Purpose of This PDQ Summary
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 and Ovarian Cancer Risk Other Risk Factors for Breast Cancer         Age         Reproductive and menstrual history         Oral contraceptives         Radiation exposure         Alcohol intake         Physical activity and anthropometry         Benign breast disease and mammographic density         Other factors Other Risk Factors for Ovarian Cancer         Age         Reproductive history         Surgical history         Oral contraceptives Models for Prediction of Breast Cancer Risk

Major Genes

Introduction BRCA1 BRCA2 BRCA1 and BRCA2 Function Mutations in BRCA1 and BRCA2         Variants of uncertain significance Prevalence and Founder Effects Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation Penetrance of Mutations Population Estimates of the Likelihood of Having a BRCA1 or BRCA2 Mutation Role of BRCA1 and BRCA2 in Sporadic Cancer Genotype-Phenotype Correlations Pathology/Prognosis of Breast Cancer         BRCA1         BRCA2 Pathology/Prognosis of Ovarian Cancer         Pathology         Prognosis Other Rare Breast and Ovarian Cancer-Associated Syndromes         Li-Fraumeni syndrome         Cowden syndrome         Peutz-Jeghers syndrome

Low Penetrance Predisposition to Breast and Ovarian Cancer

Background Breast Cancer Susceptibility Genes Identified Through Candidate Gene Approaches         CHEK2         ATM         BRIP1         PALB2         CASP8 and TGFB1 Genome-Wide Searches

Interventions

Breast Cancer         Screening         Risk modification         Breast conservation therapy for BRCA1/2 mutation carriers         Role of BRCA1 and BRCA2 in response to chemotherapy Ovarian Cancer         Screening         Risk modification

Psychosocial Issues in Inherited Breast Cancer Syndromes

Introduction Interest in and Uptake of 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         Family communication about genetic testing and hereditary risk         Family functioning         Partners of high-risk women         At-risk males         Children         Reproductive issues Cultural/Community Effects Ethical Concerns Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Ovarian Cancer         Decision aids for persons considering risk management options for hereditary breast and ovarian cancer         Uptake of cancer-risk management options         Cancer screening and risk-reducing behaviors Psychosocial Outcome Studies         Risk-reducing mastectomy         Risk-reducing salpingo-oophorectomy Interventions: Psychological Behavioral Outcomes

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Changes to This Summary (10/02/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and ovarian cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board ¹.

The following information is included in this summary:

• Family history and other risk factors for breast and ovarian cancer.
• Models for predicting breast cancer risk.
• Major genes associated with breast and ovarian cancer risk.
• Screening and risk modification for hereditary breast and ovarian cancer.
• Psychosocial issues associated with hereditary breast and ovarian cancer and genetic testing.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview ².

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary breast and ovarian cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

General Information

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms ³. When a linked term is clicked, the definition will appear in a separate window.]

 [Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more 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 2009, an estimated 194,280 new cases will be diagnosed, and 40,610 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptor-positive cancers occurring after age 50 years, has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy following early reports from the Women’s Health Initiative.[2] Ovarian cancer is the ninth most common cancer, with an estimated 21,550 new cases in 2009, but is the fifth most deadly, with an estimated 14,600 deaths in 2009.[1] (Refer to the PDQ summary on Breast Cancer Treatment ⁴ and Ovarian Epithelial Cancer Treatment ⁵ for more information on breast cancer and ovarian cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer ⁶ and the Family History as a Risk Factor for Ovarian Cancer ⁷ sections below), and by the observation of rare families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with autosomal dominant inheritance of cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes 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.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

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 relative or a second-degree relative with breast cancer.[3-6] 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.[7] In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2).[7] Risk increases with the number of affected relatives and age at diagnosis.[4,5,7] Refer to the Penetrance of Mutations ⁸ section for a discussion of familial risk for women from families with BRCA1/2 mutations who themselves test negative for the family mutation.

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 large meta-analysis of 15 published studies estimated an odds ratio (OR) of 3.1 for the risk of ovarian cancer associated with at least one first-degree relative with ovarian cancer.[8]

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

• Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
• Both males and females can inherit and transmit an autosomal dominant cancer predisposition. 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.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome ⁹ due to TP53 mutations; of Cowden syndrome ¹⁰ due to PTEN mutations; and with mutations in CHEK2 ¹¹ .[9] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia (AT) gene ¹² and Peutz-Jeghers syndrome ¹³. Ovarian cancer has also been associated with Lynch syndrome ¹⁴, basal cell nevus (Gorlin) syndrome (OMIM ¹⁵), and multiple endocrine neoplasia type 1 (MEN1) (OMIM ¹⁶).[9] Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

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

• Cancers 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 and benign features for males and females. (Refer to the Major Genes ¹⁷ section of this summary for more information.)

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers with those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are unlikely to be of mucinous or borderline histopathology. (Refer to the Pathology/Prognosis of Breast Cancer ¹⁸ and Pathology/Prognosis of Ovarian Cancer ¹⁹ sections for more information.)

When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. 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. Breast or ovarian 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. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[10,11]

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Breast Cancer Prevention ²⁰ for more information.) These factors are considered in more detail in numerous reviews,[12,13] including among BRCA1/BRCA2 mutation carriers.[14] Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (More information about their effects in BRCA1/BRCA2 mutation carriers can be found in the section on Interventions ²¹ later in this document.)

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[15] In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.[14,16]

Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer.[17]

Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.[18-20]

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 RR 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.[21] The Women's Health Initiative ²² (WHI), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, which randomized more than 16,000 women to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[22,23] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR = 1.24; 95% CI, 1.02–1.5, P<.001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom.[24] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR = 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[25]

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.[26-30,21] 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.[23] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[21,31] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[32]

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.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 and BRCA2 mutations,[33-36] and in association with germline ATM and TP53 mutations.[37,38] Since BRCA1/2 mutation carriers are heterozygotes, however, radiation sensitivity might occur only after a somatic mutation has damaged the normal copy of the gene.

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.[39] Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of mammography and chest x-ray exposure in BRCA1 and BRCA2 mutation carriers have had conflicting results.[40,41] (Refer to text on Radiation ²³ in the Interventions ²¹ section of this summary for more information.)

The risk of breast cancer increases by approximately 10% for each 10g of daily alcohol intake (approximately 1 drink or less) in the general population.[42,43] One study of BRCA1/BRCA2 mutation carriers found no increased risk associated with alcohol consumption.[44]

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are 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.[45] These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.[46]

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).[47] There may also be an association between benign breast disease and family history of breast cancer.[48]

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[47,49,50] and breast density may have a genetic component in its etiology.[51-53]

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.[54] One study [55] found a reduced risk of breast cancer among BRCA1/2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.[56]

Factors that increase risk for ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and oral contraceptives.[57,58] (Refer to the PDQ summary on Prevention of Ovarian Cancer ²⁴ for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Risk Modification ²⁵ section for more information.)

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote; even in hereditary cancer families.[59]

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.[60] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[57,61] Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[62-65]

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[57,66,67] including in BRCA1/BRCA2 mutation carriers.[68] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy (RRSO). In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[69,70] For further information on these studies refer to the Risk-Reducing Salpingo-Oophorectomy ²⁶ section of this summary.

Use of oral contraceptives for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[57,58] A majority of, but not all, studies also support oral contraceptives being protective among BRCA1/ BRCA2 mutation carriers.[60,71-74]

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. (For further information on these models, refer to the Models for Prediction of the Likelihood of a BRCA1 or BRCA2 Mutation ²⁷ section of this summary.) 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 ²⁸, summarizes the salient aspects of two of the common risk assessment models and is designed to aid in choosing the one that best applies to a particular individual.

The Claus model [75,76] and the Gail model[77] are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models, which include more detailed family history information, are also in use and are discussed below.

