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.[8-14] (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.[15] 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.[16]

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 ubiquitination, chromatin remodeling, and cell cycle control.[17,18]

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described.[19] Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2.[20,21] 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.[22] 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.[23-26]

Germline deleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, 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.[27]

African Americans appear to have a higher rate of VUS.[28] A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period.[29] Among subjects who had no clearly deleterious mutation, 13% had VUS defined as “missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins.” The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of 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.[30] 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 [31-34] including integrated methods (see below).[35] 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,[31,36-40] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]–negative),[41] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[42,43] 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.[44-46] 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.[29]

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

• General population (excluding Ashkenazim): about 1 in 400 (~0.25%).[21,47]
• Women with breast cancer (any age): 1 in 50 (2%).[48]
• Women with breast cancer (younger than 40 years): 1 in 10 (10%).[49-51]
• Men with breast cancer (any age): 1 in 20 (5%).[52]
• Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).[53-55]

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

• General Ashkenazi Jewish population: 1 in 40 (2.5%).[56]
• Women with breast cancer (any age): 1 in 10 (10%).[57]
• Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).[57-59]
• Men with breast cancer (any age): 1 in 5 (19%).[60]
• Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).[61-63]

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 [50,64] and BRCA2 [50] 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.[50,64] The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.[50]

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%.[63] 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).[65]

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer.[50,51,64,66-74] 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.[66-69,72]
• Triple-negative breast cancer diagnosed in women younger than 50 years.[75-77]
• Ashkenazi Jewish background.[66,67,69]

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.[66-69]

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[78] the National Comprehensive Cancer Network,[79] the American Society of Human Genetics,[80] the American College of Medical Genetics, the U.S. Preventive Services Task Force,[81] and the Society of Gynecologic Oncologists,[82] 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,[29,66,67,69,72,83,84] genetic models using Bayesian analysis (BRCAPRO and BOADICEA),[72,85] and empiric observations,[47,50,53,86-88] including the Myriad prevalence tables. Two of the earliest models predicted only for BRCA1 mutations and are not clinically useful at this time.[66,67] 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.[85] 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.[89,90] 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.[91-94] 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.[95] 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.[96]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[97] There have been variable results in the performance of the BRCAPRO model among Hispanics,[98,99] and both the BRCAPRO model and Myriad tables underestimated the proportion of mutation carriers in an Asian American population.[100] 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.[104,105] One study [104] 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 [105] 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.[104] 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.[106]

One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[105] 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.[57,104,107-112] (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.[113-118] Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time.[119-121] While the average breast cancer 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,[57,122] and additional studies will be required to further characterize potential modifying factors 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 cancers are clearly the dominant cancers associated with BRCA1 and BRCA2. BRCA mutations also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of BRCA1 mutation carriers has found a 120-fold relative risk of tubal cancer among BRCA1 mutation carriers compared with the general population.[6] The risk of primary peritoneal cancer among BRCA mutation carriers with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% in the 20 years following risk-reducing salpingo-oophorectomy.[123,124] (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)

Pancreatic, male breast, and prostate cancers have also been consistently associated with BRCA mutations, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers with BRCA mutations has been more difficult to estimate because of 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.[6,8,9,125] Men carrying BRCA2 mutations, and to a lesser extent BRCA1 mutations, have an approximately threefold to sevenfold increased risk of prostate cancer.[7,8,12,88,126-128] BRCA2-associated prostate cancer also appears to be more aggressive.[129-134] (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) [135-139] and unselected series of pancreatic cancer [140-142] 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.[135-137] 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.[140,141,143] 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.[144] 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).[145] This finding was supported by some,[6,7,146] but not all,[8,56,62,88,147-149] 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.[150-152] 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.[153,154] (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. An initial study based on prospective evaluation of 353 women who tested negative for the BRCA1 mutation segregating in the family found that five incident breast cancers occurred during more than 6,000 person-years of observation, for a lifetime risk of 6.8%, a rate similar to the general population.[110] 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 [155] was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.[156-161] Three additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk.[160,162,163] 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.[160]

Results from numerous other prospective studies have found no increased risk. A study of 375 women who tested negative for a known familial 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.[164] Another 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).[165] A study of 160 BRCA1 and 132 BRCA2 mutation–positive families from the Breast Cancer Family Registry found no evidence for increased risk among noncarriers in these families.[166] Based on 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 in relatives who do not carry 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.[29] 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.[167-169]

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,[170-173] 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.[174-176] 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.[177,178] 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.[179-181] 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.[182] (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,[183] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[184,185] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[186]

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.[11,187] This is the region of the gene containing the BRCA1 C-terminal (BRCT) repeat,[188] 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.[189] 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.[190] These observations have generally been confirmed in subsequent studies.[104,191,192] 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.[193,194] 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.[193,194]

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.[195-205] 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.[75,199,206,207]

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,[208,209] particularly in women diagnosed before age 50 years.[75-77] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset.[210,211] 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.

The prevalence of germline BRCA1 mutations in women with triple-negative breast cancer is significant, both in women undergoing clinical genetic testing (and thus selected in large part for family history) and in unselected triple-negative patients, with mutations reported in 11% to 35%.[77,199,206,212-217] The highest rate reported was in a clinic-based series in women younger than 30 years with high-grade triple-negative breast cancer. In this small, highly selected population, 35% had BRCA1 mutations. Notably, studies have demonstrated a high rate of BRCA1 mutations in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. One study examined 308 individuals with triple-negative breast cancer; BRCA1 mutations were present in 45. Mutations were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%).[218] A group of researchers reported results of BRCA1/2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) mutation or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in BRCA1 mutation carriers and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with BRCA1 mutation–associated triple-negative breast cancer than in those with nonmutated triple-negative breast cancer, although this study was limited by its size.[215] A second study examining clinical outcomes in BRCA1-associated versus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one BRCA1 mutation carrier received chemotherapy.[216]

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.[219] 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.[207,220,221] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[222-224] 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;[207] 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.[225-228] 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.[75,199,227]

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,[196] also seen in two subsequent studies of BRCA1/BRCA2 carriers.[229,230] 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.[231] 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.[232,233] 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.[234] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased[235,236] and decreased prevalence.[230] 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.[237]

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%.[231,234]

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.[196,200,238] 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.[239] 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.[240] Other reports suggest that BRCA2 related tumors include an excess of lobular and tubulolobular histology.[198,200] 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.[241-244] Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease.[63,245] 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.[174] Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study.[246] 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.[247] 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.[241,248] 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.[249] 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.[250]

Histopathologic examinations 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.[251,252] Occult carcinomas have been reported in 2% to 11% of the adnexa removed at the time of risk-reducing surgery from BRCA mutation carriers. The majority of these occult carcinomas are seen within the fallopian tube, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tube. Specifically, the distal segment of the fallopian tube (fimbriae) has been implicated as a common origin for the high-grade serous cancers seen in BRCA mutation carriers based on its close proximity to the ovarian surface and peritoneal cavity and its large surface area.[253]

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.[254] The condition is due to germline mutations in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch mutations.[255] The MLH1 and MSH2 genes are the most common susceptibility genes for HNPCC, accounting for 80% to 90% of observed mutations,[256,257] followed by MSH6 and PMS2.[258-263] (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 of 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.[264-269] 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.[270,271]

Prior studies suggest breast cancer risk in individuals with HNPCC is not elevated.[272,273] 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.[273]

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.[274] This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[275,276] 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.[277] 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).[278-280]

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.[281] 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.[276] 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.[282] HER2 overexpression may be common in Li-Fraumeni-associated breast cancer.[283]

Screening for breast cancer with annual magnetic resonance imaging is recommended;[79] additional screening for other cancers has been studied and is evolving.[284,285]

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.[286,287] 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.[288] 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.[289,290] 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.[291] 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,[287] 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.[287,292] (Refer to the Major Genes section in the PDQ summary on Genetics of Colorectal Cancer for more information about Cowden 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.[293-295] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[296-300] (Refer to the Peutz-Jeghers Gene(s) section in the PDQ summary on Genetics of Colorectal Cancer for more information.) The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancy. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[301] Table 5 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome in the PDQ summary on Genetics of Colorectal Cancer.

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 biases have resulted in over-estimates of these risks should be considered.

