Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version
Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers
The proportion of individuals carrying a pathogenic variant who will manifest a certain disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 4. For adult-onset diseases, penetrance is usually described by the individual carrier's age, sex, and organ site. For example, the penetrance for breast cancer in female carriers of BRCA1 pathogenic variants is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual carrier's risk of cancer involves some level of imprecision.
Throughout this summary, we discuss studies that report on relative and absolute risks. These are two important but different concepts. Relative risk (RR) refers to an estimate of risk relative to another group (e.g., risk of an outcome like breast cancer for women who are exposed to a risk factor relative to the risk of breast cancer for women who are unexposed to the same risk factor). RR measures that are greater than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is higher than the risk for those captured in the denominator (i.e., the unexposed). RR measures that are less than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is lower than the risk for those captured in the denominator (i.e., the unexposed). Measures with similar relative interpretations include the odds ratio (OR), hazard ratio, and risk ratio.
Absolute risk measures take into account the number of people who have a particular outcome, the number of people in a population who could have the outcome, and person-time (the period of time during which an individual was at risk of having the outcome), and reflect the absolute burden of an outcome in a population. Absolute measures include risks and rates and can be expressed over a specific time frame (e.g., 1 year, 5 years) or overall lifetime. Cumulative risk is a measure of risk that occurs over a defined time period. For example, overall lifetime risk is a type of cumulative risk that is usually calculated on the basis of a given life expectancy (e.g., 80 or 90 years). Cumulative risk can also be presented over other time frames (e.g., up to age 50 years).
Large relative risk measures do not mean that there will be large effects in the actual number of individuals at a population level because the disease outcome may be quite rare. For example, the relative risk for smoking is much higher for lung cancer than for heart disease, but the absolute difference between smokers and nonsmokers is greater for heart disease, the more-common outcome, than for lung cancer, the more-rare outcome.
Therefore, in evaluating the effect of exposures and biological markers on disease prevention across the continuum, it is important to recognize the differences between relative and absolute effects in weighing the overall impact of a given risk factor. For example, the magnitude is in the range of 30% (e.g., ORs or RRs of 1.3) for many breast cancer risk factors, which means that women with a risk factor (e.g., alcohol consumption, late age at first birth, oral contraceptive use, postmenopausal body size) have a 30% relative increase in breast cancer in comparison with what they would have if they did not have that risk factor. But the absolute increase in risk is based on the underlying absolute risk of disease. Figure 5 and Table 2 show the impact of a relative risk factor in the range of 1.3 on absolute risk. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.) As shown, women with a family history of breast cancer have a much higher benefit from risk factor reduction on an absolute scale.[1]
With the increasing use of multigene panel tests, a framework for cancer risk management among individuals with pathogenic variants detected in novel genes has been described [2] that incorporates data on age-specific, lifetime, and absolute cancer risks. The framework suggests initiating screening in these individuals at the age when their 5-year cancer risk approaches that at which screening is routinely initiated for women in the general population (approximately 1% for breast cancer in the United States). As a result, the age at which to begin screening will vary depending on the gene. (Refer to the Multigene [panel] testing section in the Introduction section of this summary for more information on multigene panel tests.)
References
- Quante AS, Herz J, Whittemore AS, et al.: Assessing absolute changes in breast cancer risk due to modifiable risk factors. Breast Cancer Res Treat 152 (1): 193-7, 2015. [PUBMED Abstract]
- Tung N, Domchek SM, Stadler Z, et al.: Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 13 (9): 581-8, 2016. [PUBMED Abstract]
Genes Associated With Breast and/or Gynecologic Cancer Susceptibility
Several genes are found to be associated with the development of breast and/or gynecologic cancers. These genes are categorized as high-penetrance, moderate-penetrance, and low-penetrance in this summary. The high- and moderate-penetrance genes are summarized in Table 3. Low-penetrance genes and loci primarily include polymorphisms that have been associated with cancer susceptibility. (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes, Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer, and Low-Penetrance Genes and Loci sections of this summary for more information.)
High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes
BRCA1 and BRCA2
Introduction
Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancers. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. 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 the paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland.[1,2] It is now known that the cancer in some of these families can be explained by specific pathogenic variants in single cancer susceptibility genes. The isolation of several of these genes, which when altered 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 pathogenic variants 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.
BRCA1
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 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 pathogenic variants in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of BRCA pathogenic variants section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with pathogenic variants in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with pathogenic variants in BRCA2.
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. Pathogenic variants in BRCA2 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 BRCA pathogenic variants 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 pathogenic variants, there is often loss of the wild-type allele.
Pathogenic variants 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]
BRCA1 and BRCA2 function
Most BRCA1 and BRCA2 pathogenic variants are predicted to produce a truncated protein product, and thus loss of protein function, although some missense pathogenic variants cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 pathogenic variant 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 carriers of pathogenic variants, 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]
Pathogenic variants in BRCA1 and BRCA2
Nearly 2,000 distinct variants and sequence variations in BRCA1 and BRCA2 have already been described.[19] Approximately 1 in 400 to 800 individuals in the general population may carry a germline pathogenic variant in BRCA1 or BRCA2.[20,21] The variants 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 pathogenic variants have been found repeatedly in unrelated families, most have not been reported in more than a few families.
Variant-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism analysis and conformation-sensitive gel electrophoresis, miss nearly a third of the variants 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 is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating variants but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish (AJ) descent.[23-29] Furthermore, studies have suggested that these rearrangements may be more frequently seen in Hispanic and Caribbean populations.[27,29,30]
Variants of uncertain significance
Germline pathogenic variants 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 pathogenic variants 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 pathogenic variant detected but will have a variant of uncertain (or unknown) significance (VUS). VUS 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.[31]
A comprehensive analysis of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., described the frequency of VUS over a 3-year period.[32] Among subjects who had no clearly pathogenic variant, 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 pathogenic variants had sequence alterations that were once considered VUS but were reclassified as a polymorphism, or occasionally as a pathogenic variant.
The frequency of VUS varies by ethnicity within the U.S. population. African Americans appear to have the highest rate of VUS.[33] In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. The frequency of VUS in Asian, Middle Eastern, and Hispanic populations clusters between 10% and 14%, although these numbers are based on limited sample sizes. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely the result of improved variant classification algorithms.[34] VUS continue to be reclassified as additional information is curated and interpreted.[35,36] 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 [37-40] including integrated methods (see below).[41] 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 pathogenic variant, especially when the same VUS has been identified in conjunction with different pathogenic variants, 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,[37,42-46] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]–negative),[47] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[48,49] When attempting to interpret a VUS, all available information should be examined.
Population estimates of the likelihood of having a BRCA1 or BRCA2 pathogenic variant
Statistics regarding the percentage of individuals found to be carriers of BRCA pathogenic variants 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 pathogenic variant likelihood based on additional personal and family history characteristics.
In some cases, the same pathogenic variant has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant identified in a contemporary population can be traced to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 pathogenic variants (185delAG and 5382insC) and a BRCA2 pathogenic variant (6174delT) have been reported to be common in AJs. However, other founder pathogenic variants have been identified in African Americans and Hispanics.[30,50,51] The presence of these founder pathogenic variants 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. Nonfounder BRCA pathogenic variants in the AJ population have been reported to be between 3% and 15%.[32,52,53]
Among the general population, the likelihood of having any BRCA pathogenic variant is as follows:
- General population (excluding Ashkenazim): about 1 in 400 (~0.25%).[21,54]
- Women with breast cancer (any age): 1 in 50 (2%).[55]
- Women with breast cancer (younger than 40 y): 1 in 10 (10%).[56-58]
- Men with breast cancer (any age): 1 in 20 (5%).[59]
- Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).[60-62]
Among AJ individuals, the likelihood of having any BRCA pathogenic variant is as follows:
- General AJ population: 1 in 40 (1.1%–2.5%).[63-65]
- Women with breast cancer (any age): 1 in 10 (10%).[66]
- Women with breast cancer (younger than 40 y): 1 in 3 (30%–35%).[66-68]
- Men with breast cancer (any age): 1 in 5 (19%).[69]
- Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).[70-72]
Two large U.S. population-based studies of breast cancer patients younger than 65 years examined the prevalence of BRCA1 [57,73] and BRCA2 [57] pathogenic variants in various ethnic groups. The prevalence of BRCA1 pathogenic variants 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-AJ whites, and 8.3% to 10.2% in AJ individuals.[57,73] The prevalence of BRCA2 pathogenic variants by ethnic group was 2.6% in African Americans and 2.1% in whites.[57]
A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of BRCA1 and BRCA2 pathogenic variants. BRCA pathogenic variants were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2);[74] 21 of the 189 (11%) BRCA pathogenic variants identified were large rearrangements, of which 13 (62%) were the BRCA1 exon 9–12 deletion. An unselected cohort of 810 women of Mexican ancestry with breast cancer were tested; 4.3% had a BRCA pathogenic variant. Eight of the 35 pathogenic variants identified also were the BRCA1 exon 9–12 deletion.[75] In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 exon 9–12 deletion was found in three patients, suggesting that this variant may be a Mexican founder pathogenic variant and may represent 10% to 12% of all BRCA1 pathogenic variants in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent pathogenic variants, which accounted for 53% of all variants observed in this cohort, suggesting the existence of additional founder pathogenic variants in this population.
A retrospective review of 29 AJ patients with primary fallopian tube tumors identified germline BRCA pathogenic variants in 17%.[72] Another study of 108 women with fallopian tube cancer identified pathogenic variants in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[76] Estimates of the frequency of fallopian tube cancer in carriers of BRCA pathogenic variants are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.[6,72,76,77]
Population screening
Population screening has identified carriers in a number of AJ populations who would not have met criteria for family-based testing.[64,78-80] This could potentially expand the number of individuals who could benefit from preventive strategies. A study has suggested that population screening (compared with personal/family history–based testing) for AJ founder variants is cost-effective on the basis of data from the United States and the United Kingdom.[81] The authors used a decision-analytic model that estimated lifetime costs and the effects of genetic testing to assess cost-effectiveness; the model included costs of pretest genetic counseling and genetic testing and the anticipated risk of cardiovascular outcomes. Additional analyses conducted by the same group also suggested cost-effectiveness when testing was expanded to include all pathogenic variants in BRCA1, BRCA2, RAD51C, RAD51D, and PALB2.[82] These studies are based on various assumptions, some of which are imprecise (e.g., population prevalence estimates for some genes). Furthermore, as acknowledged by the authors, these types of efforts would require implementation of clinical support across the care continuum, in order for patients identified with pathogenic variants to benefit from this information. Consequently, there remain significant resource implications as population screening efforts are considered, which are the focus of ongoing research efforts. Because the detection rate is highly dependent on the prevalence of pathogenic variants in a population, it is not clear how applicable this approach would be for other populations, including other founder pathogenic variant populations. Another unanswered question is whether adequate genetic counseling can be provided for whole populations.
Clinical criteria and models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant
Several studies have assessed the frequency of BRCA1 or BRCA2 pathogenic variants in women with breast or ovarian cancer.[57,58,73,83-91] Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 pathogenic variant include the following:
- Breast cancer diagnosed at an early age. (Some studies use age 40 y as a cutoff, while others use age 50 y.)
- Ovarian cancer.
- Bilateral breast cancer.
- A history of both breast and ovarian cancer.
- Breast cancer diagnosed in a male at any age.[83-86,89]
- Triple-negative breast cancer diagnosed in women younger than 60 years.[92-95]
- AJ background.[83,84,86]
Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 pathogenic variant include the following:
Clinical criteria and practice guidelines for identifying individuals who may have a BRCA1 or BRCA2 pathogenic variant
Several professional organizations and expert panels, including the American Society of Clinical Oncology,[96] the National Comprehensive Cancer Network (NCCN),[97] the American Society of Human Genetics,[98] the American College of Medical Genetics and Genomics,[99] the National Society of Genetic Counselors,[99] the U.S. Preventive Services Task Force,[100] and the Society of Gynecologic Oncologists,[101] have developed clinical criteria and practice guidelines that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 pathogenic variant.
Models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant
Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 pathogenic variants in individuals or families. These models include those using logistic regression,[32,83,84,86,89,102,103] genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]),[89,104] and empiric observations,[54,57,60,105-107] including the Myriad prevalence tables.
In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (refer to Table 4). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for these models' ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.
BOADICEA is a polygenetic model that uses complex segregation analysis to examine both breast cancer risk and the probability of having a BRCA1 or BRCA2 pathogenic variant.[104] 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 carriers of BRCA1/BRCA2 pathogenic variants.[108,109] 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 pathogenic variant status.[110] One study has shown that the prediction models for genetic risk are sensitive to the amount of family history data available and do not perform as well with limited family information.[111] BOADICEA is being expanded to incorporate additional risk variants (genome-wide association study [GWAS] single nucleotide polymorphisms [SNPs]) to better predict pathogenic variant status and to improve the accuracy of breast cancer and ovarian cancer risk estimates.[112]
The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[113] There have been variable results in the performance of the BRCAPRO model among Hispanics,[114,115] and both the BRCAPRO model and Myriad tables underestimated the proportion of carriers of pathogenic variants in an Asian American population.[116] BOADICEA was developed and validated in British women. Thus, the major models used for both overall risk (Table 1) and genetic risk (Table 4) have not been developed or validated in large populations of racially and ethnically diverse women. Of the commonly used clinical models for assessing genetic risk, only the Tyrer-Cuzick model contains nongenetic risk factors.
The power of several of the models has been compared in different studies.[117-120] Four breast cancer genetic-risk models, BOADICEA, BRCAPRO, IBIS, and eCLAUS, were evaluated for their diagnostic accuracy in predicting BRCA1/BRCA2 pathogenic variants in a cohort of 7,352 German families.[121] The family member with the highest likelihood of carrying a pathogenic variant from each family was screened for BRCA1/BRCA2 pathogenic variants. Carrier probabilities from each model were calculated and compared with the actual variants detected. BRCAPRO and BOADICEA had significantly higher diagnostic accuracy than IBIS or eCLAUS. Accuracy for the BOADICEA model was further improved when statuses of the tumor markers ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) were included in the model. The inclusion of these biomarkers has been shown to improve the performance of BRCAPRO.[122,123]
Genetic testing for BRCA1 and BRCA2 pathogenic variants 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 pathogenic variant, but risk assessment continues to be an art. 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 risk-reducing surgeries).
Penetrance of BRCA pathogenic variants
The proportion of individuals carrying a pathogenic variant who will manifest the disease is referred to as penetrance. (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section of this summary for more information.)
Numerous studies have estimated breast and ovarian cancer penetrance in carriers of BRCA1 and BRCA2 pathogenic variants. Risk of both breast and ovarian cancer is consistently estimated to be higher in carriers of BRCA1 pathogenic variants than in carriers of BRCA2 pathogenic variants. Results from two large meta-analyses are shown in Table 5.[128,129] One study [128] analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 pathogenic variant–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 [129] combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 pathogenic variant–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for carriers of BRCA1 pathogenic variants and 45% to 47% for carriers of BRCA2 pathogenic variants. Ovarian cancer risks were 39% for carriers of BRCA1 pathogenic variants and 11% to 17% for carriers of BRCA2 pathogenic variants.
While the cumulative risks of developing cancer by age 70 years are higher for carriers of BRCA1 pathogenic variants than for BRCA2 pathogenic variants, the relative risks (RRs) of breast cancer decline more with age in carriers of BRCA1 pathogenic variants.[128] Studies of penetrance for carriers of specific individual variants are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder pathogenic variants have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder pathogenic variants from their larger meta-analyses and found that the estimated penetrance for the individual pathogenic variants was very similar to the corresponding estimates among all carriers.[131] A later study of 4,649 women with BRCA pathogenic variants reported significantly lower RRs of breast cancer in those with the BRCA2 6174delT variant than in those with other BRCA2 variants (hazard ratio [HR], 0.35; confidence interval [CI], 0.18–0.69).[132]
One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages.[129] Nonetheless, making precise penetrance estimates in an individual carrier is difficult. The lifetime risks of ovarian cancer are 5.2% in carriers of RAD51C pathogenic variants, 5.8% in carriers of BRIP1 pathogenic variants, and 12% in carriers of RAD51D pathogenic variants. Risk-reducing salpingo-oophorectomy (RRSO) may be considered for these patients upon completion of childbearing.[133,134]
Data from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), comprising 19,581 carriers of BRCA1 pathogenic variants and 11,900 carriers of BRCA2 pathogenic variants, were analyzed to estimate HRs for breast cancer and ovarian cancer by pathogenic variant type, function, and nucleotide position.[135] Breast cancer cluster regions and ovarian cancer cluster regions were found in both genes. Risks for incidence of breast cancer and ovarian cancer and age at diagnosis differed by variant class. Further evaluation of these findings is needed before they can be translated into clinical practice.
Another study from the CIMBA group looked at the phenotype of women with breast cancer who had inherited pathogenic variants in both BRCA1 and BRCA2.[136] The majority of women carried the common Jewish pathogenic variants. Compared with women who were heterozygous for the same pathogenic variant (heterozygote controls), women who were heterozygous for both BRCA1 and BRCA2 were more likely to be diagnosed with breast cancer than women who were heterozygote controls, and more likely to be diagnosed with ovarian cancer than women who were heterozygote controls with BRCA2, but not those with BRCA1 pathogenic variants. Similarly, age at onset of breast cancer was younger in carriers of both variants compared with women who were heterozygote controls with BRCA2, but not compared with those with BRCA1 pathogenic variants. The percentage of women with both variants and estrogen receptor–positive and progesterone receptor–positive breast cancer was intermediate between the heterozygote controls with BRCA1 pathogenic variants and those with BRCA2 pathogenic variants. The authors concluded that women who inherit pathogenic variants in both BRCA1 and BRCA2 may be managed similarly to carriers of only a BRCA1 variant.
