Abstract 112P
Background
Atypical BRAF mutations at codons aside from V600 (non-V600) and BRAF fusions activate the MAP kinase/ERK-signaling pathway, however the landscape of these alterations has yet to be well-defined. While selective inhibitors of BRAF V600 plus MEK inhibitor combinations are EMA- and FDA-approved for melanoma, NSCLC and anaplastic thyroid cancer, drug development for atypical BRAF alterations has been staggered. Here, we present a comprehensive analysis of non-BRAF V600 mutations and BRAF fusions in pan-cancer adult malignancies.
Methods
We analyzed 136,096 samples from 121,221 patients available from AACR Project GENIE v.11 database for the prevalence of non-BRAF V600 BRAF mutations and BRAF fusions in a range of cancer types.
Results
3624 unique non-V600 BRAF mutations were identified in 3340 samples (2.5%), most frequently in lung (21.3%,772), melanoma (16.8%,608), colorectal cancer (12.7%,461). 2938 missense mutations (81%) were identified, most identified as driver mutations (62%);1115 missense mutations were variants of uncertain significance (VUS)(38%). Missense mutations occurred across codons, most frequently involving codon 469 (13.8%, 405), 594 (12.7%, 374) 601 (7.9%, 232) 466 (7.5%, 221), 581 (161,5.5%). 126 truncating mutations (3.5%) were identified, 156 in-frame alterations (4.3%). BRAF fusions were detected in 0.4% of tumor samples (539), most identified as likely oncogenic events (83%). Variant fusion partners were diverse (137 identified), most frequently seen in pilocytic astrocytoma (32%,117), melanoma (11%,39), prostate (10%,37), lung (6.5%, 24). Aside from intragenic fusions, all fusion partners were likely oncogenic. Common fusion gene partners included KIAA1549, SND1, MKRN1 and AGK. (34%, 3.9%, 3.5%, 3.3% of 539 samples). BRAF amplification occurred in 0.15% of tested samples.
Conclusions
Atypical non-V600 BRAF mutations and BRAF fusions represent a rare, but distinct cohort across tumor types. Most missense mutations and fusion events are described as oncogenic, highlighting the urgent need to develop drugs beyond current BRAF V600 indications. Further functional characterization of atypical BRAF variants and basket trial enrollment are warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology, Blueprint Medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. All other authors have declared no conflicts of interest.