and continuing uncertainty following disclosure of genetic test results.[70] Formal, objective evaluation of these outcomes are now emerging. (Refer to the sections below on Emotional Outcomes ³¹ and Behavioral Outcomes ³².)

Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication.[3,71-76] Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors.[77]

Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 mutation accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy and risk-reducing oophorectomy, and the complexity of existing psychosocial risks.[3] A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities.[46] These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.[46]

It is not yet clearly established to what extent findings derived from special research populations, at least some of which have long awaited genetic testing for breast/ovarian cancer risk, are generalizable to other populations. For example, there are data to suggest that the BRCA1/2 penetrance estimates derived from these dramatically affected families are substantial overestimates and do not apply to most families presenting for counseling and possible testing.[78]

The few studies conducted to date of psychological outcomes associated with genetic testing for mutations in breast/ovarian cancer predisposition genes have shown low levels of distress among those found to be carriers and even lower levels among noncarriers.[21,62,79] A systematic review found that the studies assessing measures of distress (9 of 11 studies) found no change, or a decrease, in those parameters (including anxiety, depression, general distress, and situation distress) in people who had undergone testing at assessments done at 1 month or less, and 3 to 6 months later.[80] Few studies have conducted longer term follow-up. One long-term study of 65 female participants explored the psychosocial consequences of carrying a BRCA1/2 mutation 5 years after genetic testing. Carriers did not differ from noncarriers on several distress measures. Although both groups showed significant increases in depression and anxiety compared with one year postdisclosure, these scores remained within normal limits for the general population.[81] Caution is advised by authors of these studies in interpretation of the results as they are all from programs in which results disclosure was preceded by extensive genetic counseling about risks and benefits of BRCA1/2 testing, psychological assessment, and even, occasionally, exclusion of a few individuals who appeared highly distressed.[3] Intrusive thoughts (measured by the Impact of Events Scale (IES)) [82] about cancer diminished after results disclosure for both mutation-positive and mutation-negative individuals in 1 Dutch study.[83]

Despite generally positive findings regarding diminished distress in tested individuals, most studies also report increased distress among small subsets of tested individuals. Most, but not all, of these increases are within the normal range of distress. Increased distress has been noted by individuals receiving both positive and negative test results. Studies suggest that the psychological impact of an individual test result is highly influenced by the test result status of other family members. A 1999 study found that an individual’s response to learning his or her own BRCA1/2 test result was significantly influenced by his or her gender and by the genetic test result status of other family members. Adverse, immediate outcomes were experienced by male carriers who were the first tested in their family or by noncarrier men whose siblings were all positive. In addition, female carriers who were the first in their families to be tested or whose siblings were all negative had significantly higher distress than other female carriers.[24] Another study found that spousal anxiety about genetic testing and supportiveness differentiated the impact of BRCA1/2 test results. When the spouse was highly anxious and nonsupportive in style, the mutation carrier had significantly higher levels of distress. These studies illustrate that genetic test results are not received in a vacuum, and that researchers need to consider the context of the tested individual in determining which individuals applying for genetic testing may require additional emotional support.[68]

In another study, depression rates postdisclosure were unchanged for mutation carriers and markedly decreased for noncarriers.[25] An analysis of the distress of individuals receiving BRCA1 results in the context of their siblings' results, however, revealed patterns of response suggesting that certain subgroups of tested individuals have markedly increased levels of distress after disclosure that were not apparent when the analysis focused only on comparing the mean scores for carriers versus noncarriers.[24] Early optimistic findings may not sufficiently reflect the true complexity of response to disclosure of BRCA1/2 test results. Female carriers who had no carrier siblings had distress scores (IES) similar to those found in cancer patients 10 weeks after their diagnosis. The distress of male subjects was highly correlated with the status of their siblings’ test results or lack thereof.[24] One pilot study suggested that women diagnosed more recently were more distressed after counseling.[84] A survey of women enrolled in a high-risk clinic found that heightened levels of distress may be more related to living with the awareness of a familial risk for cancer than with the genetic testing process itself. Obtaining genetic testing may be less stressful than living with the awareness of familial risk for cancer.[85] (Note: For more detailed information about depression and anxiety associated with a cancer diagnosis, refer to the PDQ Supportive Care summaries on Anxiety Disorder ³³; Depression ³⁴; and Normal Adjustment, Psychosocial Distress, and the Adjustment Disorders ³⁵.) Case descriptions have supported the importance of family relationships and test outcomes in shaping the distress of tested individuals.[86,87]

Although there are not yet reports of large-scale studies of the reactions of affected individuals to genetic testing, there are indications from several smaller studies that affected individuals who undergo genetic counseling and testing experience more distress than had been expected by professionals [88,89] and are less able themselves to anticipate the intensity of their reactions following result disclosure.[90] Female mutation carriers who have had breast cancer are often surprised by their high level of risk for ovarian cancer. Women mutation carriers who have had breast cancer worried more than unaffected women about developing ovarian cancer, though, in general, worry about ovarian cancer risk was found to be unrealistically low.[89] In addition, some distress related to the “burden” of conveying genetic information to relatives has been noted among those who are the first in their families to be tested.[88,91]

Several studies have compared the provision of breast cancer genetics services by different providers and the psychological impact on women at high and low risk for cancer. In a study of 735 women at all levels of risk for hereditary breast/ovarian cancer, the services of a multidisciplinary team of genetics specialists was compared with services provided by surgeons. There were no significant differences between groups in anxiety, cancer worry, or perceived risk.[92] In a Scottish study of 373 participants, an alternative model of cancer genetics services using genetics nurse specialists in community-based services was compared with standard genetics regional services. There was no difference in cancer worry or change in health behaviors between the 2 groups. Cancer worry decreased for both groups over a 6-month period. Women who dropped out of the study tended to be in the nurse provider arm or were at low risk of breast cancer.[93] In a small US study, an evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing was conducted to compare outcomes of pretest education about breast cancer susceptibility. Four genetic counselors and 2 nurses completed specialized training in cancer genetics. Women receiving pretest education from nurses were as satisfied with information received and had equal degrees of perceived autonomy and partnership. The study findings suggest that with proper training and supervision, both genetic counselors and nurses can be effective in providing pretest education to women considering genetic susceptibility testing for breast cancer risk.[94]

There has been little empirical research in the communication of risk assessments to individuals at risk of breast/ovarian cancer syndromes. When asked to choose a preferred method, individuals undergoing genetic counseling for breast and ovarian cancer appear to prefer quantitative to qualitative presentation of risk information.[95,96] One study indicated that most women wanted information given both ways.[19] Information about the risk of developing breast cancer among women with a family history of breast cancer may be more accurately recalled when presented as odds ratios rather than in other forms.[97]

Preferences for delivery of breast cancer genetic testing are reported in 1 study [96] to include counseling conducted by a genetic counselor (42%) or oncologist (22%) rather than by a primary care physician (6%), nurse (12%), or gynecologist (5%). Patients in that study preferred results disclosure by an oncologist. Younger women especially expressed a need for individual consideration of their personal values and goals or potential emotional reactions to testing; 67% believed emotional support and counseling were a necessary part of posttest counseling. Most women (82%) wanted to be able to self-refer for genetic testing, without a physician referral.

