The complementary value of ctDNA and tissue NGS in lung cancer.

Abstract

e20672 Background: This study compares the concordance and clinical utility of ctDNA-based plasma testing with Next-Generation Sequencing (NGS) performed on tumor tissue, providing insights into their respective roles in personalized cancer care. Methods: We retrospectively analyzed genomic data from 112 patients (p) diagnosed with stage III-IV lung cancer and with tissue biopsies deemed suitable for tissue-based NGS (Oncomine Precision Assay[OPA]) who underwent concurrent plasma-based NGS (VHIO360, an ISO15189 accredited ctDNA panel using Guardant360 technology), within a 40-day window, between July 2022 and April 2024. Liquid biopsy specimens were always obtained at the time of diagnosis or disease progression. Concordance between techniques was evaluated with overlap coefficient and Jaccard index. Results: Among the 112 p, 62(55.3%) were male. All had stage III (9.8%) or IV (90.2%) disease. 93 (82%) with lung adenocarcinoma, 6 (5.3%) with large cell neuroendocrine carcinoma, 2 (1.8%) with squamous carcinoma, and 2 (1.8%) with small cell carcinoma. Tumor tissue had inadequate DNA/RNA quality for analysis in 5 p (4.5%). Liquid biopsy found no mutations in 16 p (14.3%). A total of 71 p showed concordant pathogenic mutations (mut) in both tissue and plasma samples. Gene fusions were detected in 8 tissue samples and 6 in plasma samples. ESCAT I-II genomic alterations (alt) were identified in 59 p (52.7%); 57 p detected by tissue and 39 p through plasma. The overlap coefficient for ESCAT I-II alt was 94.9%, whereas Jaccard index was 62.7%. Particularly, Jaccard index was 100% for EGFR uncommon mut, ERBB2 , RET and ROS1 fusions and 50% for EGFR exon 20 insertions (ins), ALK fusion and MET amplifications (Table 1). Regarding TP53 mut, 80 patients ≥ 1pathogenic TP53 mut detected by at least one of both panels. Among these, 41.3% (33/80) were associated with ESCAT I-II alt, and 58.7% (47/80) were not. Conclusions: ctDNA and tissue NGS presented similar ESCAT I-II genomic alterations identification, particularly when adequate tissue samples are available. However, in certain cases, clinically meaningful mut were detected by only one method, demonstrating the utility of complementary testing, specially for EGFR exon 20 ins. Additionally, some relevant alt, such as concomitant mut in TP53 , were identified differently by the two approaches, further emphasizing their complementary roles. Genomic alt in tissue-NGS and plasma-NGS. Gene alt OPA VHIO 360 Same alt in both OPA only VHIO360 only Overlap coefficient (%) Jaccard Index (%) EGFR (L858R, deletion exon 19)* (exon 20 ins)* (G719, L861Q, S768I)* 2514 1924 1914 600 010 100100100 7650100 ALK fusions* 5 4 3 2 1 75 50 KRAS G12C* 12 9 8 4 0 88.9 61.5 RET fusions* 1 1 1 0 0 100 100 ROS1 fusions* 1 1 1 0 0 100 100 BRAF (V600E)* 1 0 0 1 0 0 0 MET Mut exon 14 skipping Amplifications 42 01 01 41 00 0100 050 ERBB2* 1 1 1 0 0 100 100 TP53 mut 45 70 33 12 37 73.3 41.3 *Genomic alterations level I/II according to ESCAT. Mosele, M.F. et al. Ann Oncol.2022; 35: 588-606.