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245. 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]
     
     
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248. 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]
     
     
249. 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]
     
     
250. 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]
     
     
251. 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]
     
     
252. 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]
     
     
253. Medeiros F, Muto MG, Lee Y, et al.: The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30 (2): 230-6, 2006.  [PUBMED Abstract]
     
     
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256. 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]
     
     
257. 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]
     
     
258. 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]
     
     
259. 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]
     
     
260. 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]
     
     
261. 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]
     
     
262. 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]
     
     
263. 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]
     
     
264. Watson P, Lynch HT: Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1 (1): 57-60, 2001.  [PUBMED Abstract]
     
     
265. 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]
     
     
266. 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]
     
     
267. Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993.  [PUBMED Abstract]
     
     
268. 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]
     
     
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270. 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]
     
     
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278. 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]
     
     
279. 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]
     
     
280. 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]
     
     
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283. 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]
     
     
284. 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]
     
     
285. 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]
     
     
286. 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]
     
     
287. 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]
     
     
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289. 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]
     
     
290. 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]
     
     
291. 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]
     
     
292. 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]
     
     
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300. 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]
     
     
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Low-Penetrance Predisposition to Breast and Ovarian Cancer

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed in the Major Genes section of this summary 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 million 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, moderate-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 have suggested that the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[22,23] Furthermore, 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.[24] Similarly, a Polish study reported that CHEK2 truncating mutations confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%.[25] Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 mutations, this may be dependent on mutation type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[13,18,26-31] The contribution of CHEK2 mutations to breast cancer may depend on the population studied, with a potentially higher mutation prevalence in Poland.[32] CHEK2 mutation carriers in Poland may be more susceptible to ER-positive breast cancer.[33]

Currently, the clinical applicability of CHEK mutations remains uncertain because of low mutation prevalence and lack of guidelines for clinical management.[34]

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).[35] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[36] ATM proteins have been shown to play a role in cell cycle control.[37-39] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[40]

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.[41-51] 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.[51,52] 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. Biallelic mutations in BRIP1 are a cause of Fanconi anemia,[53-55] 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.[56]

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.[57] PALB2 mutations have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[58-68] Mutation prevalence has ranged from 0.4% to 3.4%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[59] A Finnish PALB2 founder mutation (c.1592delT) has been reported to confer a 40% risk of breast cancer to age 70 years [60] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[61] Mutations have been observed in early-onset and familial breast cancer in many populations.[62,63]

Male breast cancer has been observed in PALB2 mutation–positive breast cancer families.[58,64] In a study of 115 male breast cancer cases in which 18 men had BRCA2 mutations, an additional two men had either a pathogenic or predicted pathogenic PALB2 mutation (accounting for about 10% of germline mutations in the study and 1%–2% of the total sample).[58] Following the identification of PALB2 mutations in pancreatic tumors and the detection of germline mutations in 3% of 96 familial pancreatic patients,[69] numerous studies have pointed to a role for PALB2 in pancreatic cancer. A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/2-negative, PALB2 mutation–positive breast cancer probands.[64] PALB2 mutations were detected in 3.7% of 81 familial pancreatic cancer families [70] and in 2.1% of 94 BRCA1/2 mutation–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[71] Two relatively small studies, one of 77 BRCA1/2 mutation–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of Ashkenazi Jewish descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer, failed to detect any PALB2 mutations.[72,73]

The observed prevalence of PALB2 mutations in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed mutation rate was less than 4%. The relative risk of breast cancer appears moderate, and the risk of other cancers (e.g., pancreatic) is poorly defined; therefore, the clinical utility of testing is not clear. There is insufficient evidence to support routine screening of PALB2 when tests of the more common genes, namely BRCA1/2, are negative.

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.[74]

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,[75,76] most studies have not found an association between RAD51C and heritable breast and ovarian cancer.[77,78] 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 million SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[79,80] 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.[81-83] 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,[84] including breast cancer.[85-88] 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.[85] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk, but these regions are included only once in Table 6. Subsequent genome-wide studies have replicated these loci and identified additional ones, as summarized in Table 6.[86,87,89,89-94] SNPs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor–positive disease;[95] however, some are associated primarily or exclusively with other subtypes, including triple-negative disease.[96,97] 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.

Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian 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. No interaction between the SNPs and epidemiologic risk factors for breast cancer have been identified.[116,117] 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.[118-120] 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 breast cancer 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 breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. It remains unclear whether such information has clinical utility.[118,121]

More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of over 10,000 cases and 13,000 controls have been carried out for ovarian cancer.[112,113,115] The seven loci that reached genome-wide significance are shown in Table 7. As in other GWAS, the odds ratios are modest, generally about 1.2 or weaker, but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase (PARP), molecules that may be important in BRCA1/BRCA2-deficient cells.

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98. 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]
    
    
99. Antoniou AC, Kartsonaki C, Sinilnikova OM, et al.: Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 20 (16): 3304-21, 2011.  [PUBMED Abstract]
    
    
100. Kim HC, Lee JY, Sung H, et al.: A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res 14 (2): R56, 2012.  [PUBMED Abstract]
     
     
101. 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]
     
     
102. Milne RL, Goode EL, García-Closas M, et al.: Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer. Cancer Epidemiol Biomarkers Prev 20 (10): 2222-31, 2011.  [PUBMED Abstract]
     
     
103. Kirchhoff T, Chen ZQ, Gold B, et al.: The 6q22.33 locus and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 18 (9): 2468-75, 2009.  [PUBMED Abstract]
     
     
104. Long J, Cai Q, Sung H, et al.: Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer. PLoS Genet 8 (2): e1002532, 2012.  [PUBMED Abstract]
     
     
105. Cai Q, Long J, Lu W, et al.: Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet 20 (24): 4991-9, 2011.  [PUBMED Abstract]
     
     
106. Antoniou AC, Kuchenbaecker KB, Soucy P, et al.: Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res 14 (1): R33, 2012.  [PUBMED Abstract]
     
     
107. Fletcher O, Johnson N, Orr N, et al.: Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103 (5): 425-35, 2011.  [PUBMED Abstract]
     
     
108. Couch FJ, Gaudet MM, Antoniou AC, et al.: Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 21 (4): 645-57, 2012.  [PUBMED Abstract]
     
     
109. Ghoussaini M, Fletcher O, Michailidou K, et al.: Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44 (3): 312-8, 2012.  [PUBMED Abstract]
     
     
110. Figueroa JD, Garcia-Closas M, Humphreys M, et al.: Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20 (23): 4693-706, 2011.  [PUBMED Abstract]
     
     
111. Antoniou AC, Wang X, Fredericksen ZS, et al.: A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42 (10): 885-92, 2010.  [PUBMED Abstract]
     
     
112. Goode EL, Chenevix-Trench G, Song H, et al.: A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42 (10): 874-9, 2010.  [PUBMED Abstract]
     
     
113. 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]
     
     
114. 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]
     
     
115. Bolton KL, Tyrer J, Song H, et al.: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42 (10): 880-4, 2010.  [PUBMED Abstract]
     
     
116. Campa D, Kaaks R, Le Marchand L, et al.: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103 (16): 1252-63, 2011.  [PUBMED Abstract]
     
     
117. Milne RL, Gaudet MM, Spurdle AB, et al.: Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study. Breast Cancer Res 12 (6): R110, 2010.  [PUBMED Abstract]
     
     
118. 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]
     
     
119. 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]
     
     
120. 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]
     
     
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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 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 an inherited risk of 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 of 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 8, Summary of MRI Screening Studies in Women at Hereditary Risk of 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 of 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-oophorectomy (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. The authors have developed an online tool.[64] 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.[65]

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.[66] 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,[67,68] 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.[69] 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).[70] 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 in both BRCA1 and BRCA2 mutation carriers, the risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[71] 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).[72]

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).[73]

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.[74] 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 [75] or 70 months,[76] respectively. In one trial, however, reduction in breast cancer risk was seen among a subgroup who also used hormone replacement therapy (HRT).[75] 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).[77]

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.[78-80] In one study involving approximately 600 BRCA1/BRCA2 mutation carriers, tamoxifen use was associated with a 51% reduction in contralateral breast cancer.[78] 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.[80] 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.[79] 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. [81] 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.[82] 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).[83]

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.[84] 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.[85,86] 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.[87]

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.[88-90] Parity has more consistently been associated with a reduced risk of breast cancer in BRCA1 mutation carriers.[88-92] Of note, neither therapeutic nor spontaneous abortions appear to be associated with an increased breast cancer risk.[90,93]

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,[94] 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.[95] No such reduced risk was observed among BRCA2 mutation carriers. A second study failed to confirm this association.[93]

There is no consistent evidence that the use of oral contraceptives (OCs) increases the risk of breast cancer in the general population.[96] (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,[97,98] a meta-analysis concluded that the associated risk is not significant with more recent OC formulations.[99] However, OCs formulated before 1975 were associated with an increased risk of breast cancer.[99] A large proportion of patients upon which this meta-analysis was based were drawn from three large studies summarized in Table 9.[100-102]

