Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations

Kim A. Reiss; Shun Yu; Renae Judy; Heather Symecko; Katherine L. Nathanson; Susan M. Domchek

Disclosures

JCO Precis Oncol 

In This Article

Abstract and Introduction

Abstract

Purpose: Germline mutations in the homologous recombination (HR) genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in HR genes are sensitive to DNA-damaging agents, such as platinum chemotherapies. We hypothesized that patients with PDAC with germline BRCA1, BRCA2, or PALB2 mutations may benefit preferentially from platinum-based chemotherapy.

Materials and Methods: Twenty-nine individuals with deleterious germline mutations in BRCA1, BRCA2, or PALB2 and a diagnosis of advanced PDAC (mut-positive) were matched 2:1 to patients who were noncarrier or untested (control) by age at diagnosis, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at the University of Pennsylvania: the Basser Center for BRCA Registry or the University of Pennsylvania Electronic Medical Patient Record. Treatment history, including exposure to platinum-based chemotherapy, was ascertained. Primary objective was overall survival (OS).

Results: Patients who were mut-positive had an OS of 21.8 months; control patients had an OS of 8.1 months (hazard ratio [HR], 0.35; 95% CI, 0.2 to 0.62; P < .001). With platinum exposure, patients who were mut-positive had an undefined OS (median follow-up, 20.1 months), versus an OS of 15.5 months in the control patients (HR, 0.25;95%CI, 0.1 to 0.61;P= .002). In patients not treated with platinum, there was no significant difference in OS between groups (HR, 0.54; 95% CI, 0.25 to 1.17; P = .12). When treated with platinum therapy, patients who were mut-positive had a 1-year OS of 94%, compared with a 1-year OS of 60% in control patients.

Conclusion: Platinum-based therapy may confer a survival benefit in patients with advanced PDAC who carry a deleterious germline BRCA1, BRCA2, or PALB2 mutation.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly prevalent and often rapidly fatal malignancy.[1–3] Even with the relatively recent introduction of gemcitabine plus paclitaxel[4] and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX)[5] chemotherapy regimens, the median overall survival for patients with inoperable disease remains abysmal at < 1 year. However, PDAC that develops in the setting of a germline BRCA1, BRCA2, or PALB2 mutation may represent a biologically different group compared with sporadic PDAC.

It is estimated that in an unselected population of patients with PDAC, the incidence of a germline BRCA1 or BRCA2 mutation is < 4%,[6,7] with higher rates observed in those with a strong personal or family history of pancreatic cancer or BRCA-related malignancies.[8] The incidence of germline PALB2 mutations in persons with PDAC is estimated to be between 0.6% and 2.1%.[7,9,10]

BRCA1 and BRCA2 are key proteins involved in homologous recombination,[11,12] and PALB2 is an essential regulator of BRCA2 function.[13] Loss of function of these genes leads to homologous recombination deficiency (HRD). Because of the inability to effectively repair double-strand DNA breaks, tumors that harbor an HRD are particularly sensitive to DNA damaging and cross-linking agents,[14,15] such as the platinum chemotherapies. Clinically, breast and ovarian cancers associated with BRCA1 and BRCA2 mutations have heightened sensitivity to platinum-based chemotherapies and to PARP inhibitors.[16–22] These observations suggest that patients with PDAC due to BRCA1, BRCA2, or PALB2 germline mutations with resulting HRD might also benefit from similar therapeutic strategies.

Early data have suggested that patients with advanced PDAC and a germline BRCA1/2 mutation who received platinum treatment had higher tumor response rates and improved overall survival compared with those who did not receive platinum.[23] However, because of their high toxicity, platinum-based therapies such as FOLFIRINOX are often reserved for the younger, healthier patients. Therefore, without an age-matched control group, it is unclear whether the inherent bias to select platinum-based treatment in healthier patients might have affected these results.

We performed a retrospective cohort study of patients with unresectable PDAC. We evaluated 29 patients who harbored a germline BRCA1, BRCA2, or PALB2 mutation (mut-positive). These were matched 2:1 with patients who either had not been tested or were known not to have a germline deleterious mutation (referred to collectively as control) by age at diagnosis, year of diagnosis, stage at diagnosis, and sex. We hypothesized that patients who were mut-positive would respond superiorly to platinum-based treatment and that this therapy would positively affect their survival.

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