The actionable genomic mutational landscape in solid tumours.

Abstract

e13642 Background: The recent exponential increase in targeted agents and immunotherapies provide new therapeutic opportunities for patients with advanced cancers who have failed first line therapy. However, lack of comprehensive precision oncology testing as part of routine pathology assessment means potential therapeutic opportunities are difficult to identify or remain undiscovered for many patients. Methods: To address this unmet clinical need we established Oncofocus, a clinically validated, ISO15189/2012 and CLIA accredited, precision oncology test optimized for analysis of small diagnostic PWET clinical biopsy samples (sample acceptance 94%). Oncofocus detects actionable genetic variants in 505 genes linked to 764 anti-cancer targeted therapy protocols, either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials. Oncofocus trending data was analyzed for a real-life cohort of 1111 patients with the aim of determining the frequency of actionable mutations in this population. This cohort represent patients with advanced stage disease who underwent Oncofocus testing having failed first line treatment protocols. Results: Analysis of trending data revealed a complex mutational landscape in which 90% of solid tumors harbored actionable mutations. The majority of patients harbored one or more actionable mutations (median 2, range 0-13) affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signaling pathways, DNA-damage repair pathways and cell cycle checkpoints. Actionable genetic variants across 33 DNA Damage and Repair (DDR) genes were identified in 30% of tumors. Using a defined predictive cut point of > 10% for tumor proportion score, PD-L1 expression levels were significantly raised in 19% of cases. Abrogation of DDR function and elevated PD-L1 levels were identified in 5% of patients, a subpopulation potentially more responsive to immunotherapy. Notably, many of the actionable mutations identified did not show linkage with histological type or site of origin. Conclusions: Our data indicates that comprehensive precision oncology testing should be strongly considered as part of the diagnostic work up for all patients with advanced cancers, independent of tumor type, thereby ensuring capture of all targeted therapy opportunities and accelerating “site agnostic” molecular basket clinical trials. Comprehensive precision oncology testing was performed successfully on routine biopsy samples circumventing the requirement for fresh tissue or large sample specimens.