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.[103-106] 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.[105,106] 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.[106] 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.[107] 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.[106]

Breast cancer risk associated with postmenopausal HRT has been variably reported to be increased [108-110] or unaffected by a family history of breast cancer;[85,111,112] risk did not vary by family history in the meta-analysis.[96] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations.[106] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk in the general population.[113]

The effect of HRT on breast cancer risk among carriers of a BRCA1 or BRCA2 mutation has been examined in two studies. In a prospective study of 462 BRCA1 or BRCA2 mutation carriers, bilateral risk-reducing salpingo-oophorectomy (RRSO) (n = 155) was significantly associated with breast cancer risk reduction overall (HR, 0.40; 95% CI, 0.18–0.92). Using mutation carriers without bilateral RRSO or HRT as the comparison group, HRT use (n = 93) did not significantly alter the reduction in breast cancer risk associated with bilateral RRSO (HR, 0.37; 95% CI, 0.14–0.96).[114] In a matched case-control study of 472 postmenopausal women with BRCA1 mutations, HRT use was associated with an overall reduction in breast cancer risk (odds ratio [OR], 0.58; 95% CI, 0.35–0.96; P = .03). A nonsignificant reduction in risk was observed both in women who had undergone bilateral oophorectomy and in those who had not. Women taking estrogen alone had an OR of 0.51 (95% CI, 0.27–0.98; P = .04), while the association with estrogen and progesterone was not statistically significant (OR, 0.66; 95% CI, 0.34–1.27; P = .21).[115] Especially given the differences in estimated risk associated with HRT between observational studies and the WHI, these findings should be confirmed in randomized prospective studies,[116] but they suggest that HRT in BRCA1/BRCA2 mutation carriers neither increases breast cancer risk nor negates the protective effect of oophorectomy.

Level of evidence: 3aii

Refer to the PDQ summary on Ovarian 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. The latter also outlines the five requirements that must be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice.

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

Level of evidence: None assigned

In the general population, transvaginal ultrasound (TVUS) appears to be superior to transabdominal ultrasound in the preoperative diagnosis of adnexal masses. Both techniques have lower specificity in premenopausal women than in postmenopausal women due to the cyclic menstrual changes in premenopausal ovaries (e.g., transient corpus luteum cysts) that can cause difficulty in interpretation. The randomized prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO-1) found no reduction in mortality with the annual use of combined TVUS and cancer antigen (CA) 125 in screening asymptomatic postmenopausal women at general-population risk of ovarian cancer.[117]

Data are limited regarding the potential benefit of TVUS in screening women at inherited risk of ovarian cancer. A number of retrospective studies have reported experience with ovarian cancer screening in high-risk women using TVUS with or without CA 125.[7,118-128] However, there is little uniformity in the definition of high-risk criteria and compliance with screening, and in whether cancers detected were incident or prevalent. One of the largest reported studies included 888 BRCA1/BRCA2 mutation carriers who were screened annually with TVUS and CA 125. Ten women developed ovarian cancer; five of the ten developed interval cancers after normal screening results within 3 to 10 months before diagnosis. Five of the ten ovarian cancers were screen-detected incident cases, which had normal screening results within 6 to 14 months before diagnosis. Of these five cases, four were stage IIIB or IV.[118]

A similar study reported the results of annual TVUS and CA 125 in a cohort of 312 high-risk women (152 BRCA1/BRCA2 mutation carriers).[120] Of the four cancers that were detected due to abnormal TVUS and CA 125, all four patients were symptomatic, and three had advanced-stage disease. Annual screening of BRCA1/BRCA2 mutation carriers with pelvic ultrasound, TVUS, and CA 125 failed to detect early-stage ovarian cancer among 241 BRCA1/BRCA2 mutation carriers in a study from the Netherlands.[129] Three cancers were detected over the course of the study, all advanced stage IIIC disease.[129] Finally, a study of 1,100 moderate- and high-risk women who underwent annual TVUS and CA 125 reported that ten of 13 ovarian tumors were detected due to screening. Only five of ten were stage I or II.[119] There are limited data related to the efficacy of semiannual screening with TVUS and CA 125.[7,127]

The first prospective study of TVUS and CA 125 with survival as the primary outcome was completed in 2009. Of the 3,532 high-risk women screened, 981 were BRCA mutation carriers, of which 49 developed ovarian cancer. The 5- and 10-year survival was 58.6% (95% CI, 50.9–66.3) and 36% (95% CI, 27–45), respectively, and there was no difference in survival between carriers and noncarriers. A major limitation of the study was the absence of a control group. Despite limitations, this study suggests that annual surveillance by TVUS and CA 125 level appear to be ineffective in detecting tumors at an early stage to substantially influence survival.[130]

Level of evidence: 4

Serum CA 125 screening for ovarian cancer in high-risk women has been evaluated in combination with TVUS in a number of retrospective studies, as described in the previous section.[7,118-127]

The National Institutes of Health (NIH) Consensus Statement on Ovarian Cancer recommended against routine screening of the general population for ovarian cancer with serum CA 125. (Refer to the Combined Screening With CA 125 and TVU section of the Ovarian Cancer Screening summary for more information.) The NIH Consensus Statement did, however, recommend that women at inherited risk of ovarian cancer undergo TVUS and serum CA 125 screening every 6 to 12 months, beginning at age 35 years.[131] The Cancer Genetics Studies Consortium task force has recommended that female carriers of a deleterious BRCA1 mutation undergo annual or semiannual screening using TVUS and serum CA 125 levels, beginning at age 25 to 35 years.[9] Both recommendations are based solely on expert opinion and best clinical judgment.

Level of evidence: 5

The need for effective ovarian cancer screening is particularly important for women carrying mutations in BRCA1 and BRCA2, and the mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2), disorders in which the risk of ovarian cancer is high. There is a special sense of urgency for BRCA1 mutation carriers, in whom cumulative lifetime risks of ovarian cancer may exceed 40%.

Thus, it is expected that many new ovarian cancer biomarkers (either singly or in combination) will be proposed as ovarian cancer screening strategies during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, at present, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in women at increased genetic risk.

Before addressing information related to emerging ovarian cancer biomarkers, it is important to consider the several steps that are required to develop and, more importantly, validate a new biomarker. One useful framework is that published by the National Cancer Institute Early Detection Research Network investigators.[132] They indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being screened. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use in the population to be screened. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test, because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific.

Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of ovarian cancer; the remaining nine surgeries would represent false-positive test findings. In general, the ovarian cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable, given the morbidity related to bilateral salpingo-oophorectomy. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of women with advanced ovarian cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in women with early stage disease, which is essential if the screening test is to be clinically useful.

It has been suggested that there are five general phases in biomarker development and validation:

Phase I — Preclinical exploratory studies

• Identify potentially discriminating biomarkers.
• Usually done by comparing gene over- or under-expression in the tumor compared with normal tissue.
• Since many exploratory analyses in large numbers of genes are performed at this stage, one or more may seem to have good discriminating ability between cancers and normal tissue by random chance alone.

Phase 2 — Clinical assay development for clinical disease

• Develop a clinical assay that can be obtained on noninvasively obtained samples (e.g., a blood specimen).
• Often the test targets the protein product of one of the genes found to be of interest in phase I.
• The goal is to describe the performance characteristics of the assay for distinguishing between subjects with and without cancer. At this point, the assay should be in its final configuration and remain stable throughout the following phases.
• IMPORTANT: Since the case subjects in a phase 2 study already have cancer, with assay results obtained at the time of disease diagnosis, one cannot determine if disease can be detected early with a given biomarker.

Phase 3 — Retrospective longitudinal repository studies

• Compare clinical specimens collected from cancer case subjects before their clinical diagnosis with specimens from subjects who have not developed cancer.
• Evaluate, as a function of time before clinical diagnosis, the biomarker’s ability to detect preclinical disease.
• Define the criteria for a positive screening test in preparation for phase 4.
• Explore the influence of other patient characteristics (e.g., age, gender, smoking status, medication use) on the ability of the biomarker to discriminate between those with and without preclinical disease.

Phase 4 — Prospective screening studies

• Determine the operating characteristics of the biomarker-based screening test in a population for which the test is intended.
• Measure the detection rate (number of abnormal tests among all those with the disease) and the false-positive rate (the number of abnormal tests among all those who do not have the disease).
• Evaluate whether the cancers detected by the test are being found at an early stage, a point at which treatment is more likely to be curative.
• Assess whether the test is acceptable in a population of persons for whom it is intended. Will subjects comply with the test schedule and results?

