Major Genes

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 affected relatives in the same biologic line) 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 in an apparent autosomal dominant pattern of transmission (through either the maternal or paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland.[1,2] It is now known 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, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

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 studies 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, MSH2, MSH6, and PMS2, 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) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of Mutations section of this summary 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) 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 of Mutations section of this summary for more information.) BRCA2 is 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 (nonmutated) 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, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitylation, chromatin remodeling, and cell cycle control.[16,17]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[18] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2.[19,20] 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.[21] In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these are commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish descent.[22-25]

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, the classification of nucleotide changes to predict their functional impact as deleterious or benign 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 challenges 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, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.[26]

African Americans appear to have a higher rate of VUS.[27] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period.[28] 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 subjects with no clear deleterious mutations had sequence alterations that were once considered VUS, but were reclassified as a polymorphism, or occasionally as a deleterious mutation. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely due to improved mutation classification algorithms.[29] VUS continue to be reclassified as additional information is accumulated. 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 [30-33] including integrated methods (see below).[34] 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. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes,[30,35-39] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER] negative),[40] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[41,42] When attempting to interpret a VUS, all available information should be examined.

Statistics regarding the percentage of individuals 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 additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. However, other founder mutations have been identified in African Americans and Hispanics.[43-45] 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 limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.[28]

Among the general population, the likelihood of having any BRCA mutation is as follows:

• General population (excluding Ashkenazim): about 1 in 400 (~0.25%).[20,46]
• Women with breast cancer (any age): 1 in 50 (2%).[47]
• Women with breast cancer (younger than 40 years): 1 in 10 (10%).[48-50]
• Men with breast cancer (any age): 1 in 20 (5%).[51]
• Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).[52-54]

Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[55]
• Women with breast cancer (any age): 1 in 10 (10%).[56]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).[56-58]
• Men with breast cancer (any age): 1 in 5 (19%).[59]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).[60-62]

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 [49,63] and BRCA2 [49] mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals.[49,63] The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.[49]

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[62] Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[64]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer.[49,50,63,65-73] Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

• Breast cancer diagnosed at an early age. (Some studies use age 40 years, while others use age 50 years as a cutoff.)
• Ovarian cancer.
• Bilateral breast cancer.
• A history of both breast and ovarian cancer.
• Breast cancer diagnosed in a male at any age.[65-68,71]
• Triple-negative breast cancer diagnosed in women younger than 50 years.[74-76]
• Ashkenazi Jewish background.[65,66,68]

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

• Multiple cases of breast cancer.
• Both breast and ovarian cancer.
• One or more breast cancers in male family members.
• Ashkenazi Jewish background.[65-68]

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[77] the National Comprehensive Cancer Network,[78] the American Society of Human Genetics,[79] the American College of Medical Genetics, the U.S. Preventive Services Task Force,[80] and the Society of Gynecologic Oncologists,[81] have developed clinical criteria that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 mutation.

Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 mutations in individuals or families. These models include those using logistic regression,[28,65,66,68,71,82,83] genetic models using Bayesian analysis (BRCAPRO and BOADICEA),[71,84] and empiric observations,[46,49,52,85-87] including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[65,66] 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.[84] Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be identified as BRCA1/BRCA2 mutation carriers.[88,89] The power of several of the models has been compared in different studies, and currently there is no one model that is consistently superior to others.[90-93] 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.[94] One study has shown that the risk models are sensitive to the amount of family history data available and do not perform as well with limited family information.[95]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[96] There have been variable results in the performance of the BRCAPRO model among Hispanics,[97,98] and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.[99] Further information is needed to determine which model performs best in each ethnic group.

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. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).

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/BRCA2 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.

Numerous studies have estimated breast and ovarian cancer penetrance in BRCA1 and BRCA2 mutation carriers. Risk of both breast and ovarian cancer is consistently estimated to be higher in BRCA1 than in BRCA2 mutation carriers. Results from two large meta-analyses are shown in Table 3.[103,104] One study [103] analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 mutation-positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study [104] combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 mutation-positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for BRCA1 and 45% to 47% for BRCA2 mutation carriers. Ovarian cancer risks were 39% for BRCA1 and 11% to 17% for BRCA2 mutation carriers.

While the cumulative risks of cancer by age 70 years are higher for BRCA1 than BRCA2 mutation carriers, the relative risks (RR) of breast cancer decline with age more in BRCA1 mutation carriers.[103] Studies of penetrance for carriers of specific individual mutations are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder mutations have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder mutations from their larger meta-analyses and found that the estimated penetrance for the individual mutations was very similar to the corresponding estimates among all mutation carriers.[105]

One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[104] Nonetheless, making precise penetrance estimates in an individual carrier is difficult.

Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk.[56,103,106-111] (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors.[112-117] Genetic modifiers of penetrance of breast and ovarian cancer are increasingly under study but are not clinically useful at this time.[118-120] 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, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts,[56,121] 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.

Female breast and ovarian are clearly the dominant cancers associated with BRCA1 and BRCA2. Male breast, prostate, and pancreatic cancers have also been consistently associated, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers has been more difficult to estimate due to the lower numbers of these cancers observed in mutation carriers.

Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively.[6,8,9,122] Men carrying BRCA2 mutations, and to a lesser extent BRCA1 mutations, have an approximately 3- to 7-fold increased risk of prostate cancer.[7,8,12,87,123-125] BRCA2-associated prostate cancer also appears to be more aggressive.[126-131] (Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Prostate Cancer summary for more information.)

Studies of familial pancreatic cancer (FPC) [132-136] and unselected series of pancreatic cancer [137-139] have also supported an association with BRCA2, and to a lesser extent, BRCA1.[7] Overall, it appears that between 3% to 15% of families with FPC may have germline BRCA2 mutations, with risks increasing with more affected relatives.[132-134] Similarly, studies of unselected pancreatic cancers have reported BRCA2 mutation frequencies between 3% to 7%, with these numbers approaching 10% in those of Ashkenazi Jewish descent.[137,138,140] The lifetime risk of pancreatic cancer in BRCA2 carriers is estimated to be 3% to 5% [8,12] compared with an estimated lifetime risk of 0.5% by age 70 years in the general population.[141] Other cancers associated with BRCA2 mutations in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime) and are less well studied.[12]

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).[142] This finding was supported by some,[6,7,143] but not all,[8,55,61,87,144-146] family-based studies. However, 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.[147-149] 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 for colorectal cancer.

No increased prevalence of hereditary BRCA mutations was found among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.[150,151] (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)

There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 mutation segregating in the 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%.[109] A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 mutation in the family [152] was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.[153-158] Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk.[157,159,160] Several studies have involved retrospective analyses; all studies have been based on small observed numbers of cases and have been of uncertain statistical and clinical significance. No cases of ovarian cancer have been reported in these studies.[157] Results from a prospective study of 375 women who tested negative for a known family mutation in BRCA1 or BRCA2 reported two invasive breast cancers, two in situ breast cancers, and no ovarian cancers diagnosed with a mean follow-up of 4.9 years. Four invasive breast cancers were expected, whereas two were observed.[161] A second study of similar size but longer follow-up (395 women and 7,008 person-years of follow-up) also found no statistically significant overall increase in breast cancer risk among mutation-negative women (observed/expected [O/E] 0.82, 95% CI 0.39–1.51), although women who had at least one first-degree relative with breast cancer had a nonsignificant increased risk (O/E 1.33, 95% CI 0.41–2.91).[162] On the basis of the currently available data, it appears that women testing negative for known familial BRCA1/BRCA2 mutations can adhere to general population screening guidelines unless they have sufficient additional risk factors, such as a personal history of atypical hyperplasia of the breast or family history of breast cancer, that are not accounted for by the familial mutation.

The majority of families with site-specific breast cancer test negative for BRCA1/BRCA2 and have no features consistent with Cowden syndrome or Li-Fraumeni syndrome.[28] Three studies using population-based and clinic-based approaches have demonstrated no increased risk of ovarian cancer in such families. Although ovarian cancer risk was not increased, breast cancer risk remained elevated.[163-165]

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,[166-169] 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.[170-172] 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.[173,174] 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.[175-177] BRCA1-related tumor characteristics have also been associated with constitutional methylation of the BRCA1 promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline BRCA1 mutations, methylation of BRCA1 in peripheral blood was observed in 31% of women whose tumors had multiple BRCA1-associated pathological characteristics (e.g., high mitotic index, growth pattern including multinucleated cells) compared with less than 4% methylation in controls.[178] (Refer to the BRCA1 pathology section for more information.) Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[179] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[180,181] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[182]

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. 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. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,183] This is the region of the gene containing the BRCA1 C-terminal (BRCT) repeat,[184] which has 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.[185] 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.[186] These observations have generally been confirmed in subsequent studies.[103,187,188] 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.[189,190] 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 years in BRCA2:6174delT mutation carriers.[189,190]

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, trabecular growth pattern, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 mutations.[191-201] 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.[74,195,202,203] A study of 54 women with triple-negative breast cancer aged 40 years or younger, who were not considered candidates for BRCA testing because of the lack of a strong family history, showed five with BRCA1 mutations and one with a BRCA2 mutation (11% mutation prevalence).[76,204]

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancer,[205,206] particularly in women diagnosed before age 50 years.[74-76] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset.[207,208] These ER-positive cancers have clinical behavior features that are "intermediate" between ER-negative BRCA1 cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.

