Retrospective case series analysis of RAF family alterations in pancreatic cancer: Real-world outcomes from targeted and standard therapies Journal Article


Authors: Hendifar, A.; Blais, E. M.; Wolpin, B.; Subbiah, V.; Collisson, E.; Singh, I.; Cannon, T.; Shaw, K.; Petricoin, E. F. 3rd; Klempner, S.; Lyons, E.; Wang-Gillam, A.; Pishvaian, M. J.; O’Reilly, E. M.
Article Title: Retrospective case series analysis of RAF family alterations in pancreatic cancer: Real-world outcomes from targeted and standard therapies
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. © 2021 by American Society of Clinical Oncology
Keywords: survival; braf gene; mutations; patient; efficacy; inhibition; ductal adenocarcinoma; vemurafenib; trametinib; reveal
Journal Title: JCO Precision Oncology
Volume: 5
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2021-08-25
Start Page: 1325
End Page: 1338
Language: English
DOI: 10.1200/po.20.00494
PROVIDER: scopus
PMCID: PMC8407652
PUBMED: 34476331
DOI/URL:
Notes: Article -- Export Date: 2 November 2021 -- Source: Scopus
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  1. Eileen O'Reilly
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  2. Isha Singh
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