Several studies have suggested that BRCA pathogenic variants may be associated with genetic anticipation. One study evaluated 176 families with BRCA1 or BRCA2 pathogenic variants and at least two consecutive generations of the same cancer. The probands’ generations were diagnosed with breast cancer an estimated 6.8 years earlier than the parents’ generations and 9.8 years earlier than the grandparents' generations.[137] Similarly, another study showed a difference in age at breast cancer diagnosis between 80 mother-and-daughter paired pathogenic variant carriers but only if the mother was diagnosed with breast cancer after age 50 years.[138] Another cohort study of 106 paired women from two consecutive generations with a known BRCA pathogenic variant in the family estimated a 6- to 8-year earlier age at onset in subsequent generations.[139]
RRSO and/or use of oral contraceptives have been associated with the risk of breast cancer.[66,128,140-145] (Refer to the RRSO section and the Oral contraceptives section of this summary for more information.) Other potentially modifiable reproductive and hormonal factors can also affect risk.[146-150] Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time.[151-153] (Refer to the Modifiers of risk in carriers of BRCA1 and BRCA2 pathogenic variants section for more information.) 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,[64,66,139] 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.
Contralateral breast cancer (CBC) in carriers of BRCA pathogenic variants
The increased risk of CBC among carriers of BRCA1 and BRCA2 pathogenic variants has been confirmed in several large studies, with fairly consistent results, as summarized in Table 6.
Published results include a large study by the German Consortium for Hereditary Breast and Ovarian Cancer, which estimated the risk of CBC in members of families with known BRCA1 and BRCA2 pathogenic variants. At 25 years after 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.[154]
Subsequently, results from the Women's Environmental Cancer and Radiation Epidemiology (WECARE) study, a large, population-based, nested case-control study of CBC, reported a 10-year risk of CBC of 15.9% among carriers of BRCA1/BRCA2 pathogenic variants and a risk of 4.9% among noncarriers. Risks were also inversely related to age at first diagnosis in this study and were 1.8-fold higher in those with a first-degree relative (FDR) with breast cancer.[155]
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%, respectively).[156]
A comparison of 655 women with BRCA1/BRCA2 pathogenic variants undergoing either breast-conserving therapy or 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 pathogenic variants than in women with BRCA2 pathogenic variants, and among women whose first breast cancer occurred at or before age 35 years.[161]
In a study of 810 women with stage I or stage II breast cancer who had a BRCA1 or BRCA2 pathogenic variant identified in the family, 149 (18.4%) developed CBC; the 15-year actuarial risk was 36.1% among carriers of BRCA1 pathogenic variants and 28.5% among carriers of BRCA2 pathogenic variants.[157] Risks were higher among women diagnosed before age 50 years than among women diagnosed at age 50 years or older (37.6% vs. 16.8%; P = .003). Furthermore, the risk of CBC varied by family history among women whose initial breast cancer was diagnosed before age 50 years. For these women, the CBC risk among those with 0, 1, or 2 or more FDRs with breast cancer diagnosed before age 50 years was 33.4%, 39.1%, and 49.7%, respectively.
The risk of CBC after a first breast cancer in BRCA1 and BRCA2 carriers has been examined in both retrospective and prospective observational epidemiological studies. A systematic review and quantitative meta-analysis of these epidemiologic studies (18 retrospective and 2 prospective cohort studies) reported 5-year cumulative risks of CBC of 15% (95% CI, 9.50%–20%) in BRCA1 carriers and 9% (95% CI, 5%–14%) in BRCA2 carriers.[158] When the prospective studies were analyzed separately, the 5-year cumulative risk increased to 23.4% (95% CI, 9.1%–39.5%) in BRCA1 carriers and to 17.5% (95% CI, 9.1%–39.5%) in BRCA2 carriers. The discrepancies in the reported frequencies may be inherent due to the potential for biases introduced in retrospective series.
Similarly, in a Dutch cohort of 6,294 patients (including 200 BRCA1 carriers and 71 BRCA2 carriers) with invasive breast cancer diagnosed before age 50 years, and a median follow-up of 12.5 years, the 10-year risks of CBC were 21.1% (95% CI, 15.4%–27.4%) for BRCA1 carriers, 10.8% (95% CI, 4.7%–19.6%) for BRCA2 carriers, and 5.1% (95% CI, 4.5%–5.7%) for noncarriers.[160] Age at first breast cancer diagnosis was predictive of the 10-year cumulative risk of CBC among BRCA1/BRCA2 carriers only. Specifically, the CBC risk among BRCA1/BRCA2 carriers diagnosed before age 41 years was 23.9% (BRCA1, 25.5%; BRCA2, 17.2%); in contrast, CBC among those diagnosed between 41 and 49 years was 12.6% (BRCA1, 15.6%; BRCA2, 7.2%).
In an English study of 506 BRCA1 carriers and 505 BRCA2 carriers with a diagnosis of breast cancer at any age and median follow-up of 7.8 years, the 10-year risks for CBC were 25.7% for BRCA1 carriers and 19.5% for BRCA2 carriers.[159] Earlier age at first breast cancer diagnosis for BRCA1 and BRCA2 carriers combined was significantly associated with a higher CBC risk, with a 20-year rate of 55.4% among those younger than 40 years, compared with 36.4% among those older than 50 years. Additionally, differences were more pronounced among BRCA1 carriers compared with BRCA2 carriers.
An international, multicenter, prospective cohort study followed 1,305 BRCA1 and 908 BRCA2 female carriers with a diagnosis of breast cancer (without any other cancers) for a median follow-up time of 4 years (range, 2–7 y).[130] Participants had a median age of 47 years (range, 40–55 y) at the start of follow-up. The authors reported a cumulative risk of CBC 20 years after the initial breast cancer diagnosis of 40% (95% CI, 35%–45%) for BRCA1 carriers and 26% (95% CI, 20%–33%) for BRCA2 carriers. These 20-year estimates are in line with the 10-year cumulative risk estimates reported in Table 6.
