Circulating Methylated SEPT9 DNA Analyses to Predict Recurrence Risk and Adjuvant Chemotherapy Benefit in Stage II to III Colorectal Cancer.

ABSTRACT

BACKGROUND We aimed to evaluate the ability of circulating cell-free methylated SETP9 DNA (mSEPT9) to identify recurrence and to determine its clinical utility in adjuvant chemotherapy (ACT) regimen decisions. MATERIAL AND METHODS This study enrolled 426 patients with stage II-III CRC who received radical resection between January 8, 2018, and November 30, 2020. The median follow-up duration was 15.8 months (range, 8.1-43.4 months). The primary endpoint was recurrence-free survival (RFS). A propensity score matching model was used to minimize potential confounding covariates and to confirm our findings. RESULTS In stage II-III CRC patients, postoperative (within 1 month after surgery) mSEPT9 positivity was significantly correlated with worse RFS (HR=6.21, P<0.001), and it remained the strongest independent predictor in multivariate Cox regression analysis (HR=5.83, P<0.001), which was significantly superior to CEA, CA19-9, and CA242. During disease surveillance, mSEPT9 positivity preceded radiographic recurrence by a median of 5.0 months. The postoperative mSEPT9-positive patients benefited more from CAPEOX compared to FOLFOX (HR=3.97, P=0.017), while for mSEPT9-negative patients, CAPEOX and FOLFOX resulted in similar RFS (HR=1.70, P=0.322). Furthermore, 3 months of CAPEOX was more effective than 3 and 6 months of FOLFOX (HR=4.40, P=0.065; HR=1.56, P=0.073, respectively). CONCLUSIONS Our results revealed that mSEPT9 detection after radical resection could identify minimal residual disease (MRD) and could predict a high risk of recurrence in patients with stage II-III CRC. Furthermore, we show pioneering work that mSEPT9 detection could be used to guide the selection of an adjuvant chemotherapy regimen to improve RFS.