Family communication about genetic testing for cancer susceptibility, and specifically about the results of BRCA1/2 genetic testing, is complex; there are few systematic data available on this topic. Gender appears to be a significant variable in family communication and psychological outcomes. One study documents that female carriers are more likely to disclose their status to other family members (especially sisters and children aged 14-18 years) than are male carriers.[98] Among males, noncarriers were more likely than carriers to tell their sisters and children the results of their tests. BRCA1/2 carriers who disclosed their results to sisters had a slight decrease in psychological distress, compared with a slight increase in distress for carriers who chose not to tell their sisters.

A few in-depth qualitative studies have looked at issues associated with family communication about genetic testing. Although the findings from these studies may not be generalizable to the larger population of at-risk persons, they illustrate the complexity of issues involved in conveying hereditary cancer risk information in families.[99] On the basis of 15 interviews conducted with women attending a familial cancer genetics clinic, the authors concluded that while women felt a sense of duty to discuss genetic testing with their relatives, they also experienced conflicting feelings of uncertainty, respect, and isolation. Decisions on whom in the family to inform and how to inform them about hereditary cancer and genetic testing may be influenced by tensions between women's need to fulfill social roles and their responsibilities toward themselves and others.[99]

There is a small but growing body of literature regarding psychological effects in men who have a family history of breast cancer and who are considering or have had BRCA testing. A qualitative study of 22 men from 16 high-risk families in Ireland revealed that more men in the study with daughters were tested than men without daughters. These men reported little communication with relatives about the illness, with some men reporting being excluded from discussion about cancer among female family members. Some men in the study also reported actively avoiding open discussion with daughters and other relatives.[100] In contrast, a study of 59 men testing positive for a BRCA1/2 mutation recruited from Creighton University and the University of Toronto cancer centers found that most men participated in family discussions about breast and/or ovarian cancer. However, fewer than half of the men participated in family discussions about risk-reducing surgery. The main reason given for having BRCA testing was concern for their children and a need for certainty about whether they could have transmitted the mutation to their children. In this study, 79% of participating men had at least one daughter. Most of these men described how their relationships had been strengthened after receipt of BRCA results, helping communication in the family and greater understanding.[101] Men in both studies expressed fears of developing cancer themselves. Irish men especially reported fear of cancer in sexual organs.

A study of Dutch men at increased risk of having inherited a BRCA1 mutation reported a tendency for the men to deny or minimize the emotional effects of their risk status, and to focus on medical implications for their female relatives. Men in these families, however, also reported considerable distress in relation to their female relatives.[102] In another study of male psychological functioning during breast cancer testing, 28 men belonging to 18 different high-risk families (with a 25% or 50% risk of having inherited a BRCA1/2 mutation) participated. The study purpose was to analyze distress in males at risk of carrying a BRCA1/2 mutation who applied for genetic testing. Of the men studied, most had low pretest distress; scores were lowest for men who were optimistic or who did not have daughters. Most mutation carriers had normal levels of anxiety and depression and reported no guilt, although some anticipated increased distress and feelings of responsibility if their daughters developed breast or ovarian cancer. None of the noncarriers reported feeling guilty.[103] In one study,[101] adherence to recommended screening guidelines after testing was analyzed. In this study, more than half of male carriers of mutations did not adhere to the screening guidelines recommended after disclosure of genetic test results. These findings are consistent with those for female carriers of BRCA1/2 mutations.[101,104]

Testing for BRCA1/2 has been almost universally limited to adults older than 18 years. The risks of testing children for adult-onset disorders (such as breast and ovarian cancer), as inferred from developmental data on children’s medical understanding and ability to provide informed consent, have been outlined in several reports.[105-107] Surveys of parental interest in testing children for late-onset hereditary cancers suggest that parents are more eager to test their children than to be tested themselves for a breast cancer gene, suggesting potential conflicts for providers.[108,109] In a general population survey in the United States, 71% of parents said that it was moderately, very, or extremely likely that if they carried a breast-cancer predisposing mutation, they would test a 13-year-old daughter now to determine her breast cancer gene status.[108] To date, no data exist on the testing of children for BRCA1/2, although some researchers believe it is necessary to test the validity of assumptions underlying the general prohibition of testing of children for breast/ovarian cancer and other adult-onset disease genes.[110-112] In 1 study, 20 children (aged 11–17 years) of a selected group of mothers undergoing genetic testing (80% of whom previously had breast cancer and all of whom had discussed BRCA1/2 testing with their children) completed self-report questionnaires on their health beliefs and attitudes toward cancer, feelings related to cancer, and behavioral problems.[113] Ninety percent of children thought they would want cancer risk information as adults; half worried about themselves or a family member developing cancer. There was no evidence of emotional distress or behavioral problems. Another study by this group [114] found that 1 month after disclosure of BRCA1/2 genetic test results, 53% of 42 enrolled mothers of children aged 8–17 years had discussed their result with 1 or more of their children. Age of the child rather than mutation status of the mother influenced whether they were told, as did family health communication style.

In 1 study, participants who told children younger than 13 years about their carrier status had increased distress, and those who did not tell their young children experienced a slight decrease in distress. Communication with young children was found to be influenced by developmental variables such as age and style of parent/child communication.[114]

Prenatal diagnosis of breast/ovarian cancer predisposition is generally discouraged.[115] Adult age at onset, good prognosis for many breast cancer patients, and the expectation of greater medical progress by the time disease onset might be expected decades into the future make the prospect of prenatal diagnosis an uncomfortable one for many geneticists, leading potentially to charges of eugenics.[108,116] Limited data on the use of this technology are available. In a small series, 26 mutation carriers indicated that pregnancy termination based on mutation status would not be acceptable. Interestingly, a small percentage of non–mutation carriers felt termination of a pregnancy where the fetus was a mutation carrier was acceptable.[117] Historically, in Huntington’s disease, the uptake of prenatal diagnosis and termination is low.[118,119]

The recognition that BRCA1/2 mutations are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups,[120] has led to considerable discussion of the ethical, psychological, and other implications of having one’s ethnicity be a factor in determination of disease predisposition. Fears of genetic reductionism and the creation of a genetic underclass [121] have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.[122]

A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches.[66,123-126]

The above data are associated with the subgroups that have been most intensively studied to date, but there will be an emerging literature on this topic.

The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies,[127] essays,[70,128] and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.

Studies have shown that 62% of studied family members were aware of the family history, and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Expressed concern about cancer in third-degree relatives, or relatives farther removed, was about the same as that for first- or second-degree relatives of the proband.[129] Only half of surveyed first-degree relatives of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/2 test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people.[39] Many professional groups have made recommendations regarding informed consent.[34,39,74,130,131] There is some evidence that not all practitioners are aware of or follow these guidelines.[41] Research shows that many BRCA1/2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed,[130] and they omit highly relevant points of information.[41] In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members.[132] These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk.

