Impact of Germline <i>BRCA</i> Mutation Status on Antitumor Activity of Modified FOLFIRINOX in Patients With Advanced Pancreatic Cancer: An Exploratory Analysis.

Abstract

Germline <i>BRCA</i> (g<i>BRCA</i>) mutations confer increased sensitivity to platinum-based chemotherapy and have been associated with improved survival across several malignancies. This study investigated the effect of g<i>BRCA</i> mutation status on the antitumor activity of modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX; mFFX) in patients with advanced pancreatic cancer (APC). This multicenter retrospective study was performed in 178 patients with histologically confirmed APC who received mFFX, comprising 17 g<i>BRCA</i>-positive and 161 g<i>BRCA</i>-negative individuals. Efficacy outcomes, including progression-free survival (PFS), objective response rate (ORR), and normalization rate of carbohydrate antigen 19-9 (CA19-9), were compared between groups using univariate and multivariate analyses. Median PFS was significantly longer in g<i>BRCA</i>-positive than in g<i>BRCA</i>-negative patients (10.6 <i>v</i> 5.3 months, <i>P</i> = .005). Independent predictors of PFS included g<i>BRCA</i> mutation (hazard ratio [HR], 3.65), disease extent (HR, 2.34), and previous chemotherapy (HR, 1.66). g<i>BRCA-</i>positive patients demonstrated a significantly higher ORR (82% <i>v</i> 34%, odds ratio, 0.11, <i>P</i> < .001) and CA19-9 normalization rate (69% <i>v</i> 10%, <i>P</i> < 0.01). ORR was associated with g<i>BRCA</i> status (HR, 0.04), disease extent (HR, 0.11), and treatment history (HR, 0.27). Among 68 responders, sustained shrinkage of both primary and metastatic tumors and continued CA19-9 decline were observed during the first 6 months in g<i>BRCA-</i>positive patients, whereas responses in g<i>BRCA</i>-negative patients plateaued after 3 months. Subgroup analysis revealed that most patient subgroups demonstrated superior PFS and ORR in the g<i>BRCA</i>-positive cohort compared with those in the g<i>BRCA</i>-negative cohort. g<i>BRCA</i> mutation status was strongly associated with enhanced radiologic and biological responses to mFFX in APC. Routine screening for g<i>BRCA</i> mutations may provide essential guidance in therapeutic decision making and substantially improve clinical outcomes in this population.