Added value of tumor-stroma ratio to postsurgery circulating tumor DNA and pTN stage in risk stratification of patients with stage III colon cancer treated with adjuvant chemotherapy.

BACKGROUND: Patients with stage III colon cancer (CC) are routinely treated with resection followed by adjuvant chemotherapy (ACT). Half of patients are cured by surgery alone and overtreated with ACT, yet another ∼30% experience disease recurrence. Upfront risk stratification requires biomarkers beyond the conventional pathological stage (pTN). Detection of postsurgery circulating tumor DNA (ctDNA) is indicative of minimal residual disease and prognostic of recurrence. However, its negative predictive value is insufficient to guide treatment de-escalation. This study aimed to investigate whether adding tumor-stroma ratio (TSR) can improve patient risk stratification. PATIENTS AND METHODS: This study included 206 patients from PLCRC-PROVENC3 based on radical resection of stage III CC followed by ACT. Postsurgery ctDNA status was determined using Labcorp® Plasma Detect™. On a hematoxylin-eosin resection section, the TSR was scored by trained observers and dichotomized as stroma-low (≤50% stroma) versus stroma-high (>50%). The primary outcome was time to recurrence in univariable and multivariable Cox analyses to inform risk-group stratification, reporting hazard ratios (HR) and recurrence risks (RR). RESULTS: Postsurgery ctDNA was the strongest predictor [n = 26, 3-year RR 65.4% (95% CI 41.3% to 79.6%) versus 16.8% (95% CI 11.0% to 22.3%); HR 6.1 (95% CI 3.4-10.8)], followed by pT4/pN2 [n = 80, HR 3.0 (95% CI 1.7-5.2)] and a stroma-high tumor [n = 88, HR 3.0 (95% CI 1.7-5.2)]. Within the ctDNA-negative subgroup (n = 180), we identified a low-risk group [pT1-3N1 and stroma-low; n = 72, 3-year RR 2.9% (95% CI 0% to 6.7%)], intermediate-risk group [either pT4/N2 or stroma-high; n = 68, 3-year RR 17.2% (95% CI 7.4% to 26.0%), HR 8.2 (95% CI 1.9-36.2)], and high-risk group [pT4/N2 and stroma-high; n = 40, 3-year RR 40.3% (95% CI 22.9% to 53.9%), HR 21.5 (95% CI 5.0-92.3)]. CONCLUSIONS: Adding TSR to ctDNA and pTN stage improved risk stratification of stage III CC patients receiving ACT. One-third of the patients had none of the biomarkers and could be considered for de-escalation based on their very low RR. In addition to ctDNA-positive patients, ctDNA-negative patients with a pT4/N2 stroma-high tumor may require treatment escalation to reduce their high RR.