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

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 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 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 due to TP53 mutations, and Cowden syndrome 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 and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with basal cell nevus (Gorlin) syndrome, multiple endocrine neoplasia type 1 (MEN1), and hereditary nonpolyposis colon cancer (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 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 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 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 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 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 section of this summary.

Models to predict an individual’s lifetime risk for developing breast cancer are available. In addition, models 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, 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 for more information on Taking a Family History.) 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, 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. 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]
    
    

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