Assessing the Significance of BRCA1 and BRCA2 Mutations in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest challenges in oncology. Despite increasing research efforts, the median survival remains under 1 year for advanced stages, and even for early stage resectable disease, 5-year survival is only around 25%. While the lifetime risk of being diagnosed with PDAC remains relatively low (around 1.5%), for some people the threat of developing the disease looms much larger, as around 10% of PDAC cases are estimated to be due to a hereditary predisposition. Patients with a particularly high incidence of PDAC in their families fall into a category of familial pancreatic cancer (FPC). Despite FPC composing a substantial subset of PDAC cases, decades of work have revealed the responsible inherited genetic lesions for only a fraction of these cases. Of the germline gene mutations that have been identified to increase the risk of PDAC, mutations in BRCA2 are thought to be the most common, accounting for up to 17% of FPC kindreds. Increasing evidence across malignancies with mutations in the BRCA genes has suggested that these tumors have unique vulnerabilities to specific DNA-damaging agents and DNA repair inhibitors, however how best to identify and treat these patients remains a challenge. In the article that accompanies this editorial, Holter et al describe their systematic investigation of the prevalence rates of pathogenic germline mutationsinanumberofDNAdamageresponse(DDR)genesinpatientswith PDAC. Along with a more accurate estimation of prevalence rates, their study also offers insight into clinical predictors that may be most relevant for determining which patients to test for these mutations. Testing for BRCA1 and BRCA2 mutations in breast and ovarian cancerhasbecomeroutineinthosedeemedashighriskbyvirtueoffamily history. While patients with PDAC with BRCA mutations are smaller in number, these patients are also in a position to benefit from treatment advances made in breast and ovarian cancers. Chief among these treatments are the platinum-based chemotherapy agents and the newer class of drugs known as poly (ADP-ribose) polymerase (PARP) inhibitors. Given the incredibly poor prognosis of PDAC, there is great interest in identifying a subset of patients with mutations in DDR genes to evaluate whether these will respond better to targeted treatment strategies. However, these efforts have faced significant challenges such as small incidence rates, lack of physician awareness of the association between BRCA1/2 mutations and PDAC, lack of consensus over who to submit to genetic testing, and the rapid disease progression that limits opportunity for genetic testing as well as clinical trial entry. With the recent approval of olaparib for the treatment of ovarian cancer in BRCA-mutation carriers, there will be increasing interest in how to identify the subset of patients harboring BRCA mutations across tumor types for enrollment in appropriate clinical trials. Holteretalreportonalargeprospectiveanalysisoftheprevalenceof germline BRCA1/2 mutations in a cohort of unselected patients with incident PDAC diagnoses. Importantly, they also investigate the clinical andfamilyhistoriesofthesepatients inanattempttodeterminepredictive factors for genetic testing. Prior studies of the prevalence of BRCA mutations in patients with PDAC are difficult to extrapolate to the general population given that these have primarily been small retrospective series often focused on Ashkenazi Jewish populations, and moreover they frequently lack analysis of the BRCA1 gene. Holter et al prospectively collecteddata fromonecenteron306unselectedconsecutivepatientswithin 3 months of PDAC diagnosis. They identified germline BRCA mutations in 4.6% of the patients; BRCA1 mutations accounted for 1% and BRCA2 mutations for 3.6% of cases. Notably, they also evaluated the first 79 patients for PALB2 mutations (partner of BRCA2), a gene that had previously been suggested to be a gene involved in PDAC risk. However, no PALB2 mutations were detected in the first 79 patients and therefore they did not test subsequent patients in the study. They found that of the Ashkenazi Jewish population in the study, 12.1% were BRCA-mutation carriers, compared with 3.7% of the non-Ashkenazi Jewish patients. In addition to Ashkenazi Jewish heritage, they also found that meeting the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care BRCA1 and BRCA2 genetic testing criteria was significantly associated with BRCA-mutation carrier status. Importantly, Holter et al did not find a statistically significant correlation of BRCA-mutation status with personal history of cancer, family history of PDAC, or family history of breast or ovarian cancer, and none of the BRCA-mutation carriers met the criteria for familial PDAC. Thus, the majority of these patients with BRCA mutations would not have met the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care BRCA1 and BRCA2 genetic testing criteria. Holter et al recommend that patients with PDAC of Ashkenazi Jewish decent or those meeting rigorous predetermined BRCA1/2 genetic testing criteria should be tested, but the fact remains that these parameters would miss the majority of BRCA-mutation carriers that could have benefited from clinical trial enrollment or genetic testing and counseling for their families. The question arises, how broadly should we be testing for BRCA mutations in patients with pancreatic cancer? JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 28 OCTOBER 1 2015