Treatment of metastatic pancreatic cancer with concurrent BRAF V600E mutation and germline BRCA2 mutation: a case report.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) with concurrent somatic BRAF V600E and germline BRCA2 mutations is exceedingly rare. While BRAF mutations define a distinct KRAS-wildtype subset, and BRCA2 mutations are associated with homologous recombination deficiency and sensitivity to platinum-based therapy/PARP inhibitors, the clinical behavior and optimal treatment strategy for tumors harboring both alterations remain unknown. This case report adds to the limited literature by detailing the therapeutic course and inherent challenges in managing this unique molecular subtype.

Case description: A 61-year-old male underwent distal pancreatectomy for moderately differentiated PDAC (pT2N1M0). Molecular profiling revealed a somatic BRAF V600E mutation and a germline BRCA2 pathogenic mutation (p.F1241Vfs*17) with somatic second-hit inactivation (p.E2953*), indicating biallelic loss. Post-operative adjuvant gemcitabine/nab-paclitaxel was administered. Upon recurrence, platinum-based therapy (S-1/oxaliplatin) was poorly tolerated and ineffective. Subsequent olaparib maintenance achieved a transient partial response (PR) [progression-free survival (PFS): 5.5 months] before progression. Therapy was then switched to dabrafenib/trametinib (BRAF/MEK inhibition), which led to initial tumor shrinkage but was followed by rapid disease progression with malignant ascites. The patient died 22 months post-surgery despite combined targeted therapy and intraperitoneal chemotherapy.

Conclusions: This case highlights that the co-occurrence of BRAF V600E and biallelic BRCA2 mutations may confer a unique clinical phenotype with suboptimal or transient responses to both BRCA-directed therapies (platinum, olaparib) and BRAF/MEK inhibition. It underscores the complexity of precision oncology in PDAC, where genotype does not always predict therapeutic response, potentially due to factors like tumor heterogeneity, stromal barriers, or undiscovered resistance mechanisms. Future large-scale studies are needed to define prognostic implications and explore potential combination strategies (e.g., BRAF/MEK + PARP inhibitors) for this rare molecular cohort.