Abstract
BackgroundRetrospective 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.MethodsTwenty-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.ResultsThe 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).ConclusionMut-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.
Highlights
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
BRCA1 and BRCA2 are key proteins involved in homologous recombination,[11,12] and PALB2 is an essential regulator of BRCA2 function.[13]
Patient characteristics Overall, 26 mut-positive patients with either locally advanced or metastatic Pancreatic ductal adenocarcinoma (PDAC) were identified with the following mutational breakdown: BRCA1 (n = 5), BRCA2 (n = 17) and PALB2 (n = 4)
Summary
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). CONCLUSION: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy These findings may have implications in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC. Unique biological subsets of PDAC with distinctive clinical characteristics, including sensitivity to specific therapies, have become increasingly recognised.[4] One such subgroup includes carriers of a mutation in one of the homologous recombination genes BRCA1, BRCA2 or PALB2 This phenomenon occurs in approximately 6% of the overall PDAC population, with higher rates in those with a personal or family history of BRCA-related malignancies.[5,6,7,8,9,10]. Due to the inability to effectively repair double strand DNA breaks, tumours that harbour a HRD are sensitive to DNA damaging and cross-linking agents such as platinum-based chemotherapy.[14,15] Clinically, breast and ovarian cancers associated with BRCA1 and BRCA2 mutations show heightened sensitivity to platinum-based chemotherapy.[16,17]
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