Germline mutations in BRCA1
are estimated to occur in up to 7% of patients with PAC, whereas in patients with familial PAC, the frequency of BRCA1
mutation carriers is estimated at 11%–17% [2
]. All but one of the 15 patients we identified as carrying a BRCA1
germline mutation had either a personal history of a prior malignancy or a documented case of BRCA
-associated malignancy in a first-degree relative, which may reflect the biased sample assessed in that such observations prompted referral for genetic testing. However, it is worth noting that seven of the 10 female carriers identified had a prior history of breast cancer. The median age at diagnosis of PAC was 62 years, 10 years below the average age at diagnosis in an unselected population reported from the Surveillance, Epidemiology, and End Results (SEER) data.
One patient with acinar cell carcinoma of the pancreas, a rare histological subtype of pancreatic malignancy, and a BRCA1
mutation was identified; an association between these two conditions has not been described previously. That patient had a complex past medical history with prior diagnoses including acromegaly, colonic adenocarcinoma, and papillary renal cell carcinoma and reported a significant family history of early-onset breast cancer in multiple first- and second-degree relatives. Colon cancer, thyroid cancer, and renal cell cancer have not been demonstrated to occur at significantly higher rates in BRCA1
mutation carriers [8
Over 6,000 patients were evaluated at MSKCC with a diagnosis of PAC in 2000–2010; the identification of 15 BRCA1
mutation carriers and PAC in 2003–2010 is likely to be a substantial underestimation of the true frequency of mutation carriers in this population because the vast majority of patients do not undergo genetic testing. In a prior study at our institution of 38 breast cancer survivors who subsequently developed PAC, just two of the 38 women in that group had undergone BRCA1
]. In contrast to breast and ovarian cancers, for which referral for genetic counseling and testing is routine, the majority of patients with PAC and a personal or family history suggestive of BRCA
mutation do not undergo genetic testing. Several barriers to genetic testing in this population exist, including a lack of awareness of the association between BRCA
mutation and PAC among treating professionals and patients, difficulty in obtaining reimbursement for the cost of genetic testing, and rapid disease progression precluding attendance for genetic counseling and testing. With greater recognition, better access, and a more rapid turnaround time for BRCA
genetic testing, we anticipate that in the near future at least some of these current barriers to genetic counseling and testing for PAC patients can be overcome.
In this series of BRCA
mutation–associated PAC patients, clinical and partial radiologic responses were seen in two of the three patients treated with the combination of a PARP inhibitor and gemcitabine, and one additional patient had a partial radiographic response to single-agent PARP inhibitor treatment. Five of six patients (83%) treated with platinum-based first-line chemotherapy for metastatic disease demonstrated a radiographic complete or partial response by the RECIST. This observation lends support to the hypothesis that PARP inhibitors are synthetically lethal in BRCA
-deficient PAC. PARP-1 and PARP-2 are key components of the cellular DNA repair mechanism for single-strand breaks and nucleoside base damage; inhibition of PARP in tumor cells leads to transformation of background single-strand breaks into double-strand breaks (DSBs) [10
]. These lesions are cytotoxic in cells without functional BRCA1 or BRCA2 because they are unable to effectively repair DSBs by homologous recombination and instead rely on the error-prone nonhomologous end-joining repair mechanism. Platinum chemotherapy drugs exert their cytotoxic effect by binding directly to DNA, causing crosslinking of DNA strands and thereby inducing DNA DSBs, which also are ineffectively repaired in cells lacking functioning BRCA1 or BRCA2. Pancreatic cancer cell lines deficient in BRCA2 or another component of the Fanconi anemia pathway have been shown to have marked sensitivity to DNA crosslinking agents [11
]. Previous anecdotal reports also indicate a substantial response to alkylating agents in patients with a known BRCA
mutation and PAC [12
]. Notably, all patients treated with a PARP inhibitor experienced progression of disease after several months of therapy, despite an initial clinical and radiographic response. The mechanism of acquired resistance in vivo to PARP inhibition is unknown, but it may potentially occur as a result of a secondary mutation resulting in restored competency of homologous repair in BRCA
-mutant cells [13
Interpretation of survival outcomes in this series is limited by the small number of patients and varying stages of disease at presentation. The possibility of survival bias must also be considered because patients who live longer are more likely to present for genetic testing. In this cohort of 15 patients, only five of whom underwent surgical resection, the overall median survival duration for the cohort was 27.6 months. Although this appears better than the reported SEER survival data in unselected PAC cases [1
], the prognostic significance of BRCA
mutation remains unclear.
We believe that there is a strong therapeutic rationale for the development of PARP inhibitors for BRCA1 or BRCA2 mutation–associated PAC. In collaboration with other investigators and in partnership with the Cancer Therapeutic and Evaluation Program and the Lustgarten Foundation, we plan a randomized phase II trial evaluating the addition of PARP inhibition to platinum-based therapy in a genetically selected population of BRCA1, BRCA2, or PALB2 mutation carriers with PAC. Selected other PARP inhibitor trials in pancreas cancer are noted in .
Trials of PARP inhibitors including pancreas adenocarcinoma patients
In conclusion, BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. Improved awareness of the association between BRCA mutation and PAC among patients and physicians is important to identify potential mutation carriers on the basis of a family or personal history of malignancy or a predisposing genetic background. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population and provide a first “proof of principle” of a targeted therapy approach in PAC patients. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification and refinement of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC cases.