590P Assessment of circulating tumor (ct)DNA in patients (pts) with locally advanced rectal cancer (LARC) pts treated with neoadjuvant therapy (NAT)

Approximately 30% of colorectal cancers arise from the rectum with surgical resection being the mainstay of treatment. For rectal cancers with high-risk pathological features or cases of LARC, preoperative NAT followed by total mesorectal excision +/- adjuvant therapy is recommended. However, this paradigm is associated with questionable survival benefits and high morbidity. Post-NAT and post-surgical risk stratification using ctDNA may help predict outcomes in LARC pts. Plasma samples (n=90) from pts with LARC (N=30, median age: 67 years) were analyzed retrospectively. A tumor-informed assay (Signatera™) was used to quantify ctDNA pre-NAT, post-NAT, and post-surgery. Neoadjuvant rectal (NAR) score was calculated and compared to ctDNA status to predict recurrence risk and survival outcomes. At the pre-NAT time point, ctDNA detection rate was 90% (27/30). Pts who were ctDNA-positive either post-NAT (N=5) or post-surgery (N=3) had worse recurrence-free survival (RFS) (HR 8.4, 95%CI: 2.3-30, p<0.001 and HR 14, 95%CI: 3.1-66, p<0.001, respectively), when compared to ctDNA-negative pts. Similarly, pts with a high NAR score exhibited an inferior RFS when compared to those with a low-risk score (HR: 21, 95%CI: 2.6-2731, p=0.001). When utilized in combination with ctDNA status in the post-NAT setting, ctDNA-positive with an intermediate-high NAR score exhibited an inferior RFS compared to ctDNA-negative pts with a low NAR score (HR 33.5, 95%CI: 3.7-4419, p<0.001) with 100% recurrence rate. Likewise, post-surgery, ctDNA-positive pts with an intermediate-high NAR score exhibited an inferior RFS, with a recurrence rate of 37.5%, when compared to ctDNA-negative pts with a low NAR score, none of whom recurred (HR 75, 95%CI: 2.6-4916, p<0.001). In multivariate analysis, ctDNA status post-surgery (p=0.039) and pathological nodal status (p=0.033) were the most significant risk factors associated with recurrence. Post-treatment ctDNA status either as a sole surrogate outcome measure or as an adjunct to the NAR score may predict NAT response, improve risk stratification and potentially improve outcomes in LARC pts.