Table 1. Characteristics of the Gail and Claus Models^a

Enlarge ²⁹

	Gail Model	Claus Model
aAdapted from Domchek et al.,[78] Rubenstein et al.,[79] and Rhodes.[80]
Data derived from	Breast Cancer Detection Demonstration Project Study	Cancer and Steroid Hormone Study
Study population	2,852 cases, aged ≥35 years	4,730 cases, aged 20–54 years
	In situ and invasive cancer	Invasive cancer
	3,146 controls	4,688 controls
	Caucasian	Caucasian
	Annual breast 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 at 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 at onset of breast cancer in relatives
	All known risk factors for breast cancer [80]
Best application	For individuals with no family history of breast cancer or 1 first-degree relative with breast cancer, aged ≥50 years	For individuals with 0, 1, or 2 first-degree or second-degree relatives with breast cancer
	For determining eligibility for chemoprevention studies

It is important to note that the Gail and the Claus models will significantly underestimate breast cancer risk for women in families with hereditary breast cancer susceptibility syndromes. Generally, the Claus or the Gail models should not be the sole model used for families with one of the following characteristics:

• Three individuals with breast or ovarian cancer (especially when one 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 one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model is the basis for the Breast Cancer Risk Assessment Tool ³⁰, 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. 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.[81-85] 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:

• Nonadherent women (i.e., does not adhere to screening recommendations).[81,82]
• Women in the highest risk strata.[84]

Risk could be underestimated in the lowest risk strata.[84] Earlier studies [81,82] suggested risk was overestimated in younger women and underestimated in older women. More recent studies [83,84] 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.[85] Recently, modifications have been made to the Breast Cancer Risk Assessment Tool ³⁰ incorporating data from the Women’s Contraceptive and Reproductive Experiences (CARE) study. This study of over 1,600 African American women with invasive breast cancer and over 1,600 controls was used to develop a breast cancer risk assessment model with improved race-specific calibration.[86]

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk.[87] The two models were positively correlated (r = .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 Tyrer-Cuzick model incorporates both genetic and non-genetic factors.[88] A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The BOADICEA model examines family history to estimate breast cancer risk and also incorporates both BRCA1/2 and non-BRCA1/2 genetic risk factors.[89]

Other models incorporating breast density have been developed but are not ready for clinical use.[90,91] In the future, models may be developed or refined to include such factors as breast density and other biomarkers.

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32. Rebbeck TR, Friebel T, Wagner T, et al.: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 23 (31): 7804-10, 2005.  [PUBMED Abstract]
    
    
33. 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]
    
    
34. 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]
    
    
35. Abbott DW, Thompson ME, Robinson-Benion C, et al.: BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem 274 (26): 18808-12, 1999.  [PUBMED Abstract]
    
    
36. 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]
    
    
37. Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66 (6 Suppl): S177-82, 1994.  [PUBMED Abstract]
    
    
38. 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]
    
    
39. 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]
    
    
40. Narod SA, Lubinski J, Ghadirian P, et al.: Screening mammography and risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet Oncol 7 (5): 402-6, 2006.  [PUBMED Abstract]
    
    
41. Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.  [PUBMED Abstract]
    
    
42. Smith-Warner SA, Spiegelman D, Yaun SS, et al.: Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279 (7): 535-40, 1998.  [PUBMED Abstract]
    
    
43. Hamajima N, Hirose K, Tajima K, et al.: Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87 (11): 1234-45, 2002.  [PUBMED Abstract]
    
    
44. McGuire V, John EM, Felberg A, et al.: No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 15 (8): 1565-7, 2006.  [PUBMED Abstract]
    
    
45. McTiernan A: Behavioral risk factors in breast cancer: can risk be modified? Oncologist 8 (4): 326-34, 2003.  [PUBMED Abstract]
    
    
46. 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]
    
    
47. Chen J, Pee D, Ayyagari R, et al.: Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst 98 (17): 1215-26, 2006.  [PUBMED Abstract]
    
    
48. 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]
    
    
49. 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]
    
    
50. 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]
    
    
51. 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]
    
    
52. 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]
    
    
53. 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]
    
    
54. 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]
    
    
55. Brunet JS, Ghadirian P, Rebbeck TR, et al.: Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90 (10): 761-6, 1998.  [PUBMED Abstract]
    
    
56. Ghadirian P, Lubinski J, Lynch H, et al.: Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer 110 (3): 413-6, 2004.  [PUBMED Abstract]
    
    
57. 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]
    
    
58. John EM, Whittemore AS, Harris R, et al.: Characteristics relating to ovarian cancer risk: collaborative analysis of seven U.S. case-control studies. Epithelial ovarian cancer in black women. Collaborative Ovarian Cancer Group. J Natl Cancer Inst 85 (2): 142-7, 1993.  [PUBMED Abstract]
    
    
59. Amos CI, Struewing JP: Genetic epidemiology of epithelial ovarian cancer. Cancer 71 (2 Suppl): 566-72, 1993.  [PUBMED Abstract]
    
    
60. 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]
    
    
61. 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]
    
    
62. 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]
    
    
63. 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]
    
    
64. 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]
    
    
65. 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]
    
    
66. Tortolero-Luna G, Mitchell MF: The epidemiology of ovarian cancer. J Cell Biochem Suppl 23: 200-7, 1995.  [PUBMED Abstract]
    
    
67. 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]
    
    
68. 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]
    
    
69. 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]
    
    
70. 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]
    
    
71. 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]
    
    
72. 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]
    
    
73. Whittemore AS, Balise RR, Pharoah PD, et al.: Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer 91 (11): 1911-5, 2004.  [PUBMED Abstract]
    
    
74. McGuire V, Felberg A, Mills M, et al.: Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. Am J Epidemiol 160 (7): 613-8, 2004.  [PUBMED Abstract]
    
    
75. 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]
    
    
76. Claus EB, Risch N, Thompson WD: The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 28 (2): 115-20, 1993.  [PUBMED Abstract]
    
    
77. 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]
    
    
78. 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]
    
    
79. 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]
    
    
80. 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]
    
    
81. 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]
    
    
82. 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]
    
    
83. 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]
    
    
84. 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]
    
    
85. Bondy ML, Newman LA: Breast cancer risk assessment models: applicability to African-American women. Cancer 97 (1 Suppl): 230-5, 2003.  [PUBMED Abstract]
    
    
86. Gail MH, Costantino JP, Pee D, et al.: Projecting individualized absolute invasive breast cancer risk in African American women. J Natl Cancer Inst 99 (23): 1782-92, 2007.  [PUBMED Abstract]
    
    
87. 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]
    
    
88. Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004.  [PUBMED Abstract]
    
    
89. Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.  [PUBMED Abstract]
    
    
90. Barlow WE, White E, Ballard-Barbash R, et al.: Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst 98 (17): 1204-14, 2006.  [PUBMED Abstract]
    
    
91. Tice JA, Cummings SR, Ziv E, et al.: Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat 94 (2): 115-22, 2005.  [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 four relatives in the same biologic line affected) is not present. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations through either the maternal or paternal lines in an apparent autosomal dominant pattern of transmission and familial association with tumors of other organs, particularly the ovary and prostate gland.[1,2] We now know that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, only 5% to10% of individuals who develop breast cancer are known to carry highly penetrant gene mutations.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families.[3] 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, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1 and MSH2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

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.[4] 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.[5] The BRCA1 gene (OMIM ³²) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance section ⁸ for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

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 (OMIM ³³) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.[8-13] (Refer to the Penetrance section ⁸ for more information.) BRCA2 is also a large gene with 27 exons that encode a protein of 3,418 amino acids.[14] 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. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (unmutated) allele.

Mutations in BRCA1 and BRCA2 appear 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.[15]

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, however, 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.[16,17]

In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in a myriad of functions within cells including homologous DNA repair, genomic stability, transcriptional regulation, and cell cycle control.[18,19]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[20] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic mutation in BRCA1 and BRCA2.[21,22] 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-stranded conformational polymorphism (SSCP) analysis and conformation-sensitive gel electrophoresis (CSGE), miss nearly a third of the mutations that are detected by DNA sequencing.[23] In addition, large genomic rearrangements are missed by most of the techniques, including direct DNA sequencing, but testing for these is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less common in BRCA2 and in individuals of Ashkenazi Jewish descent.[24-26]

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, classifying deleterious nucleotide changes to predict their functional impact relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial problems in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient’s personal and family cancer history, as well as the likelihood that the VUS is deleterious, thus an improved classification and reporting system may be of clinical utility.[27].

African Americans appear to have a higher rate of VUS.[28] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratory over a 3-year period.[29] Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “ missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of individuals had sequence alterations that were once considered VUS, but were reclassified, usually as a polymorphism though occasionally as a deleterious mutation. As additional information is accumulated, VUS are reclassified and such information may impact the continuing care of affected individuals.

A number of methods for discriminating deleterious from neutral VUS exist and others are in development [30-32] including integrated methods (see below).[33] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. Variant tracking is accomplished by testing parents and all affected family members (these costs are generally covered by Myriad Genetic Laboratory). The Myriad Genetic Laboratory typically provides additional information when a VUS is reported, including available data on cosegregation and whether the VUS has been seen in conjunction with a known deleterious mutation. In general, a VUS observed in subjects who also have a deleterious mutation, especially when it occurs with different mutations, is not felt to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been based on sequence conservation, biochemical properties of amino acid changes,[30,34-38] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor (ER)negative),[39] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[40,41] When attempting to interpret a VUS, all available information should be examined.

