Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation

Abstract

Background: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined.

Methods: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS.

Results: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068).

Conclusion: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

Fig. 1

Best Objective Response to Platinum Based Treatment. Waterfall plots showing best percentage change in target-lesion size from time of initiation of platinum-based therapy. a Best overall change in tumour size in control patients. For the control cohort, 13 patients were not included due to undefined change in tumour size. b Best overall change in tumour size in mut-positive patients. For the mut-positive cohort, two patients were not included due to undefined change in tumour size. The upper dashed line indicates a 20% increase in tumour size and the lower dashed line indicates a 30% reduction in tumour size

Fig. 2

Real World Progression Free Survival. a The rwPFS was 10.1 months in the mut-positive cohort as compared to 6.9 months in the control cohort (HR 0.43; 95% CI 0.25–0.74; p = 0.0068). b A subset analysis comparing rwPFS with platinum use, by line of therapy. The rwPFS of mut-positive patients who received platinum-based chemotherapy in the first-line setting was 21.2 months as compared to 7.9 months for control patients treated with platinum in the first-line setting (p = 0.0046) and 2.5 months for mut-positive patients treated with platinum in the second-line setting (p = 0.0001). Kaplan-Meier methodology was used to estimate rwPFS. The hazard ratio was estimated by means of the log-rank test