National clinical study

Neoadjuvant chemotherapy vs. standard upfront surgery in locally advanced colon cancer: A pioneering randomized study evaluating ctDNA as a biomarker to guide neoadjuvant, adjuvant therapy selcetion

In locally advanced colon cancer, determining the efficacy of neoadjuvant chemotherapy remains a clinical challenge. While neoadjuvant chemotherapy is theorized to reduce recurrence, especially in high-risk patients, there is limited insight into patient selection to neoadjuvant therapy. Circulating tumor DNA (ctDNA) has shown potential as a marker of tumor burden or spread, providing prognostic information across cancers. This study proposes ctDNA analysis as a tool to enhance patient stratification and predict disease-free survival (DFS) in the randomized NeoCol trial’s setting of neoadjuvant chemotherapy.

Abstract

Background: In locally advanced colon cancer, determining the efficacy of neoadjuvant chemotherapy remains a clinical challenge. While neoadjuvant chemotherapy is theorized to reduce recurrence, especially in high-risk patients, there is limited insight into patient selection to neoadjuvant therapy. Circulating tumor DNA (ctDNA) has shown potential as a marker of tumor burden or spread, providing prognostic information across cancers. This study proposes ctDNA analysis as a tool to enhance patient stratification and predict disease-free survival (DFS) in the randomized NeoCol trial’s setting of neoadjuvant chemotherapy.

Objectives: The primary aim is to evaluate ctDNA as an independent factor for DFS and overall survival (OS) in patients receiving neoadjuvant chemotherapy. Secondary aims include assessing ctDNA dynamics between baseline and surgery as predictors of response and potential indicators of recurrence risk.

Methods: NeoCol is a phase III, randomized, open-label trial that enrolls patients with histologically confirmed, locally advanced (T3/T4) colon cancer. Participants are randomized to either conventional treatment (surgery and adjuvant chemotherapy, as indicated) or an intervention arm with neoadjuvant chemotherapy followed by surgery. A total of 250 patients have been enrolled, with blood samples stored in a biobank at three key points: baseline, post-chemotherapy, and post-surgery. In this study, ctDNA will be extracted from these samples and analyzed using methylation markers, NPY, via digital droplet PCR (ddPCR). This technique enables sensitive ctDNA quantification and allows for analysis of ctDNA changes as a prognostic marker.

Results and Interpretation: Over 95% of baseline samples and more than 70% of follow-up samples have been successfully collected, totally around 500 samples. Analysis planned for Q1 2025. The literature suggest that ctDNA presence at baseline is associated with poorer DFS with the potential to select neoadjuvant therapy. The detection of ctDNA between baseline and surgery may stratify patients into distinct risk categories, informing both adjuvant chemotherapy decisions and long-term surveillance. A significant correlation between ctDNA levels and DFS would confirm ctDNA as a valuable tool in personalizing treatment for locally advanced colon cancer.

Expected outcomes: This is the first study to test ctDNA in a randomized phase III trial setting for locally advanced colon cancer. We hypothesize that elevated baseline ctDNA will correlate with lower DFS. The results will clarify if ctDNA can serve as a reliable marker for selecting patients for neoadjuvant chemotherapy, potentially surpassing imaging in identifying high-risk individuals who may benefit most from preoperative treatment. Patients with minimal or no ctDNA post-chemotherapy may be eligible for less intensive adjuvant therapy, sparing them from unnecessary toxicity.

Conclusion: Integrating ctDNA analysis into the NeoCol trial represents an innovative approach to refine neoadjuvant therapy strategies for colon cancer. If successful, ctDNA monitoring could guide decisions on neoadjuvant chemotherapy, improve risk stratification, and ultimately enhance clinical outcomes. These results would support broader implementation of ctDNA-guided therapies in colon cancer, advancing the goal of personalized oncology care.

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