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1[42,43] and BRCA2[43] mutations in various ethnic groups. The prevalence of mutations by ethnic group was as follows:

BRCA1

• 3.5% Hispanic.
• 1.3% to 1.4% African American.
• 0.5% Asian American.
• 2.2% to 2.9% non-Ashkenazi Caucasian.
• 8.3 % to 10.2% Ashkenazi Jewish.[42,43]

BRCA2

• 2.6% African American.
• 2.1% Caucasian.[43]

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 three relatives with breast cancer (20%, 95% CI, 6%–44%). A family history of ovarian cancer in a first-degree relative (FDR) was also associated with an increased prevalence of BRCA1 mutations (25%, 95% CI, 3.2%–65.1%).[44] In a second study, 263 women with familial breast cancer were analyzed.[45] 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.[43,46,47]

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, two 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.[48-51] Altogether, the frequency of these three 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.[52,53] Additional founder mutations have been described in multiple non-Ashkenazi Jewish populations including the Netherlands (BRCA1 2804delAA and several large deletion mutations), Iceland (BRCA2, 999del5), Portugal (BRCA2, exon 3 Alu insertion),[54] and Sweden (BRCA1, 3171ins5).[55-58]

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 up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[29]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer.[42,43,45,59-65] 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 one or more male family members.[45,59-61,64]

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 two primary cancers.
• Ashkenazi Jewish background.[45,59-61]

Many models have been developed to predict the probability of identifying germline BRCA1/2 mutations in individuals or families. These models include those using logistic regression,[29,45,59,61,64,66,67], “genetic” models using Bayesian analysis (BRCAPRO and BOADICEA),[64,68] and empiric observations,[43,46,48,49,69,70] including the Myriad prevalence tables ³⁴. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[45,59] More recently, using complex segregation analysis, a polygenetic model (BOADICEA) examining both breast cancer risk and the probability of having a BRCA1 or BRCA2 mutation has been published.[68] Prediction models have been shown to increase the discrimination power of even experienced providers in identifying patients in whom BRCA1/2 mutations are likely to be found.[71,72] Many of the models have been compared with each other in different studies and currently there is no one model that is consistently superior to others.[73-76] Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 mutation status.[77] One study has shown that the risk models are sensitive to the amount of family history data available and perform less well with limited family information.[78]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series French Canadian families.[79] There have been variable results in the performance of the BRCAPRO model among Hispanics,[80,81] and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.[82] Further information is needed to determine which model performs best in each ethnic group.

Table 2. Characteristics of Common Models for Estimating the Likelihood of a BRCA 1/2 Mutation

Enlarge ³⁵

	Myriad Prevalence Tables 34 [61]	BRCAPRO [64,77]	BOADICEA [64,68]	Tyrer-Cuzick [83]
AJ = Ashkenazi Jewish; BOADICEA = Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm; BRCAPRO = Berry-Aguilar-Parmigiani Model; FDR = first-degree relatives; SDR = second-degree relatives
Method	Empiric data from Myriad Genetics based on family and personal history reported on requisition forms	Statistical model	Statistical model	Statistical model
Features of the Model	Proband may or may not have breast or ovarian cancer	Proband may or may not have breast or ovarian cancer	Proband may or may not have breast or ovarian cancer	Proband must be unaffected
	Considers age of breast cancer diagnosis as <50, >50	Considers exact age at breast and ovarian cancer diagnosis
	Does not consider affected relatives	Considers prior genetic testing in family (i.e., BRCA1/2 mutation negative relatives)	Considers exact age at breast and ovarian cancer diagnosis
	Does not consider number of affected relatives	Considers oophorectomy status	Includes all FDR and SDR with and without cancer	Also includes reproductive factors and body mass index to estimate breast cancer risk
	Includes AJ ancestry	Includes all FDR and SDR with and without cancer	Includes AJ ancestry
	Very easy to use	Includes AJ ancestry
Limitations	Simplified view of family structure	Requires computer software and time-consuming data entry	Requires computer software and time-consuming data entry	Designed for individuals unaffected with breast cancer
		Incorporates only FDR and SDR; may need to change proband to best capture risk	Incorporates only FDR and SDR; may need to change proband to best capture risk
		May overestimate risk in bilateral breast cancer [84]
		May perform better in Caucasians than minority populations [81,85]

Genetic testing for BRCA1 and BRCA2 mutations 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 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, paucity of women, or ethnicity).

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.[12,15,46,47,50,69,70,86-99] 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.[15,86,87] 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.[86,87] 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 four affected relatives in the same biologic lineage) and therefore, these estimates may not apply.

In addition to the estimates from multiple-case families and patients from high-risk genetics clinics,[12,15,86,87,89,92,98,100] 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.[46,47,50,69,70,90-97] 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,[50,69,88,90,93,94,96] compared with complete sequencing of the two genes required in most populations. The first study of a community-based series was carried out in the Washington, D.C., area. Blood samples and family medical histories were collected from more than 5,000 Ashkenazi Jewish individuals.[50] Study participants were tested for three 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 twofold increased risk of prostate cancer in BRCA2 mutation carriers.[69,101,102].

Table 3. Penetrance of Cancer in BRCA1 and BRCA2 Mutation Carriers

Enlarge ³⁶

Cancer Sites [6-8,12,50,103]		BRCA1 Mutation Carrier		BRCA2 Mutation Carrier
		Strength of Evidence	Magnitude of Absolute Risk	Strength of Evidence	Magnitude of Absolute Risk
Known to be associated (well studied)
Breast (female)		+++	A	+++	A
Ovary, fallopian tube, peritoneum		+++	A	+++	B
Breast (male)		+	U	+++	C
Pancreas		++	C	+++	C
Prostate		+	U	+++	A
Thought not to be associated
Colon/rectum		-		-
Not adequately studied
Melanoma (skin)				+	C
Uterus		+/-	C
Melanoma (uveal)				+/-	C
Stomach				+/-	C
Testicular		+/-	C
Gallbladder/bile duct				+/-	C
Bladder
Head and neck

+++ Multiple studies demonstrated association and are relatively consistent.

++ Multiple studies and the predominance of the evidence is positive.

+ May be an association, predominantly single studies; smaller limited studies and/or inconsistent but weighted toward positive.

+/- Mixed (some studies demonstrate an association and others do not).

- No association shown in studies of adequate size.

A = High (> 20%); B = Moderate (10–20%); C = Low (<10%); U = Undefined.

The first Breast Cancer Linkage Consortium study investigating cancer risks reported an excess of colorectal cancer in BRCA1 carriers (RR = 4.1; 95% CI, 2.4–7.2).[86] This finding was supported by some family-based studies [6,7,104] but not all.[8,50,69,93,105-107] Furthermore, unselected series of colorectal cancer that have been exclusively performed in the Ashkenazi Jewish population have not shown elevated rates of BRCA1 or BRCA2 mutations.[108-110] Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, BRCA1 mutation carriers should adhere to population-screening recommendations.

Many subsequent studies, whether in founder or predominantly out bred populations, have estimated breast cancer risks by age 70 years of approximately 60% or lower and ovarian cancer risks of approximately 40% or lower, though often with large confidence limits because, even in studies of founder populations, the number of identified mutation carriers is relatively small. A meta-analysis of ten studies estimates risks among BRCA1 and BRCA2 mutation carriers of 57% and 49% for breast cancer and 40% and 18% for ovarian cancer.[111] Most studies have done molecular testing on the proband only and have done no,[46,50,69,70,88,90,92-94,96,97] or limited,[91,98] 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.[47] 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.[97] 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 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. A case series of 491 women with stage I or stage II breast cancer and a known or suspected deleterious BRCA1/2 mutation was reviewed for incidence of ovarian cancer. The actuarial risk of developing ovarian cancer at 10 years following diagnosis of breast cancer was 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers. Eight of 83 cancer deaths (9.6%) in this series were because of ovarian cancer. Systemic treatment for the primary breast cancer did not alter these findings.[112] Several studies have suggested that cancer risks in BRCA1/BRCA2 mutation carriers are affected by the type of cancer of the index case. Relatives of breast cancer index cases were more likely to develop breast cancer, and relatives of ovarian cancer index cases were more likely to develop ovarian cancer.[97,113-115] Risk of breast cancer appears increased in more recent birth cohorts.[47,113]

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, such as differing rates of oophorectomy.[47,97,116-120] A large population-based family study found that the risk of breast cancer for relatives of probands with deleterious BRCA1/2 mutations demonstrated significant interfamilial variation, even when controlling for age at diagnosis of the proband and the presence of contralateral breast cancer.[121] While the average breast and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, 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 common 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 ³⁷ ” and “ Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer ³⁸ ” review the incidence of breast and ovarian cancer among BRCA1 and BRCA2 mutation carriers.