Risk-reducing mastectomy is 1 of the options for risk reduction recommended for discussion with women who have an increased risk of developing breast cancer due to inherited cancer predisposition.[131] It is also offered to some women with a strong family history of breast cancer who have had, or who are contemplating, removal of 1 breast because of the presence of tumor,[133] and to women with premalignant breast disease or extreme cancer fear.[134] Recommendation for risk-reducing mastectomy has been controversial because of the lack of clarity in criteria for its appropriate use [135] and limited data on the emotional and social ramifications.[136] Reports of >90% risk reduction for women at high and moderate risk for breast cancer strengthen the likelihood that providers will discuss risk-reducing mastectomy with women at increased hereditary risk.[23,137]

Caution is advised in interpreting the value and advisability of risk-reducing mastectomy among women at increased genetic risk because of the need to consider the psychological and other costs of surgery.[138]

On the other hand, many women found to be mutation carriers express interest in risk-reducing mastectomy in hopes of minimizing their risk of breast cancer. In 1 study of a number of unaffected women with no previous risk-reducing surgery who received results of BRCA1 testing following genetic counseling, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) intended to have oophorectomies.[21] In a later study of the same population, risk-reducing mastectomy was considered an important option by 35% of women who tested positive, whereas risk-reducing oophorectomy was considered an important option by 76%. Initial interest does not always translate into the decision for surgery. One study found that only 3% (½9) of mutation carriers had a risk-reducing mastectomy in the year following result disclosure.[104] In a study of patients in the United Kingdom, data were collected during observations of genetic consultations and in semistructured interviews with 41 women following their attendance at genetic counseling.[139] The option of risk-reducing surgery was raised in 29 consultations and discussed in 35 of the postclinic interviews. Fifteen women said they would consider having an oophorectomy in the future, and 9 said they would consider having a mastectomy. The implications of undergoing oophorectomy and mastectomy were discussed in postclinic interviews. Risk-reducing surgery was described by the counselees as providing individuals with a means to (a) fulfill their obligations to other family members and (b) reduce risk and contain their fear of cancer. The costs of this form of risk management were described by the respondents as:

• Compromising social obligations.
• Upsetting the natural balance of the body.
• Not receiving protection from cancer.
• Operative and postoperative complications.
• The onset of menopause.
• The effects of body image, gender, and personal identity.
• Potential effects on sexual relationships.[139]

A number of women choose to undergo risk-reducing mastectomy and risk-reducing oophorectomy without genetic testing because:

• Testing is not readily accessible.
• They do not wish exposure to the psychosocial risks of genetic testing.
• They do not trust that a negative genetic test result means they are not at increased risk.
• They find any level of risk, even baseline population risk, unacceptable.[140,141]

In an early report, among first-degree relatives of breast cancer patients attending a surveillance clinic, women selecting risk-reducing mastectomy tended to be those with more cancer worry, more previous biopsies, and higher subjective breast cancer risk estimates compared with women who were uninterested in risk-reducing mastectomy.[142] Fourteen women in that study who had undergone risk-reducing mastectomy 6 to 30 months earlier reported overall satisfaction with their surgery decision, but 29% expressed little or no satisfaction with their reconstruction decision.

For the woman having her breasts removed prophylactically, the decision about whether to have reconstruction is often difficult. Despite assurances that reconstruction will not interfere with their detection of any cancer that might develop, some women choose no reconstruction to avoid any continuing worry about a cancer hidden under a reconstructed breast or because of fears about health problems which might develop due to ruptured or leaking implants.

A prospective study conducted in the Netherlands found that among 26 BRCA1/2 mutation carriers, the 14 women who chose mastectomy had higher distress both before test result disclosure and 6 and 12 months later, compared with the 12 carriers who chose surveillance and compared with 53 nonmutation carriers. Overall, however, anxiety declined in women undergoing prophylactic mastectomy; at 1 year, their anxiety scores were closer to those of women choosing surveillance and to the scores of nonmutation carriers.[143] Interestingly, women opting for prophylactic mastectomy had lower pretest satisfaction with their breasts and general body image than carriers who opted for surveillance or noncarriers of BRCA1/2 mutations. Of the women who had a prophylactic mastectomy, all but 1 did not regret the decision at 1 year posttest disclosure, but many had difficulties with body image, sexual interest and functioning, and self-esteem. The perception that doctors had inadequately informed them about the consequences of prophylactic mastectomy was associated with regret.[143] At 5-year follow-up, women who had undergone risk-reducing mastectomy had less favorable body image and changes in sexual relationships, but also had a significant reduction in the fear of developing cancer.[81]

Mixed psychosocial outcomes were reported in a follow-up study (mean 14 years) of 609 women who received prophylactic mastectomies at the Mayo Clinic. Seventy percent were satisfied with prophylactic mastectomy, 11% were neutral, and 19% were dissatisfied. Eighteen percent believed that if they had the choice to make again, they probably or definitely would not have a prophylactic mastectomy. About three quarters said their worry about cancer was diminished by surgery. Half reported no change in their satisfaction with body image; 16% reported improved body image following surgery. Thirty-six percent said they were dissatisfied with their body image following prophylactic mastectomy. About a quarter of the women reported adverse impact of prophylactic mastectomy on their sexual relationships and sense of femininity, and 18% had diminished self-esteem. Factors most strongly associated with satisfaction with prophylactic mastectomy were postsurgical satisfaction with appearance, reduced stress, no reconstruction or lack of problems with implants, and no change or improvement in sexual relationships. Women who cited physician advice as the primary reason for choosing prophylactic mastectomy tended to be dissatisfied following prophylactic mastectomy.[144]

Quality of life in 59 women who underwent risk-reducing oophorectomy was assessed at 24 months postprocedure.[145] Overall quality of life was similar to the general population and breast cancer survivors, with approximately 20% reporting depression. The 30% of subjects reporting vaginal dryness and dyspareunia were more likely to report dissatisfaction with the procedure.

Very little about how the results of genetic testing affect treatment decisions at the time of cancer diagnosis is known. Two studies explored genetic counseling and BRCA1/2 genetic testing at the time of breast cancer diagnosis.[146,147] One of these studies found that genetic testing at the time of diagnosis significantly altered surgical decision making, with more mutation carriers than noncarriers opting for bilateral mastectomy. Bilateral prophylactic mastectomy was chosen by 48% of mutation-positive women [146] and by 100% of mutation-positive women in a smaller series [147] of women undergoing testing at the time of diagnosis. Of women in whom no mutation was found, 24% also opted for bilateral mastectomy.[146] Physician recommendation was an important determinant of surgical decisions.

Several psychological interventions have been proposed for women who may have hereditary risk of breast cancer, but few of these have been rigorously tested. Issues faced by these women include the following:

• Confronting the meaning of one’s risk status, as well as venting strong feelings of fear of harm, disfigurement, pain, or death.
• Addressing guilt about passing on genetic risk or not doing enough for loved ones.
• Managing stress, cancer-related worry, and intrusive thoughts.
• Coaching in problem-solving.
• Facilitating effective decision-making strategies and teaching positive, active coping behaviors.

Psychotherapy for women interested in prophylactic mastectomy is discussed in 1 report.[148] Another recommends rehearsal of affective state in the context of all potential outcomes of cancer genetic testing for BRCA1/2.[149] As genetic testing programs grow and the psychological outcomes and behavioral impact of testing are further defined, there will be an increasing demand for interventions to maximize the benefits of cancer genetic testing and minimize the risks to carriers and family members.

