Clinical Impact of Presurgery Circulating Tumor DNA after Total Neoadjuvant Treatment in Locally Advanced Rectal Cancer: A Biomarker Study from the GEMCAD 1402 Trial

Abstract

Purpose: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. Experimental Design: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/− aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. Results: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P < 0.0001). Conclusions: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…As part of the GEMCAD 1402 phase II randomized trial enrolling high-risk LARC patients to receive TNT, 23 subjects with paired baseline and post-TNT/pre-surgery samples using a tumor-uninformed, plasma ctDNA assay showed ctDNA clearance following neoadjuvant treatment (66%) [ 58 ]. Although this was a preplanned analysis limited by small sample size, ctDNA detection was not a predictive biomarker of treatment response on the primary tumor as measured by pCR or neoadjuvant rectal score (NAR, Table 3 ).…”

“…However, one common theme appears to be that post-chemoradiation ctDNA status is a critical ctDNA assessment timepoint and most strongly predictive of RFS and various tumor response parameters including tumor regression grade and pCR ( Table 3 ). Several groups have noted that ctDNA following neoadjuvant therapy in LARC cannot differentiate between minimal and no residual disease, and instead ctDNA more specifically reflects the presence of systemic disease rather than local minimal disease [ 51 , 58 ]. In this regard, future investigations into the role of ctDNA in the treatment paradigm of LARC may focus on identifying those who may be adequately treated with neoadjuvant chemoradiation and TME alone vs. those who would benefit from intensified TNT upfront based on baseline or pretreatment ctDNA positivity [ 55 ].…”

Liquid biopsies to monitor and direct cancer treatment in colorectal cancer

“…• 3-year RFS rate: 33% for the post-operative ctDNA-positive patients versus 87% for the post-operative ctDNA-negative patients, irrespective of clinicopathological risk factors (HR 6.0; p < 0.001). Vidal et al 2021 [ 75 ] II–III NGS (Guardant Reveal) 72 0/72 • Detectable pre-surgery ctDNA after chemotherapy significantly associated with systemic recurrence, shorter DFS (HR 4; p = 0.033), and shorter OS (HR 23; p < 0.0001). • No significant association between ctDNA status and pathologic response.…”

“…Tie and colleagues, found a recurrence rate significantly higher in 13 and 19 of 159 patients with detectable ctDNA both after pre-operative treatment and after surgery, with a hazard ratio (HR) of 6.6 and 13, respectively [ 74 ]. Similarly, in a cohort of 72 patients undergoing TNT in the GEMCAD 1402 trial, pre-surgery ctDNA detected MRD in 15% and was significantly associated with shorter DFS (HR 4; P = 0.033) and OS (HR 23; P < 0.0001) [ 75 ]. In another study, the overall margin-negative, node-negative resection rate significantly doubled in 17 patients with undetectable versus 9 patients with pre-operative detectable ctDNA (88 vs 44%; P = 0.007) [ 76 ].…”

ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC)

“…In contrast to the previously described studies, Vidal et al [89] have recently published a study in which the concept of MMD (minimal metastatic disease) was introduced. This term refers to the detection of ctDNA following TNT and before surgery in patients that are likely to recur at distant sites.…”