Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

PURPOSE To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.


INTRODUCTION
It is well established that pathogenic variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are associated with increased risks of breast and ovarian cancers in women for which reliable risk estimates are available. 1 Accumulated evidence indicates that BRCA1/2 PVs are also suggested, including colorectal, liver, and stomach cancers for BRCA1/2 PVs; cervical, corpus uteri, kidney, and testis cancers for BRCA1 PVs; 3,4,6,8,18,19 and bone, brain, blood, and gallbladder cancers and malignant melanoma for BRCA2 PVs. 2, 5,6,8,20 However, these associations are based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates.
The National Comprehensive Cancer Network and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers and prostate cancer screening particularly for BRCA2 carriers. Notably, National Comprehensive Cancer Network guidelines recently addressed testing and management for pancreatic cancer risk in BRCA1/2 carriers, but only in the presence of a positive family history of the disease. 21,22 Overall, current guidelines suggest that men and women with BRCA1/2 PVs should consider participation in investigational screening studies and receive education regarding signs and symptoms of cancers possibly associated with BRCA1/2 PVs. 21 The availability of more precise risk estimates will aid translation into evidence-based clinical guidelines for the cancer risk management in BRCA1/2 carriers and may guide treatment options for patients with cancer.
To inform clinical management strategies and optimize guidelines for cancer risk management in female and male BRCA1/2 carriers, we comprehensively assess the associations of BRCA1/2 PVs with risks of 22 cancers, other than female breast and ovarian cancers.

Study Sample
Data on 7,618 families with at least one family member having a BRCA1 or BRCA2 PV were obtained from 26 study groups in the Consortium of Investigators of Modifiers of BRCA1/2 (Data Supplement, online only). 23 Only families with a clearly PV identified were included. 24 The majority of families (7,281) were ascertained through an index individual attending cancer family clinics, mainly because of having multiple affected relatives, and 337 families were ascertained through an index case with breast or ovarian cancer, unselected for family history. All index individuals were age $ 18 years. For each family member, data including familial relationship, BRCA1/2 PV status, sex, year of birth, and years or age at pedigree data collection, death, and cancer diagnoses were collected (Data Supplement). All participants provided written informed consent and participated in studies at the host institutions under ethically approved protocols.

Statistical Analysis
BRCA1 and BRCA2 families were analyzed separately. Complex segregation analysis, 25 which considered the observed phenotype and observed or inferred genotype information of all family members, was used to estimate relative risks (RRs) for 22 first primary cancer sites, excluding female breast and ovarian cancers (Table 1). This involved comparing the observed cancer incidences for carriers with the age-, country-and birth cohort-specific population incidences (Cancer Incidence in Five Continents 26 ); thus, the estimated RRs were equivalent to standardized incidence ratios. Noncarriers were assumed to develop the cancers according to population incidences. Pedigree likelihoods were constructed and maximized using the pedigree analysis software MENDEL. 27 Individuals were followed from birth until the age of the first primary cancer diagnosis, death, age at pedigree-data collection, risk-reducing mastectomy and/or salpingooophorectomy (if these occurred at least 1 year before breast or ovarian cancer diagnoses, respectively), or age 80 years, whichever occurred first. Missing year of birth and cancer diagnosis age were imputed (Data Supplement).
Each individual was assumed to be at risk of developing the cancer of interest, as well as breast or ovarian cancer. The RRs for female breast and ovarian cancers were assumed CONTEXT Key Objective The associations of pathogenic variants (PVs) in BRCA1 and BRCA2 with cancers other than female breast and ovarian cancers remain uncertain. Precise risk estimates are required to inform effective cancer risk management. This study investigates the associations between the risks of 22 cancers and BRCA1/2 PVs using data from 5,341 families segregating BRCA1 or BRCA2 PVs. Knowledge Generated BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, and stomach cancers; male BRCA2 carriers are also at increased prostate cancer risk. No associations were found with risks of other cancers. The cumulative risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.