A pilot study demonstrated the usefulness of a 6-session psychoeducational support group for women at high genetic risk of breast cancer who were considering prophylactic mastectomy. The themes for the group sessions included overestimation of and anxiety about risk, desire for “hard data,” emotional impact of watching a mother die of breast cancer, concerns about spouse reactions, self-image and body image, the decision-making process, and confusion over whom to trust in decision-making. Both the participants and the multidisciplinary leaders concluded that as a supplement to individual counseling, a support group is a beneficial and cost-effective treatment modality.[150]

A study [151] of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a BRCA1/2 mutation) women who are members of hereditary breast cancer families found a range of screening practices. Even the presence of known mutations in their families was not associated with good adherence to recommended screening practices. Sixty-nine percent of women aged 50 to 64 years and 83% of women aged 40 to 49 years had had a screening mammogram in the previous year. Twenty percent of participants had ever had a CA 125 test and 31% had ever had a pelvic or transvaginal ultrasound. Further analysis of this study population [151] looking specifically at 107 women with informative BRCA test results found good use of breast cancer screening, although the uptake rate in younger carriers is lower. The reason for the lower uptake rate was not explored in this study.[152] While motivations cited for pursuing genetic testing often include increased adherence to breast and/or ovarian screening recommendations,[14,17,35,151] limited data exist about how much participants in genetic testing alter their screening behaviors over time and about other variables that may influence those behaviors, such as insurance coverage and physician recommendations or attitudes.

This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative as well as those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.

In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors following genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of breast self-exam, for which compliance is negatively associated with procedure-specific anxiety.[53] Further research designed to clarify this potential concern would highlight the need for comprehensive genetic counseling to discuss the need for follow-up screening.

Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years prior to genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, breast self-examination, and ovarian cancer screening (periodic vaginal ultrasound and serum CA 125 measurements), along with the value of preventive interventions.

The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of several ongoing trials, and an area of much needed ongoing study.

References

1. Lynch HT, Fitzsimmons ML, Lynch J, et al.: A hereditary cancer consultation clinic. Nebr Med J 74 (12): 351-9, 1989.  [PUBMED Abstract]
   
   
2. Eeles RA, ed.: Genetic Predisposition to Cancer. London, England: Chapman and Hall Medical, 1996. 
   
   
3. Baty BJ, Venne VL, McDonald J, et al.: BRCA1 testing: genetic counseling protocol development and counseling issues. J Genet Couns 6(2): 223-244, 1997. 
   
   
4. Hoskins IA: Genetic counseling for cancer patients and their families. Oncology (Huntingt) 3 (1): 84-92; discussion 92, 95-8, 1989.  [PUBMED Abstract]
   
   
5. Lynch HT, Lynch J: Genetic counseling for hereditary cancer. Oncology (Huntingt) 10 (1): 27-34, 1996.  [PUBMED Abstract]
   
   
6. McKinnon WC, Guttmacher AE, Greenblatt MS, et al.: The Familial Cancer Program of the Vermont Cancer Center: development of a cancer genetics program in a rural area. J Genet Couns 6(2): 131-145, 1997. 
   
   
7. Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998. 
   
   
8. Peters JA: Familial cancer risk, part II: breast cancer risk counseling and genetic susceptibility testing. J Oncol Manag 3 (6): 14-22, 1994. 
   
   
9. Ponder BA: Setting up and running a familial cancer clinic. Br Med Bull 50 (3): 732-45, 1994.  [PUBMED Abstract]
   
   
10. Collins FS, Thomson EJ: Findings from the cancer genetic studies consortium. Cancer Epidemiol Biomarkers Prev 8 (special issue): 325, 1999. 
    
    
11. Gwyn K, Vernon SW, Conoley PM: Intention to pursue genetic testing for breast cancer among women due for screening mammography. Cancer Epidemiol Biomarkers Prev 12 (2): 96-102, 2003.  [PUBMED Abstract]
    
    
12. Durfy SJ, Bowen DJ, McTiernan A, et al.: Attitudes and interest in genetic testing for breast and ovarian cancer susceptibility in diverse groups of women in western Washington. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 369-75, 1999.  [PUBMED Abstract]
    
    
13. Kash KM, Ortega-Verdejo K, Dabney MK, et al.: Psychosocial aspects of cancer genetics: women at high risk for breast and ovarian cancer. Semin Surg Oncol 18 (4): 333-8, 2000.  [PUBMED Abstract]
    
    
14. Lerman C, Seay J, Balshem A, et al.: Interest in genetic testing among first-degree relatives of breast cancer patients. Am J Med Genet 57 (3): 385-92, 1995.  [PUBMED Abstract]
    
    
15. Lipkus IM, Iden D, Terrenoire J, et al.: Relationships among breast cancer concern, risk perceptions, and interest in genetic testing for breast cancer susceptibility among African-American women with and without a family history of breast cancer. Cancer Epidemiol Biomarkers Prev 8 (6): 533-9, 1999.  [PUBMED Abstract]
    
    
16. Richards CS, Ward PA, Roa BB, et al.: Screening for 185delAG in the Ashkenazim. Am J Hum Genet 60 (5): 1085-98, 1997.  [PUBMED Abstract]
    
    
17. Struewing JP, Lerman C, Kase RG, et al.: Anticipated uptake and impact of genetic testing in hereditary breast and ovarian cancer families. Cancer Epidemiol Biomarkers Prev 4 (2): 169-73, 1995.  [PUBMED Abstract]
    
    
18. Lerman C, Daly M, Masny A, et al.: Attitudes about genetic testing for breast-ovarian cancer susceptibility. J Clin Oncol 12 (4): 843-50, 1994.  [PUBMED Abstract]
    
    
19. Bluman LG, Rimer BK, Berry DA, et al.: Attitudes, knowledge, and risk perceptions of women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2. J Clin Oncol 17 (3): 1040-6, 1999.  [PUBMED Abstract]
    
    
20. Biesecker BB, Ishibe N, Hadley DW, et al.: Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families. Am J Med Genet 93 (4): 257-63, 2000.  [PUBMED Abstract]
    
    
21. Lerman C, Narod S, Schulman K, et al.: BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 275 (24): 1885-92, 1996.  [PUBMED Abstract]
    
    
22. Lerman C, Schwartz MD, Lin TH, et al.: The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 65 (3): 414-20, 1997.  [PUBMED Abstract]
    
    
23. Meijers-Heijboer EJ, Verhoog LC, Brekelmans CT, et al.: Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355 (9220): 2015-20, 2000.  [PUBMED Abstract]
    
    
24. Smith KR, West JA, Croyle RT, et al.: Familial context of genetic testing for cancer susceptibility: moderating effect of siblings' test results on psychological distress one to two weeks after BRCA1 mutation testing. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 385-92, 1999.  [PUBMED Abstract]
    
    
25. Lerman C, Hughes C, Lemon SJ, et al.: What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing. J Clin Oncol 16 (5): 1650-4, 1998.  [PUBMED Abstract]
    
    
26. Armstrong K, Calzone K, Stopfer J, et al.: Factors associated with decisions about clinical BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 9 (11): 1251-4, 2000.  [PUBMED Abstract]
    
    
27. Lee SC, Bernhardt BA, Helzlsouer KJ: Utilization of BRCA1/2 genetic testing in the clinical setting: report from a single institution. Cancer 94 (6): 1876-85, 2002.  [PUBMED Abstract]
    
