A number of studies have shown that the third most common cancer associated with BRCA1/2 mutations is pancreatic cancer [15
]. This study is the largest to date examining pancreatic cancer as the primary outcome in families with BRCA1/2 mutations. In our retrospective cohort, approximately 11% of families with BRCA1/2 mutations had at least 1 relative with pancreatic cancer, consistent with previously published reports [8
The population characteristics of BRCA1/2 mutation carriers with pancreatic cancer differed from those of individuals with pancreatic cancer in the general population. Generally, individuals with pancreatic cancer from families with known BRCA1/2 mutations were younger, and in BRCA1 families, showed a 2:1 male:female ratio. This ratio in BRCA1 families differs from SEER data, which shows a 0.96:1 male:female ratio. One possible explanation for the predominance of pancreatic cancer in males in BRCA1 families is the competing mortality for breast and ovarian cancer in their female relatives [17
]. The risk of ovarian cancer in BRCA1 families is estimated to be as high as 66%, as compared with 27% in BRCA2 families. The aggressive nature of the disease may contribute to a significantly increased risk of mortality in BRCA1 positive women [19
]. For this reason, we believe that recommendations for genetic testing to members of a family with a strong breast and ovarian cancer history should also include male relatives, as they represent an understudied group of at-risk individuals.
In most BRCA1/2 testing programs, less than 10% of the individuals tested are men, even though there is an equal gender distribution in the population of male and female BRCA1/2 carriers. Because an estimated 500,000 Americans carry BRCA1 mutations alone [20
], the population-attributable risk of cancer in both male and female BRCA1/2 carriers is significant. Also, a growing number of studies show that BRCA1/2 families are affected by cancers other than breast and ovarian [5
], and males are likely to be the group most at-risk for these cancers.
As BRCA1/2 testing becomes more widely utilized, particularly in people unaffected by cancer, it is important to inform carriers that they are at risk for early cancer detection. The importance of screening for early cancer detection is growing given the general aging of the population coupled with improvements in treating other chronic diseases such as heart disease and diabetes. These factors contributing to increased longevity make it more likely that BRCA1/2 mutation carriers will develop other cancers, such as pancreatic, in their advanced age. While data support early screening for breast and ovarian cancer in BRCA1/2 carriers [21
], pancreatic cancer screening is not currently recommended outside of research protocols [22
]. We agree that any screening program should be conducted in a research setting and that patients should be educated about not only the procedure-related risks of screening but also the risks associated with the work-up of false positive results.
The observational nature of this study only allows conclusions based on associations and thus, this study (and others of similar design), can not claim a causative link between BRCA1 and BRCA2 mutations and pancreatic cancer. Also, as 56% of the study population is of Ashkenazi Jewish ancestry it is unclear to what extent the conclusions of this study are applicable to the general population. Finally, most patient referrals for BRCA testing came from gynecology and breast clinics so there may be a referral bias toward breast and ovarian cancers. However, these limitations only highlight the fact that the 11% prevalence in this study is most likely an underestimate of the true prevalence of pancreatic cancers in BRCA1 and BRCA2 families. This study also excluded pancreatic cancer patients with sequence variants of unknown significance which may later be found to be pathologic [23
]. This may further underestimate the prevalence found in this study. Also, there may be other unknown factors that place BRCA1/2 carriers of Ashkenazi Jewish ancestry at an even more elevated risk based on the findings of this study. This relationship has been proposed in a paper studying germline BRCA2 mutations in Ashkenazi Jewish patients with pancreatic cancer [24
] and may warrant further investigation.
In conclusion, we found that pancreatic cancer differentially affects males in BRCA1/2 families and that males represent an underrepresented at-risk population outside of the usual population referred for BRCA1/2 testing. We recommend that males in families with a strong history of breast, ovarian, and pancreatic cancer be considered for BRCA1/2 testing along with their female relatives.