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.[209] 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.[203,210,211] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[212-214] 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;[203] 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 epidermal growth factor receptor.[215-218] 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.[74,195,217]

There is growing evidence that preinvasive lesions are a component of the BRCA phenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers,[192] also seen in two subsequent studies of BRCA1/BRCA2 carriers.[219,220] However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 mutations were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients.[221] A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 mutation-negative cases.[222,223] A study of Ashkenazi Jewish women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects.[224] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased[225,226] and decreased prevalence.[220] Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/BRCA2 mutation.[227]

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of mutations in DCIS patients, unselected for family history, is less than 5%.[221,224]

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.[192,196,228] 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.[229] 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.[230] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[194,196] In summary, histologic characteristics associated with BRCA2 mutations have been inconsistent.

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.[231-233] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[62,234] 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.[170] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study.[235] In contrast to high-grade serous ovarian cancer, low-grade serous ovarian cancer is not likely to be part of the spectrum of BRCA1- or BRCA2-related ovarian cancer.[236] 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.[231,237] 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 that may ultimately distinguish them histologically.[238] Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.[239]

There are now several lines of evidence indicating that primary fallopian tube cancer should be considered a part of the BRCA1/BRCA2 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.[240,241]

HNPCC is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[242] The condition is due to germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations.[243] The MLH1 and MSH2 genes are the most common susceptibility genes for HNPCC, accounting for 80% to 90% of observed mutations,[244,245] followed by MSH6 and PMS2.[246-251] (Refer to the Lynch syndrome (LS) section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

The lifetime risk for ovarian carcinoma in females with HNPCC is estimated to be up to 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected HNPCC.[252-257] Characteristics of HNPCC-associated ovarian cancers may include over-representation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), under-representation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.[258,259]

Prior studies suggest breast cancer risk in individuals with HNPCC is not elevated.[260,261] However, in approximately 50% of individuals with HNPCC who develop breast cancer, there is loss of MMR protein expression, which corresponds with the MMR gene mutation segregating in the family.[261]

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) (OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented.[262] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[263,264] 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.[265] 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.

Germline TP53 mutations were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing. All families with a TP53 mutation had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 mutation, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 mutations were found. TP53 mutations are uncommon in women with breast cancer before age 30 years with no other indications for TP53 screening (e.g., a family history of sarcoma). In three studies, the numbers of women with TP53 mutations were 0 (of 95), 1 (of 14), and 2 (of 52).[266-268]

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. It is also an active component of programmed cell death.[269] 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.[264] 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.[270] HER2 overexpression may be common in Li-Fraumeni-associated breast cancer.[271]

Screening for breast cancer with annual magnetic resonance imaging is recommended;[78] additional screening for other cancers has been studied and is evolving.[272,273]

One of the more than 50 cancer-related genodermatoses, Cowden syndrome (OMIM) is characterized by multiple hamartomas, an excess of breast cancer, gastrointestinal malignancies, endometrial cancer, and thyroid disease, both benign and malignant.[274,275] 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.[276] 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.[277,278] Germline mutations in the PTEN gene (OMIM), which is located on chromosome 10q23 and encodes a tyrosine phosphatase protein with homology to tensin, are responsible for Cowden 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.[279] 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,[275] 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.[275,280] (Refer to the Major Genes section in the PDQ summary on Genetics of Colorectal Cancer for more information about Cowden syndrome.)

Peutz-Jeghers syndrome (PJS) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips and the perioral and buccal regions and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[281-283] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[284-288] (Refer to the Peutz-Jeghers Gene(s) section of the PDQ summary on Genetics of Colorectal Cancer for more information.) A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93%.[289] Table 5 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to various screening recommendations. (Refer to the PDQ summary on Genetics of Colorectal Cancer for more information.)

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral bias have resulted in overestimates of these risks should be considered.

References

1. Phipps RF, Perry PM: Familial breast cancer. Postgrad Med J 64 (757): 847-9, 1988.  [PUBMED Abstract]
   
   
2. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994.  [PUBMED Abstract]
   
   
3. Newman B, Austin MA, Lee M, et al.: Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proceedings of the National Academy of Sciences 85(9): 3044-3048, 1988. 
   
   
4. Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990.  [PUBMED Abstract]
   
   
5. Narod SA, Feunteun J, Lynch HT, et al.: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338 (8759): 82-3, 1991.  [PUBMED Abstract]
   
   
6. Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002.  [PUBMED Abstract]
   
   
7. Thompson D, Easton DF; Breast Cancer Linkage Consortium.: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002.  [PUBMED Abstract]
   
   
8. Risch HA, McLaughlin JR, Cole DE, et al.: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98 (23): 1694-706, 2006.  [PUBMED Abstract]
   
   
9. Tai YC, Domchek S, Parmigiani G, et al.: Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99 (23): 1811-4, 2007.  [PUBMED Abstract]
   
   
10. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.  [PUBMED Abstract]
    
    
11. Gayther SA, Mangion J, Russell P, et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15 (1): 103-5, 1997.  [PUBMED Abstract]
    
    
12. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.  [PUBMED Abstract]
    
    
13. Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004.  [PUBMED Abstract]
    
    
14. Tonin P, Weber B, Offit K, et al.: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 (11): 1179-83, 1996.  [PUBMED Abstract]
    
    
15. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.  [PUBMED Abstract]
    
    
16. Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 (2): 171-82, 2002.  [PUBMED Abstract]
    
    
17. Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4 (9): 665-76, 2004.  [PUBMED Abstract]
    
    
18. An Open Access On-Line Breast Cancer Mutation Data Base [Database]. Bethesda, Md: National Human Genome Research Institute, 2002. Available online. Last accessed August 8, 2011. 
    
    
19. Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57 (6): 1457-62, 1995.  [PUBMED Abstract]
    
    
20. Whittemore AS, Gong G, John EM, et al.: Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev 13 (12): 2078-83, 2004.  [PUBMED Abstract]
    
    
21. Eng C, Brody LC, Wagner TM, et al.: Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet 38 (12): 824-33, 2001.  [PUBMED Abstract]
    
    
22. Unger MA, Nathanson KL, Calzone K, et al.: Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67 (4): 841-50, 2000.  [PUBMED Abstract]
    
    
23. Walsh T, Casadei S, Coats KH, et al.: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295 (12): 1379-88, 2006.  [PUBMED Abstract]
    
    
24. Palma MD, Domchek SM, Stopfer J, et al.: The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 68 (17): 7006-14, 2008.  [PUBMED Abstract]
    
    
25. Stadler ZK, Saloustros E, Hansen NA, et al.: Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 123 (2): 581-5, 2010.  [PUBMED Abstract]
    
    
26. Plon SE, Eccles DM, Easton D, et al.: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29 (11): 1282-91, 2008.  [PUBMED Abstract]
    
    
27. Nanda R, Schumm LP, Cummings S, et al.: Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294 (15): 1925-33, 2005.  [PUBMED Abstract]
    
    
28. Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002.  [PUBMED Abstract]
    
    
29. Hall MJ, Reid JE, Burbidge LA, et al.: BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115 (10): 2222-33, 2009.  [PUBMED Abstract]
    
    
30. Goldgar DE, Easton DF, Deffenbaugh AM, et al.: Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75 (4): 535-44, 2004.  [PUBMED Abstract]
    
    
31. Thompson D, Easton DF, Goldgar DE: A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73 (3): 652-5, 2003.  [PUBMED Abstract]
    
    
32. Spearman AD, Sweet K, Zhou XP, et al.: Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 26 (33): 5393-400, 2008.  [PUBMED Abstract]
    
    
33. Gómez García EB, Oosterwijk JC, Timmermans M, et al.: A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res 11 (1): R8, 2009.  [PUBMED Abstract]
    
    
34. Goldgar DE, Easton DF, Byrnes GB, et al.: Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 29 (11): 1265-72, 2008.  [PUBMED Abstract]
    
    
35. Fleming MA, Potter JD, Ramirez CJ, et al.: Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci U S A 100 (3): 1151-6, 2003.  [PUBMED Abstract]
    
    
36. Tavtigian SV, Deffenbaugh AM, Yin L, et al.: Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43 (4): 295-305, 2006.  [PUBMED Abstract]
    
    
37. Mirkovic N, Marti-Renom MA, Weber BL, et al.: Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64 (11): 3790-7, 2004.  [PUBMED Abstract]
    
    
38. Abkevich V, Zharkikh A, Deffenbaugh AM, et al.: Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41 (7): 492-507, 2004.  [PUBMED Abstract]
    
    
39. Couch FJ, Rasmussen LJ, Hofstra R, et al.: Assessment of functional effects of unclassified genetic variants. Hum Mutat 29 (11): 1314-26, 2008.  [PUBMED Abstract]
    
    
40. Chenevix-Trench G, Healey S, Lakhani S, et al.: Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66 (4): 2019-27, 2006.  [PUBMED Abstract]
    
    
41. Ostrow KL, McGuire V, Whittemore AS, et al.: The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity. Cancer Genet Cytogenet 153 (2): 177-80, 2004.  [PUBMED Abstract]
    
    
42. Wu K, Hinson SR, Ohashi A, et al.: Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res 65 (2): 417-26, 2005.  [PUBMED Abstract]
    