Relevance
The findings provide age-specific cancer risk estimates and will allow for improved cancer risk assessment of male and female carriers. to be equal to previous estimates 28 ; therefore, we only estimated the RR for the cancer of interest. We fitted models in which the RRs were assumed to be constant with age, birth cohort, sex, and study group and separate models with sex-specific RRs. For cancers with significant associations, we investigated whether the RRs varied by age. RRs from the best fitting models were used to estimate age-specific absolute risks on the basis of UK cancer incidences in year 2008-2012 (Data Supplement).
Because family ascertainment varied across study groups, we adjusted for the ascertainment of each family separately using an ascertainment-assumption-free approach. [29][30][31] Pedigree likelihoods were computed conditional on any data that may be relevant to the ascertainment (Data Supplement). Noninformative families, in which no additional information beyond the data relevant to the ascertainment was available, were excluded from analysis. Since cancer family history was self-reported, we assessed the possibility of systematic underreporting of specific cancers at the individual study group level and excluded any study groups in which under-reporting was likely relative to the population incidences (Data Supplement).
Sensitivity analyses under alternative inclusion, censoring, or ascertainment assumptions were performed for cancers that demonstrated associations: (1) stratifying by geographical region (Asian countries v others); (2) including study groups with possible cancer under-reporting; (3) excluding individuals with missing age at diagnosis; (4) individuals with risk-reducing bilateral mastectomy and/or salpingo-oophorectomy were still considered to be at risk of developing the other cancers, except breast and ovarian cancers; and (5) assuming the data relevant to the ascertainment for clinic-based families do not include the family history of cancer of interest. To account for population differences in melanoma skin pigmentation, we also conducted sensitivity analyses for melanoma by using (1) only families from Australia, Northern Europe, and North America; (2) only families in which probands self-identified as White European; and (3) only the families satisfying both (1) and (2).
All statistical tests were two-sided, and associations with a nominal P , .05 were considered statistically significant.

RESULTS
After ascertainment adjustment, 3,184 BRCA1 families and 2,157 BRCA2 families were informative for inclusion in the analysis, including 14,979 carriers, 9,296 noncarriers,

Sensitivity Analysis
The results are described in detail in the Data Supplement. There was no significant difference in the RR estimates by geographical region. The observed cancer associations were robust to all sensitivity analyses, except for colorectal and gallbladder cancers. No association was found for melanoma even when analyses were restricted to families from Australia, Northern Europe, and North America or families in which probands self-identified as White European.

Absolute Risks
RRs from the main analysis best-fitting models were used to calculate age-specific absolute cancer risks (

