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
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.
Family History as a Risk Factor for 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]
Family History as a Risk Factor for Ovarian Cancer
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 Predisposition
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.)
Difficulties in Identifying a Family History of Breast Cancer Risk
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
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.
Age
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]
Reproductive and Menstrual History
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]
Hormone Therapy
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.
Radiation Exposure
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.
Lifestyle Factors
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.
History of Breast Disease
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 Factors
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
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.
Age
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]
Demographic
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.
Reproductive
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.
Surgical History
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 for Prediction of Breast Cancer Risk
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).
Characteristics of the Gail and Claus Models*
| Gail Model
| Claus Model
| *Adapted from Domcheck et al.,[80] Rubenstein et al.,[81] and Rhodes.[82] | Data derived from | Breast Cancer Detection Demonstration Project (BCDDP) Study | Cancer and Steroid Hormone (CASH) Study | Study population | 2,852 cases, age ≥35 years | 4,730 cases, age 20-54 years | In situ and invasive cancer | Invasive cancer | 3,146 controls | 4,688 controls | Caucasian | Caucasian | Annual screening | Not routinely screened | Family history characteristics | First-degree relatives with breast cancer | First-degree or second-degree relatives with breast cancer | Age of onset in relatives | Other characteristics | Current age | Current age | Age at menarche | Age at first live birth | Number of breast biopsies | Atypical hyperplasia in breast biopsy | Race (included in the most current version of the Gail model) | Strengths | Incorporates: | Incorporates: | Risk factors other than family history | Paternal as well as maternal history | Age of onset of breast cancer | Family history of ovarian cancer | Limitations | Underestimates risk in hereditary families | May underestimate risk in hereditary families | Number of breast biopsies without atypical hyperplasia may cause inflated risk estimates | May not be applicable to all combinations of affected relatives | Does not include risk factors other than family history | Does not incorporate: | | Paternal family history of breast cancer or any family history of ovarian cancer | Age of onset of breast cancer in relatives | All known risk factors for breast cancer [82] | Best application | For individuals with no family history of breast cancer or 1 first-degree relative with breast cancer at ≥age 50 years | For individuals with 0, 1, or 2 first-degree or second-degree relatives with breast cancer | For determining eligibility for chemoprevention studies |
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.
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