Table 4. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Breast Cancer

Enlarge ³⁹

	Cumulative Incidence of Breast Cancer to Given Age
	BRCA1		BRCA2		BRCA1/2
Population	50 y	70 y	50 y	70 y	50 y	70 y
Linkage analysis-maximization of logarithm of the odd (LOD) score
—214 breast-ovary families (BCLC) [15]					59%	82%
—BRCA1-linked families (BCLC) [87]	51%	85%
—237 breast and breast-ovarian cancer families (BCLC) [89]	49%	71%	28%	84%
Incidence of second cancers after breast cancer
—33 BRCA1-linked families (BCLC) [86]	73%	87%
—BRCA1-linked families (BCLC) [87]	50%	65%
Analysis of family members
—Jewish ovarian cancer cases, 7 BRCA1, 3 BRCA2 [88]	30%a	50%a	16%a	23%a
—Jewish breast-ovary families, 16 BRCA1, 9 BRCA2 [88]	37%a	64%a	18%a	49%a
Kin cohort using family and cancer registries
—Unselected Icelandic breast cancer patients, 56 female and 13 male BRCA2 995del5 [90]			17%	37%
Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes
—173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) [12]			37%	52%
Modified segregation analysis - all available relatives tested (MENDEL)
—Australian population-based breast cancer, aged <40 years, 9 BRCA1, 9 BRCA2 [91]					10%	40%
Kin cohort
—Community-based Washington, D.C. area Jews, 61 BRCA1, 59 BRCA2 [50]	38%	59%	26%	51%	33%	56%
—Jewish women with breast cancer, 34 BRCA1, 15 BRCA2 [69]		60%		28%
—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 [93]	31%b	44%c	6%b	37%c
—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 [46]		68%d		14%d
Modified segregation analysis (MENDEL)
—Breast cancer cases, aged <55 years, 8 BRCA1, 16 BRCA2 [70]	32%	47%	18%	56%	21%	54%
—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 [92]	39%	72%	19%	71%
—Unselected cases ovarian cancer, 12 BRCA1 [92]	34%	50%
—164 BRCA2-positive families from BCLC [95]				41%
—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 [97]	38%	65%	15%	45%
—Australian multiple-case families, 28 BRCA1, 23 BRCA2 [98]		48%		74%
Relative risk times population rates
—Jewish hospital-based ovarian cancer patients, 103 BRCA1, 44 BRCA2 founder mutations [94]	18%	59%	6%	38%
Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive
—Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 [47]	39%	69%	34%	74%
Mendelian retrospective likelihood approach
—U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 [99]		46%		43%

BCLC = Breast Cancer Linkage Consortium

aOutcome is breast OR ovarian cancer.

bIncidence to age 55 years.

cIncidence to age 75 years.

dIncidence to age 80 years.

Table 5. Studies of Cancer Penetrance Among BRCA1 and BRCA2 Mutation Carriers: Cumulative Incidence of Ovarian Cancer

Enlarge ⁴⁰

	Cumulative Incidence of Ovarian Cancer to Given Age
	BRCA1		BRCA2		BRCA1/2
Population	50 y	70 y	50 y	70 y	50 y	70 y
Incidence of second cancers after breast cancer
—33 BRCA1-linked families (BCLC) [86]	29%	44%
—BRCA1-linked families (BCLC) [87]	29%	44%
Linkage analysis - maximization of LOD score
—BRCA1-linked families (BCLC) [87]	23%	63%
—237 breast and breast-ovarian cancer families (BCLC) [89]			0%	27%
Kin cohort
—Community-based Washington, D.C. area Jews, 61 BRCA1, 59 BRCA2 [50]	8%	16%	5%	18%	7%	16%
—Unselected cases ovarian cancer, 39 BRCA1, 21 BRCA2 [46]		36%a		10%a
Second or contralateral cancer incidence; focus was on nonbreast and ovary outcomes
—173 breast-ovarian cancer families either BRCA2-positive or BRCA2-linked (BCLC) [12]			3%	16%
Modified segregation analysis (MENDEL)
—Breast cancer cases, aged <55 years, 8 BRCA1, 16 BRCA2 [70]	11%	36%	3%	10%	4%	16%
—Families with 2+ cases ovarian cancer, 40 BRCA1, 11 BRCA2 [92]	17%	53%	1%	31%
—Unselected cases ovarian cancer, 12 BRCA1 [92]	21%	68%
—164 BRCA2-positive families from BCLC [95]				14%
—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 [97]	13%	39%	1%	11%
Relative risk times population rates
—Jewish women with ovarian cancer, 44 BRCA1, 24 BRCA2 [93]		>40%b		20%b
—Unselected cases ovarian or breast cancer from 22 studies, 289 BRCA1, 221 BRCA2 [96]	11%	37%	3%	21%
Direct Kaplan-Meier estimates restricted to relatives known to be mutation positive
—Unselected Jewish breast cancer patients from NY, 67 BRCA1, 37 BRCA2 [47]	21%	46%	2%	12%
Mendelian retrospective likelihood approach
—U.S.-based through the Cancer Genetics Network, most counseling clinic-based, although smaller number population-based, 238 BRCA1, 143 BRCA2 [99]		40%		22%

BCLC = Breast Cancer Linkage Consortium; LOD = logarithm of the odd

aIncidence to age 80 years

bIncidence to age 75 years

There is conflicting evidence as to the residual familial risk among women who themselves test negative for the BRCA1/BRCA2 mutation segregating in their family. Based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family, five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%.[119] A report that the risk may be as high as five-fold in women who tested negative for the BRCA1 or BRCA2 mutation in the family [122] was followed by numerous letters suggesting that ascertainment biases account for much of this observed excess risk.[123-127] Three additional analyses have suggested an approximately 1.5-fold to 2-fold excess risk.[127-129] Several studies have involved retrospective analyses and all studies have been based on small observed numbers of cases, and have been of uncertain statistical and clinical significance. Additional prospective analyses will be required to determine whether women from BRCA1/BRCA2 families who test negative in families are at the general population risk for breast cancer and require differential clinical management.[127] No information has been published regarding ovarian cancer risk in this setting.

Statistics regarding the percentage of women found to be BRCA mutation carriers among samples of women and men 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 (0.2%).[130]
• Women with breast cancer (all ages): 1 in 50 (2%).[131]
• Women with breast cancer (younger than 40 years): 1 in 11 (9%).[132]
• Men with breast cancer (regardless of age): 1 in 20 (5%).[133]
• Women with ovarian cancer (all ages): 1 in 10 (10%).[46,134]

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

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[50]
• Women with breast cancer (all ages): 1 in 10 (10%).[47]
• Women with breast cancer (younger than 40 years): 1 in 3 (30% – 35%).[47,135,136]
• Men with breast cancer (regardless of age): 1 in 5 (19%).[137]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36% – 41%).[93,138,139]

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. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors,[140-143] there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[144-146] Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer.[147,148] Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, progesterone receptor negative, human epidermal growth factor receptor 2 [HER2] negative, cytokeratin 5/6 positive), more commonly have BRCA1 dysregulation than other tumor types.[149-151] Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[152] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[153,154] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[155]

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,89] 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.[95] 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.[156] These observations have generally been confirmed in subsequent studies.[97,98,157] Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene.[96,158] The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 in BRCA2:6174delT mutation carriers.[96,158] None of the studies have 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.

Several studies evaluating pathologic patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 mutations.[159-168] Additionally, the triple-negative breast cancer phenotype (i.e. negative for ER, progesterone receptor [PR], and HER2), which also carries an adverse prognosis, accounts for 80% to 90% of BRCA1-associated breast cancers.[163,169-171]

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are more common in BRCA1-associated breast cancer.[172,173]

It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[174] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically- and clinically-meaningful groups.[170,175,176] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[177-179] Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype;[170] however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, progesterone receptor, and HER2, and stain positive for cytokeratin 5/6, or EGFR.[180-183] Based on these methods to measure protein expression, a number of studies have shown that the majority of BRCA1-associated breast cancers are positive for basal epithelial markers.[163,171,182]

The prevalence of high-risk, preinvasive lesions in BRCA mutation carriers is controversial, and results of prior studies have been inconsistent. The Breast Cancer Linkage Consortium reported a relative lack of an in situ component in BRCA1-associated breast cancers,[160] also seen in two subsequent studies of BRCA1/2 carriers.[184,185] However, another study reported a similar prevalence of in situ cancers in BRCA1/2 carriers to that previously reported in studies of invasive breast cancer patients.[186] A study of Ashkenazi Jewish women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of ductal carcinoma in situ (DCIS) and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects.[187] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased[188,189] and decreased prevalence.[185]

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[186,187]

The distinct features of BRCA1-associated breast tumors, as outlined above ⁴¹, are also important in prognosis. In addition, there appears to be accelerated growth in BRCA1-associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status.[185,190] These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that BRCA1 mutation carriers with breast cancer may have a poorer prognosis compared with sporadic cases.[165,191,192] These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in BRCA1 mutation carriers.[193,194] A retrospective cohort study of 496 Ashkenazi Jewish breast cancer patients from two centers compared the relative survival among 56 BRCA1/2 mutation carriers followed for a median of 116 months. BRCA1 mutations were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy.[195] A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in overall survival for carriers of BRCA1 founder mutations (n = 76) compared with noncarriers (n = 1,189).[196] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers.[197]

In summary, BRCA1-associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features, which indicate a more aggressive phenotype. BRCA1 mutation carriers who do not receive chemotherapy may have a worse prognosis. However, because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine if BRCA1-associated breast cancers should receive different therapy than sporadic tumors. Refer to the Role of BRCA1 and BRCA2 in response to chemotherapy ⁴² section for more information.