DISCUSSION
This study assessed the risks associated with BRCA1/2 PVs for 22 first primary cancers, other than female breast and ovarian cancers, and further clarified the cancer spectrum associated with BRCA1/2 PVs.
The associations of BRCA1/2 PVs with the risks of male breast and pancreatic cancers were confirmed and refined, as well as the association of prostate cancer with BRCA2 PVs, regardless of age and aggressiveness.
The lifetime male breast cancer risks were previously reported to be 2%-6% for BRCA1 and 7%-13% for BRCA2 carriers (Data Supplement). 3,6,[9][10][11][12][13] We estimated these risks to be somewhat lower, 0.4% (95% CI, 0.1 to 1.5) and 3.8% (95% CI, 1.9 to 7.7), respectively. The pancreatic cancer associations were consistent with previously reported RRs of 2-3 and lifetime risks of 1%-4% for BRCA1 carriers 3,4,6 and RRs of 3-6 and lifetime risks of 3%-5% for BRCA2 carriers (Data Supplement Among the suggested associations with other cancers, the association between BRCA1/2 PVs and stomach cancer is   In the present study, previously suggested associations of BRCA1/2 PVs with risks of other genitourinary cancers and melanoma 2,8 were not replicated. Although associations of BRCA1 PVs with colorectal and gallbladder cancers were observed, the results were not robust in the sensitivity analyses performed. Increased risks of bone and liver cancer have also been reported for BRCA1 or BRCA2 carriers. [4][5][6] However, liver and bone are common metastatic sites for breast, prostate, or pancreatic cancers and could be the presenting cancer. Since no pathology confirmation data were available, we did not examine these associations in the main analysis. If we assume that the reported bone and liver cancers in the data set are indeed first primaries, the data suggest no association with BRCA1 PVs, but that BRCA2 carriers are at seven-fold increased risk of bone cancer and five-fold increased risk of liver cancer without significant differences between males and females (Data Supplement). However, no conclusion for these associations can be drawn without pathology confirmation.
Overall, the estimated age-specific relative and absolute risks suggest that, in addition to breast and ovarian cancers, the clinical management of BRCA1/2 carriers should focus on cancer sites, which now show robust associations, such as prostate (BRCA2 carriers only), pancreatic, and possibly stomach cancers. Notably, although rare, pancreatic and stomach cancers are associated with poor prognosis and their incidences have been rising over time, and thus, our results highlight the importance of screening for upper gastrointestinal tract malignancies for BRCA1 and BRCA2 carriers, particularly for age , 65 years. On the other hand, some cancers previously taken into consideration for screening for BRCA1/2 carriers, like melanoma, may be reconsidered, to further optimize cancer prevention screening strategies and eventually reduce carriers' distress. Given that the cancer risk associations were found for both male and female carriers, the results also suggest that male relatives of known BRCA1/2 carriers should be informed about their individual cancer risk and encouraged to be tested. 35,36 It has been shown that knowing the germline BRCA1/2 PV status can influence treatment options for patients with cancer, leading to improved prognosis. For example, poly (ADP-ribose) polymerase inhibitor therapies that have been used successfully in the treatment of BRCA-related breast and ovarian cancers 37 are now beginning to be used for pancreatic and prostate cancers, 38,39 and in the near future, they might also be used for stomach cancer. 40 To avoid biases in the risk estimates related to the ascertainment of clinic-based families, on the basis of multiple affected family members, we used a conservative ascertainment adjustment approach by conditioning on the family histories of cancers of breast and ovary and the cancer site under investigation. When only family history of female breast and ovarian cancers was considered in the ascertainment, the RR estimates were somewhat higher for most cancers but with narrower CIs (Data Supplement). Therefore, conditioning on the family history of the cancer of interest is unlikely to have led to substantial underestimation of risk. A notable exception was male breast cancer, where much higher RR estimates were obtained. However, this estimate is most likely biased because male breast cancer family history has been an important factor in considering BRCA1/2 germline genetic testing since the discovery of BRCA1/2.
This study has several limitations. First, this is a retrospective family-based study, with self-reported cancer family history, which may be inaccurate. 41,42 Second, 7%-40% of reported cancer cases had missing age at diagnosis, with stomach cancer having the largest proportion.
To minimize these potential biases, we performed sensitivity analyses excluding any study groups in which underreporting was likely and any cases with missing age at diagnosis, and conclusions remained similar for most cancers. Third, we presented our results without any multiple testing adjustment. However, even using a false discovery rate adjustment, all the observed associations for BRCA2 carriers and the pancreatic cancer association for BRCA1 carriers had false discovery rates , 0.05. Fourth, the ethnicity of the family proband was not systematically collected by all studies because of variations in local data collection protocols. Among those with recorded ethnicity, in Asia-based studies, 97.7% of probands were Asian and in the rest of the studies 86.1%, 5.2%, 3.7%, 1.3%, and 1.1% of probands were White European, Ashkenazi, Hispanic, Black, and Asian, respectively. Therefore, the power to investigate the associations by all ethnic groups was limited. However, we did not find evidence of heterogeneity in the RRs by geographical region (Asia v others). Whether our risk estimates are applicable to non-European populations requires further investigation. Fifth, we did not have data on other genetic and environmental factors, so we were unable to investigate the modification effects of these factors; therefore, our risk estimates should be interpreted as the average risks across all potential genetic and environmental modifiers.
In conclusion, this study confirms that, aside from female breast and ovarian cancers, BRCA1/2 PVs are associated with increased risks of breast cancer in men, and pancreatic and stomach cancers in both sexes, and that only BRCA2 carriers are at elevated prostate cancer risk. BRCA1/2 PVs were not associated with the risks of any other cancers previously suggested. The association results and estimated age-specific risks will improve the cancer risk management for men and women with BRCA1/2 PVs.