    
28. Bloch M, Fahy M, Fox S, et al.: Predictive testing for Huntington disease: II. Demographic characteristics, life-style patterns, attitudes, and psychosocial assessments of the first fifty-one test candidates. Am J Med Genet 32 (2): 217-24, 1989.  [PUBMED Abstract]
    
    
29. Craufurd D, Dodge A, Kerzin-Storrar L, et al.: Uptake of presymptomatic predictive testing for Huntington's disease. Lancet 2 (8663): 603-5, 1989.  [PUBMED Abstract]
    
    
30. Lerman C, Hughes C, Trock BJ, et al.: Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA 281 (17): 1618-22, 1999.  [PUBMED Abstract]
    
    
31. Quaid KA, Morris M: Reluctance to undergo predictive testing: the case of Huntington disease. Am J Med Genet 45 (1): 41-5, 1993.  [PUBMED Abstract]
    
    
32. Bowen DJ, Patenaude AF, Vernon SW: Psychosocial issues in cancer genetics: from the laboratory to the public. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 326-8, 1999.  [PUBMED Abstract]
    
    
33. Lodder L, Frets PG, Trijsburg RW, et al.: Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing. Am J Med Genet 119A (3): 266-72, 2003.  [PUBMED Abstract]
    
    
34. Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996.  [PUBMED Abstract]
    
    
35. Jacobsen PB, Valdimarsdottier HB, Brown KL, et al.: Decision-making about genetic testing among women at familial risk for breast cancer. Psychosom Med 59 (5): 459-66, 1997 Sep-Oct.  [PUBMED Abstract]
    
    
36. Hughes C, Lerman C, Schwartz M, et al.: All in the family: evaluation of the process and content of sisters' communication about BRCA1 and BRCA2 genetic test results. Am J Med Genet 107 (2): 143-50, 2002.  [PUBMED Abstract]
    
    
37. Wagner Costalas J, Itzen M, Malick J, et al.: Communication of BRCA1 and BRCA2 results to at-risk relatives: a cancer risk assessment program's experience. Am J Med Genet 119C (1): 11-8, 2003.  [PUBMED Abstract]
    
    
38. Claes E, Evers-Kiebooms G, Boogaerts A, et al.: Communication with close and distant relatives in the context of genetic testing for hereditary breast and ovarian cancer in cancer patients. Am J Med Genet 116A (1): 11-9, 2003.  [PUBMED Abstract]
    
    
39. Geller G, Doksum T, Bernhardt BA, et al.: Participation in breast cancer susceptibility testing protocols: influence of recruitment source, altruism, and family involvement on women's decisions. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 377-83, 1999.  [PUBMED Abstract]
    
    
40. Lerman C, Hughes C, Benkendorf JL, et al.: Racial differences in testing motivation and psychological distress following pretest education for BRCA1 gene testing. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 361-7, 1999.  [PUBMED Abstract]
    
    
41. Durfy SJ, Buchanan TE, Burke W: Testing for inherited susceptibility to breast cancer: a survey of informed consent forms for BRCA1 and BRCA2 mutation testing. Am J Med Genet 75 (1): 82-7, 1998.  [PUBMED Abstract]
    
    
42. Kash KM, Holland JC, Halper MS, et al.: Psychological distress and surveillance behaviors of women with a family history of breast cancer. J Natl Cancer Inst 84 (1): 24-30, 1992.  [PUBMED Abstract]
    
    
43. Lerman C, Schwartz M: Adherence and psychological adjustment among women at high risk for breast cancer. Breast Cancer Res Treat 28 (2): 145-55, 1993.  [PUBMED Abstract]
    
    
44. Armstrong K, Stopfer J, Calzone K, et al.: What does my doctor think? Preferences for knowing the doctor's opinion among women considering clinical testing for BRCA1/2 mutations. Genet Test 6 (2): 115-8, 2002 Summer.  [PUBMED Abstract]
    
    
45. Winer E, Winer N, Bluman L, et al.: Attitudes and risk perceptions of women with breast cancer considering testing for BRCA1/2. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A1937, 537a, 1997. 
    
    
46. Braithwaite D, Emery J, Walter F, et al.: Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. J Natl Cancer Inst 96 (2): 122-33, 2004.  [PUBMED Abstract]
    
    
47. Hallowell N, Statham H, Murton F: Women's understanding of their risk of developing breast/ovarian cancer before and after genetic counseling. J Genet Couns 7(4): 345-364, 1998. 
    
    
48. MacDonald DJ, Choi J, Ferrell B, et al.: Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment. J Med Genet 39 (7): 526-30, 2002.  [PUBMED Abstract]
    
    
49. Iglehart JD, Miron A, Rimer BK, et al.: Overestimation of hereditary breast cancer risk. Ann Surg 228 (3): 375-84, 1998.  [PUBMED Abstract]
    
    
50. Bluman LG, Rimer BK, Regan Sterba K, et al.: Attitudes, knowledge, risk perceptions and decision-making among women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2 and their spouses. Psychooncology 12 (5): 410-27, 2003 Jul-Aug.  [PUBMED Abstract]
    
    
51. McCaul KD, O'Donnell SM: Naive beliefs about breast cancer risk. Womens Health 4 (1): 93-101, 1998 Spring.  [PUBMED Abstract]
    
    
52. Huiart L, Eisinger F, Stoppa-Lyonnet D, et al.: Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after the consultation. J Clin Epidemiol 55 (7): 665-75, 2002.  [PUBMED Abstract]
    
    
53. Lindberg NM, Wellisch D: Anxiety and compliance among women at high risk for breast cancer. Ann Behav Med 23 (4): 298-303, 2001 Fall.  [PUBMED Abstract]
    
    
54. Ritvo P, Irvine J, Robinson G, et al.: Psychological adjustment to familial-genetic risk assessment for ovarian cancer: predictors of nonadherence to surveillance recommendations. Gynecol Oncol 84 (1): 72-80, 2002.  [PUBMED Abstract]
    
    
55. Meiser B, Halliday JL: What is the impact of genetic counselling in women at increased risk of developing hereditary breast cancer? A meta-analytic review. Soc Sci Med 54 (10): 1463-70, 2002.  [PUBMED Abstract]
    
    
56. Green J, Richards M, Murton F, et al.: Family communication and genetic counseling: the case of hereditary breast and ovarian cancer. J Genet Couns 6(1): 45-60, 1997. 
    