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR.[160,164,198] A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors compared with sporadic controls; however, a single BRCA2 founder mutation (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[199] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins, fewer tubules and lower mitotic counts.[200] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[162,164] In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.

Studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[196,197,201]

Ovarian cancer arising in women with BRCA1 and BRCA2 mutations is more likely to be invasive serous adenocarcinoma, and less likely to be mucinous or borderline.[202-204] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[139,205] Approximately 60% of sporadic ovarian cancers have serous histology, but a survey of all published data shows that 94% of BRCA1 related ovarian cancers have this type of histology.[144] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/2 carriers in a Dutch case-control study.[206] Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression.[202,207] The histopathologic profile of BRCA2 related ovarian cancer has not been well defined. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology suggests distinct molecular pathways of carcinogenesis, which may ultimately distinguish them histologically.[208]

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/2 phenotype. Histopathologic examination of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype.[209,210] A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[139]

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations.[208,211-216] A nationwide, population-based case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls.[212] Five-year follow-up in the same cohort showed improved survival for carriers of both BRCA1 and BRCA2 mutations (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors.[217] In a U.S. study of Ashkenazi Jewish women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival, compared with both Ashkenazi Jewish women with ovarian cancer who did not have a BRCA mutation and two large groups of advanced-stage ovarian cancer clinical trial patients.[215] In a retrospective, U.S., hospital-based study, BRCA Ashkenazi heterozygotes had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and overall survival, compared with sporadic cases.[213] A U.S. population-based study showed improvement in overall survival in BRCA2, but not in BRCA1, carriers.[218] However, the study included only 12 BRCA2 mutation carriers and 20 BRCA1 mutation carriers. A study in Japanese patients found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.[214]

In contrast, several studies have not found improved overall survival among ovarian cancer patients with BRCA mutations.[191,219-221] A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years.[191] Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared to sporadic controls, but no difference in longer-term survival.[219] A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls.[220] Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing.[221] In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.

There are compelling data to show improved survival in Ashkenazi Jewish ovarian cancer patients with BRCA1 or BRCA2 founder mutations; however, further large studies in other populations with appropriate controls are needed to determine whether this survival advantage applies more broadly to all BRCA1- or BRCA2-related ovarian cancers.

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM ⁴³), in which germline mutations of the TP53 gene (OMIM ⁴⁴) on chromosome 17p have been documented.[222] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[223,224] 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.[225] Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at 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.[226] 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.[224] 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. Germline mutations in TP53 are thought to account for fewer than 1% of breast cancer cases.[227]

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM ⁴⁵) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant.[228,229] Lifetime estimates for breast cancer among women with Cowden syndrome range from 25% to 50%. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[230] 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 syndrome. Central nervous system manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[231,232] Germline mutations in PTEN (OMIM ⁴⁶), 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.[233] Disruption of PTEN appears to occur late in tumorigenesis and may act as a regulatory molecule of cytoskeletal function. Although PTEN mutations, which are estimated to occur in 1 in 200,000 individuals,[229] account 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.[229,234] (Refer to the PDQ summary Genetics of Colorectal Cancer Major Genes ⁴⁷ section for more information on Cowden syndrome.)

Peutz-Jeghers syndrome (PJS) (OMIM ⁴⁸) 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.[235-237] Mutations in the STK11 gene (OMIM ⁴⁹) at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[238] have been identified as one cause of PJS.[239,240] Germline mutations in STK11, also known as LKB1, have been reported and appear to be responsible for about 50% of the cases of PJS.[239-244] A large series of 419 patients had a cumulative incidence of cancer of 85% by age 70 years, commonly affecting the GI tract. In addition, the cumulative risk of breast cancer was 31% by age 60 years; only two ovarian cancers were seen in this series.[245] Elevated cancer risks have also been seen in smaller series and a meta-analysis, including a higher risk of sex cord stromal tumors of the ovary.[246-250]

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Low Penetrance Predisposition to Breast and Ovarian Cancer

Background

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the excess familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved.[3] Each locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as “polymorphisms”, meaning that the gene or locus occurs in several “forms” within the population (and more formally defined as polymorphic when at least 1% of chromosomes at a position vary from each other). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed “disease-associated polymorphisms” or “functionally relevant polymorphisms.” This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer.[4] Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens.[5]

Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5–2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[3] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[6]

Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and has been relatively disappointing [6,7] despite some confirmed associations, as described below. It has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1,000,000 or more) are chosen within the genome and tested largely without regard to their possible biological function, but instead to capture more uniformly all genetic variation throughout the genome.

CHEK2 (OMIM ⁵¹), a gene involved in the DNA damage repair response pathway, was initially evaluated as a potential cause of Li-Fraumeni syndrome (LFS).[8] It does not appear to be a common cause of LFS.[9] However, based on numerous studies, a polymorphism, 1100delC, appears to be a rare, low-penetrance cancer susceptibility allele.[10-15] 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.[10] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation.[16] In both Europe and the United States (where the mutation appears to be slightly less common), additional studies, including a large prospective study,[17] have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[18-21] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.[22] One study suggests the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[23] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[19] Although the initial report [15] and at least one other [24] suggested that male mutation carriers were at a significantly increased risk of breast cancer, several other studies have failed to confirm the association.[25-28] The contribution of CHEK2 mutations to breast cancer may be dependent on the population studied. A study of 3,228 women diagnosed with breast cancer before age 51 years, and 5,496 population controls demonstrated that the 1100delC and two additional founder alleles (I157T, S428F) in CHEK2 contributed to 8% of early onset breast cancer in Poland.[29] Although a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer,[30] the clinical applicability of this finding remains uncertain due to low mutation prevalence and lack of guidelines for clinical management.[31]

Ataxia telangiectasia (AT) (OMIM ⁵²) 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 ATM mutations(OMIM ⁵³).[32] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[33] ATM proteins have been shown to play a role in cell cycle control.[34-36] In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[37]

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[38-48] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0.[48,49] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further work is needed.

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallellic mutations in BRIP1 are a cause of Fanconi anemia,[50-52] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. Over 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = 0.003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval (CI), 1.2–3.2, P = 0.012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.[53]

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia.[54] PALB2 mutations were found in 10 of 923 (1.1%) individuals with BRCA1 and BRCA2 mutation negative familial breast cancer, compared to none of 1084 (0%) controls (P = .0004). One of the ten families with a PALB2 mutation included a case of male breast cancer, raising the possibility that male breast cancer is included in the spectrum of PALB2. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[55] A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years.[56]

The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP80 D302H and TGFB1 L10P, were associated with invasive breast cancer with relative risks of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11) respectively.[57]

In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of 100,000 to 1,000,000 SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[58,59] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[60-62] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is the causal one.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases [63] including breast cancer.[64-66] The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators.[64] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. Subsequent genome-wide studies have replicated these loci and identified additional ones, as summarized in the following table.[65-67,67-72] An online catalog ⁵⁴ of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is available.

