Abstract 6559: Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study

Abstract Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, only 15-20% of patients benefit from ACT, as half of patients are cured by surgery, and 25-30% still experience a recurrence. Detection of circulating tumor DNA (ctDNA) after resection of the primary tumor is a strong prognostic biomarker in non-metastatic colon cancer and offers a promising approach to better stratify stage III colon cancer patients for ACT treatment decisions. Aim: The PROVENC3 study aims to determine the clinical validity of post-surgery ctDNA detection in patients with stage III colon cancer treated with ACT. Methods: Blood was collected pre-surgery, post-surgery and post-ACT for stage III colon cancer patients treated with ACT. Tumor-informed detection of ctDNA was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), germline DNA (40x), and plasma cell-free DNA (30x). The primary outcome was time to recurrence (TTR). Results: Results from 209 patients (median follow up: 40 months) show that ctDNA-positive patients post-surgery (n=28) had a higher risk of developing a recurrence than ctDNA-negative patients (HR: 6.3, [95%CI: 3.5-11.3], P<10−8). 38% of patients with a recurrence within 3 years were ctDNA-positive post-surgery. Combination of post-surgery ctDNA status with established clinicopathological risk classification of low-risk (T1-3 and N1) and high-risk (T4 and/or N2) resulted in a 3-year cumulative recurrence risk of 82% for clinical high-risk ctDNA-positive patients compared to 7% for clinical low-risk ctDNA-negative patients (HR 28.9 [95%CI: 10.6-78.2]; P<10−10). Results from 170 patients with post-ACT blood available showed that post-ACT ctDNA-positive patients (n=24) were at a higher risk of developing a recurrence (HR 7.9 [95%CI: 3.5-15.9]; P<10−8) than ctDNA-negative patients. The patients experiencing a recurrence had higher aggregate ctDNA variant allele frequencies than patients not experiencing a recurrence post-surgery or post-ACT (P<0.001 and P<0.001, respectively). Conclusion: Post-surgery ctDNA detection by tumor-informed WGS is a strong prognostic biomarker in stage III colon cancer patients, and improves the current risk stratification. Importantly, the post-surgery ctDNA-positive patients who did not experience a recurrence were likely cured by ACT. These data enable the design of clinical practice-changing ctDNA-guided interventional trials in stage III colon cancer to personalize adjuvant treatment decisions. Citation Format: Carmen Rubio Alarcon, Andrew Georgiadis, Ingrid A. Franken, Haoyue Wang, Sietske C. van Nassau, Suzanna J. Schraa, Dave E. van der Kruijssen, Karlijn van Rooijen, Theodora C. Linders, Pien Delis-van Diemen, Maartje Alkemade, Anne Bolijn, Marianne Tijssen, Margriet Lemmens, Lana Meiqari, Steven L. Ketelaars, Adria Closa Mosquera, Miranda M. van Dongen, Mirthe Lanfermeijer, Birgit I. Lissenberg-Witte, Linda J. Bosch, Teunise Bisschop-Snetselaar, Bregje Adriaans, Amy Greer, David Riley, James R. White, Christopher Greco, Liam Cox, Jesse Fox, Kaitlin Victor, Catherine Leech, Samuel V. Angiuoli, Niels F. Kok, Cornelis J. Punt, Daan van den Broek, Miriam Koopman, Gerrit A. Meijer, Victor E. Velculescu, Jeanine M. Roodhart, Veerle M. Coupé, Mark Sausen, Geraldine R. Vink, Remond J. Fijneman. Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study [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 6559.