    
43. Weitzel JN, Lagos V, Blazer KR, et al.: Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 14 (7): 1666-71, 2005.  [PUBMED Abstract]
    
    
44. Weitzel JN, Lagos VI, Herzog JS, et al.: Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 16 (8): 1615-20, 2007.  [PUBMED Abstract]
    
    
45. Mefford HC, Baumbach L, Panguluri RC, et al.: Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 65 (2): 575-8, 1999.  [PUBMED Abstract]
    
    
46. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer 83 (10): 1301-8, 2000.  [PUBMED Abstract]
    
    
47. Papelard H, de Bock GH, van Eijk R, et al.: Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients. Br J Cancer 83 (6): 719-24, 2000.  [PUBMED Abstract]
    
    
48. Loman N, Johannsson O, Kristoffersson U, et al.: Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93 (16): 1215-23, 2001.  [PUBMED Abstract]
    
    
49. Malone KE, Daling JR, Doody DR, et al.: Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66 (16): 8297-308, 2006.  [PUBMED Abstract]
    
    
50. Newman B, Mu H, Butler LM, et al.: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279 (12): 915-21, 1998.  [PUBMED Abstract]
    
    
51. Basham VM, Lipscombe JM, Ward JM, et al.: BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4 (1): R2, 2002.  [PUBMED Abstract]
    
    
52. Risch HA, McLaughlin JR, Cole DE, et al.: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68 (3): 700-10, 2001.  [PUBMED Abstract]
    
    
53. Rubin SC, Blackwood MA, Bandera C, et al.: BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol 178 (4): 670-7, 1998.  [PUBMED Abstract]
    
    
54. Pal T, Permuth-Wey J, Betts JA, et al.: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104 (12): 2807-16, 2005.  [PUBMED Abstract]
    
    
55. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.  [PUBMED Abstract]
    
    
56. 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]
    
    
57. Gershoni-Baruch R, Dagan E, Fried G, et al.: Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36 (8): 983-6, 2000.  [PUBMED Abstract]
    
    
58. Hodgson SV, Heap E, Cameron J, et al.: Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 36 (5): 369-73, 1999.  [PUBMED Abstract]
    
    
59. Struewing JP, Coriaty ZM, Ron E, et al.: Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 65 (6): 1800-2, 1999.  [PUBMED Abstract]
    
    
60. Hirsh-Yechezkel G, Chetrit A, Lubin F, et al.: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89 (3): 494-8, 2003.  [PUBMED Abstract]
    
    
61. Moslehi R, Chu W, Karlan B, et al.: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66 (4): 1259-72, 2000.  [PUBMED Abstract]
    
    
62. Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003.  [PUBMED Abstract]
    
    
63. John EM, Miron A, Gong G, et al.: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA 298 (24): 2869-76, 2007.  [PUBMED Abstract]
    
    
64. Vicus D, Finch A, Cass I, et al.: Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol 118 (3): 299-302, 2010.  [PUBMED Abstract]
    
    
65. Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997.  [PUBMED Abstract]
    
    
66. Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997.  [PUBMED Abstract]
    
    
67. 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]
    
    
68. Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.  [PUBMED Abstract]
    
    
69. Chang-Claude J, Dong J, Schmidt S, et al.: Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes. J Med Genet 35 (2): 116-21, 1998.  [PUBMED Abstract]
    
    
70. Couch FJ, Hartmann LC: BRCA1 testing--advances and retreats. JAMA 279 (12): 955-7, 1998.  [PUBMED Abstract]
    
    
71. Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62 (1): 145-58, 1998.  [PUBMED Abstract]
    
    
72. Ready K, Litton JK, Arun BK: Clinical application of breast cancer risk assessment models. Future Oncol 6 (3): 355-65, 2010.  [PUBMED Abstract]
    
    
73. Amir E, Freedman OC, Seruga B, et al.: Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 102 (10): 680-91, 2010.  [PUBMED Abstract]
    
    
74. Lakhani SR, Reis-Filho JS, Fulford L, et al.: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11 (14): 5175-80, 2005.  [PUBMED Abstract]
    
    
75. Kwon JS, Gutierrez-Barrera AM, Young D, et al.: Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol 28 (27): 4214-20, 2010.  [PUBMED Abstract]
    
    
76. Young SR, Pilarski RT, Donenberg T, et al.: The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer 9: 86, 2009.  [PUBMED Abstract]
    
    
77. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.  [PUBMED Abstract]
    
    
78. National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2011. Rockledge, PA : National Comprehensive Cancer Network, 2010. Available online with free registration. Last accessed December 8, 2011. 
    
    
79. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994.  [PUBMED Abstract]
    
    
80. U.S. Preventive Services Task Force.: Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 143 (5): 355-61, 2005.  [PUBMED Abstract]
    
    
81. Lancaster JM, Powell CB, Kauff ND, et al.: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 107 (2): 159-62, 2007.  [PUBMED Abstract]
    
    
82. Evans DG, Eccles DM, Rahman N, et al.: A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41 (6): 474-80, 2004.  [PUBMED Abstract]
    
    
83. Apicella C, Dowty JG, Dite GS, et al.: Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women. Clin Genet 72 (2): 87-97, 2007.  [PUBMED Abstract]
    
    
84. 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]
    
    
85. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.  [PUBMED Abstract]
    
    
86. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.  [PUBMED Abstract]
    
    
87. Warner E, Foulkes W, Goodwin P, et al.: Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91 (14): 1241-7, 1999.  [PUBMED Abstract]
    
    
88. Euhus DM, Smith KC, Robinson L, et al.: Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 94 (11): 844-51, 2002.  [PUBMED Abstract]
    
    
89. de la Hoya M, Díez O, Pérez-Segura P, et al.: Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics. J Med Genet 40 (7): 503-10, 2003.  [PUBMED Abstract]
    
    
90. Berry DA, Parmigiani G, Sanchez J, et al.: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89 (3): 227-38, 1997.  [PUBMED Abstract]
    
    
91. Barcenas CH, Hosain GM, Arun B, et al.: Assessing BRCA carrier probabilities in extended families. J Clin Oncol 24 (3): 354-60, 2006.  [PUBMED Abstract]
    
    
92. Kang HH, Williams R, Leary J, et al.: Evaluation of models to predict BRCA germline mutations. Br J Cancer 95 (7): 914-20, 2006.  [PUBMED Abstract]
    
    
93. Antoniou AC, Hardy R, Walker L, et al.: Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet 45 (7): 425-31, 2008.  [PUBMED Abstract]
    
    
94. Katki HA: Incorporating medical interventions into carrier probability estimation for genetic counseling. BMC Med Genet 8: 13, 2007.  [PUBMED Abstract]
    
    
95. Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007.  [PUBMED Abstract]
    
    
96. Oros KK, Ghadirian P, Maugard CM, et al.: Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70 (4): 320-9, 2006.  [PUBMED Abstract]
    
    
97. Vogel KJ, Atchley DP, Erlichman J, et al.: BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol 25 (29): 4635-41, 2007.  [PUBMED Abstract]
    
    
98. Kurian AW, Gong GD, John EM, et al.: Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 18 (4): 1084-91, 2009.  [PUBMED Abstract]
    
    
99. Kurian AW, Gong GD, Chun NM, et al.: Performance of BRCA1/2 mutation prediction models in Asian Americans. J Clin Oncol 26 (29): 4752-8, 2008.  [PUBMED Abstract]
    
    
100. 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]
     
     
101. Ready KJ, Vogel KJ, Atchley DP, et al.: Accuracy of the BRCAPRO model among women with bilateral breast cancer. Cancer 115 (4): 725-30, 2009.  [PUBMED Abstract]
     
     
102. Huo D, Senie RT, Daly M, et al.: Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based African American, Hispanic, and Other Minority Families in the United States. J Clin Oncol 27 (8): 1184-90, 2009.  [PUBMED Abstract]
     
     
103. Antoniou A, Pharoah PD, Narod S, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 (5): 1117-30, 2003.  [PUBMED Abstract]
     
     
104. Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25 (11): 1329-33, 2007.  [PUBMED Abstract]
     
     
105. Antoniou AC, Pharoah PD, Narod S, et al.: Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet 42 (7): 602-3, 2005.  [PUBMED Abstract]
     
     
106. Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001.  [PUBMED Abstract]
     
     
107. Levy-Lahad E, Lahad A, Eisenberg S, et al.: A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A 98 (6): 3232-6, 2001.  [PUBMED Abstract]
     
     
108. Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2 (2): 113-23, 2002.  [PUBMED Abstract]
     
     
109. Kramer JL, Velazquez IA, Chen BE, et al.: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 23 (34): 8629-35, 2005.  [PUBMED Abstract]
     
     
110. Antoniou AC, Spurdle AB, Sinilnikova OM, et al.: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82 (4): 937-48, 2008.  [PUBMED Abstract]
     
     
111. Iodice S, Barile M, Rotmensz N, et al.: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46 (12): 2275-84, 2010.  [PUBMED Abstract]
     
     
112. Antoniou AC, Rookus M, Andrieu N, et al.: Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 18 (2): 601-10, 2009.  [PUBMED Abstract]
     
     
113. Milne RL, Osorio A, Ramón y Cajal T, et al.: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119 (1): 221-32, 2010.  [PUBMED Abstract]
     
     
114. Friedman E, Kotsopoulos J, Lubinski J, et al.: Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 8 (2): R15, 2006.  [PUBMED Abstract]
     