    
57. Theis B, Boyd N, Lockwood G, et al.: Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev 3 (4): 321-7, 1994.  [PUBMED Abstract]
    
    
58. Breuer B, Kash KM, Rosenthal G, et al.: Reporting bilaterality status in first-degree relatives with breast cancer: a validity study. Genet Epidemiol 10 (4): 245-56, 1993.  [PUBMED Abstract]
    
    
59. Parent ME, Ghadirian P, Lacroix A, et al.: The reliability of recollections of family history: implications for the medical provider. J Cancer Educ 12 (2): 114-20, 1997 Summer.  [PUBMED Abstract]
    
    
60. Kerber RA, Slattery ML: Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146 (3): 244-8, 1997.  [PUBMED Abstract]
    
    
61. Kerr B, Foulkes WD, Cade D, et al.: False family history of breast cancer in the family cancer clinic. Eur J Surg Oncol 24 (4): 275-9, 1998.  [PUBMED Abstract]
    
    
62. Schwartz MD, Peshkin BN, Hughes C, et al.: Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol 20 (2): 514-20, 2002.  [PUBMED Abstract]
    
    
63. Green MJ, Biesecker BB, McInerney AM, et al.: An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility. Am J Med Genet 103 (1): 16-23, 2001.  [PUBMED Abstract]
    
    
64. Green MJ, McInerney AM, Biesecker BB, et al.: Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor. Am J Med Genet 103 (1): 24-31, 2001.  [PUBMED Abstract]
    
    
65. Dabney MK, Huelsman K: Counseling by computer: breast cancer risk and genetic testing. Developed by the University of Wisconsin-Madison Department of Medicine and the Program in Medical Ethics. Genet Test 4 (1): 43-4, 2000.  [PUBMED Abstract]
    
    
66. Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003.  [PUBMED Abstract]
    
    
67. Calzone KA: Predisposition testing for breast and ovarian cancer susceptibility. Semin Oncol Nurs 13 (2): 82-90, 1997.  [PUBMED Abstract]
    
    
68. Wylie JE, Smith KR, Botkin JR: Effects of spouses on distress experienced by BRCA1 mutation carriers over time. Am J Med Genet 119C (1): 35-44, 2003.  [PUBMED Abstract]
    
    
69. Kelly PT: Understanding Breast Cancer Risk. Philadelphia, Pa: Temple University Press, 1991. 
    
    
70. Hubbard R, Lewontin RC: Pitfalls of genetic testing. N Engl J Med 334 (18): 1192-4, 1996.  [PUBMED Abstract]
    
    
71. Richards MP, Hallowell N, Green JM, et al.: Counseling families with hereditary breast and ovarian cancer: a psychosocial perspective. J Genet Couns 4(3): 219-233, 1995. 
    
    
72. Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995.  [PUBMED Abstract]
    
    
73. Schneider KA: Genetic counseling for BRCA1/BRCA2 testing. Genet Test 1 (2): 91-8, 1997.  [PUBMED Abstract]
    
    
74. McKinnon WC, Baty BJ, Bennett RL, et al.: Predisposition genetic testing for late-onset disorders in adults. A position paper of the National Society of Genetic Counselors. JAMA 278 (15): 1217-20, 1997.  [PUBMED Abstract]
    
    
75. Cummings S, Olopade O: Predisposition testing for inherited breast cancer. Oncology (Huntingt) 12 (8): 1227-41; discussion 1241-2, 1998.  [PUBMED Abstract]
    
    
76. Lipkus IM, Klein WM, Rimer BK: Communicating breast cancer risks to women using different formats. Cancer Epidemiol Biomarkers Prev 10 (8): 895-8, 2001.  [PUBMED Abstract]
    
    
77. Lerman C, Audrain J, Croyle RT: DNA-testing for heritable breast cancer risks: lessons from traditional genetic counseling. Ann Behav Med 16(4): 327-333, 1994. 
    
    
78. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.  [PUBMED Abstract]
    
    
79. Croyle RT, Smith KR, Botkin JR, et al.: Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol 16 (1): 63-72, 1997.  [PUBMED Abstract]
    
    
80. Broadstock M, Michie S, Marteau T: Psychological consequences of predictive genetic testing: a systematic review. Eur J Hum Genet 8 (10): 731-8, 2000.  [PUBMED Abstract]
    
    
81. van Oostrom I, Meijers-Heijboer H, Lodder LN, et al.: Long-term psychological impact of carrying a BRCA1/2 mutation and prophylactic surgery: a 5-year follow-up study. J Clin Oncol 21 (20): 3867-74, 2003.  [PUBMED Abstract]
    
    
82. Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 41 (3): 209-18, 1979.  [PUBMED Abstract]
    
    
83. DudokdeWit AC, Tibben A, Duivenvoorden HJ, et al.: Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup. J Med Genet 35 (9): 745-54, 1998.  [PUBMED Abstract]
    
    
84. Wood ME, Mullineaux L, Rahm AK, et al.: Impact of BRCA1 testing on women with cancer: a pilot study. Genet Test 4 (3): 265-72, 2000.  [PUBMED Abstract]
    
    
85. Coyne JC, Kruus L, Racioppo M, et al.: What do ratings of cancer-specific distress mean among women at high risk of breast and ovarian cancer? Am J Med Genet 116A (3): 222-8, 2003.  [PUBMED Abstract]
    
    
86. DudokdeWit AC, Tibben A, Frets PG, et al.: BRCA1 in the family: a case description of the psychological implications. Am J Med Genet 71 (1): 63-71, 1997.  [PUBMED Abstract]
    
    
87. Macke E: A family history of breast and ovarian cancer. In: Marteau T, Richards M, eds.: The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge, England: Cambridge University Press, 1996, pp 31-37. 
    
    
88. Bonadona V, Saltel P, Desseigne F, et al.: Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result. Cancer Epidemiol Biomarkers Prev 11 (1): 97-104, 2002.  [PUBMED Abstract]
    
    
89. Bish A, Sutton S, Jacobs C, et al.: Changes in psychological distress after cancer genetic counselling: a comparison of affected and unaffected women. Br J Cancer 86 (1): 43-50, 2002 Jan 7.  [PUBMED Abstract]
    
    
90. Dorval M, Patenaude AF, Schneider KA, et al.: Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: findings from p53 and BRCA1 testing programs. J Clin Oncol 18 (10): 2135-42, 2000.  [PUBMED Abstract]
    
    
91. Hallowell N, Foster C, Ardern-Jones A, et al.: Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching. Genet Test 6 (2): 79-87, 2002 Summer.  [PUBMED Abstract]
    
    
92. Brain K, Norman P, Gray J, et al.: A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk. Br J Cancer 86 (2): 233-8, 2002.  [PUBMED Abstract]
    
    
93. Fry A, Cull A, Appleton S, et al.: A randomised controlled trial of breast cancer genetics services in South East Scotland: psychological impact. Br J Cancer 89 (4): 653-9, 2003.  [PUBMED Abstract]
    
    
94. Bernhardt BA, Geller G, Doksum T, et al.: Evaluation of nurses and genetic counselors as providers of education about breast cancer susceptibility testing. Oncol Nurs Forum 27 (1): 33-9, 2000 Jan-Feb.  [PUBMED Abstract]
    
    
95. Hallowell N, Statham H, Murton F, et al.: "Talking about chance": the presentation of risk information during genetic counseling for breast and ovarian cancer. J Genet Couns 6(3): 269-286, 1997. 
    
    
96. Audrain J, Rimer B, Cella D, et al.: Genetic counseling and testing for breast-ovarian cancer susceptibility: what do women want? J Clin Oncol 16 (1): 133-8, 1998.  [PUBMED Abstract]
    
    
97. Watson M, Duvivier V, Wade Walsh M, et al.: Family history of breast cancer: what do women understand and recall about their genetic risk? J Med Genet 35 (9): 731-8, 1998.  [PUBMED Abstract]
    
    
98. Lerman C, Peshkin BN, Hughes C, et al.: Family disclosure in genetic testing for cancer susceptibility: determinants and consequences. Journal of Health Care Law and Policy 1(2): 353-373, 1998. 
    
