Utility of plasma cell-free DNA and tissue next generation sequencing (NGS) in detecting genetic mutations in non-small cell lung cancer (NSCLC).

e20514 Background: NSCLC is defined by molecular alterations driving tumor progression and therapeutic response. Genetic profiling traditionally relies on tissue biopsies, often hindered by insufficient samples, tumor heterogeneity, or inability to perform repeat biopsies. ctDNA analysis has emerged as a complementary approach. The Oncomine Pan-Cancer Cell-Free Assay is a robust NGS platform detecting diverse genetic alterations in ctDNA. This study evaluated the utility and concordance of the Oncomine ctDNA NGS assay in suspected advanced NSCLC cases and its role when tissue-based testing could not be performed. Methods: A prospective cohort study analyzed ctDNA from patients with suspected advanced NSCLC using the Oncomine Pan-Cancer Cell-Free Assay. Conducted at the Anna and Peter Brojde Lung Cancer Centre with support from the McGill Rossy Cancer Network. Results: Of 68 patients tested with ctDNA NGS Oncomine, 44/68 (65%) were positive, 15/68 (22%) negative for mutations, and 9/68 (13%) inconclusive, likely due to low ctDNA fractions or technical sensitivity. Among positive results, 19/44 (43%) had targetable mutations, including EGFR (12/19), KRAS (6/19), and BRAF (1/19), while 25/44 (57%) were non-targetable. Inconclusive cases revealed 6 targetable mutations via SOC NGS: BRAF (2), EGFR (2), ERBB2 (1), and KRAS (1). The correlation of mutation detection between the ctDNA NGS test and the standard-of-care (SOC) tissue NGS test (Table 1) was assessed on 57/68 cases as for 11/68 cases the SOC genetic tissue testing was not performed: 5 were SCLC, and 6 had other diagnoses. Among cases tested on both 42/57 (74%) were highly concordant: 27/57 (47%) were positive and 15/57 (26%) were negative on both tests. Conversely 15 (26%) cases were discordant: 9 of SOC-negative cases were found to be positive by Oncomine with 2/9 (both were EGFR) being targetable. Another 6 cases were negative on Oncomine but positive on SOC NGS. Conclusions: This study highlights the complementary benefit of incorporating ctDNA to SOC NGS in the initial diagnosis of advanced NSCLC. Oncomine ctDNA was able to identify mutations in 9 patients with negative SOC NGS molecular testing. Similarly, SOC NGS identified 9 pts with mutations that were negative on Oncomine ctDNA. In addition, there are still inconclusive results from the ctDNA – oncomine testing, thus requiring SOC tissue NGS for results. Further advances in technology may improve ctDNA sensitivity to eventually surpass tissue SOC NGS. Concordance between ctDNA and SOC tissue NGS tests. SOC NGS Oncomine-ctDNA Positive Negative Total P value Positive 27 (43%) 9 (14%) 36 (57%) <0.001 Negative 6 (10%) 15 (23%) 21 (33%) Inconclusive* 6 (10%) 0 (0%) 6 (10%) Total 39 (63%) 24 (37%) 63 (100%) *6/9 inconclusive ctDNA had SOC NGS done.

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