Table 6. High-probability breast cancer susceptibility loci for sporadic breast cancer identified through genome-wide association studies

Enlarge ⁵⁵

Putative Gene(s)	Chromosome	SNP(s)	Study Citations*
* Initial study that provided convincing evidence for each locus.
FGFR2	10q26.13	rs2981582	[64]
TOX3	16q12.1	rs3803662	[64]
MAP3K1	5q11.2	rs889312	[64]
Intergenic	8q24.21	rs13281615	[64]
LSP1	11p15.5	rs3817198	[64]
Intergenic	2q35	rs13387042	[65]
ESR1	6q25.1	rs2046210	[68]
MRPS30	5p12	rs10941679	[71]
Intergenic	1p11.2	rs11249433	[73]
RAD51B	14q24.1	rs999737	[73]
SLC4A7,NEK10	3p24	rs4973786	[72]
COX11	17q23.2	rs6504950	[72]

Although the statistical evidence for an association between genetic variation at these loci and breast cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically odds ratio < 1.5), with more risk variants likely to be identified. At this time, because their individual and collective influences on cancer risk have not been evaluated prospectively, they are not considered clinically relevant. Furthermore, recent reports have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment.[74,75] However, they may be of potential utility in risk stratification to improve the efficiency of population screening programs.[74]

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70. Murabito JM, Rosenberg CL, Finger D, et al.: A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet 8 (Suppl 1): S6, 2007.  [PUBMED Abstract]
    
    
71. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40 (6): 703-6, 2008.  [PUBMED Abstract]
    
    
72. Ahmed S, Thomas G, Ghoussaini M, et al.: Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41 (5): 585-90, 2009.  [PUBMED Abstract]
    
    
73. Thomas G, Jacobs KB, Kraft P, et al.: A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41 (5): 579-84, 2009.  [PUBMED Abstract]
    
    
74. Pharoah PD, Antoniou AC, Easton DF, et al.: Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358 (26): 2796-803, 2008.  [PUBMED Abstract]
    
    
75. Gail MH: Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100 (14): 1037-41, 2008.  [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.[1-5] 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 Breast Cancer Screening ⁵⁶ 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.[6] 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 Breast Cancer Screening ⁵⁶ 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, five breast cancers were detected by self-examination less than a year after a previous screen (as compared with one 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.[7] In another series of BRCA1/2 mutation carriers, four of nine incident cancers were diagnosed as palpable masses after a reportedly normal mammogram, further suggesting the potential value of self-examination.[8] 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.”[9]

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.[9]

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 Breast Cancer Screening ⁵⁶ 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.[10] 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.[11] Preliminary data suggest that mammography sensitivity is lower in BRCA1 and BRCA2 carriers than in noncarriers.[8] Subsequent observational studies have found that the positive predictive value (PPV) of mammography increases with age and is highest among older women and among women with a family history of breast cancer.[12] Higher PPVs may be due to increased breast cancer incidence, higher sensitivity, and/or higher specificity.[13] 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 two of whom had a BRCA2 mutation. Pushing margins, characteristic of medullary histology, is associated with an absence of fibrotic reaction.[14] In addition, rapid tumor doubling times may lead to tumors presenting shortly after an apparently normal study. In one study, mean tumor doubling time in BRCA1/2 carriers was 45 days, compared with 84 days in noncarriers.[15] Another study that evaluated mammographic breast density in women with BRCA mutations found no association between mutation status and mammographic density; however, in both carriers and noncarriers, increased breast density was associated with increased breast cancer risk.[16]

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.[17] 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) = 0.78–1.33). 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 six women at a mean of 20.2 months after receipt of BRCA results.[7] 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.”[9] 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.[18-20]

Certain observations have led to the concern that BRCA mutation carriers may be more prone to radiation-induced breast cancer than women without mutations. The BRCA1 and BRCA2 proteins are known to be important in cellular mechanisms of DNA damage repair, including those involved in repairing radiation-induced damage. Mouse embryos lacking Brca1 or Brca2 are hypersensitive to the effects of ionizing radiation. Some studies have suggested intermediate radiation sensitivity in cells that are heterozygous for a BRCA mutation, but this is not consistent and varies by experimental system and endpoint. A large international case-control study of 1,601 mutation carriers described an increased risk of breast cancer (hazard ratio (HR) = 1.54) among women who were ever exposed to chest x-rays, with risk being highest in women age 40 years and younger, born after 1949, and those exposed to x-rays only before age 20 years.[21] In contrast, two studies of the effect of mammogram exposure on carriers (n = 1,600, n = 162) did not support an association between such exposure and subsequent breast cancer risk.[22,23] In a small study,[23] there was a modest association between lifetime mammogram exposure and risk in BRCA1 mutation carriers (HR = 1.08, P = .03). No significant effect was seen after exclusion of postdiagnosis mammograms. At this time there is insufficient evidence to suggest that mutation carriers should avoid mammography.

Level of evidence: 3

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 (MRI), breast ultrasound, breast ductal lavage, and digital mammography.

Because of the relative insensitivity of mammography in women at hereditary risk for breast cancer, a number of screening modalities have been proposed and investigated in high-risk women, including BRCA mutation carriers. Several studies have described the experience with breast MRI screening in women at risk for breast cancer, including descriptions of relatively large multi-institutional trials.[24-30] Several considerations must be kept in mind when reviewing these reports:

• The studies are variable in terms of the underlying population being studied, equipment and signal processing protocols, the manner of reporting results, and the manner in which sensitivity and specificity are calculated.
• The different screening tests (MRI and mammogram with or without ultrasound) are performed nearly simultaneously in these studies, and the screening modalities are compared to each other. Therefore, sensitivity is defined somewhat differently in these studies than in the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) of follow-up and outcome reporting.
• The number of screening rounds is limited, and the distinction between prevalent (first round) and incident cancer detection rates is often unclear.

Despite these caveats, the reported studies consistently demonstrate that breast MRI is more sensitive than either mammography or ultrasound for the detection of hereditary breast cancer. The results of four large studies are presented in Table 7 ⁵⁷, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer.[24-28] Most cancers in these programs were screen detected with only 6% of cancers presenting in the interval between screenings. The sensitivity of MRI (as defined by the study methodology) ranged from 71% to 100%. Of the combined studies, 82% of the cancers were identified by MRI compared with 40% by mammography.

Concerns have been raised about the reduced specificity of MRI compared with other screening modalities. In one study, after the initial MRI screen, 16.5% of the patients were recalled for further evaluation, and 7.6% of subjects were recommended to undergo a short-interval follow-up examination at 6 months.[28] These rates declined significantly during later screening rounds, with fewer than 10% of the subjects recalled for more detailed MRI and fewer than 3% recommended to have short interval follow-up. In a second study, Magnetic Resonance Imaging for Breast Screening (MARIBS), the recall rate for additional evaluation was 10.7% per year.[27] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[28] In the MARIBS study, the aggregate surgical biopsy rate was 9 per 1,000 screening episodes, though this may underestimate the burden because follow-up ultrasounds, core-needle biopsies, and fine-needle aspirations have not been included in the numerator of the MARIBS calculation.[27] The PPV of MRI has been calculated differently in the various series and fluctuates somewhat, depending on whether all abnormal examinations or only the examinations that result in a biopsy are counted in the denominator. Generally, the PPV of a recommendation for tissue sampling (as opposed to further investigation) is in the range of 50% in most series.

These trials appear to establish that MRI is superior to mammography in the detection of hereditary breast cancer, and that women participating in these trials including annual MRI screening were less likely to have a cancer not detected by screening.[31] However, mammography clearly identifies some cancers that are not identified by MRI. Most of these mammographically detected cancers in women with a negative MRI appear to be ductal carcinomas in situ, presumably presenting as microcalcifications without significant ductal enhancement. While MRI does appear to be more sensitive than mammogram, it is unknown whether MRI screening results in a survival benefit or even in downstaging compared to mammography alone. One screening study demonstrated that patients were more likely to be diagnosed with small tumors and node-negative disease than women in two nonrandomized control groups.[25] However, a randomized study of screening with or without MRI using tumor stage or mortality as an endpoint has not been performed. Despite the apparent sensitivity of MRI screening, some women in MRI-based programs will nevertheless develop life-threatening breast cancer. The American Cancer Society and the National Comprehensive Cancer Network (NCCN) have recommended the use of annual MRI screening for women at hereditary risk for breast cancer.[3,32]

Table 7. Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer

Enlarge ⁵⁸

Series		Kriege [25]	Warner [28]	MARIBS [27]	Kuhl [33]	Totals
N Patients	Overall	1,909	236	649	529	3,323
	BRCA1/2 Carriers	354	236	120	43	753
N Screening Episodes		4,169	457	1,881	1,542	8,049
N Cancers	Baseline	22	13	20	14	69
	Subsequent	23	9	15	29	76
Annual Incidence		9.5/1,000		19/1,000	25/1,000
Detected at Planned Screening		41	21	33	40a	135 (93%)
N Detected by Each Modality	Mammography	18	8	14	14	54 (37%)
	MRI	32	17	27	39	115 (79%)
	Ultrasoundb		7		17	24 (37%)

aTwo additional cancers detected at planned 6-month interval ultrasound screening (not included in ultrasound detection proportion).

bRestricted to studies in which ultrasound was performed.