    
99. Foster C, Eeles R, Ardern-Jones A, et al.: Juggling roles and expectations: dilemmas faced by women talking to relatives about cancer and genetic testing. Psychol Health 19 (4): 439-55, 2004. 
    
    
100. McAllister MF, Evans DG, Ormiston W, et al.: Men in breast cancer families: a preliminary qualitative study of awareness and experience. J Med Genet 35 (9): 739-44, 1998.  [PUBMED Abstract]
     
     
101. Liede A, Metcalfe K, Hanna D, et al.: Evaluation of the needs of male carriers of mutations in BRCA1 or BRCA2 who have undergone genetic counseling. Am J Hum Genet 67 (6): 1494-504, 2000.  [PUBMED Abstract]
     
     
102. DudokdeWit AC, Tibben A, Frets PG, et al.: Males at-risk for the BRCA1 gene, the psychological impact. Psychooncology 5(3): 251-257, 1996. 
     
     
103. Lodder L, Frets PG, Trijsburg RW, et al.: Men at risk of being a mutation carrier for hereditary breast/ovarian cancer: an exploration of attitudes and psychological functioning during genetic testing. Eur J Hum Genet 9 (7): 492-500, 2001.  [PUBMED Abstract]
     
     
104. Lerman C, Hughes C, Croyle RT, et al.: Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing. Prev Med 31 (1): 75-80, 2000.  [PUBMED Abstract]
     
     
105. Patenaude AF: Cancer susceptibility testing: risks, benefits, and personal beliefs. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 145-156. 
     
     
106. Richards M: The genetic testing of children: adult attitude's and children's understanding. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 169-179. 
     
     
107. Wertz DC, Fanos JH, Reilly PR: Genetic testing for children and adolescents. Who decides? JAMA 272 (11): 875-81, 1994.  [PUBMED Abstract]
     
     
108. Wertz DC: International perspectives. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 271-287. 
     
     
109. Benkendorf JL, Reutenauer JE, Hughes CA, et al.: Patients' attitudes about autonomy and confidentiality in genetic testing for breast-ovarian cancer susceptibility. Am J Med Genet 73 (3): 296-303, 1997.  [PUBMED Abstract]
     
     
110. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.  [PUBMED Abstract]
     
     
111. Michie S, Marteau TM: Predictive genetic testing in children: the need for psychological research. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 169-182. 
     
     
112. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000.  [PUBMED Abstract]
     
     
113. Tercyak KP, Peshkin BN, Streisand R, et al.: Psychological issues among children of hereditary breast cancer gene (BRCA1/2) testing participants. Psychooncology 10 (4): 336-46, 2001 Jul-Aug.  [PUBMED Abstract]
     
     
114. Tercyak KP, Peshkin BN, DeMarco TA, et al.: Parent-child factors and their effect on communicating BRCA1/2 test results to children. Patient Educ Couns 47 (2): 145-53, 2002.  [PUBMED Abstract]
     
     
115. Wagner TM, Ahner R: Prenatal testing for late-onset diseases such as mutations in the breast cancer gene 1 (BRCA1). Just a choice or a step in the wrong direction? Hum Reprod 13 (5): 1125-6, 1998.  [PUBMED Abstract]
     
     
116. Dickens BM, Pei N, Taylor KM: Legal and ethical issues in genetic testing and counseling for susceptibility to breast, ovarian and colon cancer. CMAJ 154 (6): 813-8, 1996.  [PUBMED Abstract]
     
     
117. Lodder LN, Frets PG, Trijsburg RW, et al.: Attitudes towards termination of pregnancy in subjects who underwent presymptomatic testing for the BRCA1/BRCA2 gene mutation in The Netherlands. J Med Genet 37 (11): 883-4, 2000.  [PUBMED Abstract]
     
     
118. Tibben A, Frets PG, van de Kamp JJ, et al.: On attitudes and appreciation 6 months after predictive DNA testing for Huntington disease in the Dutch program. Am J Med Genet 48 (2): 103-11, 1993.  [PUBMED Abstract]
     
     
119. Adam S, Wiggins S, Whyte P, et al.: Five year study of prenatal testing for Huntington's disease: demand, attitudes, and psychological assessment. J Med Genet 30 (7): 549-56, 1993.  [PUBMED Abstract]
     
     
120. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.  [PUBMED Abstract]
     
     
121. Rothenberg KH: Breast cancer, the genetic "quick fix," and the Jewish community. Ethical, legal, and social challenges. Health Matrix Clevel 7 (1): 97-124, 1997 Winter.  [PUBMED Abstract]
     
     
122. Foster MW, Bernsten D, Carter TH: A model agreement for genetic research in socially identifiable populations. Am J Hum Genet 63 (3): 696-702, 1998.  [PUBMED Abstract]
     
     
123. Burhansstipanov L, Bemis LT, Dignan MB: Native American cancer education: genetic and cultural issues. J Cancer Educ 16 (3): 142-5, 2001 Autumn.  [PUBMED Abstract]
     
     
124. Hughes C, Fasaye GA, LaSalle VH, et al.: Sociocultural influences on participation in genetic risk assessment and testing among African American women. Patient Educ Couns 51 (2): 107-14, 2003.  [PUBMED Abstract]
     
     
125. Julian-Reynier CM, Bouchard LJ, Evans DG, et al.: Women's attitudes toward preventive strategies for hereditary breast or ovarian carcinoma differ from one country to another: differences among English, French, and Canadian women. Cancer 92 (4): 959-68, 2001.  [PUBMED Abstract]
     
     
126. Phillips KA, Warner E, Meschino WS, et al.: Perceptions of Ashkenazi Jewish breast cancer patients on genetic testing for mutations in BRCA1 and BRCA2. Clin Genet 57 (5): 376-83, 2000.  [PUBMED Abstract]
     
     
127. Freedman TG: Genetic susceptibility testing: ethical and social quandaries. Health Soc Work 23 (3): 214-22, 1998.  [PUBMED Abstract]
     
     
128. Parens E: Glad and terrified: on the ethics of BRACA1 and 2 testing. Cancer Invest 14 (4): 405-11, 1996.  [PUBMED Abstract]
     
     
129. Winter PR, Wiesner GL, Finnegan J, et al.: Notification of a family history of breast cancer: issues of privacy and confidentiality. Am J Med Genet 66 (1): 1-6, 1996.  [PUBMED Abstract]
     
     
130. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.  [PUBMED Abstract]
     
     
131. Burke W, Daly M, Garber J, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 277 (12): 997-1003, 1997.  [PUBMED Abstract]
     
     
132. Hallowell N, Foster C, Eeles R, et al.: Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information. J Med Ethics 29 (2): 74-9; discussion 80-3, 2003.  [PUBMED Abstract]
     
     
133. Goin MK, Goin JM: Psychological reactions to prophylactic mastectomy synchronous with contralateral breast reconstruction. Plast Reconstr Surg 70 (3): 355-9, 1982.  [PUBMED Abstract]
     
     
134. Perez FM: Subcutaneous mastectomy: a review. Am Surg 45 (1): 21-5, 1979.  [PUBMED Abstract]
     
     
135. Nemecek JR, Young VL, Lopez MJ: Indications for prophylactic mastectomy. Mo Med 90 (3): 136-40, 1993.  [PUBMED Abstract]
     
     
136. Stefanek M, Hartmann L, Nelson W: Risk-reduction mastectomy: clinical issues and research needs. J Natl Cancer Inst 93 (17): 1297-306, 2001.  [PUBMED Abstract]
     
     
137. Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999.  [PUBMED Abstract]
     
     
138. Eisen A, Weber BL: Prophylactic mastectomy--the price of fear. N Engl J Med 340 (2): 137-8, 1999.  [PUBMED Abstract]
     
     
139. Hallowell N: 'You don't want to lose your ovaries because you think 'I might become a man". Women's perceptions of prophylactic surgery as a cancer risk management option. Psychooncology 7 (3): 263-75, 1998 May-Jun.  [PUBMED Abstract]
     
     
140. Schneider KA, Stopfer JE, Peters JA, et al.: Complexities in cancer risk counseling: presentation of three cases. J Genet Couns 6(2): 147-168, 1997. 
     
