Abstract LB287: Mutational profile of ‘therapy-naïve’ non small cell lung cancers (NSCLC) in western Indian population reveals an alarming preponderance of ‘resistance-causing’ genomic alterations necessitating deeper questioning of prevalent ‘standa

Abstract Most private cancer hospitals in India have moving population of patients who may not pursue treatment-lifecycles at the same institution and may migrate from one centre to another for logistic reasons. From a retrospective dataset of 2 years, we identified a subset of 242 treatment-naïve patients of NSCLC who presented at our centre and continued medical oncology care at our hospital/s till present day or till death. Of these therapy-naïve patients, a remarkable 58% (140) revealed the presence of ‘therapeutically resistant’ mutational patterns at baseline, wherein, approved first-line chemotherapeutic or target regimes are not likely to be fully effective. While we continue to follow-up these patients for response to administered therapeutic regimes, this staggering propensity of molecular resistance pattern highlights the need to perform comprehensive genomic profiling of all lung cancers before taking first-line therapeutic decisions. Of the above, 53% (74) revealed co-occurrence of actionable and resistance-causing mutations, with further following subdivisions:A. 66% (n=48) had co-occurrence of EGFR with another single downstream resistance-causing mutation.B. 16% (n=12) had EGFR co-mutations along with other complex resistance mutations (involving more than two downstream pathways).C. 19% (n=13) had non-EGFR actionable mutations (Like ALK) alongside another single resistance-causing mutation. The other subset of 47% (65) revealed presence of only resistance-causing mutations, with further following subdivisions:A. 31%: KRAS mutations B. 8%: PIK3CA mutationsC. 40%: TP53 mutations (considering that presence of isolated somatic TP53 LOF mutations lead to suboptimal response to chemotherapy)D. 21%: Other downstream resistance-causing mutations (eg MYC amplification) This study demonstrates that while actionable mutations were hitherto considered to be commonly prevalent in treatment-naïve NSCLC patients, the preponderance of resistance-causing mutations can significantly impact treatment outcomes, contributing to early disease progression and resistance to targeted therapies as well to standard of care chemotherapies. Comprehensive genome profiling of all NSCLCs at baseline may be crucial to personalize therapeutic regimes for ensuring durable response to first line treatment. Citation Format: Chirantan Bose, Karishma Todi, Ashish Joshi, Vashishth Maniar, Kshitij Joshi, Pritam Kalaskar, Udip Maheshwari, Pradip Kendre, Tushar Patil, Ashwin Rajbhoj, Sanjay Singh, Priyanka Singh. Mutational profile of ‘therapy-naïve’ non small cell lung cancers (NSCLC) in western Indian population reveals an alarming preponderance of ‘resistance-causing’ genomic alterations necessitating deeper questioning of prevalent ‘standard-or-care’ approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB287.