Spectrum of BRAF mutations in Indian patients with NSCLC: A molecular kaleidoscope.

Abstract

e21199 Background: Mutations in the BRAF gene (0.8%-8% cases of NSCLC) comprise a molecularly heterogeneous group, with the canonical V600E mutation as well as myriad variants. Traditionally, diagnostics utilize modalities like mutation specific IHC or allele specific real-time PCR for detection of V600E variant and may underestimate the true prevalence of non-V600E variants. Broader panel next generation sequencing (NGS) testing may be a better modality for detecting them and this may have potential therapeutic implications. This retrospective study of patients with BRAF mutated NSCLC looked at their molecular and clinicopathologic spectrum. Methods: 260 patients underwent panel based NGS testing between 2017-2020. BRAF mutant cases, detected at any point during the course of their disease, were reviewed for clinical, pathologic, molecular features; as well as associated treatment and outcomes. Results: BRAF alterations were seen in 14/260 (5.38%) patients. Median age of the cohort was 62 years (range: 39-86 years) with a female predilection (8/14, 57.1%). BRAF V600E mutation was seen in 6 (42.9%) patients and 8 (57.1%) harbored a non-V600E alteration; the spectrum of which included G466E, G469A, N581I, V600_K601delins, D594G, L597Q, G649V and a TRIM24-BRAF fusion. All patients were never smokers with an adenocarcinoma histology.11 (78.6%) patients had extra thoracic metastases, and 2 (14.3%) cases had metastases to the brain at diagnosis. 11/14 (78.6%) patients had presence of liver metastases (V600E vs non V600E: 43% vs 57%, p = 0.09). 11 patients took treatment at our centre and two patients received anti-BRAF therapy. One patient with V600E mutation received vemurafenib. The other patient with a nonV600E mutation (V600_601delins, detected on NGS) received combination dabrafenib-trametinib with an ongoing partial response at 6 months. 8 patients received chemotherapy and median PFS was 4.8 months, similar for all mutation types. Median OS for the entire cohort was not reached owing to high censorship. Conclusions: This single centre study depicts distinct clinicopathologic features in Indian patients with BRAF mutant NSCLC. The higher prevalence of non-V600E mutation may be attributed to increased use of broader panel based NGS testing as opposed to sequential single gene testing. One of the patients with a non-V600E mutation responded to targeted therapy, hence clinicians should be aware of this spectrum of potentially targetable BRAF mutations.