Abstract 966: Longitudinal comparative analysis of circulating tumor DNA and matched tumor tissue DNA in patients with metastatic colorectal cancer receiving palliative first-line systemic anti-cancer therapy

Abstract Background: Plasma circulating tumor DNA (ctDNA) analysis has become an attractive method for precision oncology. This study compared mutational landscapes of ctDNA with matched tumor tissue DNA (ttDNA) to explore clinical applicability and to better understand clonal evolution in patients with metastatic colorectal cancer receiving palliative first-line systemic anti-cancer therapy (SACT). Methods: We performed unique molecular identifier-based targeted sequencing of 88 cancer-associated genes using the following samples: ttDNA, germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). Results: Of the 208 consecutively enrolled patients, 84 were selected (41 males; median age 59, ranging from 35 to 90) with access to all four samples. Excluding duplicated mutations, a total of 202 driver mutations were discovered in 34 genes. ttDNA exhibited the highest occurrence of mutations (N=232), followed by baseline-ctDNA (N=155) and PD-ctDNA (N=117). Genotype concordance for the ten most mutated genes was highest between baseline-ctDNA and PD-ctDNA, at 94. 3%, while the concordance rates for ttDNA were 85. 5% with baseline-ctDNA and 83. 6% with PD-ctDNA. Overall, 40 of the 84 patients (47. 6%) benefited from sequencing ctDNA in addition to ttDNA as it identified additional mutations. Compared to ttDNA and baseline-ctDNA, PD-ctDNA identified 13 novel mutations in ten patients (11. 9%). Notably, 7 mutations in five patients (6. 0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, patients with maximal variant allele frequency (VAF) values of 0. 059 showed significantly worse progression-free survival (median 10. 5 vs. 17. 1 months, P=0. 036) and overall survival (median 18. 1 vs. 40. 3 months, P=0. 010). Moreover, overall survival was significantly worse in those with higher VAF values of APC (median 18. 1 vs. 36. 8 months, P=0. 012), TP53 (median 24. 7 vs. 40. 3 months, P=0. 012), and KRAS (median 13. 7 vs. 27. 6 months, P=0. 005) mutations. Conclusions: While ttDNA remains more sensitive than ctDNA, our unique molecular identifier-based ctDNA platform demonstrated the validity and potential value when ttDNA was unavailable. Furthermore, post-SACT analysis of PD-ctDNA revealed new pathogenic mutations, indicating the clonal evolution of cancer. In addition, the VAF values of baseline-ctDNA predicted prognosis after SACT. Citation Format: Ji-Won Kim, Seung-been Lee, Hong-Geun Kim, Sung-Hyun Hwang, Kui-Jin Kim, Ju Hyun Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Nak-Jung Kwon, Keun-Wook Lee. Longitudinal comparative analysis of circulating tumor DNA and matched tumor tissue DNA in patients with metastatic colorectal cancer receiving palliative first-line systemic anti-cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 966.