Background:

The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes.

Methods:

Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.

Results:

Overall, 71 patients with PDAC and BRCA1 (n= 21), BRCA2 (n= 49) or both (n= 1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7%(n= 58) had any family history of malignancy; 30%(n= 21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P= 0.039).

Conclusion:

Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Main

Familial clustering is found in∼ 10% of pancreatic ductal adenocarcinoma (PDAC), often with an apparent autosomal dominant pattern of genetic transmission, suggestive of an inherited cancer syndrome (Shah and Kurtz, 2010). Pancreatic ductal adenocarcinoma is notably over-represented in families with a clustering of breast and ovarian cancers (Easton et al, 1996; Lal et al, 2000; Hahn et al, 2003; Friedenson, 2005). In a subset of these cancer-prone families, germline mutations in either the BRCA1 or BRCA2 genes are found, conferring a substantially higher lifetime risk for breast (50%–85% lifetime risk) and ovarian cancer (up to 64% lifetime risk; King et al, 2003). The association of mutations in these two genes with increased risk to other cancer types is also well established (Giusti et al, 2003; Friedenson, 2005). The Breast Cancer Linkage Consortium reported estimated relative risks for PDAC in BRCA2 mutation carriers of 3.5 (95% CI 1. 87–6.58; Easton, 1999). Recently, Narod et al reported a near doubling of risk for PDAC among BRCA1 and BRCA2 mutation carrier (Iqbal et al, 2012). Among Ashkenazi Jews, three predominant mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) are detected in the majority of high-risk families, and also in 2.5% of the general Ashkenazi population (Oddoux et al, 1996; Roa et al, 1996). The prevalence of the 6174delT BRCA2 mutation among Ashkenazi Jewish PDAC patients ranges from 5.5% to 13%(Ozcelik et al, 1997; Figer et al, 2001; Ferrone et al, 2009). The prevalence of BRCA2 mutations in familial PDAC in non-Jewish, ethnically diverse populations has been reported to range from 6% to 17%(Murphy et al, 2002; Hahn et al, 2003; Couch et al, 2007).