     
115. Jernström H, Lubinski J, Lynch HT, et al.: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96 (14): 1094-8, 2004.  [PUBMED Abstract]
     
     
116. Terry P, Jain M, Miller AB, et al.: Dietary carotenoids and risk of breast cancer. Am J Clin Nutr 76 (4): 883-8, 2002.  [PUBMED Abstract]
     
     
117. Breast Cancer Family Registry., Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia)., Ontario Cancer Genetics Network (Canada).: Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 109 (1): 67-75, 2008.  [PUBMED Abstract]
     
     
118. Antoniou AC, Beesley J, McGuffog L, et al.: Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70 (23): 9742-54, 2010.  [PUBMED Abstract]
     
     
119. Ramus SJ, Kartsonaki C, Gayther SA, et al.: Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 103 (2): 105-16, 2011.  [PUBMED Abstract]
     
     
120. Milne RL, Antoniou AC: Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. Ann Oncol 22 (Suppl 1): i11-7, 2011.  [PUBMED Abstract]
     
     
121. Litton JK, Ready K, Chen H, et al.: Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer 118 (2): 321-5, 2012.  [PUBMED Abstract]
     
     
122. Evans DG, Susnerwala I, Dawson J, et al.: Risk of breast cancer in male BRCA2 carriers. J Med Genet 47 (10): 710-1, 2010.  [PUBMED Abstract]
     
     
123. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.  [PUBMED Abstract]
     
     
124. Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.  [PUBMED Abstract]
     
     
125. van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42 (9): 711-9, 2005.  [PUBMED Abstract]
     
     
126. Mitra A, Fisher C, Foster CS, et al.: Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 98 (2): 502-7, 2008.  [PUBMED Abstract]
     
     
127. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007.  [PUBMED Abstract]
     
     
128. Agalliu I, Gern R, Leanza S, et al.: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 15 (3): 1112-20, 2009.  [PUBMED Abstract]
     
     
129. Narod SA, Neuhausen S, Vichodez G, et al.: Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 99 (2): 371-4, 2008.  [PUBMED Abstract]
     
     
130. Edwards SM, Evans DG, Hope Q, et al.: Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 103 (6): 918-24, 2010.  [PUBMED Abstract]
     
     
131. Gallagher DJ, Gaudet MM, Pal P, et al.: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16 (7): 2115-21, 2010.  [PUBMED Abstract]
     
     
132. Couch FJ, Johnson MR, Rabe KG, et al.: The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16 (2): 342-6, 2007.  [PUBMED Abstract]
     
     
133. Hahn SA, Greenhalf B, Ellis I, et al.: BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95 (3): 214-21, 2003.  [PUBMED Abstract]
     
     
134. Murphy KM, Brune KA, Griffin C, et al.: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 62 (13): 3789-93, 2002.  [PUBMED Abstract]
     
     
135. Real FX, Malats N, Lesca G, et al.: Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancer. Gut 50 (5): 653-7, 2002.  [PUBMED Abstract]
     
     
136. Dagan E: Predominant Ashkenazi BRCA1/2 mutations in families with pancreatic cancer. Genet Test 12 (2): 267-71, 2008.  [PUBMED Abstract]
     
     
137. Goggins M, Schutte M, Lu J, et al.: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56 (23): 5360-4, 1996.  [PUBMED Abstract]
     
     
138. Lal G, Liu G, Schmocker B, et al.: Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 60 (2): 409-16, 2000.  [PUBMED Abstract]
     
     
139. Ozçelik H, Schmocker B, Di Nicola N, et al.: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16 (1): 17-8, 1997.  [PUBMED Abstract]
     
     
140. Ferrone CR, Levine DA, Tang LH, et al.: BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 27 (3): 433-8, 2009.  [PUBMED Abstract]
     
     
141. DevCan: Probability of Developing or Dying of Cancer Software. Version 6.5.0. Bethesda, Md: Statistical Research and Applications Branch, National Cancer Institute, 2010. Available online. Last accessed August 22, 2011. 
     
     
142. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.  [PUBMED Abstract]
     
     
143. Anton-Culver H, Cohen PF, Gildea ME, et al.: Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer. Eur J Cancer 36 (10): 1200-8, 2000.  [PUBMED Abstract]
     
     
144. Peelen T, de Leeuw W, van Lent K, et al.: Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis. Int J Cancer 88 (5): 778-82, 2000.  [PUBMED Abstract]
     
     
145. Berman DB, Costalas J, Schultz DC, et al.: A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 56 (15): 3409-14, 1996.  [PUBMED Abstract]
     
     
146. Aretini P, D'Andrea E, Pasini B, et al.: Different expressivity of BRCA1 and BRCA2: analysis of 179 Italian pedigrees with identified mutation. Breast Cancer Res Treat 81 (1): 71-9, 2003.  [PUBMED Abstract]
     
     
147. Kirchhoff T, Satagopan JM, Kauff ND, et al.: Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. J Natl Cancer Inst 96 (1): 68-70, 2004.  [PUBMED Abstract]
     
     
148. Niell BL, Rennert G, Bonner JD, et al.: BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. J Natl Cancer Inst 96 (1): 15-21, 2004.  [PUBMED Abstract]
     
     
149. Chen-Shtoyerman R, Figer A, Fidder HH, et al.: The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients. Br J Cancer 84 (4): 475-7, 2001.  [PUBMED Abstract]
     
     
150. Levine DA, Lin O, Barakat RR, et al.: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80 (3): 395-8, 2001.  [PUBMED Abstract]
     
     
151. Goshen R, Chu W, Elit L, et al.: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79 (3): 477-81, 2000.  [PUBMED Abstract]
     
     
152. Smith A, Moran A, Boyd MC, et al.: Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 44 (1): 10-15, 2007.  [PUBMED Abstract]
     
     
153. Goldgar D, Venne V, Conner T, et al.: BRCA phenocopies or ascertainment bias? J Med Genet 44 (8): e86; author reply e88, 2007.  [PUBMED Abstract]
     
     
154. Eisinger F: Phenocopies: actual risk or self-fulfilling prophecy? J Med Genet 44 (8): e87; author reply e88, 2007.  [PUBMED Abstract]
     
     
155. Sasieni P: Phenocopies in families seen by cancer geneticists. J Med Genet 44 (6): e82, 2007.  [PUBMED Abstract]
     
     
156. Tilanus-Linthorst MM: No screening yet after a negative test for the family mutation. J Med Genet 44 (5): e79, 2007.  [PUBMED Abstract]
     
     
157. Katki HA, Gail MH, Greene MH: Breast-cancer risk in BRCA-mutation-negative women from BRCA-mutation-positive families. Lancet Oncol 8 (12): 1042-3, 2007.  [PUBMED Abstract]
     
     
158. Raskin L, Lejbkowicz F, Barnett-Griness O, et al.: BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev 18 (5): 1617-23, 2009.  [PUBMED Abstract]
     
     
159. Gronwald J, Cybulski C, Lubinski J, et al.: Phenocopies in breast cancer 1 (BRCA1) families: implications for genetic counselling. J Med Genet 44 (4): e76, 2007.  [PUBMED Abstract]
     
     
160. Rowan E, Poll A, Narod SA: A prospective study of breast cancer risk in relatives of BRCA1/BRCA2 mutation carriers. J Med Genet 44 (8): e89; author reply e88, 2007.  [PUBMED Abstract]
     
     
161. Domchek SM, Gaudet MM, Stopfer JE, et al.: Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat 119 (2): 409-14, 2010.  [PUBMED Abstract]
     
     
162. Korde LA, Mueller CM, Loud JT, et al.: No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families. Breast Cancer Res Treat 125 (1): 169-73, 2011.  [PUBMED Abstract]
     
     
163. Kauff ND, Mitra N, Robson ME, et al.: Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst 97 (18): 1382-4, 2005.  [PUBMED Abstract]
     
     
164. Lee JS, John EM, McGuire V, et al.: Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev 15 (2): 359-63, 2006.  [PUBMED Abstract]
     
     
165. Metcalfe KA, Finch A, Poll A, et al.: Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 100 (2): 421-5, 2009.  [PUBMED Abstract]
     
     
166. Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994.  [PUBMED Abstract]
     
     
167. Lancaster JM, Wooster R, Mangion J, et al.: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13 (2): 238-40, 1996.  [PUBMED Abstract]
     
     
168. Miki Y, Katagiri T, Kasumi F, et al.: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13 (2): 245-7, 1996.  [PUBMED Abstract]
     
     
169. Teng DH, Bogden R, Mitchell J, et al.: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13 (2): 241-4, 1996.  [PUBMED Abstract]
     
     
170. Berchuck A, Heron KA, Carney ME, et al.: Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 4 (10): 2433-7, 1998.  [PUBMED Abstract]
     
     
171. Thompson ME, Jensen RA, Obermiller PS, et al.: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9 (4): 444-50, 1995.  [PUBMED Abstract]
     
     
172. Dobrovic A, Simpfendorfer D: Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57 (16): 3347-50, 1997.  [PUBMED Abstract]
     
     
173. Cleton-Jansen AM, Collins N, Lakhani SR, et al.: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72 (5): 1241-4, 1995.  [PUBMED Abstract]
     
     
174. Hamann U, Herbold C, Costa S, et al.: Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer. Cancer Res 56 (9): 1988-90, 1996.  [PUBMED Abstract]
     
     
175. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al.: Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8 (4): R38, 2006.  [PUBMED Abstract]
     
     
176. Turner NC, Reis-Filho JS, Russell AM, et al.: BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26 (14): 2126-32, 2007.  [PUBMED Abstract]
     
     
177. Rakha EA, El-Sheikh SE, Kandil MA, et al.: Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39 (6): 857-65, 2008.  [PUBMED Abstract]
     
     
178. Wong EM, Southey MC, Fox SB, et al.: Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 4 (1): 23-33, 2011.  [PUBMED Abstract]
     
     
179. Hilton JL, Geisler JP, Rathe JA, et al.: Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94 (18): 1396-406, 2002.  [PUBMED Abstract]
     
     
180. Quinn JE, James CR, Stewart GE, et al.: BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13 (24): 7413-20, 2007.  [PUBMED Abstract]
     
     
181. Geisler JP, Hatterman-Zogg MA, Rathe JA, et al.: Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94 (1): 61-7, 2002.  [PUBMED Abstract]
     
     
182. Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (7035): 917-21, 2005.  [PUBMED Abstract]
     
     
183. Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.  [PUBMED Abstract]
     
     
184. Koonin EV, Altschul SF, Bork P: BRCA1 protein products ... Functional motifs... Nat Genet 13 (3): 266-8, 1996.  [PUBMED Abstract]
     
     
185. Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001.  [PUBMED Abstract]
     
     
186. Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11 (4): 329-36, 2002.  [PUBMED Abstract]
     
     
187. Scott CL, Jenkins MA, Southey MC, et al.: Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 112 (5-6): 542-51, 2003.  [PUBMED Abstract]
     
     
188. Lubinski J, Phelan CM, Ghadirian P, et al.: Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 3 (1): 1-10, 2004.  [PUBMED Abstract]
     
     
189. Satagopan JM, Boyd J, Kauff ND, et al.: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8 (12): 3776-81, 2002.  [PUBMED Abstract]
     
     
190. Rennert G, Dishon S, Rennert HS, et al.: Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel. Eur J Cancer Prev 14 (4): 357-61, 2005.  [PUBMED Abstract]
     
     
191. Eisinger F, Jacquemier J, Charpin C, et al.: Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 58 (8): 1588-92, 1998.  [PUBMED Abstract]
     
     
192. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349 (9064): 1505-10, 1997.  [PUBMED Abstract]
     
     
193. Lorenzo Bermejo J, Hemminki K: A population-based assessment of the clustering of breast cancer in families eligible for testing of BRCA1 and BRCA2 mutations. Ann Oncol 16 (2): 322-9, 2005.  [PUBMED Abstract]
     
     
194. Armes JE, Egan AJ, Southey MC, et al.: The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 83 (11): 2335-45, 1998.  [PUBMED Abstract]
     
     
195. Foulkes WD, Stefansson IM, Chappuis PO, et al.: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95 (19): 1482-5, 2003.  [PUBMED Abstract]
     
     
196. Marcus JN, Watson P, Page DL, et al.: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77 (4): 697-709, 1996.  [PUBMED Abstract]
     
     
197. Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351 (9099): 316-21, 1998.  [PUBMED Abstract]
     
     
198. Møller P, Borg A, Evans DG, et al.: Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy. Int J Cancer 101 (6): 555-9, 2002.  [PUBMED Abstract]
     
     
199. Veronesi A, de Giacomi C, Magri MD, et al.: Familial breast cancer: characteristics and outcome of BRCA 1-2 positive and negative cases. BMC Cancer 5: 70, 2005.  [PUBMED Abstract]
     
     
200. Manié E, Vincent-Salomon A, Lehmann-Che J, et al.: High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res 69 (2): 663-71, 2009.  [PUBMED Abstract]
     
     
201. Southey MC, Ramus SJ, Dowty JG, et al.: Morphological predictors of BRCA1 germline mutations in young women with breast cancer. Br J Cancer 104 (6): 903-9, 2011.  [PUBMED Abstract]
     
     
202. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al.: The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20 (9): 2310-8, 2002.  [PUBMED Abstract]
     
     
203. Sorlie T, Tibshirani R, Parker J, et al.: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100 (14): 8418-23, 2003.  [PUBMED Abstract]
     
     
204. Rakha EA, Elsheikh SE, Aleskandarany MA, et al.: Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15 (7): 2302-10, 2009.  [PUBMED Abstract]
     
     
205. Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22 (11): 1233-9; discussion 1239-40, 1243, 2008.  [PUBMED Abstract]
     
     
206. Atchley DP, Albarracin CT, Lopez A, et al.: Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26 (26): 4282-8, 2008.  [PUBMED Abstract]
     
     
207. Tung N, Wang Y, Collins LC, et al.: Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res 12 (1): R12, 2010.  [PUBMED Abstract]
     
     
208. Lakhani SR, Khanna KK, Chenevix-Trench G: Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic? Breast Cancer Res 12 (2): 104, 2010.  [PUBMED Abstract]
     
     
209. Foulkes WD: BRCA1 functions as a breast stem cell regulator. J Med Genet 41 (1): 1-5, 2004.  [PUBMED Abstract]
     
     
210. Perou CM, Sørlie T, Eisen MB, et al.: Molecular portraits of human breast tumours. Nature 406 (6797): 747-52, 2000.  [PUBMED Abstract]
     
     
211. Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001.  [PUBMED Abstract]
     
     
212. Hedenfalk I, Duggan D, Chen Y, et al.: Gene-expression profiles in hereditary breast cancer. N Engl J Med 344 (8): 539-48, 2001.  [PUBMED Abstract]
     
     
213. Wessels LF, van Welsem T, Hart AA, et al.: Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62 (23): 7110-7, 2002.  [PUBMED Abstract]
     
     
214. Palacios J, Honrado E, Osorio A, et al.: Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9 (10 Pt 1): 3606-14, 2003.  [PUBMED Abstract]
     
     
215. Nielsen TO, Hsu FD, Jensen K, et al.: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10 (16): 5367-74, 2004.  [PUBMED Abstract]
     
     
216. Palacios J, Honrado E, Osorio A, et al.: Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90 (1): 5-14, 2005.  [PUBMED Abstract]
     
     
217. Laakso M, Loman N, Borg A, et al.: Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod Pathol 18 (10): 1321-8, 2005.  [PUBMED Abstract]
     
     
218. Cheang MC, Voduc D, Bajdik C, et al.: Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14 (5): 1368-76, 2008.  [PUBMED Abstract]
     
     
219. Hwang ES, McLennan JL, Moore DH, et al.: Ductal carcinoma in situ in BRCA mutation carriers. J Clin Oncol 25 (6): 642-7, 2007.  [PUBMED Abstract]
     
     
220. Adem C, Reynolds C, Soderberg CL, et al.: Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97 (1): 1-11, 2003.  [PUBMED Abstract]
     
     
221. Claus EB, Petruzella S, Matloff E, et al.: Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293 (8): 964-9, 2005.  [PUBMED Abstract]
     
     
222. Arun B, Vogel KJ, Lopez A, et al.: High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers. Cancer Prev Res (Phila Pa) 2 (2): 122-7, 2009.  [PUBMED Abstract]
     
     
223. Garber JE: BRCA1/2-associated and sporadic breast cancers: fellow travelers or not? Cancer Prev Res (Phila Pa) 2 (2): 100-3, 2009.  [PUBMED Abstract]
     
     
224. Smith KL, Adank M, Kauff N, et al.: BRCA mutations in women with ductal carcinoma in situ. Clin Cancer Res 13 (14): 4306-10, 2007.  [PUBMED Abstract]
     
     
225. Hoogerbrugge N, Bult P, Bonenkamp JJ, et al.: Numerous high-risk epithelial lesions in familial breast cancer. Eur J Cancer 42 (15): 2492-8, 2006.  [PUBMED Abstract]
     
     
226. Kauff ND, Brogi E, Scheuer L, et al.: Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97 (7): 1601-8, 2003.  [PUBMED Abstract]
     
     
227. Hall MJ, Reid JE, Wenstrup RJ: Prevalence of BRCA1 and BRCA2 mutations in women with breast carcinoma In Situ and referred for genetic testing. Cancer Prev Res (Phila) 3 (12): 1579-85, 2010.  [PUBMED Abstract]
     
     
228. Marcus JN, Watson P, Page DL, et al.: BRCA2 hereditary breast cancer pathophenotype. Breast Cancer Res Treat 44 (3): 275-7, 1997.  [PUBMED Abstract]
     
     
229. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al.: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 47 (2): 121-7, 1998.  [PUBMED Abstract]
     
     
230. Lakhani SR, Jacquemier J, Sloane JP, et al.: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90 (15): 1138-45, 1998.  [PUBMED Abstract]
     
     
231. Lakhani SR, Manek S, Penault-Llorca F, et al.: Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 10 (7): 2473-81, 2004.  [PUBMED Abstract]
     
     
232. Evans DG, Young K, Bulman M, et al.: Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet 73 (4): 338-45, 2008.  [PUBMED Abstract]
     
     
233. Tonin PN, Maugard CM, Perret C, et al.: A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6 (4): 491-7, 2007.  [PUBMED Abstract]
     
     
234. Crum CP, Drapkin R, Kindelberger D, et al.: Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 5 (1): 35-44, 2007.  [PUBMED Abstract]
     
