Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes

Abstract

Background: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC).

Methods: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method.

Results: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2).

Conclusions: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

Keywords: BRCA; biallelic; germline; pancreas; platinum; somatic; zygosity.

Figure 1.

This is a CONSORT (Consolidated Standards for Reporting Trials) diagram of the current study.

Figure 2.

(A) Median overall survival is illustrated (A) for patients with stage IV pancreas cancer who did and did not receive frontline platinum therapy and (B) for patients with stage IV pancreas cancer who received frontline platinum therapy according to zygosity. (C) Platinum therapy and poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) therapy are illustrated in patients who had oncogenic BRCA1/BRCA2 alterations. This Swimmer plot indicates the months on therapy (either platinum-based or PARPi therapy) for 12 evaluable patients who had pancreatic cancer harboring an oncogenic* BRCA1/BRCA2 mutation (BRCA mut). Platinum response analysis was restricted to patients who had stage IV disease. Two patients with stage IV disease received platinum therapy followed by maintenance PARPi, and only their PARPi duration is captured on the plot. One patient who received a PARPi had a BRCA2 mutation of unknown significance. POD indicates progression of disease; PR, partial response; SD, stable disease.

Figure 3.

Median overall survival is illustrated (A) for the entire cohort and (B) according to disease stage at diagnosis.