Phase 5 — Cancer control studies

• Ideally, conduct randomized controlled clinical trials in clinically relevant populations, in which one arm is subjected to screening and appropriate intervention if screen-positive, while the other arm is not screened.
• Determine whether the death rate of the cancer being screened for is reduced among those who use the screening test.
• Obtain information about the costs of screening and treatment of screen-detected cancers.

Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.[133]

Ovarian cancer poses a unique challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early stage disease, and clinically-significant early stage cancer may not be grossly visible at the time of exploratory surgery.[134] Consequently, it is likely that some patients will only be reassured that their abnormal test does not indicate the presence of cancer by having their ovaries and fallopian tubes surgically removed and examined microscopically. High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary surgery and induction of premature menopause in false positive women.

An ovarian cancer symptom index for predicting the presence of cancer was evaluated in 75 cases and 254 high-risk controls (BRCA mutation carriers or women with a strong family history of breast and ovarian cancer).[135] Women had a positive symptom index if they reported any of the predefined symptoms (bloating or increase in abdominal size, abdominal or pelvic pain, and difficulty eating or feeling full quickly) more than 12 times per month occurring only within the prior 12 months. CA 125 values greater than 30 U/mL were considered abnormal. The symptom index independently predicted the presence of ovarian cancer, after controlling for CA 125 levels (P < .05). The combination of an elevated CA 125 and a positive symptom index correctly identified 89.3% of the cases. The symptom index correlated with the presence of cancer in 50% of the affected women who did not have elevated CA 125 levels, but 11.8% of the high-risk controls without cancer also had a positive symptom index. The authors suggested that a composite index including both CA 125 and the symptom index had better performance characteristics than either test used alone, and that this strategy might be used as a first screen in a multi-step screening program. Additional test performance validation and determination of clinical utility are required in unselected screening populations.

Level of evidence: 5

A novel modification of CA 125 screening is based on the hypothesis that rising CA 125 levels over time may provide better ovarian cancer screening performance characteristics than simply classifying CA 125 as normal or abnormal based on an arbitrary cut-off value. This has been implemented in the form of the risk of ovarian cancer algorithm (ROCA), an investigational statistical model that incorporates serial CA 125 test results and other covariates into a computation which produces an estimate of the likelihood that ovarian cancer is present in the screened subject. The first report of this strategy, based on reanalysis of 5,550 average-risk women from the Stockholm Ovarian Cancer screening trial, suggested that ovarian cancer cases and controls could be distinguished with 99.7% sensitivity, 83% specificity, and a PPV of 16%. That PPV represents an eightfold increase over the 2% PPV reported with a single measure of CA 125.[136] This report was followed by applying the ROCA to 33,621 serial CA 125 values obtained from the 9,233 average-risk postmenopausal women in a prospective British ovarian cancer screening trial.[137] The area under the receiver operator curve increased from 84% to 93% (P = .01) for ROCA compared with a fixed CA 125 cutoff. These observations represented the first evidence that preclinical detection of ovarian cancer might be improved using this screening strategy. A prospective study of 13,000 normal volunteers aged 50 years and older in England used serial CA 125 values and the ROCA to stratify participants into low, intermediate, and elevated risk subgroups.[138] Each had its own prescribed management strategy, including TVUS and repeat CA 125 either annually (low risk) or at 3 months (intermediate risk). Using this protocol, ROCA was found to have a specificity of 99.8% and a PPV of 19%.

Two prospective trials in England utilized the ROCA. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) randomly assigned normal-risk women to either (1) no screening, (2) annual ultrasound, or (3) multimodal screening (N = 202,638; accrual completed; follow-up ends in 2014), and the U.K. Familial Ovarian Cancer Screening Study (UKFOCSS) targeted high-risk women (accrual completed). There are also two high-risk cohorts using the ROCA under evaluation in the United States: the Cancer Genetics Network ROCA Study (N = 2,500; follow-up complete; analysis underway) and the Gynecologic Oncology Group Protocol 199 (GOG-0199; enrollment complete; follow-up ends in late 2011).[139] Thus, additional data regarding the utility of this currently investigational screening strategy will become available within the next few years.

Level of evidence: 4

A wide array of new candidate ovarian cancer biomarkers has been described during the past decade, including HE4; mesothelin; kallikreins 6, 10, and 11; osteopontin; prostasin; M-CSF; OVX1; lysophosphatidic acid; vascular endothelial growth factor (VEGF) B7-H4; and interleukins 6 and 8, to name just a few.[140-142] These have been singly studied, in combination with CA 125, or in various other permutations. Most of the study populations are relatively small and comprise highly-selected known ovarian cancer cases and healthy controls of the type evaluated in early biomarker development phases 1 and 2. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.

Level of evidence: 5

Initially, mass spectroscopy of serum proteins was combined with complex analytic algorithms to identify protein patterns that might distinguish between ovarian cancer cases and controls.[143] This approach assumed that pattern recognition alone would be sufficient to permit such discrimination, and that identification of the specific proteins responsible for the patterns identified was not required. Subsequently, this strategy has been modified, using similar laboratory tools, to identify finite numbers of specific known serum markers that may be used in place of, or in conjunction with, CA 125 measurements for the early detection of cancer.[144] These studies [142,145] have generally been small case-control studies that are limited by sample size and the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers identified in this fashion have clinical utility for the early detection of ovarian cancer in the unselected clinical population of interest.

Level of evidence: 5

Because individual biomarkers have not met the criteria for an effective screening test, it has been suggested that it may be necessary to combine multiple ovarian cancer biomarkers in order to obtain satisfactory screening test results. This strategy was employed to quantitatively analyze six serum biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA 125), using a multiplex, bead-based platform.[146] A similar assay was available commercially under the trade name OvaSure™ until its voluntary withdrawal from the market by the manufacturer.[Response to FDA Warning Letter]

The cases in this study were newly-diagnosed ovarian cancer patients who had blood collected just prior to surgery: 36 were stage I and II; 120 were stage III and IV. The controls were healthy age-matched individuals who had not developed ovarian cancer within 6 months of blood draw. Neither cases nor controls in this study were well characterized regarding their familial and or genetic risk status, but they have been suggested to comprise a high-risk population. First, 181 controls and 113 ovarian cancer cases were tested to determine the initial panel of biomarkers that best discriminated between cases and controls (training set). The resulting panel was applied to an additional 181 controls and 43 ovarian cancer cases (test set). Pooling both early- and late-stage ovarian cancer across the combined training and test sets, performance characteristics were reported as a sensitivity of 95.3% and a specificity of 99.4%, with a PPV of 99.3% and a negative predictive value of 99.2%, using a formula that assumed an ovarian cancer prevalence of about 50%, as seen in the highly selected research population.

In order to avoid biases which may make test performance appear to be better than it really is, it is worth noting that combining training and test populations in analyses of this sort is generally not recommended.[147] The most appropriate prevalence to use is the disease prevalence in the unselected population to be screened. The prevalence of ovarian cancer in the general population is 1 in 2,500. In a recently published correction to their manuscript,[146] the authors assumed that the prevalence of ovarian cancer in the screened population was 1/2,500 (0.04%) and recalculated the PPV to be only 6.5%. On that basis the investigators have retracted their claim that this test is suitable for population screening. If this test were used in patients at increased risk of ovarian cancer, the actual prevalence in such a target population is likely to be higher than that observed in the general population, but well below the assumed 50% figure used in the published analysis. This revised PPV of 6.5% indicates that approximately 1 in 15 women with a positive test would in fact have ovarian cancer, and only a fraction of those with ovarian cancer would be stages I or II. The remaining 14 positive tests would represent false-positives, and these women would be at risk of exposure to needless anxiety and potentially morbid diagnostic procedures, including bilateral salpingo-oophorectomy.

Viewed in the context of the criteria previously described,[132] this assay would be classified as phase 2 in its development. While this appears to be a promising avenue of ovarian cancer screening research, additional validation is required, particularly in an unselected population representative of the clinical screening population of interest. A recent position statement by the Society of Gynecologic Oncologists regarding this assay indicated “it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an Institutional Review Board.”