     
235. Piek JM, Torrenga B, Hermsen B, et al.: Histopathological characteristics of BRCA1- and BRCA2-associated intraperitoneal cancer: a clinic-based study. Fam Cancer 2 (2): 73-8, 2003.  [PUBMED Abstract]
     
     
236. Vineyard MA, Daniels MS, Urbauer DL, et al.: Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer? Gynecol Oncol 120 (2): 229-32, 2011.  [PUBMED Abstract]
     
     
237. Schorge JO, Muto MG, Lee SJ, et al.: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res 60 (5): 1361-4, 2000.  [PUBMED Abstract]
     
     
238. Jazaeri AA, Yee CJ, Sotiriou C, et al.: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94 (13): 990-1000, 2002.  [PUBMED Abstract]
     
     
239. Gourley C, Michie CO, Roxburgh P, et al.: Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J Clin Oncol 28 (15): 2505-11, 2010.  [PUBMED Abstract]
     
     
240. Piek JM, van Diest PJ, Zweemer RP, et al.: Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195 (4): 451-6, 2001.  [PUBMED Abstract]
     
     
241. Carcangiu ML, Radice P, Manoukian S, et al.: Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol 23 (1): 35-40, 2004.  [PUBMED Abstract]
     
     
242. Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4 (3): 219-25, 2005.  [PUBMED Abstract]
     
     
243. Jascur T, Boland CR: Structure and function of the components of the human DNA mismatch repair system. Int J Cancer 119 (9): 2030-5, 2006.  [PUBMED Abstract]
     
     
244. Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994.  [PUBMED Abstract]
     
     
245. Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997.  [PUBMED Abstract]
     
     
246. Akiyama Y, Sato H, Yamada T, et al.: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57 (18): 3920-3, 1997.  [PUBMED Abstract]
     
     
247. Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997.  [PUBMED Abstract]
     
     
248. Huang J, Kuismanen SA, Liu T, et al.: MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer Res 61 (4): 1619-23, 2001.  [PUBMED Abstract]
     
     
249. Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994.  [PUBMED Abstract]
     
     
250. Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130 (2): 312-22, 2006.  [PUBMED Abstract]
     
     
251. Worthley DL, Walsh MD, Barker M, et al.: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128 (5): 1431-6, 2005.  [PUBMED Abstract]
     
     
252. Watson P, Lynch HT: Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1 (1): 57-60, 2001.  [PUBMED Abstract]
     
     
253. Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996.  [PUBMED Abstract]
     
     
254. Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995.  [PUBMED Abstract]
     
     
255. Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993.  [PUBMED Abstract]
     
     
256. Brown GJ, St John DJ, Macrae FA, et al.: Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol 80 (3): 346-9, 2001.  [PUBMED Abstract]
     
     
257. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999.  [PUBMED Abstract]
     
     
258. Grindedal EM, Renkonen-Sinisalo L, Vasen H, et al.: Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet 47 (2): 99-102, 2010.  [PUBMED Abstract]
     
     
259. Pal T, Permuth-Wey J, Sellers TA: A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer 113 (4): 733-42, 2008.  [PUBMED Abstract]
     
     
260. Jensen UB, Sunde L, Timshel S, et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120 (3): 777-82, 2010.  [PUBMED Abstract]
     
     
261. Walsh MD, Buchanan DD, Cummings MC, et al.: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res 16 (7): 2214-24, 2010.  [PUBMED Abstract]
     
     
262. Garber JE, Goldstein AM, Kantor AF, et al.: Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 51 (22): 6094-7, 1991.  [PUBMED Abstract]
     
     
263. Bottomley RH, Condit PT: Cancer families. Cancer Bull 20: 22-24, 1968. 
     
     
264. Malkin D: The Li-Fraumeni syndrome. Cancer: Principles and Practice of Oncology Updates 7(7): 1-14, 1993. 
     
     
265. Olivier M, Goldgar DE, Sodha N, et al.: Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63 (20): 6643-50, 2003.  [PUBMED Abstract]
     
     
266. Gonzalez KD, Noltner KA, Buzin CH, et al.: Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27 (8): 1250-6, 2009.  [PUBMED Abstract]
     
     
267. Ginsburg OM, Akbari MR, Aziz Z, et al.: The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 8 (4): 563-7, 2009.  [PUBMED Abstract]
     
     
268. Mouchawar J, Korch C, Byers T, et al.: Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 70 (12): 4795-800, 2010.  [PUBMED Abstract]
     
     
269. Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993.  [PUBMED Abstract]
     
     
270. Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992.  [PUBMED Abstract]
     
     
271. Wilson JR, Bateman AC, Hanson H, et al.: A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47 (11): 771-4, 2010.  [PUBMED Abstract]
     
     
272. Villani A, Tabori U, Schiffman J, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12 (6): 559-67, 2011.  [PUBMED Abstract]
     
     
273. Masciari S, Van den Abbeele AD, Diller LR, et al.: F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA 299 (11): 1315-9, 2008.  [PUBMED Abstract]
     
     
274. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
     
     
275. Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004.  [PUBMED Abstract]
     
     
276. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
     
     
277. Nelen MR, Padberg GW, Peeters EA, et al.: Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13 (1): 114-6, 1996.  [PUBMED Abstract]
     
     
278. Lachlan KL, Lucassen AM, Bunyan D, et al.: Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 44 (9): 579-85, 2007.  [PUBMED Abstract]
     
     
279. Lynch ED, Ostermeyer EA, Lee MK, et al.: Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 61 (6): 1254-60, 1997.  [PUBMED Abstract]
     
     
280. Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997.  [PUBMED Abstract]
     
     
281. Peutz JL: On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921. 
     
     
282. Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 241(25): 993-1005, 1949. 
     
     
283. Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989.  [PUBMED Abstract]
     
     
284. Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005.  [PUBMED Abstract]
     
     
285. Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.  [PUBMED Abstract]
     
     
286. Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.  [PUBMED Abstract]
     
     
287. Boudeau J, Kieloch A, Alessi DR, et al.: Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Hum Mutat 21 (2): 172, 2003.  [PUBMED Abstract]
     
     
288. Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003.  [PUBMED Abstract]
     
     
289. van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010.  [PUBMED Abstract]
     
     
290. Westerman AM, Entius MM, de Baar E, et al.: Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353 (9160): 1211-5, 1999.  [PUBMED Abstract]
     
     
291. Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000.  [PUBMED Abstract]
     
     
292. Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006.  [PUBMED Abstract]
     
     
293. Mehenni H, Resta N, Park JG, et al.: Cancer risks in LKB1 germline mutation carriers. Gut 55 (7): 984-90, 2006.  [PUBMED Abstract]
     
     
294. Lim W, Olschwang S, Keller JJ, et al.: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126 (7): 1788-94, 2004.  [PUBMED Abstract]
     
     

Low-Penetrance Predisposition to Breast and Ovarian Cancer

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the 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] On its own, each low-penetrance 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 a specific variation in a given locus occurs in more than 1% of the population). 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 individuals 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 to 2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the general population, their contribution to cancer risk overall is estimated to be much greater 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, despite some confirmed associations (described below), has been relatively disappointing [6,7] The candidate gene approach 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, mostly without regard to their possible biological function, but instead to capture all genetic variation throughout the genome more uniformly.

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several different studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

CHEK2 (OMIM) is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, low-penetrance cancer susceptibility allele.[8-13] One study identified the mutation in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[8] 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.[14] In additional European and U.S. (where the mutation appears to be slightly less common) studies, including a large prospective study,[15] the frequency of CHEK2 mutations detected in familial breast or ovarian cancer cases has ranged from 0% [16] to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[15,17-20] 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.[21] Two studies suggest that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[22,23] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[18] Although the initial report [13] and at least one other report [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 depend on the population studied, with a potentially higher mutation prevalence in Poland.[29] CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer.[30] 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,[31] the clinical applicability of this finding remains uncertain due to low mutation prevalence and lack of guidelines for clinical management.[32]

Ataxia telangiectasia (AT) (OMIM) 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).[33] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[34] ATM proteins have been shown to play a role in cell cycle control.[35-37] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[38]

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.[39-49] 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.[49,50] 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 investigation 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,[51-53] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 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 = .003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval (CI), 1.2–3.2, P = .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.[54]

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.[55] 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.[56] A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years,[57] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[58] Mutations have been observed in early-onset and familial breast cancer in many populations.[59,60]

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, CASP8 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.[61]

RAD51C is involved in DNA damage repair through homologous recombination and interaction with numerous DNA repair proteins. Like PALB2 and BRCA2, the RAD51C gene has been evaluated as a breast and ovarian cancer susceptibility gene and as one of the causes of Fanconi anemia. Despite a possible role in German breast-ovarian cancer families and a single German family with Fanconi anemia–like features,[62,63] most studies have not found an association between RAD51C and heritable breast and ovarian cancer.[64,65] It is unclear what role this gene may play in breast and ovarian cancer susceptibility.

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.[66,67] 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.[68-70] 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 causal.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases [71] including breast cancer.[72-75] 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.[72] 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.[73,74,76,76-81] SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor-positive disease.[82] An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is available.

