Multigene profiling to identify clinically relevant actionable mutations in head and neck cancers: An Indian study.

Abstract

e18529 Background: Head and Neck squamous cell carcinoma (HNSCC) represents approximately 5-10% of malignancies worldwide. Despite the advances in treatment modalities there lies a disparity in response, owing to the underlying molecular and genetic make up. In the era of precision medicine, it is important to profile each disease and customise treatment to improve the outcomes by identifying predictive or prognostic indicators at the molecular and genetic level. Methods: 100 patients with HNSCC, diagnosed at our centre from April 2015-17 were profiled by targeted deep sequencing for hotspot mutations in 48 cancer-related genes using Illumina’s TSCAP panel and MiSeq technology. The average coverage across 220 hot spots was greater than 1000X. Data was processed using Strand Avadis NGS. Mutations identified in the tumor were assessed for ‘actionability’ i.e. response to therapy and impact on prognosis. The clinical data for these patients was collected retrospectively and analysed for treatment outcomes with standard therapy. The association of mutations with habits, stage at presentation, poor treatment outcomes and prognosis was also analysed. Results: Somatic variants were detected in 63.1% of cases. Genetic aberrations were identified in major RAS/RAF signalling pathway in 10 % of cases out of which HRAS activating mutations were the most common (n=4). HRAS was co-mutated with PI3KCA (n=3) and PTEN deletions (n=2). Based on the result, Cetuximab was discontinued in 2 patients with metastatic HNSCC. Other targetable mutations included ATM (n=1), STK11 (n=1), RB1 (n=1) and BRAF (n=1). Disruptive and non-disruptive mutations in TP53 alone were found in 43.8% of H&N cancers, varying widely among different histology with variable treatment outcome. Interestingly all metastatic/recurrent patients, with very short progression free survival of 9-12 months (PFS) post Cisplatinum based chemotherapy, were found to have mutated TP53. TP53 was also found to be co- mutated with ATM gene (n=1), an important prognostic marker, indicating poor response to chemotherapy and radiotherapy. The patients with recurrence and poorer prognosis (n =5) showed point mutations in codon regions 173 -273. Conclusions: Indian patients with HNSCC display a wide mutational landscape with specific actionable targets. Although traditional treatment modalities remain the standard of care, specific mutations may be utilised to customise treatment, prognosticate and predict outcomes.