Editor’s note: The 14 ACS Advisory Councils, which serve as liaisons in the communication of information to and from surgical societies and the Regents, periodically submit articles on notable initiatives taking place in their respective specialties.
This week’s issue features a submission from the Advisory Council for Colon and Rectal Surgery.
Kellie Mathis, MD, FACS
Circulating tumor DNA (ctDNA) has emerged as a powerful marker of minimal residual disease (MRD) after curative-intent resection for colon cancer. Postoperative ctDNA detection is strongly associated with subsequent recurrence and provides prognostic information beyond traditional clinicopathologic risk factors.
The magnitude of this association is substantial. In the GALAXY study, which included more than 1,000 patients with resected stage II–IV colorectal cancer, ctDNA positivity approximately 4 weeks after surgery was associated with roughly a 10-fold increased risk of recurrence. Similarly, among patients with stage III colon cancer in the Alliance N0147 study, 5-year disease-free survival was 28% for ctDNA-positive patients and 77% for ctDNA-negative patients. Thus, postoperative ctDNA identifies a population at particularly high risk of recurrence despite apparently curative surgery.
ctDNA may also enable earlier detection of recurrence during surveillance. Molecular recurrence often precedes radiographic evidence of disease by several months. In the randomized FIND trial, ctDNA-guided surveillance increased the proportion of recurrences treated with curative intent (48% versus 24%), yielding a lead time of approximately 4 months. Whether this earlier detection translates into improved survival remains unknown.
A major question is whether ctDNA should guide adjuvant chemotherapy. In the randomized DYNAMIC trial of patients with resected stage II colon cancer, ctDNA-guided management reduced chemotherapy use from 28% to 15% without compromising recurrence-free survival. 5-year recurrence-free survival was similar in both groups (88% versus 87%). These results support the potential use of ctDNA to identify patients who may safely avoid adjuvant therapy.
Results in stage III disease have been less definitive. DYNAMIC-III randomized patients to ctDNA-guided or standard management. ctDNA-negative patients underwent treatment de-escalation, whereas ctDNA-positive patients received treatment escalation. De-escalation reduced oxaliplatin exposure, but 3-year recurrence-free survival did not meet the prespecified noninferiority threshold (85% vs 88%).
Importantly, treatment intensification in ctDNA-positive patients, including escalation to FOLFOXIRI, did not improve ctDNA clearance or recurrence-free survival. These findings highlight an important distinction: ctDNA is a powerful prognostic biomarker, but evidence that it is a predictive biomarker capable of identifying who benefits from more or less chemotherapy remains limited.
Other potential applications include monitoring response and detecting resistance in metastatic colorectal cancer, assessing response during neoadjuvant therapy, and conducting surveillance in rectal cancer patients managed with a watch-and-wait strategy.
For surgeons, the message is straightforward: postoperative ctDNA provides valuable information about residual disease and recurrence risk, but how best to act on it remains uncertain. Current National Comprehensive Cancer Network guidelines recognize its prognostic value but do not recommend routine ctDNA use to guide adjuvant treatment decisions or for standard surveillance outside a clinical trial.
