Retrospective Case Series Analysis of RAF Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies. (2021)

• Record Type: Journal Article
• Authors: Hendifar, Andrew; Blais, Edik M.; Wolpin, Brian; Subbiah, Vivek; Collisson, Eric; Singh, Isha; Cannon, Timothy; Shaw, Kenna; Petricoin, Emanuel F.; Klempner, Samuel; Lyons, Emily; Wang-Gillam, Andrea; Pishvaian, Michael J.; O'Reilly, Eileen M.
• Is Part Of: JCO precision oncology. Volume 5(2021)
• Publication Date: 2021
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.20.00494
• Languages: English
• ISSNs: 2473-4284

Abstract

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