Thus, in summary, despite differences in study design, study sites, and sample sizes, the data on CBC among women with BRCA1/BRCA2 pathogenic variants 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, and thus is inversely associated with age.
Risk-reducing strategies
Refer to the Risk-reducing mastectomy section of this summary for information about the use of risk-reducing surgery in carriers of BRCA pathogenic variants. Refer to the Chemoprevention section of this summary for information about the use of tamoxifen as a risk-reduction strategy for CBC in carriers of BRCA pathogenic variants.
Breast cancer as a second malignancy in carriers of BRCA pathogenic variants
Two genetic registry–based studies have recently explored the risk of primary breast cancer after BRCA-related ovarian cancer. In one study, 164 BRCA1/BRCA2 carriers with primary epithelial ovarian, fallopian tube or primary peritoneal cancer were followed for subsequent events.[162] The risk of metachronous breast cancer at 5 years after a diagnosis of ovarian cancer was lower than previously reported for unaffected BRCA1/BRCA2 carriers. In this series, overall survival was dominated by ovarian cancer-related deaths. A similar study compared the risk of primary breast cancer in BRCA-related ovarian cancer patients and unaffected carriers.[163] The 2-year, 5-year, and 10-year risks of primary breast cancer were all statistically significantly lower in patients with ovarian cancer. The risk of CBC among women with a unilateral breast cancer before their ovarian cancer diagnosis was also lower than in women without ovarian cancer, although the difference did not reach statistical significance. These studies suggest that treatment for ovarian cancer, namely oophorectomy and platinum-based chemotherapy, may confer protection against subsequent breast cancer. In a single-institution cohort study of 364 patients with epithelial ovarian cancer who underwent BRCA pathogenic variant testing, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 pathogenic variant. Of the 135 BRCA1/BRCA2 carriers, 12 (8.9%) developed breast cancer. All breast cancers were stage 0 to stage II and diagnosed as follows: mammogram (7), palpable mass (3), and incidental finding during risk-reducing mastectomy (2). At median follow-up of 6.3 years, of the 12 patients with breast cancer after ovarian cancer, three died of recurrent ovarian cancer and one died of metastatic breast cancer.[164] The majority of these cancers were detected with mammogram or clinical exam, suggesting additional breast surveillance with other modalities or risk-reducing surgery may be of questionable value. Mathematical modeling suggests that for women with BRCA-associated ovarian cancer, breast cancer screening should consist of mammography and clinical breast exam. The consideration of breast magnetic resonance imaging (MRI) and/or risk-reducing mastectomies may be beneficial for women with early-stage ovarian cancer or for long-term ovarian cancer survivors.[165]
Cancers other than female breast/ovarian
Female breast and ovarian cancers are clearly the dominant cancers associated with BRCA1 and BRCA2. BRCA pathogenic variants also confer an increased risk of fallopian tube and primary peritoneal carcinomas. One large study from a familial registry of carriers of BRCA1 pathogenic variants has found a 120-fold RR of fallopian tube cancer among carriers of BRCA1 pathogenic variants compared with the general population.[6] The risk of primary peritoneal cancer among carriers of BRCA pathogenic variants with intact ovaries is increased but remains poorly quantified, despite a residual risk of 3% to 4% in the 20 years after RRSO.[166,167] (Refer to the RRSO 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 pathogenic variants, particularly with BRCA2. Other cancers have been associated in some studies. The strength of the association of these cancers with BRCA pathogenic variants has been more difficult to estimate because of the lower numbers of these cancers observed in carriers of pathogenic variants.
Men with BRCA2 pathogenic variants, and to a lesser extent BRCA1 pathogenic variants, are at increased risk of breast cancer with lifetime risks estimated at 5% to 10% and 1% to 2%, respectively.[6,8,9,168] Men carrying BRCA2 pathogenic variants, and to a lesser extent BRCA1 pathogenic variants, have an approximately threefold to sevenfold increased risk of prostate cancer.[7,8,12,107,169-172] BRCA2-associated prostate cancer also appears to be more aggressive.[173-178] (Refer to the BRCA1 and BRCA2 section in the PDQ summary on Genetics of Prostate Cancer for more information.)
Studies of familial pancreatic cancer (FPC) [179-183] and unselected series of pancreatic cancer [184-186] 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 pathogenic variants, with risks increasing with more affected relatives.[179-181] Similarly, studies of unselected pancreatic cancers have reported BRCA2 pathogenic variant frequencies between 3% to 7%, with these numbers approaching 10% in those of AJ descent.[184,185,187] 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.[188] A large, single-institution study of more than 1,000 carriers of pathogenic variants found a 21-fold increased risk of pancreatic cancer among BRCA2 carriers and a 4.7-fold increased risk among carriers of BRCA1 pathogenic variants, compared with incidence in the general population.[172] Other cancers associated with BRCA2 pathogenic variants in some, but not all, studies include melanoma, biliary cancers, and head and neck cancers, but these risks appear modest (<5% lifetime risk) 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).[189] This finding was supported by some,[6,7,190] but not all,[8,63,71,107,191-193] family-based studies. However, unselected series of colorectal cancer that have been exclusively performed in the AJ population have not shown elevated rates of BRCA1 or BRCA2 pathogenic variants.[194-196] Taken together, the data suggest little, if any, increased risk of colorectal cancer, and possibly only in specific population groups. Therefore, at this time, carriers of BRCA1 pathogenic variants should adhere to population-screening recommendations for colorectal cancer.
No increased prevalence of hereditary BRCA pathogenic variants was found among 200 Jewish women with endometrial carcinoma or 56 unselected women with uterine papillary serous carcinoma.[197,198] (Refer to the Risk-reducing salpingo-oophorectomy section in the Ovarian cancer section of this summary for more information.)