More limited data are available regarding ovarian cancer risk.[84,85]

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, theoretical models have suggested that common moderate-risk SNPs have limited potential to improve models for individualized risk assessment.[86-88] These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A more recent study used ROC curve analysis to examine the utility of SNPs in a clinical dataset of greater than 5,500 cases and nearly 6,000 controls, using a model with traditional risk factors compared to a model using both standard risk factors and ten previously identified SNPs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of risk when genetic information was included in assessment of their risk, and 20.4% in a lower quintile of risk. It remains unclear whether such information has clinical utility.[86,89]

References

1. Easton DF: How many more breast cancer predisposition genes are there? Breast Cancer Res 1 (1): 14-7, 1999.  [PUBMED Abstract]
   
   
2. Smith P, McGuffog L, Easton DF, et al.: A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45 (7): 646-55, 2006.  [PUBMED Abstract]
   
   
3. Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. Chen YC, Hunter DJ: Molecular epidemiology of cancer. CA Cancer J Clin 55 (1): 45-54; quiz 57, 2005 Jan-Feb.  [PUBMED Abstract]
   
   
6. Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98 (19): 1382-96, 2006.  [PUBMED Abstract]
   
   
7. Dunning AM, Healey CS, Pharoah PD, et al.: A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8 (10): 843-54, 1999.  [PUBMED Abstract]
   
   
8. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31 (1): 55-9, 2002.  [PUBMED Abstract]
   
   
9. Kuschel B, Auranen A, Gregory CS, et al.: Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 12 (8): 809-12, 2003.  [PUBMED Abstract]
   
   
10. Sodha N, Bullock S, Taylor R, et al.: CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87 (12): 1445-8, 2002.  [PUBMED Abstract]
    
    
11. Ingvarsson S, Sigbjornsdottir BI, Huiping C, et al.: Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res 4 (3): R4, 2002.  [PUBMED Abstract]
    
    
12. Vahteristo P, Bartkova J, Eerola H, et al.: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71 (2): 432-8, 2002.  [PUBMED Abstract]
    
    
13. Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003.  [PUBMED Abstract]
    
    
14. Schmidt MK, Tollenaar RA, de Kemp SR, et al.: Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25 (1): 64-9, 2007.  [PUBMED Abstract]
    
    
15. Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al.: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25 (1): 57-63, 2007.  [PUBMED Abstract]
    
    
16. Iniesta MD, Gorin MA, Chien LC, et al.: Absence of CHEK2*1100delC mutation in families with hereditary breast cancer in North America. Cancer Genet Cytogenet 202 (2): 136-40, 2010.  [PUBMED Abstract]
    
    
17. Offit K, Pierce H, Kirchhoff T, et al.: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4 (1): 1, 2003.  [PUBMED Abstract]
    
    
18. Oldenburg RA, Kroeze-Jansema K, Kraan J, et al.: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63 (23): 8153-7, 2003.  [PUBMED Abstract]
    
    
19. Neuhausen S, Dunning A, Steele L, et al.: Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108 (3): 477-8, 2004.  [PUBMED Abstract]
    
    
20. Ohayon T, Gal I, Baruch RG, et al.: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108 (3): 479-80, 2004.  [PUBMED Abstract]
    
    
21. CHEK2 Breast Cancer Case-Control Consortium.: CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74 (6): 1175-82, 2004.  [PUBMED Abstract]
    
    
22. Johnson N, Fletcher O, Naceur-Lombardelli C, et al.: Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet 366 (9496): 1554-7, 2005 Oct 29-Nov 4.  [PUBMED Abstract]
    
    
23. Fletcher O, Johnson N, Dos Santos Silva I, et al.: Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls. Cancer Epidemiol Biomarkers Prev 18 (1): 230-4, 2009.  [PUBMED Abstract]
    
    
24. Wasielewski M, den Bakker MA, van den Ouweland A, et al.: CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 116 (2): 397-400, 2009.  [PUBMED Abstract]
    
    
25. Osorio A, Rodríguez-López R, Díez O, et al.: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108 (1): 54-6, 2004.  [PUBMED Abstract]
    
    
26. Syrjäkoski K, Kuukasjärvi T, Auvinen A, et al.: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108 (3): 475-6, 2004.  [PUBMED Abstract]
    
    
27. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
    
    
28. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
    
    
29. Cybulski C, Górski B, Huzarski T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12 (16): 4832-5, 2006.  [PUBMED Abstract]
    
    
30. Cybulski C, Huzarski T, Byrski T, et al.: Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clin Genet 75 (1): 72-8, 2009.  [PUBMED Abstract]
    
    
31. Weischer M, Bojesen SE, Ellervik C, et al.: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26 (4): 542-8, 2008.  [PUBMED Abstract]
    
    
32. Offit K, Garber JE: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26 (4): 519-20, 2008.  [PUBMED Abstract]
    
    
33. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.  [PUBMED Abstract]
    
    
34. Telatar M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62 (1): 86-97, 1998.  [PUBMED Abstract]
    
    
35. Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.  [PUBMED Abstract]
    
    
36. Ahmed M, Rahman N: ATM and breast cancer susceptibility. Oncogene 25 (43): 5906-11, 2006.  [PUBMED Abstract]
    
    
37. Khanna KK, Chenevix-Trench G: ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia 9 (3): 247-62, 2004.  [PUBMED Abstract]
    
    
38. Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.  [PUBMED Abstract]
    
    
39. FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997.  [PUBMED Abstract]
    
    
40. Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.  [PUBMED Abstract]
    
    
41. Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998.  [PUBMED Abstract]
    
    
42. Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.  [PUBMED Abstract]
    
    
43. Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001.  [PUBMED Abstract]
    
    
44. Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001.  [PUBMED Abstract]
    
    
45. Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002.  [PUBMED Abstract]
    
    
46. Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.  [PUBMED Abstract]
    
    
47. Cavaciuti E, Laugé A, Janin N, et al.: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer 42 (1): 1-9, 2005.  [PUBMED Abstract]
    
    
48. Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer 93 (2): 260-5, 2005.  [PUBMED Abstract]
    
    
49. Renwick A, Thompson D, Seal S, et al.: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38 (8): 873-5, 2006.  [PUBMED Abstract]
    
    
50. Thompson D, Duedal S, Kirner J, et al.: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97 (11): 813-22, 2005.  [PUBMED Abstract]
    
    
51. Levitus M, Waisfisz Q, Godthelp BC, et al.: The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 37 (9): 934-5, 2005.  [PUBMED Abstract]
    
    
52. Levran O, Attwooll C, Henry RT, et al.: The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37 (9): 931-3, 2005.  [PUBMED Abstract]
    
    
53. Litman R, Peng M, Jin Z, et al.: BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8 (3): 255-65, 2005.  [PUBMED Abstract]
    
    
54. Seal S, Thompson D, Renwick A, et al.: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38 (11): 1239-41, 2006.  [PUBMED Abstract]
    
    
55. Reid S, Schindler D, Hanenberg H, et al.: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2): 162-4, 2007.  [PUBMED Abstract]
    
    
56. Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007.  [PUBMED Abstract]
    
    
57. Erkko H, Dowty JG, Nikkilä J, et al.: Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res 14 (14): 4667-71, 2008.  [PUBMED Abstract]
    
    
58. Heikkinen T, Kärkkäinen H, Aaltonen K, et al.: The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res 15 (9): 3214-22, 2009.  [PUBMED Abstract]
    
    
59. Ding YC, Steele L, Chu LH, et al.: Germline mutations in PALB2 in African-American breast cancer cases. Breast Cancer Res Treat 126 (1): 227-30, 2011.  [PUBMED Abstract]
    
    
60. Foulkes WD, Ghadirian P, Akbari MR, et al.: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 9 (6): R83, 2007.  [PUBMED Abstract]
    
    
61. Cox Angela, Dunning Alison, Garcia-Closas Montserrat, et al.: Nature genetics. Nat Genet 39 (5): 352-8, 2007. 
    
    
62. Meindl A, Hellebrand H, Wiek C, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42 (5): 410-4, 2010.  [PUBMED Abstract]
    
    
63. Vaz F, Hanenberg H, Schuster B, et al.: Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42 (5): 406-9, 2010.  [PUBMED Abstract]
    
    
64. Akbari MR, Tonin P, Foulkes WD, et al.: RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res 12 (4): 404, 2010.  [PUBMED Abstract]
    
    
65. Zheng Y, Zhang J, Hope K, et al.: Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124 (3): 857-61, 2010.  [PUBMED Abstract]
    
    
66. The International HapMap Consortium.: The International HapMap Project. Nature 426 (6968): 789-96, 2003.  [PUBMED Abstract]
    
    
67. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.  [PUBMED Abstract]
    
    
68. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.  [PUBMED Abstract]
    
    
69. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.  [PUBMED Abstract]
    
    
70. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.  [PUBMED Abstract]
    
    
71. Wellcome Trust Case Control Consortium.: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.  [PUBMED Abstract]
    
    
72. Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007.  [PUBMED Abstract]
    
    
73. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007.  [PUBMED Abstract]
    
    
74. Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007.  [PUBMED Abstract]
    
    
75. Turnbull C, Ahmed S, Morrison J, et al.: Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42 (6): 504-7, 2010.  [PUBMED Abstract]
    
    
76. Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008.  [PUBMED Abstract]
    
    
77. Zheng W, Long J, Gao YT, et al.: Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41 (3): 324-8, 2009.  [PUBMED Abstract]
    
    
78. Kibriya MG, Jasmine F, Argos M, et al.: A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114 (3): 463-77, 2009.  [PUBMED Abstract]
    
    
79. 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]
    
    
80. 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]
    
    
81. 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]
    
    
82. Reeves GK, Travis RC, Green J, et al.: Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci. JAMA 304 (4): 426-34, 2010.  [PUBMED Abstract]
    
    
83. 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]
    
    
84. Song H, Ramus SJ, Tyrer J, et al.: A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet 41 (9): 996-1000, 2009.  [PUBMED Abstract]
    
    
85. Song H, Ramus SJ, Kjaer SK, et al.: Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study. Hum Mol Genet 18 (12): 2297-304, 2009.  [PUBMED Abstract]
    
    
86. 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]
    
    
87. 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]
    
    
88. Gail MH: Value of adding single-nucleotide polymorphism genotypes to a breast cancer risk model. J Natl Cancer Inst 101 (13): 959-63, 2009.  [PUBMED Abstract]
    
    
89. Wacholder S, Hartge P, Prentice R, et al.: Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362 (11): 986-93, 2010.  [PUBMED Abstract]
    
    

Clinical Management of BRCA Mutation Carriers

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 for information on screening in the general population, and to the PDQ summary Levels of Evidence for Cancer Genetics Studies 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 for more information.)