Level of evidence: 5

Numerous studies have found that women at inherited risk of breast and ovarian cancer have a decreased risk of ovarian cancer following risk-reducing salpingo-oophorectomy (RRSO). A retrospective study of 551 women with disease-associated BRCA1 or BRCA2 mutations found a significant reduction in risk of breast cancer (HR, 0.47; 95% CI, 0.29–0.77) and ovarian cancer (HR, 0.04; 95% CI, 0.01–0.16) after bilateral oophorectomy.[69] A prospective single-institution study of 170 women with BRCA1 or BRCA2 mutations showed a similar trend.[70] With oophorectomy, the HR was 0.15 (95% CI, 0.02–1.31) for ovarian, fallopian tube, or primary peritoneal cancer, and 0.32 (95% CI, 0.08–1.2) for breast cancer; the HR for either cancer was 0.25 (95% CI, 0.08–0.74). A prospective multicenter study of 1,079 women who were followed for a median of 30 to 35 months found that RRSO is highly effective in reducing ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. This study also showed that RRSO was associated with reductions in breast cancer risk in both BRCA1 and BRCA2 mutation carriers; however, the breast cancer risk reduction was more pronounced in BRCA2 carriers (HR, 0.28; 95% CI, 0.08–0.92).[71] In a case-control study in Israel, bilateral oophorectomy was associated with reduced ovarian/peritoneal cancer risks (OR, 0.12; 95% CI, 0.06–0.24).[148] 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 risk of ovarian or fallopian tube cancer (HR, 0.21; 95% CI, 0.12–0.39). The study also found a significant reduction in risk of breast cancer (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).[72]

In addition to a reduction in risk of ovarian and breast cancer, RRSO may also significantly improve overall survival (OS) and breast and ovarian cancer-specific survival. A prospective cohort study of 666 women with germline mutations in BRCA1 and BRCA2 found an HR for overall mortality of 0.24 (95% CI, 0.08–0.71) in women who had RRSO compared with women who did not.[149] This study provides the first evidence to suggest a survival advantage among women undergoing RRSO.

Studies on the degree of risk reduction afforded by RRSO have begun to clarify the spectrum of occult cancers discovered at the time of surgery. Primary fallopian tube cancers, primary peritoneal cancers, and occult ovarian cancers have all been reported. Several case series have reported a prevalence of malignant findings among mutation carriers undergoing risk-reducing oophorectomy. Among studies with 50 or more subjects, prevalence ranged from 2.3% to 11%.[7,70,150-156] Some of the variation in prevalence is likely due to differences in surgical technique, pathologic handling of the tissues, and age at RRSO. In addition to occult cancers, premalignant lesions have also been described in fallopian tube tissue removed for prophylaxis. In one series of 12 women with BRCA1 mutations undergoing risk-reducing surgery, 11 had hyperplastic or dysplastic lesions identified in the tubal epithelium. In several of the cases the lesions were multifocal.[157] These pathologic findings are consistent with the identification of germline BRCA1 and BRCA2 mutations in women affected with both tubal and primary peritoneal cancers.[154,158-163] One study suggests a causal relationship between early tubal carcinoma, or tubal intraepithelial carcinoma, and subsequent invasive serous carcinoma of the fallopian tube, ovary or peritoneum.[164] (Refer to the Pathology of Ovarian Cancer section of this summary for more information.)

These findings support the inclusion of fallopian tube cancers, which account for less than 1% of all gynecologic cancers in the general population, as a component of hereditary ovarian cancer syndrome and necessitate removal of the fallopian tubes at the time of risk-reducing surgery. There is clear evidence that RRSO must include routine collection of peritoneal washings and careful adherence to comprehensive pathologic evaluation of the entire adnexa using serial sectioning.[156,165,166]

The peritoneum, however, appears to remain at low risk for the development of a Müllerian-type adenocarcinoma, even after oophorectomy.[167-171] Of the 324 women from the Gilda Radner Familial Ovarian Cancer Registry who underwent risk-reducing oophorectomy, six (1.8%) subsequently developed primary peritoneal carcinoma. No period of follow-up was specified.[172] Among 238 individuals in the Creighton Registry with BRCA1/BRCA2 mutations who underwent risk-reducing oophorectomy, five subsequently developed intra-abdominal carcinomatosis (2.1%). Of note, all five of these women had BRCA1 mutations.[173] A study of 1,828 women with a BRCA1 or BRCA2 mutation found a 4.3% risk of primary peritoneal cancer at 20 years after RRSO.[174]

Given the current limitations of screening for ovarian cancer and the high risk of the disease in BRCA1 and BRCA2 mutation carriers, NCCN Guidelines recommend RRSO between the ages of 35 and 40 years or upon completion of childbearing, as an effective risk-reduction option. Optimal timing of RRSO must be individualized, but evaluating a woman's risk of ovarian cancer based on mutation status can be helpful in the decision-making process. In a large study of U.S. BRCA1 and BRCA2 families, age-specific cumulative risk of ovarian cancer at age 40 years was 4.7% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers.[175] In a combined analysis of 22 studies of BRCA1 and BRCA2 mutation carriers, risk of ovarian cancer for BRCA1 mutation carriers increases most sharply from age 40 years to age 50 years, while for BRCA2 mutation carriers the risk is low before age 50 years, but increases sharply from age 50 years to age 60 years.[176] In a population-based study of BRCA mutations in ovarian cancer patients, patients with BRCA2 mutations had a significantly later age of onset than patients with BRCA1 mutations (57.3 years [range, 40–72] vs. 52.6 years [range, 31–78]).[177] In summary, women with BRCA1 mutations may consider RRSO for ovarian cancer risk reduction at a somewhat earlier age than women with BRCA2 mutations; however, women with BRCA2 mutations may still consider early RRSO for breast cancer risk reduction.

Studies indicate that removal of the uterus is not necessary as a risk-reducing procedure. No increased BRCA mutation prevalence was seen among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.[178,179] However, small studies have reported that uterine papillary serous carcinoma may be part of the BRCA-associated spectrum of disease.[180-182] The cumulative risk of endometrial cancer among BRCA mutation carriers with ER-positive breast cancer treated with tamoxifen may be an additional factor to consider when counseling this population about prophylactic hysterectomy.[183,184] Hysterectomy might also be considered in young, unaffected BRCA mutation carriers who may want to use HRT but for whom hysterectomy would offer a simplified regimen of estrogen alone. In counseling a BRCA mutation carrier about optimal risk-reducing surgical options, aggregate data suggest that the risk from residual tubal tissue following RRSO is the least compelling reason to suggest hysterectomy. Therefore, in the absence of tamoxifen use or other underlying uterine or cervical problems, hysterectomy is not a routine component of RRSO for BRCA carriers.

For women who are premenopausal at the time of surgery, the symptoms of surgical menopause (e.g., hot flashes, mood swings, weight gain, and genitourinary complaints) can cause a significant impairment in their quality of life. To reduce the impact of these symptoms, providers have often prescribed a time-limited course of systemic HRT after surgery. (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)

Studies have examined the effect of RRSO on quality of life (QOL). One study examined 846 high-risk women of whom 44% underwent RRSO and 56% had periodic screening.[185] Of the 368 BRCA1/BRCA2 mutation carriers, 72% underwent RRSO. No significant differences were observed in QOL scores (as assessed by the Short Form-36) between those with RRSO or screening or compared with the general population; however, women with RRSO had fewer breast and ovarian cancer worries (P < .001), more favorable cancer risk perception (P < .05) but more endocrine symptoms (P < .001) and worse sexual functioning (P < .05). Of note, 37% of women used HRT following RRSO, although 62% were either perimenopausal or postmenopausal.[185] Researchers then examined 450 premenopausal high-risk women who had chosen either RRSO (36%) or screening (64%). Of those in the RRSO group, 47% used HRT. HRT users (n = 77) had fewer vasomotor symptoms than nonusers (n = 87; P < .05), but they had more vasomotor symptoms than women in the screening group (n = 286). Likewise, women who underwent RRSO and used HRT had more sexual discomfort due to vaginal dryness and dyspareunia than those in the screening group (P < .01). Therefore, while such symptoms are improved via HRT use, HRT is not completely effective and additional research is warranted to address these important issues.

The long-term nononcologic effects of RRSO in BRCA1/BRCA2 mutation carriers are unknown. In the general population, RRSO has been associated with increased cardiovascular disease, dementia, death from lung cancer, and overall mortality.[186-190] When age at oophorectomy has been analyzed, the most detrimental effect has been seen in women who undergo RRSO before age 45 years and do not take estrogen-replacement therapy.[186] BRCA1/BRCA2 mutation carriers undergoing RRSO may have an increased risk of metabolic syndrome.[191] RRSO has also been associated with an improvement in short-term mortality in this population.[149] The benefits related to cancer risk reduction following RRSO are clear, but further data on the long-term nononcologic risks and benefits are needed.