Cancer risk in individuals who test negative for a known familial BRCA1/BRCA2 pathogenic variant ("true negative")
There is conflicting evidence as to the residual familial risk among women who test negative for the BRCA1/BRCA2 pathogenic variant segregating in the family. An initial study based on prospective evaluation of 353 women who tested negative for the BRCA1 pathogenic variant 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.[143] A report that the risk may be as high as fivefold in women who tested negative for the BRCA1 or BRCA2 pathogenic variant in the family [199] was followed by numerous letters to the editor suggesting that ascertainment biases account for much of this observed excess risk.[200-205] Four additional analyses have suggested an approximate 1.5-fold to 2-fold excess risk.[204,206-208] In one study, two cases of ovarian cancer were reported.[208] 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.
Results from numerous other prospective studies have found no increased risk. A study of 375 women who tested negative for a known familial pathogenic variant 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.[209] 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 variant-negative women (observed/expected [O/E], 0.82; 95% CI, 0.39–1.51), although women who had at least one FDR with breast cancer had a nonsignificant increased risk (O/E, 1.33; 95% CI, 0.41–2.91).[210] A study of 160 BRCA1 and 132 BRCA2 pathogenic variant–positive families from the Breast Cancer Family Registry found no evidence for increased risk among noncarriers in these families.[211] In a large study of 722 variant-negative women from Australia in whom six invasive breast cancers were observed after a median follow-up of 6.3 years, the standardized incidence ratio (SIR) was not significantly elevated (SIR, 1.14; 95% CI, 0.51–2.53).[212] Based on available data, it appears that women testing negative for known familial BRCA1/BRCA2 pathogenic variants 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 pathogenic variant.
Breast and ovarian cancer risk in breast cancer families without detectable BRCA1/BRCA2 pathogenic variants ("indeterminate")
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.[32] Five 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.[211,213,213,214,214,215,215-217]
Modifiers of risk in carriers of BRCA1 and BRCA2 pathogenic variants
Pathogenic variants in BRCA1 and BRCA2 confer high risks of breast and ovarian cancers. The risks, however, are not equal in all pathogenic variant carriers and have been found to vary by several factors, including type of cancer, age at onset, and variant position.[218] This observed variation in penetrance has led to the hypothesis that other genetic and/or environmental factors modify cancer risk in carriers of pathogenic variants. There is a growing body of literature identifying genetic and nongenetic factors that contribute to the observed variation in rates of cancers seen in families with BRCA1/BRCA2 pathogenic variants.
Genetic modifiers of breast and ovarian cancer risk
The largest studies investigating genetic modifiers of breast and ovarian cancer risk to date have come from CIMBA, a large international effort with genotypic and phenotypic data on more than 15,000 BRCA1 and 10,000 BRCA2 carriers.[219] Using candidate gene analysis and GWAS, CIMBA has identified several loci associated both with increased and decreased risk of breast cancer and ovarian cancer. Some of the SNPs are related to subtypes of breast cancer, such as hormone-receptor and HER2/neu status. The risks conferred are all modest but if operating in a multiplicative fashion could significantly impact risk of cancer in carriers of BRCA1/BRCA2 pathogenic variants. Currently, these SNPs are not being tested for or used in clinical decision making.
Genotype-phenotype correlations
Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 pathogenic variant families. None of the studies have had sufficient numbers of pathogenic variant–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 pathogenic variants, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629.[11,220] A study of 164 families with BRCA2 pathogenic variants collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Pathogenic variants within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison with families with variants on either side of this region.[221] In addition, a study of 356 families with protein-truncating BRCA1 pathogenic variants collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with variants in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with variants 3’ to nucleotide 4,191.[222] These observations have generally been confirmed in subsequent studies.[128,223,224] Studies in Ashkenazim, in whom substantial numbers of families with the same pathogenic variant can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG variant, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC variant in the 3' end of the gene.[225,226] 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 carriers of the BRCA1:5382insC pathogenic variant compared with carriers of BRCA1:185delAG and BRCA2:6174delT variants. Ovarian cancer risk is considerably higher in carriers of BRCA1 pathogenic variants, and it is uncommon before age 45 years in carriers of the BRCA2:6174delT pathogenic variant.[225,226]
In an Australian study of 122 families with a pathogenic variant in BRCA1, large genomic rearrangement variants were associated with higher-risk features in breast and ovarian cancers, including younger age at breast cancer diagnosis and higher incidence of bilateral breast cancer.[227]
Pathology of breast cancer
BRCA1 pathology
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 variants.[228-235] In a large international series of 3,797 carriers of BRCA1 pathogenic variants, the median age at breast cancer diagnosis was 40 years.[235] Of breast tumors arising in BRCA1 carriers, 78% were ER-negative; 79% were PR-negative; 90% were HER2-negative; and 69% were triple-negative. These findings were consistent with multiple smaller series.[92,231,236-238] In addition, the proportion of ER-negative tumors significantly decreased as the age at breast cancer diagnosis increased.[235]
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,[239,240] particularly in women diagnosed before age 50 years.[92-94] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset.[241,242] 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 pathogenic variants 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 pathogenic variants reported in 9% to 35%.[94,95,236,243-246] Notably, studies have demonstrated a high rate of BRCA1 pathogenic variants in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 14.6% with a pathogenic variant in an inherited cancer susceptibility gene.[246] BRCA1 pathogenic variants accounted for the largest proportion (8.5%), followed by BRCA2 (2.7%); PALB2 (1.2%); and BARD1, RAD51D, RAD51C and BRIP1 (0.3%–0.5% for each gene). In this study, those with pathogenic variants in BRCA1/BRCA2 or other inherited cancer genes were diagnosed at an earlier age and had higher grade tumors than those without pathogenic variants. Specifically, among carriers of BRCA1 pathogenic variants, the average age at diagnosis was 44 years, and 94% had high-grade tumors. One study examined 308 individuals with triple-negative breast cancer; BRCA1 pathogenic variants were present in 45. Pathogenic variants were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%).[247] A meta-analysis based on 2,533 patients from 12 studies was conducted to assess the risk of a BRCA1 pathogenic variant in high-risk women with triple-negative breast cancer.[248] Results indicated that the RR of a BRCA1 pathogenic variant among women with versus without triple-negative breast cancer is 5.65 (95% CI, 4.15–7.69), and approximately two in nine women with triple-negative disease harbor a BRCA1 pathogenic variant. Interestingly, a study of 77 unselected patients with triple-negative breast cancer in which 15 (19.5%) had a germline pathogenic variant or somatic BRCA1/BRCA2 mutation demonstrated a lower risk of relapse in those with BRCA1 pathogenic variant–associated triple-negative breast cancer than in those with non-BRCA1-associated triple-negative breast cancer; this study was limited by its size.[244] 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 carrier of BRCA1 pathogenic variants received chemotherapy.[249] In contrast, HER2 positivity and young age alone in the absence of family history or a second primary cancer does not increase the likelihood of a pathogenic variant in BRCA1, BRCA2, or TP53.[250]
