Assessment of circulating tumor DNA in patients with locally advanced rectal cancer treated with neoadjuvant therapy.

Post-neoadjuvant therapy (post-NAT) and post-surgical circulating tumor DNA (ctDNA) risk stratification may enhance the management of patients with locally advanced rectal cancer (LARC). In this study, we assessed the prognostic value of ctDNA-based MRD detection in LARC patients using a personalized, tumor-informed ctDNA assay. Plasma samples from LARC patients (N = 30) were analyzed retrospectively using the Signatera™ assay. The neoadjuvant rectal (NAR) score was calculated and compared to ctDNA status to predict recurrence risk and survival outcomes. ctDNA-positive patients post-NAT and post-surgery had worse Disease Free Survival (DFS) (HR: 7.82; p = 0.001, HR: 19.65; p = 0.001) when compared to ctDNA-negative patients. In the post-NAT setting, patients who responded to NAT had superior DFS compared to patients who did not clear their ctDNA or showed no radiological response (HR: 24.7, p = 0.001 and HR: 5.1, p = 0.054, respectively). When ctDNA status is used alongside the NAR score in the post-NAT setting, patients who were ctDNA-positive with an intermediate or high NAR score showed significantly worse DFS (HR: 47.5, p < 0.001) compared to ctDNA-negative patients with either a low or intermediate/high NAR score (HR: 9.8, p = 0.0301). Post-NAT ctDNA status, whether used alone or in combination with the NAR score, may predict NAT response, and improve risk stratification.