Level of evidence: 3

Several studies have reported instances of breast cancer detected by ultrasound that were missed by mammography, as discussed in one review.[34] In a pilot study of ultrasound as an adjunct to mammography in 149 women with moderately increased risk based on family history, one cancer was detected, based on ultrasound findings. Nine other biopsies of benign lesions were performed. One was based on abnormalities on both mammography and ultrasound, and the remaining eight were based on abnormalities on ultrasound alone.[34] A large study of 2,809 women with dense breast tissue (ACRIN-6666) demonstrated that ultrasound increased the detection rate due to breast cancer screening from 7.6 per 1,000 with mammography alone to 11.8 per 1,000 for combined mammography and ultrasound.[35] However, ultrasound screening increases false-positive rates and appears to have a limited benefit in combination with MRI. In a multicenter study of 171 women (92% of whom were BRCA1/2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[29] Uncertainties about ultrasound include the effect of screening on mortality, the rate and outcome of false-positive results, and access to experienced breast ultrasonographers.

Level of evidence: None assigned

Digital mammography refers to the use of a digital detector to detect and record x-ray images. This technology improves contrast resolution,[36] 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;[37] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652 ⁵⁹) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[38] When Receiver Operating Characteristic (ROC) curves were compared, digital mammography was more accurate in women younger than 50 years, in women with radiographically dense breasts, and in premenopausal or perimenopausal women.

Level of evidence: 3

Refer to the PDQ summary on Breast Cancer Prevention ²⁰ 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 Breast Cancer Prevention ²⁰ 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.[39] 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 three or more have been associated with a lowered risk of breast cancer. A relative risk (RR) of 0.85 was estimated for each additional birth, up to five or more; however, increasing parity appeared to be associated with an increased risk of ovarian cancer.[40,41] 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.[42]

Studies of the effect of pregnancy on breast cancer risk have revealed complex results. Although the relationship of parity has been inconsistent, several studies have shown that among parous women, an increased number of full-term births is associated with a decrease in breast cancer risk. The influence of age at first birth may differ between BRCA1 and BRCA2 mutation carriers.[43-45] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[43,46]

Level of evidence: 4aii

In the general population, breastfeeding has been associated with a slight reduction in breast cancer risk in a few studies, including a large collaborative reanalysis of multiple epidemiologic studies,[47] and at least one study suggests that it may be protective in BRCA1 mutation carriers. In a multicenter breast cancer case-control study of 685 BRCA1 and 280 BRCA2 mutation carriers with breast cancer and 965 mutation carriers without breast cancer drawn from multiple-case families, among BRCA1 mutation carriers, breastfeeding for one year or more was associated with approximately a 45% reduced risk of breast cancer.[48] No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.[43]

Among the general population, oral contraceptives may produce a slight, short-term increase in breast cancer risk. (Refer to the PDQ summary on Breast Cancer Prevention ²⁰ 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.[49] 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.[50] 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%).[51]

There was no increased risk associated with use among BRCA2 mutation carriers. A Swedish population-based study of 245 women with breast cancer diagnosed before age 41 years, 19 of whom were BRCA1/BRCA2 mutation carriers, suggested that oral contraceptive use before age 20 years was associated with increased breast cancer risk in both mutation carriers and noncarriers, though the small number of carriers limits the conclusions for this subgroup.[52]

In contrast, a population-based study of 47 BRCA1 and 36 BRCA2 mutation carriers with breast cancer diagnosed before age 40 years, matched to population controls without mutations, found no increased risk of early-onset breast cancer associated with ever use of low-dose contraceptive pills for BRCA2 mutation carriers (odds ratio (OR) = 1.02) and a significantly reduced risk for BRCA1 mutation carriers (OR = 0.22; 95% CI, 0.10–0.49).[53]

One study examined proliferation of normal breast epithelium among women undergoing reduction mammoplasty.[54] 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. With regard to breast cancer risk associated with oral contraceptive use, despite conflicting results based on small numbers of carriers, several studies have found a significantly increased risk. A number of important issues remain unresolved including the potential differences between BRCA1/2 mutation carriers, age and duration of exposure, and formulation.

Level of evidence: 3aii

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with hormone replacement therapy (HRT) in the general population.[55-58] The Women’s Health Initiative ⁶⁰ (WHI) is a randomized controlled trial of approximately 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 two 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.[57,58] 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.[58] Results of a follow-up study suggest that the recent reduction in breast cancer incidence, especially among women aged 50 to 69 years, is predominantly related to decrease in use of combined estrogen plus progestin HRT.[59] 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.[58]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [60-62] or unaffected by a family history of breast cancer;[40,63,64] risk did not vary by family history in the meta-analysis.[49] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/2 mutations.[58] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[65]

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has been examined in two studies. In a prospective study of 462 BRCA1 or BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy (RRSO) (n = 155) was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95% CI, 0.18–0.92). Using mutation carriers without bilateral RRSO or HRT as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR = 0.37; 95% CI, 0.14–0.96).[66] In a matched case-control study of 472 postmenopausal women with BRCA1 mutations, HRT use was associated with an overall reduction in breast cancer risk (OR = 0.58; 95% CI, 0.35–0.96, P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Those taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98, P = .04), while the association with estrogen and progesterone was not statistically significant (OR = 0.66; 95% CI, 0.34–1.27, P = .21).[67] Especially given the differences in estimated risk associated with HRT between observational studies and the Women's Health Initiative (a randomized clinical trial), these findings should be confirmed in randomized prospective studies,[68] but they suggest that HRT in BRCA1/BRCA2 mutation carriers neither increases breast cancer risk nor negates the protective effect of oophorectomy.

Level of evidence: 3aii

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 ⁶¹), 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 significantly reduced.[69] 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 in those without a family history. These benefits were associated with an increased incidence of endometrial cancers and thrombotic events among women older than 50 years. Interim data from two European tamoxifen prevention trials did not show a reduction in breast cancer risk with tamoxifen after a median follow-up of 48 months [70] or 70 months,[71] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used HRT.[70] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention ²⁰ 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).[72]

Level of evidence: 1

In contrast to the very limited data on primary prevention in BRCA1 and BRCA2 mutation carriers with tamoxifen, several studies have found a protective effect of tamoxifen on the risk of contralateral breast cancer.[73-75] In one study involving approximately 600 BRCA1/2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[73] An update to this report examined 285 BRCA1/2 mutation carriers with bilateral breast cancer and 751 BRCA1/2 mutation carriers with unilateral breast cancer (40% of these patients were included in their initial study). Tamoxifen was associated with a 50% reduction in contralateral breast cancer risk in BRCA1 mutation carriers and a 58% reduction in BRCA2 mutation carriers. Tamoxifen did not appear to confer benefit in women who had undergone an oophorectomy, although the numbers in this subgroup were quite small.[75] Another study involving 160 BRCA1/2 mutation carriers demonstrated that tamoxifen use following treatment of breast cancer with lumpectomy and radiation was associated with a 69% reduction in the risk of contralateral breast cancer.[74] These studies are limited by their retrospective, case-control designs and the absence of information regarding estrogen-receptor status in the primary tumor.

The STAR trial ⁶² (NSABP-P-2) included more than 19,000 women and compared 5 years of raloxifene with tamoxifen in reducing the risk of invasive breast cancer.[76] There was no difference in incidence of invasive breast cancer at a mean follow-up of 3.9 years; however, there were fewer noninvasive cancers in the tamoxifen group. The incidence of thromboembolic events and hysterectomy was significantly lower in the raloxifene group. Detailed quality of life data demonstrate slight differences between the two arms.[77] Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.

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.[78] 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 (RRM) 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, three women were diagnosed with breast cancer after bilateral RRM, with a median follow-up of 14 years.[79] As 37.4 cancers were expected, the calculated risk reduction was 92% (95% CI, 76.6–98.3). In a follow-up subset analysis, 176 of the 214 high-risk women in this cohort study underwent mutation analysis of BRCA1 and BRCA2. Mutations were found in 26 women (18 deleterious, eight variants of uncertain significance). None of those women had developed breast cancer after a median follow-up of 13.4 years.[80] Two of the three women diagnosed with breast cancer after RRM 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 RRM and followed prospectively for a mean of 2.9 years. No breast cancers were observed in these women, whereas eight were identified in women undergoing regular surveillance (HR for breast cancer after RRM = 0 [95% CI, 0–0.36]).[81]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/2 mutation carriers. The rate of breast cancer in 105 mutation carriers who underwent bilateral RRM 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%.[82]

Another study evaluated the effectiveness of contralateral RRM in affected women with hereditary breast cancer. In a group of 148 BRCA1 or BRCA2 mutation carriers, 79 of whom underwent RRM, the risk of contralateral cancer was reduced by 91% and was independent of the effect of risk-reducing oophorectomy. Survival was better among women undergoing RRM, but this result was apparently caused by higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[83]

