Complementary value of a digital pathology biomarker to post-surgery circulating tumor DNA in risk stratification of stage III colon cancer patients receiving adjuvant chemotherapy.

3604 Background: The current standard of care for patients with stage III colon cancer (CC) is resection followed by adjuvant chemotherapy (ACT). About half of patients are cured by surgery and hence overtreated with ACT, whereas ~30% experience recurrence despite ACT. Several studies show that patients with no detectable circulating tumor DNA (ctDNA) after surgery are at a lower risk of recurrence (RR), although false negative ctDNA results remain a concern. Other studies show prognostic value of digital pathology biomarkers on resected CC tissue, like the Combined Analysis of Pathologists and Artificial Intelligence (CAPAI; Kleppe Lancet Oncol 2022). This study aimed to explore the potential added value of CAPAI to post-surgery ctDNA in risk stratification of patients with stage III CC receiving ACT. Methods: Patients were selected from the Prospective Dutch ColoRectal Cancer (PLCRC) cohort substudy PROVENC3 (Rubio-Alarcon AACR 2024), based on stage III CC treated with radical resection and adjuvant capecitabine or CAPOX. Post-surgery ctDNA status was determined using Labcorp Plasma Detect. From the resected tumor, a representative H&E slide was digitalized to generate a DoMore-v1-CE-CRC score, which was combined with the pT and pN stage and number of assessed lymph nodes for classification as CAPAI high-, intermediate- or low-risk. Three-year RR and Cox proportional hazard ratios (HR) were reported for ctDNA-based and CAPAI-based risk groups. Time to recurrence was compared between risk groups using the log-rank test. Results: Post-surgery ctDNA status and CAPAI risk classification were available for 163 patients. The 20 patients (12%) with detectable ctDNA had a higher recurrence risk (3-year RR 60% [32-77], HR 4.9 [2.5-9.6], p < 0.001) than patients with no detectable ctDNA (N = 143, 3-year RR 18% [11-25]). Within the subgroup with no detectable post-surgery ctDNA, 50 patients (35%) were classified as CAPAI high-risk. These CAPAI high-risk patients had a higher recurrence risk (3-year RR 35% [20-48], HR 4.2 [2.0-9.1], p < 0.001) than patients classified as CAPAI low/intermediate-risk, who were combined based on their observed similar RR (N = 93, 3-year RR 9% [3-15%]). Conclusions: In patients with stage III colon cancer treated with adjuvant CAP(OX), CAPAI risk classification has potential to further stratify RR in the subgroup with no detectable post-surgery ctDNA. These preliminary results suggest that CAPAI high-risk may help identify patients with false negative post-surgery ctDNA results. Over half of all patients had both no detectable ctDNA and were CAPAI low/intermediate-risk. Given their low RR in our preliminary results, future studies on larger patient cohorts should focus on the ability to combine biomarkers to select very low-risk patients and evaluate whether these patients can potentially be spared ACT.