     
141. Tarkan L: My Mother's Breast: Daughters Face Their Mothers' Cancer. Dallas, TX: Taylor Publishing, 1999. 
     
     
142. Stefanek ME, Helzlsouer KJ, Wilcox PM, et al.: Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 24 (4): 412-9, 1995.  [PUBMED Abstract]
     
     
143. Lodder LN, Frets PG, Trijsburg RW, et al.: One year follow-up of women opting for presymptomatic testing for BRCA1 and BRCA2: emotional impact of the test outcome and decisions on risk management (surveillance or prophylactic surgery). Breast Cancer Res Treat 73 (2): 97-112, 2002.  [PUBMED Abstract]
     
     
144. Frost MH, Schaid DJ, Sellers TA, et al.: Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy. JAMA 284 (3): 319-24, 2000.  [PUBMED Abstract]
     
     
145. Robson M, Hensley M, Barakat R, et al.: Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol 89 (2): 281-7, 2003.  [PUBMED Abstract]
     
     
146. Schwartz MD, Lerman C, Brogan B, et al.: Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 22 (10): 1823-9, 2004.  [PUBMED Abstract]
     
     
147. Weitzel JN, McCaffrey SM, Nedelcu R, et al.: Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg 138 (12): 1323-8; discussion 1329, 2003.  [PUBMED Abstract]
     
     
148. Massie MJ, Muskin PR, Stewart DE: Psychotherapy with a woman at high risk for developing breast cancer. Gen Hosp Psychiatry 20 (3): 189-97, 1998.  [PUBMED Abstract]
     
     
149. Shoda Y, Mischel W, Miller SM, et al.: Psychological interventions and genetic testing: facilitating informed decisions about BRCA1/2 cancer susceptibility. J Clin Psychol Med Settings 5(1): 3-17, 1998. 
     
     
150. Karp J, Brown KL, Sullivan MD, et al.: The prophylactic mastectomy dilemma: a support group for women at high genetic risk for breast cancer. J Genet Counsel 8 (3): 163-73, 1999. 
     
     
151. Isaacs C, Peshkin BN, Schwartz M, et al.: Breast and ovarian cancer screening practices in healthy women with a strong family history of breast or ovarian cancer. Breast Cancer Res Treat 71 (2): 103-12, 2002.  [PUBMED Abstract]
     
     
152. Peshkin BN, Schwartz MD, Isaacs C, et al.: Utilization of breast cancer screening in a clinically based sample of women after BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 1115-8, 2002.  [PUBMED Abstract]
     
     

Disclaimer

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Changes to This Summary 09/30/2004

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition ³⁶

Revised text to remove percentages on patterns of autosomal dominant inheritance. Added text to state that breast cancer among males with inherited breast cancer predisposition is rare. Added text describing suggestions of hereditary breast and ovarian cancer predisposition.

Reproductive and Menstrual History ³⁷

Added text to state that in both the general population and BRCA1 carriers, some evidence exists of a slight-to-moderate reduction in breast cancer risk with breast-feeding for at least one year (cited Collaborative Group on Hormonal Factors in Breast Cancer and Jernström et al.).

Reproductive ³⁸

Added text to state that a small subset from a large retrospective cohort study did not confirm a strong link between infertility drugs and ovarian cancer risk (cited Brinton et al.).

Surgical History ³⁹

Added text to state that a retrospective study and a prospective study have reported a >90% reduction in risk of ovarian cancer in women with documented BRCA1 or BRCA2 mutations who chose prophylactic oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer (cited Kauff et al. and Rebbeck et al.).

Penetrance of Mutations ⁴⁰

Added text to state that men carrying BRCA1 and BRCA2 mutations were at modestly increased risk of prostate cancer, reaching 16% by age 70 years. Subsequent studies have provided additional support for an approximately 2-fold increased risk of prostate cancer in BRCA2 mutation carriers (cited Warner et al., Edwards et al., and Giusti et al.).

Molecular Correlations ⁴¹

Added Lubinski et al.

Li-Fraumeni Syndrome ³

Moved text on CHEK2 mutation into its own new sub-subsection; cited CHEK2 Breast Cancer Case-Control Consortium.

Other Factors ⁴²

Added text to state that in a retrospective analysis of 104 BRCA1/2 mutation-positive families, physical exercise as a teenager was associated with a delayed onset of breast cancer (cited King et al.).

Lactation, Hormone Replacement Therapy, and Tubal Ligation ⁴³

Added ligation, hysterectomy, unilateral oophorectomy, and ovarian cystectomy as examples of gynecologic surgeries in a case-control study of ovarian cancer in Israel.

Psychosocial Issues in Inherited Breast Cancer Syndromes ⁴⁴

Revised text on what people bring to genetic testing, genetic counseling for hereditary predisposition, family effects, cultural/community effects, ethical concerns, and psychosocial outcome studies.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ⁴⁵.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ⁴⁶

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ⁴⁷

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive Care ⁴⁸

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ⁴⁹

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ⁵⁰

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ⁵¹

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ⁵²

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Glossary Terms

One of two or more DNA sequences occurring at a particular gene locus. Typically one allele (“normal” DNA sequence) is common, and other alleles (mutations) are rare.

Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).

Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).

Occurs when both alleles at a particular gene locus are the same. A person may be homozygous for the normal allele or for a mutation.

The state in which a genetic trait is expressed later in life or is expressed at no fixed time in a life history.

A change in the usual DNA sequence at a particular gene locus. Mutations (including polymorphisms) can be harmful, beneficial, or neutral.

A graphic illustration of family history.

A characteristic of a genotype; it refers to the likelihood that a clinical condition will occur when a particular genotype is present.

A common mutation. “Common” is typically defined as an allele frequency of at least 1%. All genes occur in pairs, except when x and y chromosomes are paired in males; thus a polymorphism with an allele frequency of 1% would be found in about 2% of the population, with most carriers having one copy of the polymorphism and one copy of the normal allele.

This term has two meanings. It is sometimes used to differentiate cancers occurring in people who do not have a germline mutation that confers increased susceptibility to cancer from cancers occurring in people who are known to carry a mutation. Cancer developing in people who do not carry a high-risk mutation is referred to as sporadic cancer. The distinction is not absolute, because genetic background may influence the likelihood of cancer even in the absence of a specific predisposing mutation. Alternatively, sporadic is also sometimes used to describe cancer occurring in individuals without a family history of cancer.