Bilateral salpingectomy has been suggested as an interim procedure to reduce risk in BRCA mutation carriers.[192] There are no data available on the efficacy of salpingectomy as a risk-reducing procedure. The procedure preserves ovarian function and spares the premenopausal patient the adverse effects of a premature menopause. The procedure can be performed using a minimally invasive approach, and a subsequent bilateral oophorectomy could be deferred until the patient approaches menopause. While the data make a compelling argument that some pelvic serous cancers in BRCA mutation carriers originate in the fallopian tube, clearly, some cancers arise in the ovary. Furthermore, bilateral salpingectomy could give patients a false sense of security that they have eliminated their cancer risk as completely as if they had undergone a bilateral salpingo-oophorectomy. A small study of 14 young BRCA mutation carriers documented the procedure as feasible.[193] However, efficacy and impact on ovarian function was not assessed in this study. Future prospective trials are needed to establish the validity of the procedure as a risk-reducing intervention.

OCs have been shown to have a protective effect against ovarian cancer in the general population.[194] Several studies including a large, multicenter case-control study showed a protective effect,[103,195-198] while one population-based study from Israel failed to demonstrate a protective effect.[199]

There has been great interest in determining whether a similar benefit extends to women who are at increased genetic risk of ovarian cancer. A multicenter study of 799 ovarian cancer patients with BRCA1 or BRCA2 mutations, and 2,424 control patients without ovarian cancer but with a BRCA1 or BRCA2 mutation, showed a significant reduction in ovarian cancer risk with use of OCs (OR, 0.56; 95% CI, 0.45–0.71). Compared to never use of OCs, duration up to 1 year was associated with an OR of 0.67 (95% CI, 0.50–0.89). The OR for each year of OC use was 0.95 (95% CI, 0.92–0.97) with a maximum observed protection at 3 years to 5 years of use.[198] This study included women from a prior study by the same authors and confirmed the results of that prior study.[103] A population-based case-control study of ovarian cancer did not find a protective benefit of OC use in BRCA1 or BRCA2 mutation carriers, (OR, 1.07 for ≥5 years of use), though they were protective, as expected, among noncarriers (OR, 0.53 for ≥5 years of use).[199] A small population-based case-control study of 36 BRCA1 mutation carriers, however, observed a similar, protective effect in both mutation carriers and noncarriers (OR, approximately 0.5).[197] A multicenter study of subjects drawn from numerous registries observed a protective effect of OCs among the 147 BRCA1 or BRCA2 mutation carriers, with ovarian cancer compared with the 304 matched mutation carriers without cancer (OR, 0.62 for ≥6 years of use).[196] Finally, a meta-analysis of 18 studies including 13,627 BRCA mutation carriers, of whom 2,855 had breast cancer and 1,503 had ovarian cancer, reported a significantly reduced risk of ovarian cancer (summary relative risk, 0.50; 95% CI, 0.33–0.75) associated with OC use. The authors also reported significantly greater risk reductions with longer duration of OC use (36% reduction in risk for each additional 10 years of OC use). There was no association with breast cancer risk and use of OC pills formulated after 1975.[99]

Level of evidence: 3aii

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

It has been suggested that incessant ovulation, with repetitive trauma and repair to the ovarian epithelium, increases the risk of ovarian cancer. In epidemiologic studies in the general population, physiologic states that prevent ovulation have been associated with decreased risk of ovarian cancer. It has also been suggested that chronic overstimulation of the ovaries by luteinizing hormone (LH) plays a role in ovarian cancer pathogenesis.[200] Most of these data derive from studies in the general population, but some information suggests the same is true in women at high risk due to genetic predisposition.

Among the general population, parity decreases the risk of ovarian cancer by 45% compared with nulliparity. Subsequent pregnancies appear to decrease ovarian cancer risk by 15%.[201] Earlier studies of women with BRCA1/BRCA2 mutations showed that parity decreases the risk of ovarian cancer.[199,202] In a large case-control study, parity was associated with a significant reduction in ovarian cancer risk in women with BRCA1 mutations, OR 0.67 (CI, 0.46–0.96).[198] For each birth, BRCA1 mutation carriers had an OR of 0.87 (CI, 0.79–0.95). In this same study, parity was associated with an increase in ovarian cancer risk in BRCA2 mutation carriers; however, there was no significant trend for each birth, OR 1.08 (CI, 0.90–1.29). Further studies are necessary to define the association of parity and risk of ovarian cancer in BRCA2 mutation carriers, but for BRCA1 carriers, each live birth significantly decreases risk of ovarian cancer, as it does in sporadic ovarian cancer.

In the general population, breast feeding is associated with a decrease in ovarian cancer risk.[203] In BRCA mutation carriers, data are limited. One study found no protective effect with breast feeding.[202] A case-control study among women with BRCA1 or BRCA2 mutations demonstrates a significant reduction in risk of ovarian cancer (OR, 0.39) for women who have had a tubal ligation. This protective effect was confined to those women with mutations in BRCA1 and persists after controlling for OC use, parity, history of breast cancer, and ethnicity.[195] A case-control study of ovarian cancer in Israel found a 40% to 50% reduced risk of ovarian cancer among women undergoing gynecologic surgeries (tubal ligation, hysterectomy, unilateral oophorectomy, ovarian cystectomy, excluding bilateral oophorectomy).[148] The mechanism of protection is uncertain. Proposed mechanisms of action include decreased blood flow to the ovary, resulting in interruption of ovulation and/or ovarian hormone production; occlusion of the fallopian tube, thus blocking a pathway for potential carcinogens; or a reduction in the concentration of uterine growth factors that reach the ovary.[204] (Refer to the PDQ summary on Prevention of Ovarian Cancer for information relevant to the general population.)

Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.

There are data to suggest that men with BRCA gene mutations have an increased risk of various cancers including male breast cancer and prostate cancer (see Table 4).[177,205-209] However, clinical guidelines to manage male carriers with BRCA mutations are based on consensus statements and expert opinions because information is limited.[3,210,211]

There have been suggestions that BRCA2-associated prostate cancers are associated with aggressive disease phenotype.[212-217] Specifically, two recent studies have reported the median survival of male BRCA2 carriers with prostate cancer in the range of 4 to 5 years.[215,216] Furthermore, mortality rate was reported as 60% at 5 years in one of these studies, compared with 2% to 8% reported in the recent European [218] and North American [219] PSA screening trials after comparable follow-up. The data have been more limited in BRCA1-associated prostate cancers, however a number of recent studies have suggested an aggressive disease phenotype as well.[212,214,217,220]

The benefits of PSA screening in BRCA carriers are currently unknown; however, there have been suggestions (based on very small studies) that PSA levels at prostate cancer diagnosis may be higher in carriers than non-carriers.[221,222] These findings suggest that PSA screening may be of potential utility in men with BRCA mutations, especially in view of the aggressive phenotype. Preliminary results of the IMPACT PSA screening study reported a positive predictive value of 47.6% in 21 BRCA2 carriers undergoing biopsy on the basis of elevated PSA.[223] Since screening these men detected clinically significant prostate cancer, the authors suggest that these findings provide rationale for continued screening in such men; however, a survival benefit from such screening has not been shown. Ultimately, it is possible that information on BRCA mutation status in men may inform optimal screening and treatment strategies. Furthermore, recent data that the presence of a germline BRCA2 mutation is an independent prognostic factor for survival in prostate cancer led these authors to conclude that active surveillance may not be the optimal management strategy due to the aggressive disease phenotype.[216]

Screening for male breast cancer in BRCA mutation carriers as suggested by the NCCN clinical practice guidelines [3] includes breast self-exam training and education, clinical breast exam every 6 to 12 months, and consideration of a baseline mammogram. Annual mammogram is a consideration with the presence of gynecomastia or parenchymal/glandular breast density on baseline study. Furthermore, screening guidelines for prostate cancer include PSA screening and digital rectal exam on an annual basis starting at age 40 years.[224]

Refer to the Prenatal diagnosis and preimplantation genetic diagnosis section in the Psychosocial Issues in Inherited Breast Cancer Syndromes section of this summary for more information.