Little direct prospective evidence exists regarding BSE in individuals with an increased 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/BRCA2 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 years) 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).

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]

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 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, are 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/BRCA2 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 and 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.

Digital mammography refers to the use of a digital detector to find and record x-ray images. This technology improves contrast resolution,[18] 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;[19] however, digital mammography resulted in fewer recalls. In another study (ACRIN-6652) comparing digital mammography to plain-film mammography in 42,760 women, the overall diagnostic accuracy of the two techniques was similar.[20] 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.

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.[21-23]

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. 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.[24] 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.[25,26] In a small study,[26] 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. With the routine use of magnetic resonance imaging (MRI) in BRCA1/BRCA2 mutation carriers, any potential benefit of mammographic screening must be carefully weighed against potential risks, particularly in young women.[27] However, at this time there is insufficient evidence to suggest that mutation carriers should avoid mammography, particularly since some breast cancers are identified by mammography and not MRI.

Because of the relative insensitivity of mammography in women with inherited 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.[28-36] 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 six large studies are presented in Table 7, Summary of MRI Screening Studies in Women at Hereditary Risk for Breast Cancer.[28,30,31,34,37,38] 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, 77% of the cancers were identified by MRI, and 42% were identified 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.[31] 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.[30] The benign biopsy rates in the first study were 11% at first round, 6.6% at second round, and 4.7% at third round.[31] 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.[30] 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 missed by screening.[39] However, mammography identifies some cancers, particularly DCIS, that are not identified by MRI.[40] 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 with 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.[28] 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. In a prospective study of 51 BRCA1 and 41 BRCA2 mutation carriers screened with yearly mammograms and MRIs (of whom 80 had prophylactic oophorectomy), 11 breast cancers (9 invasive and 2 DCIS) were detected. Six cancers were first detected on MRI, three were first detected by mammogram, and two were interval cancers. All breast cancers occurred in BRCA1 mutation carriers, suggesting a continued high risk of BRCA1-related breast cancer following oophorectomy in the short term. These results suggest that surveillance and prevention strategies may have differing outcomes in BRCA1 and BRCA2 mutation carriers.[35] 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.[3,41]

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.[42] 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.[42] 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.[43] 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/BRCA2 mutation carriers) undergoing simultaneous mammography, MRI, and ultrasound, no cancers were detected by ultrasound alone.[32] 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

A number of other techniques are under active investigation, including tomosynthesis, contrast-enhanced mammography, thermography, and radionuclide scanning. Additional evidence is needed before these techniques can be incorporated into clinical practice.

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.[44] 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.[45] 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.[46] 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]).[47]

The Prevention and Observation of Surgical End Points (PROSE) study group estimated the degree of breast cancer risk reduction after RRM in BRCA1/BRCA2 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%.[48]

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 associated with higher mortality due to the index cancer or metachronous ovarian cancer in the group not undergoing surgery.[49] More recently, data from ten European centers on 550 women indicated that RRM was highly effective.[50]

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.[51-53] 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, three (6%) cancers were detected at surgery.[54] In a study from Sweden among 100 women with a hereditary risk of breast cancer, unsuspected lesions were found in 13 out of 50 BRCA1/BRCA2 mutation carriers.[55] 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.[56]

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, health care 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.[57] Among women at increased risk of breast cancer due to family history, fewer than 10% opted for mastectomy.[58] 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 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.[59] In addition, self-perceived risk has been closely linked to interest in RRM.[58]

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.[60] 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.[61] 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.[62]

A computer-simulated survival analysis using a Monte Carlo model included breast MRI, mammography, RRM, and risk-reducing salpingo-oophrectomy (RRSO) and examined the impact of each of these on BRCA1 and BRCA2 mutation carriers separately.[63] The most effective strategy was found to be RRSO at age 40 years and RRM at age 25 years, in which case survival at age 70 years approached that of the general population. However, delaying mastectomy until age 40 years, or substituting RRM with screening with breast MRI and mammogram, had little impact on survival estimates. For example, replacing RRM with MRI-based screening in women with RRSO at age 40 years led to a 3% to 5% decrement in survival compared to RRM at age 25 years. As with any model, uncertainty remains due to numerous assumptions; however, this provides additional information for women and their providers who are making these difficult decisions.

The Society of Surgical Oncology has endorsed RRM as an option for women with BRCA1/BRCA2 mutations or strong family histories of breast cancer.[64]

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 Psychosocial Outcome Studies section of this summary for more information.)

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 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.[65] 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,[66,67] a retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR 0.04, 95% CI, 0.01–0.16) after RRSO.[68] 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).[69] 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).[70] 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).[71]

In addition to the reduction in incidence of both breast and ovarian cancer, a prospective multicenter cohort study of 2,482 BRCA1/BRCA2 mutation carriers has reported an association of RRSO with a reduction in all-cause mortality (HR = 0.40, 95% CI, 0.26–0.61), breast cancer–specific mortality (HR = 0.44, 95% CI, 0.26–0.76), and ovarian cancer–specific mortality (HR = 0.21, 95% CI, 0.06–0.80).[72]

Level of evidence: 3ai

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-P-1), a prospective, randomized, double-blind trial, compared tamoxifen (20 mg/day) with 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.[73] Similar reductions were noted in the risk of preinvasive breast cancer. Reductions in breast cancer risk were noted both among women with a family history of breast cancer and in those without a family history. An increased incidence of endometrial cancers and thrombotic events occurred 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 [74] or 70 months,[75] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT).[74] These trials varied considerably in study design and populations. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

A substudy of the NSABP-P-1 trial evaluated the effectiveness of tamoxifen in preventing breast cancer in BRCA1/BRCA2 mutation carriers older than 35 years. BRCA2-positive women benefited from tamoxifen to the same extent as BRCA1/BRCA2 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).[76]

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.[77-79] In one study involving approximately 600 BRCA1/BRCA2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[77] An update to this report examined 285 BRCA1/BRCA2 mutation carriers with bilateral breast cancer and 751 BRCA1/BRCA2 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.[79] Another study involving 160 BRCA1/BRCA2 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.[78] 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 (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. [80] 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.[81] Data regarding efficacy in BRCA1 or BRCA2 mutation carriers are not available.

The effect of tamoxifen on ovarian cancer risk was studied in 714 BRCA1 mutation carriers. All subjects had a prior history of breast cancer; use of tamoxifen was not associated with an increased risk of subsequent ovarian cancer (OR = 0.78, 95% CI, 0.46–1.33).[82]

Level of evidence: 1

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 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.[83] 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.[84,85] 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.[86]

Studies of the effect of pregnancy on breast cancer risk have revealed complex results and the relationship with parity has been inconsistent and may vary between BRCA1 and BRCA2 mutation carriers.[87-89] Parity has more consistently been associated with a reduced risk of breast cancer in BRCA1 mutation carriers.[87-91] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[89,92]

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,[93] 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.[94] No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.[92]

There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population.[95] (Refer to the PDQ summary on Breast Cancer Prevention for more information.)

Although several smaller studies have reported a slightly increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers,[96,97] a meta-analysis concluded that the associated risk is not significant with more recent OC formulations.[98] However, OCs formulated before 1975 were associated with an increased risk of breast cancer.[98] A large proportion of patients upon which this meta-analysis was based were drawn from three large studies summarized in the table below.[99-101]

When counseling patients about contraceptive options and preventive actions, the potential impact of OC use upon the risk of both breast and ovarian cancer and other health-related effects of OCs need to be considered. A number of important issues remain unresolved, including the potential differences between BRCA1 and BRCA2 mutation carriers, effect of age and duration of exposure, and effect of OCs on families with highly penetrant early-onset breast cancer.

Level of evidence: 3aii

(Refer to the Oral contraceptives section in the Chemoprevention section of this summary for a discussion of OC use and ovarian cancer in this population.)

Both observational and randomized clinical trial data suggest an increased risk of breast cancer associated with HRT in the general population.[102-105] The Women’s Health Initiative (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.[104,105] 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.[105] 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.[106] 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.[105]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [107-109] or unaffected by a family history of breast cancer;[84,110,111] risk did not vary by family history in the meta-analysis.[95] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations.[105] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[112]