Abstract IA28: BRCA-mutated pancreas adenocarcinoma: Emerging therapeutic implications

Abstract

Abstract Germline BRCA mutations, in particular BRCA 2, incur an increased risk of developing pancreas adenocarcinoma. BRCA mutations occur in 5-7% of an unselected pancreas adenocarcinoma population. In patients with Ashkenazi Jewish heritage and pancreas adenocarcinoma the frequency of BRCA mutations may be significantly higher at 12-15%. In patients with familial pancreatic cancer, defined as having at least one first degree relative with pancreas adenocarcinoma, the frequency of BRCA 1 or 2 mutation carriers is estimated at 11-17%. PALB2 (partner and localizer to BRCA2) mutations occur in a smaller fraction of patients with pancreas adenocarcinoma. The PALB2 protein stabilizes the BRCA 2 protein and anchors it to the nucleus, allowing it to carry out its DNA repair function. More recently, PALB2 has been shown to associate with the BRCA 1 protein, providing a linkage between BRCA 1 and 2 in homologous recombination repair of double-stranded DNA breaks. Preclinical data has demonstrated hypersensitivity of BRCA 2 deficient pancreatic cell lines to DNA cross-linking agents mitomycin and cisplatin and more recently to the novel agents, poly (ADP-ribose) polymerases (PARP) inhibitors. We and others have reported increased sensitivity to DNA damaging agents in patients with pancreas adenocarcinoma arising on a background of a known BRCA 1 or 2 germline mutation. Poly ADP ribose polymerases are a family of enzymes, two of which, PARP1 and 2, are key components of the DNA repair mechanism for cells with single-strand breaks and nucleoside base damage. PARP inhibition has particular application in tumors with pre-existing defects in homologous recombination, such as BRCA 1 or 2 deficient cells. Inhibition of PARP in these cells leads to transformation of single-strand breaks into double-strand breaks (DSB), which are cytotoxic in cells, which are unable to repair DSBs by homologous repair. This effect of synthetic lethality provides the therapeutic rationale for development of PARP inhibitors for BRCA 1 or 2 mutation associated pancreas adenocarcinoma. Veliparib (ABT-888) is an orally available, small molecule inhibitor of polyADP-ribose polymerase. Three trials are evaluating the role of role of veliparib in combination with cisplatin-based therapy in patients with BRCA or PALB2 mutated pancreas adenocarcinoma. Data will be presented on the first of these trials, which is a phase IB study designed to determine the recommended phase II dose of veliparib in combination with cisplatin and gemcitabine for patients with a either a known BRCA or PALB2 mutation or a very strong personal or family history of malignancy. Between 02/12 and 10/13, 33 patients were screened and 17 enrolled. Male = 10, Female = 7. Median age = 60 years (range 42- 72). BRCA = 9. Non-BRCA = 8. Four dose levels of veliparib were evaluated; Two dose-limiting toxicities of veliparib were observed at an 80mg daily continuous dosing schedule (neutropenia, thrombocytopenia). Overall grade 3-4 toxicities: Hematologic, fatigue and one fatal bowel perforation tumor/diverticulitis. For N= 9 BRCA patients tumor response: 5 (56%) partial responses and 4 (44%) stable disease. No objective responses were seen in the non-BRCA patients. The recommended phase II dose of Veliparib is 80 mg PO BID day 1-12 q 3 weeks with fixed dose cisplatin and gemcitabine. The triplet combination of cisplatin, gemcitabine and veliparib shows high activity in BRCA-related pancreas adenocarcinoma. A randomized phase II trial evaluating cisplatin/gemcitabine +/- veliparib is underway in BRCA/PALB2-mutated pancreas adenocarcinoma (NCT01585805). In addition to the clinical trials, there are a series of correlative science questions focused around: (1) characterization of the molecular phenotype of BRCA/PALB2 mutated pancreas adenocarcinoma, (2) mechanisms of resistance to platinum and PARP inhibition, (3) evaluation of assays for homologous repair, (4) evaluation of loss of heterozygosity at BRCA 1, 2 loci in tumor, and other considerations.