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.[251] 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.[237,252,253] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[254-256] 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;[237] 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, PR, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor.[257-260] 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.[92,231,259]
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,[229] also seen in two subsequent studies of BRCA1/BRCA2 carriers.[261,262] However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 pathogenic variants 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.[263] 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 pathogenic variant–negative cases.[264,265] A study of AJ 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.[266] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased [267,268] and decreased prevalence.[262] 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 pathogenic variant.[269]
BRCA2 pathology
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.[229,270,271] A large international series of 2,392 carriers of BRCA2 pathogenic variants found that only 23% of tumors arising in carriers of BRCA2 pathogenic variants were ER-negative; 36% were PR-negative; 87% were HER2-negative; and 16% were triple-negative.[235] A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 2.7% with a BRCA2 pathogenic variant.[246] (Refer to the BRCA1 pathology section of this summary for more information about this study.) A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors than in sporadic controls; however, a single BRCA2 founder pathogenic variant (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[272] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins (a histopathologic description of a pattern of invasion), fewer tubules and lower mitotic counts.[273] Other reports suggest that BRCA2-related tumors include an excess of lobular and tubulolobular histology.[230,270] In summary, histologic characteristics associated with BRCA2 pathogenic variants have been inconsistent.
Role of BRCA1 and BRCA2 in sporadic breast cancer
Given that germline pathogenic variants in BRCA1 or BRCA2 lead to a very high probability of developing breast 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 cancer tumors,[274-277] there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and loss of heterozygosity (LOH) (BRCA2) are frequent events. In fact, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[278-280] 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, PR negative, HER2 negative, and cytokeratin 5/6 positive) more commonly have BRCA1 dysregulation than other tumor types.[281-283] 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 pathogenic variants, 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 and growth pattern including multinucleated cells) compared with less than 4% methylation in controls.[284] (Refer to the BRCA1 pathology section for more information.) Although hypermethylation has not been reported for BRCA2 pathogenic variants, the BRCA2 locus on chromosome 13q is the target of frequent LOH in breast cancer.[285,286] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[287]
Pathology of ovarian cancer
Ovarian cancers in women with BRCA1 and BRCA2 pathogenic variants are more likely to be high-grade serous adenocarcinomas and are less likely to be mucinous or borderline tumors.[288-292] Fallopian tube cancer and peritoneal carcinomas are also part of the BRCA-associated disease spectrum.[72,293]
Histopathologic examinations of fallopian tubes removed from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that suggest a premalignant phenotype.[294,295] Occult carcinomas have been reported in 2% to 11% of adnexa removed from carriers of BRCA pathogenic variants at the time of risk-reducing surgery.[296-298] Most of these occult lesions are seen in the fallopian tubes, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tubes. Specifically, the distal segment of the fallopian tubes (containing the fimbriae) has been implicated as a common origin of the high-grade serous cancers seen in BRCA pathogenic variant carriers, based on the close proximity of the fimbriae to the ovarian surface, exposure of the fimbriae to the peritoneal cavity, and the broad surface area in the fimbriae.[299] Because of the multicentric origin of high-grade serous carcinomas from Müllerian-derived tissue, staging of ovarian, tubal, and peritoneal carcinomas is now considered collectively by the International Federation of Gynecology and Obstetrics. The term high-grade serous ovarian carcinoma may be used to represent high-grade pelvic serous carcinoma for consistency in language.[300]
High-grade serous ovarian carcinomas have a higher incidence of somatic TP53 mutations.[288,301] DNA microarray technology suggests distinct molecular pathways of carcinogenesis between BRCA1, BRCA2, and sporadic ovarian cancer.[302] Furthermore, data suggest that BRCA-related ovarian cancers metastasize more frequently to the viscera, while sporadic ovarian cancers remain confined to the peritoneum.[303]
Unlike high-grade serous carcinomas, low-grade serous ovarian cancers are less likely to be part of the BRCA1/BRCA2 spectrum.[304,305]
Role of BRCA1 and BRCA2 in sporadic ovarian cancer
Given that germline variants in BRCA1 or BRCA2 lead to a very high probability of developing 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 ovarian cancer tumors,[274-277] there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and LOH (BRCA2) are frequent events. Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[306] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[307,308] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[287]
Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancers
Lynch syndrome
Lynch syndrome 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.[309] The condition is caused by germline variants in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch variants.[310] The MLH1 and MSH2 genes are the most common susceptibility genes for Lynch syndrome, accounting for 80% to 90% of observed pathogenic variants,[311,312] followed by MSH6 and PMS2.[313-318] (Refer to the Lynch Syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)
After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[319] in 1999, the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk.[320] In addition, the Bethesda guidelines in 1997 (revised in 2004) did include endometrial and ovarian cancers as Lynch syndrome–related cancers to prompt tumor testing for Lynch syndrome.[321,322]
The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 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 Lynch syndrome.[323-328] There may be differences in ovarian cancer risk depending on the Lynch syndrome–associated pathogenic variant. In PMS2-associated Lynch syndrome, one study of 284 families was unable to identify an increased risk of ovarian cancer.[329] Another prospective registry of 3,119 Lynch syndrome–pathogenic variant carriers described the cumulative risk of ovarian cancer to range from 10% to 17% in MLH1, MSH2, and MSH6 carriers. In contrast, 0 of 67 women with a pathogenic variant in PMS2 developed ovarian cancer in 303 follow-up years.[330] Overall, there are too few cases of PMS2 pathogenic variant carriers to make definitive recommendations for ovarian cancer management. Characteristics of Lynch syndrome–associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages I and II at diagnosis (reported as 81.5%), underrepresentation 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 carriers of BRCA pathogenic variants.[331,332]
The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[333-336] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[336] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [337] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[337] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[338] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1 carriers but not in carriers of other MMR variants.[339] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[340]
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[341-344] although this has not been consistently observed.[345] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[341] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2 pathogenic variants.[342] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 10-5).[343] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[344] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[97]
Refer to the Lynch Syndrome section of the Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes section of this summary for information about clinical management of Lynch syndrome.
