Retrospective Case Series Analysis of Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies.

Purpose: In pancreatic cancer (PC), the family alterations define a rare subset of patients that may predict response to inhibition of the signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of -mutated PC may support future development of -directed strategies.

Methods: Clinical outcomes were assessed across a multi-institutional case series of 81 patients with family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications.

Results: The frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where V600E (Exon 15), (Exon 11), and fusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with or fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical variants and/or multiple oncogenic drivers. Clinical benefit from inhibitors was observed in 3 of 3 subjects within the V600 subgroup (two partial responses), 4 of 6 with fusions (two partial responses), 2 of 6 with Exon 11 mutations (one partial response), and 0 of 3 with confounding drivers. Outcomes analyses also suggested a trend favoring fluorouracil-based regimens over gemcitabine/nab-paclitaxel within the fusion subgroup ( = .027).

Conclusion: Prospective evaluation of -directed therapies is warranted in -mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials.