Abstract 2425: Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Abstract Background: Plasma cell-free DNA (cfDNA) analysis has emerged as an appealing alternative to detect somatic mutations. This study compared cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA) and tumor tissue DNA (ttDNA) in patients with metastatic gastric cancer who underwent palliative second-line paclitaxel+ramucirumab treatment. Methods: We conducted targeted sequencing of 106 cancer-related genes using germline DNA, baseline-cfDNA, and PD-cfDNA samples. The results were then compared with conventional cancer panel results using ttDNA. Results: Of 76 consecutively enrolled patients who received paclitaxel+ramucirumab treatment, 46 patients (27 males; median age 57.5 [range, 32-73] years) with access to all three samples were analyzed along with their ttDNA data. A total of 138, 145, and 80 mutations were detected in baseline-cfDNA, PD-cfDNA, and ttDNA respectively. Combined analysis of baseline-cfDNA and ttDNA revealed that TP53 (56.5%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.5%). For the top four genes, the sensitivity and positive predictive value of baseline-cfDNA compared with ttDNA were 71.8% and 51.9%, respectively. Compared with ttDNA alone, 32 patients (70.0%) benefited from baseline-cfDNA in detecting novel mutations. When combined with baseline-cfDNA and PD-cfDNA, novel mutations were discovered in 34 patients (73.9%). Of note, PD-cfDNA analysis detected 9 novel pathogenic mutations in TP53, APC, PIK3CA, CDH1, RNF43, CTNNB1, and BRCA2 genes in 8 patients (17.4%) after treatment. In baseline-cfDNA, patients with a circulating ttDNA fraction concentration at 110-160 bp of >4.3777 ng/µL had significantly shorter progression-free survival (PFS) (median 3.5 vs. 5.3 months, P=0.016). In addition, maximal variant allele frequency (VAF) values of >0.1045 (median 3.4 vs. 5.2 months, P=0.022) and the sum of VAF values of >0.2071 (median 3.4 vs. 5.2 months, P=0.028) were significantly associated with shorter PFS. In patients with TP53 mutations, those with TP53 VAF values of >0.1014 significantly had worse PFS (median 4.6 vs. 6.4 months, P=0.022). Conclusions: Although cfDNA could not entirely take over the role of ttDNA, cfDNA analysis identified additional somatic mutations that were otherwise missed by ttDNA alone. Moreover, PD-cfDNA analysis detected novel pathogenic mutations that developed during treatment, implicating the clonal evolution of cancer. In addition, baseline cfDNA predicted PFS of patients receiving paclitaxel+ramucirumab therapy. Citation Format: Ji-Won Kim, Dong Soo Kyung, Won Yeong Ko, Hwang-Phill 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, Keun-Wook Lee. Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer [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(6_Suppl):Abstract nr 2425.