Studies describing histopathologic findings in RRM specimens from women with BRCA1 or BRCA2 mutations have been somewhat inconsistent. In two 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 37% to 46% of women with mutations undergoing either unilateral or bilateral RRM.[84-86] In these series, 13% to 15% of patients were found to have previously unsuspected DCIS in the prophylactically removed breast. Among 47 cases of risk-reducing bilateral or contralateral mastectomies performed in known BRCA1 or BRCA2 mutation carriers from Australia, 3 (6%) cancers were detected at surgery.[87] In a study from Sweden among 100 women with a hereditary risk of breast cancer, 50 of whom were BRCA1 or BRCA2 mutation carriers, unsuspected lesions were found in 18 women (3 invasive, 8 in situ, and 7 atypical hyperplasia), 13 of whom were mutation carriers.[88]

These findings were not replicated in a third retrospective cohort study. In this study, proliferative fibrocystic changes were noted in none of 11 bilateral mastectomies from patients with deleterious mutations and in only two of seven contralateral unilateral risk-reducing mastectomies in affected mutation carriers.[89]

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 RRM as a treatment option, uptake varies according to culture, geography, healthcare system, insurance coverage, provider attitudes, and other social factors. For example, in one setting where the providers made one to two field trips to family gatherings for family information sessions and individual counseling, only 3% of unaffected carriers obtained RRM within 1 year of follow-up.[90] Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy.[91] 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 RRM.[91]

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, RRM would result in an average increased life expectancy of 2.9 to 5.3 years.[92] 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 RRM.[93] 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.[94]

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 RRM. Almost 90% of the RRM surgeries were performed within 1 year of DNA testing. In this study, those most likely to have RRM were women younger than 55 years and with children.[95]

The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/2 mutations or strong family histories of breast cancer.[96]

Individual psychological factors have an important role in decision-making about RRM by unaffected women. Research is emerging about psychosocial outcomes of RRM. (Refer to the Psychological Aspects of Medical Interventions ⁶³ section of this summary.)

Level of evidence: 3aii

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 Breast Cancer Prevention ²⁰ for more information.) A Mayo Clinic study of 680 women at various levels of familial risk found that in women younger than 60 years who had bilateral oophorectomy, the likelihood of breast cancers developing was reduced for all risk groups.[97] 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,[98,99] 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) as well as ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after risk-reducing salpingo-oophorectomy (RRSO).[100] A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend. With RRSO, 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).[101] A prospective multicenter study of 1,079 women followed for a median of 30 to 35 months found that, while RRSO was associated with reductions in breast cancer risk for both BRCA1 and BRCA2 mutation carriers, the risk reduction was more pronounced in BRCA2 carriers (HR = 0.28; 95% CI, 0.08–0.92).[102] A meta-analysis of all reports of RRSO and breast and ovarian/fallopian tube cancer in BRCA1/BRCA2 mutation carriers confirmed that RRSO was associated with a significant reduction in breast cancer risk (overall HR = 0.49, 95% CI, 0.37-0.65; BRCA1 HR = 0.47, 95% CI, 0.35-0.64; BRCA2 HR = 0.47,95% CI, 0.26-0.84).[103]

Level of evidence: 3aii

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is less clear. Concern about its use, particularly in women with deleterious BRCA1 and BRCA2 mutations, centers around two issues. The first is the potential for an increased rate of ipsilateral cancers in the treated breast. The second is the potential for therapeutic radiation to induce tumors in BRCA1/2 defective cells. Most of the early studies that used family history of breast/ovarian cancer as a surrogate for hereditary risk failed to find an increase in ipsilateral cancers in women treated with breast conservation.[104-108] However, with the availability of clinical genetic testing for BRCA1/2 mutations, treatment outcomes for carriers of deleterious mutations in BRCA1/2 can now be compared with those of noncarriers.

To understand the role of germline BRCA1/2 mutations in determining outcome among women treated conservatively for breast cancer, the records of Ashkenazi Jewish (AJ) women treated with lumpectomy and radiation therapy for invasive breast cancer were reviewed.[109] Archival pathology material was obtained for analysis of the three founder AJ mutations. Deleterious BRCA mutations were found in 56 (11.3%) of the cases. The rate of ipsilateral cancer for founder mutation carriers was 12% at 10 years compared with 8% for women without mutations (not statistically significant). Women with founder AJ mutations were over three times more likely than women without mutations to develop contralateral cancer, 27% versus 8% (P = .0001). The same investigators also described a separate case series of 87 women with BRCA mutations who were treated with breast conserving surgery.[110] They reported a 12.6% rate of ipsilateral breast cancer at a median of 51.8 months, and a 23% rate of contralateral breast cancer at a median of 67.4 months. No control group was included.[110]

A case-control study from the Netherlands compared women with hereditary breast cancer (identified as either BRCA1/2 positive, or by a strong family history) with women without hereditary breast cancer for treatment outcome after breast conservation therapy. Although rates of ipsilateral breast recurrence were similar at 2 years following diagnosis, by 5 years the rate was twice as high in the hereditary cases (14% vs. 7%), and remained twice as high at 10 and 15 years after diagnosis (30% and 49% in the hereditary group, and 16% and 20% in the sporadic group).[111]

A multi-institution retrospective cohort study compared outcomes after breast conserving treatment between women with known BRCA1/2 mutations and those whose family history was not suggestive of a hereditary pattern. At 10 years, overall rates of ipsilateral breast cancer were not significantly different. However, BRCA1/2 mutation status was significantly associated with a risk of ipsilateral breast cancer when those carriers who underwent oophorectomy were removed from the analysis (7.8% for noncarriers vs. 16.3% for carriers). The 10-year estimates for contralateral breast cancer were 3% for noncarriers and 26% for carriers.[74] One study reported an approximately 40% risk of contralateral breast cancer in BRCA mutation carriers, a risk which is reduced by taking tamoxifen or undergoing oophorectomy.[112]

A study of selected patients diagnosed at age 42 years or younger who had undergone conservative therapy were offered genetic testing for BRCA1/2 mutations. Of 127 participants, 22 were found to have deleterious mutations.[113] At a median of 12.7 years of follow-up, the rate of ipsilateral events was 49% in the mutation carriers and 21% in the noncarriers (P = .007). Clinical and pathological features of the ipsilateral tumors were more consistent with second primaries than with local recurrence. Similarly, the rate of contralateral cancers was 42% in the carriers and 9% in the noncarriers (P = .001). This study has been criticized as having an unacceptable rate of ipsilateral events overall, calling into question the adequacy of the local-regional treatment.[114]

As noted above, there is a growing indication that women with BRCA1/2 mutations who are treated conservatively have an increased, not decreased, rate of ipsilateral breast cancer, occurring usually after 5 years of follow-up.

The second concern stems from the emerging understanding of the role of the BRCA genes in DNA repair activities within the cell, and the implication of the loss of these functions for radiation hypersensitivity. Both BRCA1 and BRCA2 are involved in DNA double-strand break repair, and loss of function in these genes could potentially accelerate the rate of cell kill caused by ionizing radiation. Another potentially relevant mechanism is the defect in the G2-M phase checkpoint displayed by BRCA1-deficient cells, which also alters radiation sensitivity.[115] Furthermore, murine models of Brca1- and Brca2-deficient mice have demonstrated evidence of hypersensitivity to ionizing radiation.[18,116] Clinical manifestations of these findings could include:

1. An increased response to adjuvant radiation therapy with a decrease of in-breast recurrence rates.
2. An increase in ipsilateral and contralateral breast cancers secondary to genetic instability.
3. An increase in radiation-related toxicity.

In one study, the rate of local recurrence among women with strong family histories who were treated with lumpectomy was highest when radiation was omitted, suggesting that these tumors are radiosensitive.[106] Rates of contralateral disease are consistently elevated in this population, but are equal for women treated with conservative therapy and for those who chose mastectomy without radiation, indicating that the increased risk is due to the mutation, not the exposure to radiation. And finally, studies have failed to find an increase in either early acute radiation tissue reactions or late radiation reactions to the skin, underlying tissue or bone.[117-119]

These data are consistent with a model in which hereditary BRCA1/2 cancers are sterilized by radiation therapy equally well, but due to the underlying genetic predisposition, the increased risk of second primaries in the treated breast remains. The findings of a significantly increased risk of contralateral breast cancer in this population is consistent across studies, and increasingly women with BRCA1/2 mutations are considering bilateral mastectomy at the time of first diagnosis of breast cancer, regardless of stage. Finally, there is no evidence for an increase in radiation toxicity among BRCA1/2 mutation carriers.

Level of evidence: 3di

A small but growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. The absence of BRCA-mediated DNA repair could potentially increase sensitivity to these agents, which induce DNA breaks. On the other hand, the failure to activate cell cycle checkpoints in response to DNA damage could allow d