Li-Fraumeni syndrome (LFS)
Breast cancer is also a component of the rare LFS, in which germline variants of the TP53 gene on chromosome 17p have been documented. 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.[346] 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.[347,348] Widely used clinical diagnostic criteria for LFS were originally developed by Chompret et al. in 2001 (called the Chompret Criteria) [349] and revised in 2009 based on additional emerging data.[350]
LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[347,351,352]
Germline variants in TP53 are thought to account for fewer than 1% of breast cancer cases.[353] TP53-associated breast cancer is often HER2/neu-positive, in addition to being ER-positive, PR-positive, or both.[354-356] 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.
Historical criteria for defining LFS
The term Li-Fraumeni syndrome was used for the first time in 1982,[357] and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988 [358]:
- Sarcoma before age 45 years;
- An FDR with cancer before age 45 years; AND
- Another close relative (FDR or second-degree relative [SDR]) with either cancer before age 45 years or a sarcoma at any age.
Subsequently in 2001, Chompret et al. [349] systematically developed clinical criteria for recommending TP53 genetic testing, with the narrow LFS tumor spectrum defined as sarcoma, brain tumors, breast cancer, and adrenocortical carcinoma. The criteria were as follows:
- A proband affected by a narrow-spectrum tumor before age 36 years AND at least one FDR or SDR affected by a narrow-spectrum tumor (other than breast cancer if the proband is affected by breast cancer) before age 46 years or multiple primary tumors; OR
- A proband with multiple primary tumors, two of which belong to the narrow spectrum and the first of which occurred before age 36 years, irrespective of family history; OR
- A proband with adrenocortical carcinoma irrespective of the age at onset and family history.
- A proband with a tumor belonging to the LFS tumor spectrum* before age 46 years AND at least one FDR or SDR with an LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
- A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
- A patient with adrenocortical carcinoma or choroid plexus, irrespective of family history.
*The 2009 Chompret criteria defined the LFS tumor spectrum as including the following cancers: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer.
In 2015, Bougeard et al. [352] revised the criteria based on data from 415 carriers of pathogenic variants, to include the presence of childhood anaplastic rhabdomyosarcoma and breast cancer before age 31 years as an indication for testing, similar to what is recommended for choroid plexus carcinoma and adrenocortical carcinoma. The criteria were revised as follows:
- A proband with a tumor belonging to the LFS tumor spectrum** before age 46 years AND at least one FDR or SDR with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
- A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
- A patient with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
- Breast cancer before age 31 years.
**The 2015 Chompret criteria defined the LFS tumor spectrum as including the following cancers: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, and adrenocortical carcinoma.
Clinical characteristics of LFS
Germline TP53 pathogenic variants were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing.[348] All families with a TP53 pathogenic variant 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 pathogenic variant, 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 variants were found.
Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria [350] included 415 carriers of pathogenic variants from 214 families.[352] In this study, 43% of carriers had multiple malignancies, and the mean age at first tumor onset was 24.9 years. The childhood tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas, CNS tumors, and soft tissue sarcomas (present in 23%–30% collectively), whereas the adult tumor spectrum primarily encompassed breast cancer (79% of females) and soft tissue sarcomas (27% of carriers). The TP53 pathogenic variant detection rate was 6% among females younger than 31 years with breast cancer and no additional features suggestive of LFS. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants (21.3 years), compared with those with all types of loss-of-function variants (28.5 years) or genomic rearrangements (35.8 years). With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants. Among 127 female carriers of pathogenic variants with breast cancer, 31% developed CBC. Receptor status information was available for 40 tumors, which indicated 55% were HER2-positive, and 37% were triple-positive (i.e., ER-positive, PR-positive, and HER2-positive). There was an exceptionally high rate of multiple malignancies (43%) among carriers of pathogenic variants, of which 83% were metachronous. Treatment records were available for 64 carriers who received radiation therapy for treatment of their first tumor; of these, 19 (30%) developed 26 secondary tumors within a radiation field, with a latency of 2 to 26 years (mean, 10.7 y).
Similarly, results of 286 TP53 pathogenic variant–positive individuals in the National Cancer Institute’s LFS Study indicated a cumulative cancer incidence of almost 100% by age 70 years for both males and females.[360] They reported substantial variations by sex, age, and cancer type. Specifically, cumulative cancer incidence reached 50% by age 31 years in females and age 46 years in males, although male risks were higher in childhood and late adulthood. Cumulative cancer incidence by sex for the top four cancers is included in Table 8. Of those with one cancer, 49% developed at least one additional cancer after a median of 10 years. Age-specific risks for developing first and second cancers were comparable.
With the increasing use of multigene (panel) tests, it is important to recognize that pathogenic variants in TP53 are unexpectedly being identified in individuals without a family history characteristic of LFS.[361] The clinical significance of finding an isolated TP53 pathogenic variant in an individual or family who does not meet the Chompret criteria is uncertain. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline TP53 pathogenic variant, while taking into account their personal and family histories.
One cohort study evaluated 116 individuals with a germline TP53 pathogenic variant yearly at the National Institutes of Health Clinical Center using multimodality screening with and without gadolinium. Baseline screening identified a cancer in eight patients (6.9%) with a false-positive rate of 34.5% for MRI (n = 40).[362] Screening for breast cancer with annual breast MRI is recommended;[97] additional screening for other cancers has been studied and is evolving.[363,364]
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