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

Abstract

In pancreatic cancer (PC), the <i>RAF</i> family alterations define a rare subset of patients that may predict response to inhibition of the <i>BRAF/MEK/ERK</i> signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of <i>RAF</i>-mutated PC may support future development of <i>RAF</i>-directed strategies. Clinical outcomes were assessed across a multi-institutional case series of 81 patients with <i>RAF</i> family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications. The frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where <i>BRAF</i> V600E (Exon 15), <i>BRAF ΔNVTAP</i> (Exon 11), and <i>SND1-BRAF</i> fusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a <i>BRAF</i> V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with <i>BRAF</i> or <i>RAF1</i> fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical <i>RAF</i> variants and/or multiple oncogenic drivers. Clinical benefit from <i>BRAF/MEK/ERK</i> 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 (<i>P</i> = .027). Prospective evaluation of <i>RAF</i>-directed therapies is warranted in <i>RAF</i>-mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials.