Abstract 4556: Postoperative minimal residual disease detection using tumor-informed circulating tumor DNA analysis in stage II-III gastric cancer

Abstract Background: Circulating tumor DNA (ctDNA) analysis enables the detection of minimal residual disease (MRD), offering potential for improved risk stratification and guidance on decisions regarding adjuvant chemotherapy (ACT). We investigated the clinical utility of tumor-informed ctDNA analysis for postoperative MRD assessment in stage II-III gastric cancer (GC). Methods: We plan to enroll 100 patients from the 976 expected in the ongoing EXODOX study (NCT04787354), a phase III randomized trial comparing reduced-duration XELOX with the standard 6-month regimen as ACT in patients with pathologic stage II-III GC after curative resection. In this sub-study, ctDNA MRD was assessed using the CancerDetectTM assay (IMBdx, Inc.), a targeted sequencing method with a tumor-informed bespoke panel (BSP). To create the BSP, whole exome sequencing of tumor tissue and paired white blood cells identified up to 100 patient-specific variants. Whole blood (20 mL) was collected at five postoperative time points: 3-10 weeks (P0), 6 months (P1), 12 months (P2), 18 months (P3), and 24 months (P4). CtDNA MRD positivity was defined as the detection of two or more BSP variants in plasma. Results: This analysis includes 42 patients enrolled from May 2022 to August 2024, with ctDNA MRD assessed at three time points: P0 (n = 42), P1 (n = 27), and P2 (n = 17). The median age was 66 years (range, 39-96); 27 patients (64.3%) were male, all had adenocarcinoma, and 30 patients (71.4%) had stage III disease. Overall, postoperative ctDNA (P0) positivity was 45.2% (19/42), with a median of 8 somatic mutations per patient (range, 2-94). CtDNA positivity was significantly higher in stage III than in stage II patients at P0 (56.7% vs. 16.7%, P = 0.037). CtDNA MRD clearance after ACT was achieved in 46.2% (6/13) of patients who were ctDNA-positive at P0. One initially ctDNA-negative patient converted to positive, resulting in an overall ctDNA positivity rate of 29.6% (8/27) at 6 months (P1). Twelve months postoperatively, ctDNA positivity (P2) was 35.2% (6/17). After a median follow-up of 12.0 months, 7 patients experienced recurrence. CtDNA positivity at P1 and P2 was significantly associated with worse recurrence-free survival (RFS) (P = 0.003 and P = 0.038, respectively), whereas it was not significantly associated at P0 (P = 0.101). RFS differed significantly based on changes in ctDNA positivity from P0 to P1 (P = 0.010), with the persistent ctDNA-positive group showing the poorest RFS. Notably, patients who achieved ctDNA clearance after ACT had RFS similar to those who were ctDNA-negative at both P0 and P1 (P = 0.480). Conclusions: In patients with stage II-III GC, postoperative MRD was associated with recurrence risk. Temporal changes in ctDNA MRD status during monitoring reflect the response to ACT and may guide treatment decisions. To fully understand the impact of ctDNA MRD monitoring, further follow-up is planned. Citation Format: Bom Han, Hayoon Lee, Minkyu Jung, Bum Jun Kim, Yongjun Cha, Sunghoon Heo, Sun Young Rha, Hyung-Don Kim, Min-Hee Ryu, Dong-Hoe Koo, Jong Gwang Kim, Hye Sook Han, Sun Jin Sym, Jae-Joon Kim, Do-Youn Oh, Keun-Wook Lee, Hwang-Phill Kim, Duhee Bang, Sang-Hyun Song, Tae-You Kim, Dae Young Zang. Postoperative minimal residual disease detection using tumor-informed circulating tumor DNA analysis in stage II-III gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4556.