An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions

Abstract

Learning Objectives After completing this course, the reader will be able to: Describe the genetic syndromes associated with pancreas adenocarcinoma. Explain the potential role of platinum‐based therapy and PARP inhibitors in BRCA‐mutated pancreas adenocarcinoma. This article is available for continuing medical education credit at http://CME.TheOncologist.com Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA‐associated cancers have been shown to have greater sensitivity to platinum and poly(ADP‐ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA‐associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan‐Kettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum‐based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. 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. We anticipate that further study and understanding of the clinical and biologic features of BRCA‐mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

“…A similar and parallel picture with pancreatic adenocarcinoma is emerging (19,20), BRCA-related pancreatic adenocarcinoma might exhibit unique biology and natural history. In fact, it might represent components of a subset of pancreatic adenocarcinoma defined by underlying molecular biology in defective homologous recombination mechanism, as seen in other disease types.…”

“…The link between prostate cancer and BRCA1/2 mutations has been established (19,20) and worse clinical outcomes have been suggested (21)(22)(23). Not unlike observations in ovarian and breast cancers, a recent phase II study has shown that these prostate cancers demonstrated heightened response to PARP inhibition (23).…”

“…In a small retrospective series of 15 patients with pancreatic cancer and germline BRCA mutations (4 with BRCA1 and 11 with BRCA2), two patients were treated with PARP inhibitors either alone or in combination with chemotherapy in the first line non-curative setting, and enjoyed partial response lasting 2 and 6 months, respectively. Of two patients who were treated with PARP inhibitors in the second line setting, one sustained stable disease for 6 months (19).…”

Establishing a Clinic-Based Pancreatic Cancer and Periampullary Tumour Research Registry in Quebec

“…In addition, FrenchCanadian founder mutations in the BRCA1, BRCA2, and PALB2 genes have already been described [11][12][13] , providing the qpcs with a unique opportunity to study the prevalence of those founder mutations among French-Canadian participants with pdac. BRCA1-and BRCA2-associated pdac is of particular interest because those tumours can have beneficial treatment responses to dna cross-linking agents (that is, platinum salts) and parp inhibitors [41][42][43][44][45][46] .…”

Adenocarcinoma of the Pancreas

“…Indeed, several dramatic clinical responses to mitomycin C and to inhibitors of poly (ADPribose) polymerase (PARP) have been reported in pancreatic cancer patients with cancers that harbor inactivating mutations in a Fanconi anemia gene. 39,40 Similarly, germline mutations in the ATM gene predispose to pancreatic cancer, and the ataxia telangiectasia-mutated (ATM) pathway is also potentially therapeutically targetable with existing agents. 24,25 PARP inhibitors, external beam radiation therapy and DNA-PKcs (protein kinase DNA-activated catalytic polypeptide) inhibitors may all be selectively effective in these patients.…”