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

PURPOSE: Germline BRCA (gBRCA) mutations confer increased sensitivity to platinum-based chemotherapy and have been associated with improved survival across several malignancies. This study investigated the effect of gBRCA mutation status on the antitumor activity of modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX; mFFX) in patients with advanced pancreatic cancer (APC).

METHODS

This multicenter retrospective study was performed in 178 patients with histologically confirmed APC who received mFFX, comprising 17 gBRCA-positive and 161 gBRCA-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.

RESULTS

Median PFS was significantly longer in gBRCA-positive than in gBRCA-negative patients (10.6 v 5.3 months, P = .005). Independent predictors of PFS included gBRCA mutation (hazard ratio [HR], 3.65), disease extent (HR, 2.34), and previous chemotherapy (HR, 1.66). gBRCA-positive patients demonstrated a significantly higher ORR (82% v 34%, odds ratio, 0.11, P < .001) and CA19-9 normalization rate (69% v 10%, P < 0.01). ORR was associated with gBRCA 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 gBRCA-positive patients, whereas responses in gBRCA-negative patients plateaued after 3 months. Subgroup analysis revealed that most patient subgroups demonstrated superior PFS and ORR in the gBRCA-positive cohort compared with those in the gBRCA-negative cohort.

CONCLUSION

gBRCA mutation status was strongly associated with enhanced radiologic and biological responses to mFFX in APC. Routine screening for gBRCA mutations may provide essential guidance in therapeutic decision making and substantially improve clinical outcomes in this population.