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Trever G Bivona

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    OA 12 - Emerging Genomic Targets (ID 679)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)

      11:00 - 12:30  |  Presenting Author(s): Trever G Bivona

      • Abstract
      • Presentation
      • Slides

      Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.

      The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.

      A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.

      This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.

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