The distinct features of BRCA1-associated breast tumors are important in prognosis. In addition, there appears to be accelerated growth in BRCA1-associated breast cancer, which is suggested by high-proliferation indices and absence of the expected correlation of tumor size with lymph node status.[225] These pathological features are associated with a worse prognosis in breast cancer, and early studies suggested that BRCA1 mutation carriers with breast cancer may have a poorer prognosis compared with sporadic cases.[226-228] These studies particularly noted an increase in ipsilateral and contralateral second primary breast cancers in BRCA1 mutation carriers.[229,230] A retrospective cohort study found a 47.4% incidence of contralateral cancer 25 years after the first breast cancer. BRCA1 carriers had a risk 1.6 times higher than BRCA2 carriers, and risk was higher when the first breast cancer occurred before age 40 years.[231] A retrospective cohort study of 496 Ashkenazi Jewish (AJ) breast cancer patients from two centers compared the relative survival among 56 BRCA1/BRCA2 mutation carriers followed for a median of 116 months. BRCA1 mutations were independently associated with worse disease-specific survival. The poorer prognosis was not observed in women who received chemotherapy.[232] A large population-based study of incident cases of breast cancer among women in Israel failed to find a difference in OS for carriers of BRCA1 founder mutations (n = 76) compared with noncarriers (n = 1,189).[233] Similar findings were seen in a European cohort with no differences in disease-free survival in BRCA1-associated breast cancers.[234]

A group of researchers reported the results of BRCA1/2 testing in 77 unselected patients with triple-negative breast cancer. Of these, 15 (19.5%) had either a germline BRCA1 (n = 11; 14%) or BRCA2 (n = 3; 4%) mutation or a somatic BRCA1 (n = 1) mutation. The median age at cancer diagnosis was 45 years in BRCA1 mutation carriers and 53 years in noncarriers (P = .005). Interestingly, this study also demonstrated a lower risk of relapse in those with BRCA1 mutation–associated triple-negative breast cancer than in nonmutated triple-negative breast cancer, although this study was limited by its size.[235] A second study examining clinical outcome in BRCA1-associated verus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one BRCA1 mutation carrier received chemotherapy.[236]

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

Early studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[233,237-239] A small study reported statistically significant higher OS in BRCA2 mutation carriers with metastatic breast cancer.[234]

A growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. Intact BRCA1 and BRCA2 are important in DNA repair by homologous recombination. Preclinical studies of BRCA1 and BRCA2 deficient cell lines have suggested increased sensitivity to drugs which cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C.[240,241] Conversely, intact BRCA1 may be important for spindle poisons, such as taxanes, to be effective.[242,243] Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.[244,245]

Evidence of the role of BRCA1/BRCA2 mutations in humans is preliminary. A number of small studies have suggested increased clinical response rates, particularly in BRCA1 mutation carriers, but design limitations make it difficult to use these studies to guide clinical recommendations. A small study reported statistically significant higher sensitivity to first-line treatment in BRCA2 mutation carriers with metastatic breast cancer compared with those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for BRCA1 carriers with metastatic breast cancer.[234]

Retrospective and prospective studies [246-250] have suggested a higher-than-expected response rate to chemotherapy in BRCA1 mutation carriers receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin.[248] Several studies have been published regarding the Polish experience on the use of preoperative chemotherapy in BRCA1 mutation carriers. The largest report [248] includes data on 102 BRCA1 mutation carriers of which 51 were described in two prior studies.[251,246] Women were identified from a registry of 6,903 patients. Those with a Polish founder mutation in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial of whom 10 had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%), 25 received doxorubicin and docetaxel with two pCR (8%), and 51 received doxorubicin and cyclophosphamide with 11 pCR (22%). To place this in the context of other available data, several retrospective studies in BRCA1 and BRCA2 mutation carriers typically treated with anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy,[247,249] particularly in BRCA1 mutation carriers.[250] A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both BRCA1 mutation carriers in the study had a pCR.[252]

Thus, the preclinical and clinical data suggesting improved chemotherapy response rates in BRCA1-associated breast cancer are consistent with the emerging understanding of BRCA1 function in DNA-damage response and cell-cycle regulation. While these findings raise the possibility that germline status may influence treatment choices, there is insufficient evidence at this time to support treating mutation carriers with different regimens.

Another specific process to exploit in BRCA1/BRCA2-deficient tumors is the poly (ADP-ribose) polymerase (PARP) pathway. Whereas BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous recombination, PARP is involved in the repair of single-stranded breaks by base excision repair. It was hypothesized that inhibiting base excision repair in BRCA1 or BRCA2 deficient cells would lead to enhanced cell death as two separate repair mechanisms would be compromised—the concept of synthetic lethality. In vitro studies have shown that PARP inhibition kills BRCA mutant cells with high specificity.[253,254]

PARP inhibitors quickly entered clinical trials. A phase I study of an oral PARP inhibitor called olaparib has demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancer.[255] Phase II trials in breast cancer have confirmed tolerability and efficacy of olaparib in mutation carriers.[256,257] Two sequential cohorts of 27 patients, each receiving 400 mg twice daily of olaparib and 100 mg twice daily of olaparib, respectively, were examined. The women had received a median of three prior chemotherapeutic regimens. Responses were seen in both groups. In the 400 mg twice daily group, 41% (11/27) of patients had a RECIST-defined response, and another 44% (12/27) had stable disease. In the 100 mg twice daily group, 22% (6/27) had responses, and 44% (12/27) had stable disease. Although the two doses levels cannot be directly compared as they were not randomized, more responses were seen in the higher dose cohort. Several other PARP inhibitors are in development.

Preclinical models suggest that the combination of PARP inhibitors and chemotherapy may be synergistic;[258,259] however, such synergy may come at the expense of toxicity. The results of ongoing and recently completed clinical trials are awaited with interest.

(Refer to the Systemic therapy section in the Ovarian Cancer Treatment Strategies section of this summary for more information.)

While lumpectomy plus radiation therapy has become standard local-regional therapy for women with early-stage breast cancer, its use in women with a hereditary predisposition for breast cancer who do not choose immediate bilateral mastectomy is more complicated. Initial concerns about the potential for therapeutic radiation to induce tumors or cause excess toxicity in BRCA1/BRCA2 mutation carriers were unfounded.[260-262] Despite this, an increased rate of second primary breast cancer exists, which could impact treatment decisions.

Due to the established increased risk of second primary breast cancers, which may be up to 60% in younger women with BRCA1 mutations,[231] some BRCA1/BRCA2 mutation carriers choose bilateral mastectomy at the time of their initial cancer diagnosis. (Refer to the Contralateral breast cancer in BRCA mutation carriers section of this summary for more information.) However, several studies support use of breast conservation therapy as a reasonable option to treat the primary tumor.[263-265] The risk of ipsilateral recurrence at 10 years has been estimated to be between 10% to 15% and is similar to that seen in noncarriers.[231,263-266] Studies with longer follow-up demonstrate risks of ipsilateral breast events at 15 years as high as 24%, largely due to ipsilateral second breast cancers (rather than relapse of the primary tumor).[263,265] Although not entirely consistent across studies, radiation therapy, chemotherapy, oophorectomy, and tamoxifen are associated with a decreased risk of ipsilateral events,[263-266] as is the case in sporadic breast cancer. The risk of contralateral breast cancer does not appear to be different in women undergoing breast conservation therapy versus unilateral mastectomy, suggesting no added risk of contralateral breast cancer from scattered radiation.[263] Finally, no difference in OS at 15 years has been seen between BRCA1/BRCA2 mutation carriers choosing breast conservation therapy and those choosing mastectomy.[263]

Level of evidence: 3a

As early as 1995, the Breast Cancer Linkage Consortium estimated the risk of contralateral breast cancer (CBC) in BRCA1 mutation carriers to be as high as 60% by age 60 years.[267] This report has been followed by several retrospective studies of various cohorts of women with hereditary patterns of breast cancer in both the United States and Europe. One retrospective cohort study reviewed the records of 91 AJ women diagnosed with breast cancer before the age of 42 years, 30 of whom had a deleterious BRCA1 or BRCA2 mutation.[268] At a median follow-up of 63 months, the rate of CBC was 40% in the mutation carriers compared with 8.2% among noncarriers. Carriers had a shorter median interval between cancers than noncarriers (36 months vs. 63.9 months). The same group reported 5-, 10-, and 15-year probabilities of CBC of 11.9%, 37.6% and 53.2%, respectively, among 87 mutation carriers.[269] Rates of CBC in this clinical cohort did not differ by mutation type (BRCA1 vs. BRCA2) or by age at first diagnosis. A case-control study from the Netherlands compared rates of CBC between 49 women with BRCA1-related breast cancer and 196 breast cancer cases not known to have a BRCA1/BRCA2 mutation (sporadic controls).[226] At 5 years of follow-up, rates of CBC were 20.4% among mutation carriers versus 5.6% among the controls. In an expanded cohort of BRCA1-related breast cancer patients, the risk of CBC was inversely correlated with age at first diagnosis, with the majority of cases of CBC occurring among women whose first breast cancer was diagnosed at or before age 50 years.[270] A similar analysis matching 28 BRCA2 mutation–positive cases with 112 sporadic controls found a fivefold increase in CBC among cases (25% vs. 4.5%).[271] A larger study of members of BRCA1/BRCA2 families in the Netherlands reported similar 10-year risks of CBC for women from BRCA1 and BRCA2 families (34.2% and 29.2%).[272] In another study, 127 patients with early-onset breast cancer (aged ≤42 years) who had been treated with breast-conserving therapy, were genotyped for mutations in BRCA1 and BRCA2. At a median follow-up of 12 years, the rate of contralateral breast cancer among the 22 mutation-positive patients was 42% compared with 9% in the noncarriers.[229] A similar analysis from the Institut Curie in Paris reported a rate of CBC of 37% among mutation carriers compared with 7.3% in noncarriers at a median follow-up of 8.75 years.[273]

In a larger cohort of breast cancer patients (n = 336) from families with documented BRCA1/BRCA2 mutations and 9.2 years of follow-up, the rate of CBC was 28.9% at a mean interval of 5.5 years. Prior oophorectomy was associated with a 59% reduction in the risk of CBC.[274] Another case-control study of mutation carriers and noncarriers identified through ascertainment of women with bilateral breast cancer found that systemic adjuvant chemotherapy reduced CBC risk among mutation carriers (RR, 0.5; 95% CI, 0.2–1.0). Tamoxifen was associated with a nonsignificant risk reduction (RR, 0.7; 95% CI, 0.3–1.8). Similar risk reduction was seen in noncarriers; however, given the higher absolute CBC risk in carriers, there is potentially a greater impact of adjuvant treatment in risk reduction.[266] A high concordance in estrogen receptor status and tumor grade was reported among women from a registry of BRCA1/BRCA2 carriers who had bilateral breast cancer.[275] The German Consortium for Hereditary Breast and Ovarian Cancer estimated the risk of CBC in members of BRCA1 and BRCA2 mutation–positive families. At 25 years following the first breast cancer, the risk of CBC was close to 50% in both BRCA1 and BRCA2 families. The risk was also inversely correlated with age in this study, with the highest risks seen in women whose first breast cancer was before age 40 years. [231] A comparison of 655 women with BRCA1/BRCA2 mutations undergoing breast-conserving therapy versus those undergoing mastectomy noted that both treatment groups experienced high rates of CBC, exceeding 50% by 20 years of follow up. Rates were significantly higher among women with BRCA1 mutations compared with those with BRCA2 mutations, and among women whose first breast cancer occurred at or before age 35 years.[263] The WECARE study, a large population-based nested case-control study of CBC, reported a 10-year risk of CBC among BRCA1/BRCA2 mutation carriers of 15.9%, compared with a risk of 4.9% among noncarriers. Risks were also inversely related to age at first diagnosis in this study.[276]

Thus, despite differences in study design, study sites, and sample sizes, the data on CBC among women with BRCA1/BRCA2 mutations show several consistent findings:

• The risk at all time points studied is significantly higher than that among sporadic controls.
• The risk continues to rise with time since first breast cancer, and reaches 20% to 30% at 10 years of follow up, and 40% to 50% at 20 years in most studies.
• Some, but not all, studies show an excess of CBC among BRCA1 carriers compared with BRCA2 carriers.
• The risk of CBC is greatest among women whose first breast cancer occurs at a young age.

Refer to the Chemoprevention section of this summary for information about the use of tamoxifen as a risk-reduction strategy for CBC in BRCA mutation carriers.

Despite generally poor prognostic factors, several studies have found an improved survival among ovarian cancer patients with BRCA mutations.[277-283] A nationwide, population-based, case-control study in Israel found 3-year survival rates to be significantly better for ovarian cancer patients with BRCA founder mutations, compared with controls.[278] Five-year follow-up in the same cohort showed improved survival for carriers of both BRCA1 and BRCA2 mutations (54 months) versus noncarriers (38 months), which was most pronounced for women with stages III and IV ovarian cancer and for women with high-grade tumors.[284] In a U.S. study of AJ women with ovarian cancer, those with BRCA mutations had a longer median time to recurrence and an overall improved survival, compared with both AJ women with ovarian cancer who did not have a BRCA mutation and two large groups of advanced-stage ovarian cancer clinical trial patients.[282] In a retrospective U.S. hospital-based study, Ashkenazi BRCA mutation carriers had a better response to platinum-based chemotherapy, as measured by response to primary therapy, disease-free survival, and OS, compared with sporadic cases.[280] Similarly, a significant survival advantage was seen in a case-control study among women with non-AJ BRCA mutations.[285] A study from the Netherlands also showed a better response to platinum-based primary chemotherapy in 112 BRCA1/2 carriers than in 220 sporadic ovarian cancer patients.[286] A U.S. population-based study showed improvement in OS in BRCA2, but not in BRCA1, carriers.[287] However, the study included only 12 BRCA2 mutation carriers and 20 BRCA1 mutation carriers. Significantly better OS and progression-free survival were observed in 29 BRCA2 mutation–positive high-grade serous ovarian cancer cases (20 germline, 9 somatic) from The Cancer Genome Atlas study compared with BRCA mutation–negative cases. BRCA1 mutations were not significantly associated with prognosis.[288] Furthermore, a pooled analysis of 26 observational studies that included 1,213 BRCA mutation carriers and 2,666 noncarriers with epithelial ovarian cancer showed more favorable survival in mutation carriers (BRCA1: HR, 0.73; 95% CI, 0.64–0.84; P < .001; BRCA2: HR, 0.49; 95% CI, 0.39–0.61; P < .001).[289] Thus, 5-year survival in both BRCA1 and BRCA2 carriers with epithelial ovarian cancers was better than that observed in noncarriers, with BRCA2 carriers having the best prognosis. A study in Japanese patients found a survival advantage in stage III BRCA1-associated ovarian cancers treated with cisplatin regimens compared with nonhereditary cancers treated in a similar manner.[281]

In contrast, several studies have not found improved OS among ovarian cancer patients with BRCA mutations.[227,290-292] A population-based study from Sweden noted an initial survival advantage in BRCA1-associated cases, but this advantage did not persist after 3 or 4 years.[227] Similarly, a case-control study from the Netherlands found an improvement in short-term (up to 5 years) survival among women with familial ovarian cancer compared with sporadic controls, but no difference in longer-term survival.[290] A study from the United Kingdom found a worse survival rate in ovarian cancer patients with a family history of ovarian cancer, whether or not they had a BRCA mutation, compared with sporadic controls.[291] Finally, a case-control study at the University of Iowa failed to find any survival advantage for women with BRCA1 inactivation, whether by germline mutation, somatic mutation, or BRCA1 promoter silencing.[292] In this study, however, cases (women with BRCA1 inactivation) were matched to controls on several variables, including tumor grade and p53 status, thus possibly minimizing any differences between the two groups.

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

PARP pathway inhibitors are currently being studied for the treatment of BRCA1- or BRCA2-deficient ovarian cancers. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section in the Breast Cancer Treatment Strategies section of this summary for more information about PARP inhibitors.) While PARP is involved in the repair of single-stranded breaks by base excision repair, BRCA1 and BRCA2 are active in the repair of double-stranded DNA breaks by homologous combination. Therefore, it was hypothesized that inhibiting base excision repair with PARP inhibition in BRCA1- or BRCA2-deficient tumors leads to enhanced cell death, as two separate repair mechanisms would be compromised – the concept of synthetic lethality.

A phase I study of olaparib, an oral PARP inhibitor, demonstrated tolerability (with minimal side effects) and activity in BRCA1 and BRCA2 mutation carriers with ovarian, breast, and prostate cancers.[255] A phase II trial of two different doses of olaparib demonstrated tolerability and efficacy in recurrent ovarian cancer patients with BRCA1 or BRCA2 mutations.[257] The overall response rate was 33% (11 of 33 patients) in the cohort receiving 400 mg twice daily and 13% (3 of 24 patients) in the cohort receiving 100 mg twice daily. The most frequent side effects were mild nausea and fatigue. Olaparib appears to be most effective in patients who are platinum-sensitive.[293] In addition to ovarian cancer patients with germline BRCA1 or BRCA2 mutations, PARP inhibitors also may be useful in ovarian cancer patients with somatic BRCA1 or BRCA2 mutations or with epigenetic silencing of the genes.[294] The results of ongoing and recently completed clinical trials are awaited with interest.

Level of evidence: 3dii

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