Blood Test Steers Chemotherapy Decisions in Colon Cancer Trial

A major international clinical effort known as the PEGASUS trial has tested whether a simple blood test can safely guide how much chemotherapy patients receive after colon cancer surgery. The phase 2 study, described in Nature Cancer, enrolled patients with resected microsatellite-stable, high-risk stage II or stage III colon cancer and evaluated the feasibility of a dynamic strategy in which circulating tumor DNA, or ctDNA, measured in the bloodstream determined whether adjuvant therapy should be scaled back, intensified, or followed by additional postadjuvant treatment. The central question was pragmatic rather than speculative: can molecular signals detected in blood be translated into real, actionable treatment decisions in a routine clinical setting, and can the infrastructure of oncology practices support such a shift?

Adjuvant therapy, the chemotherapy given after surgical removal of a tumor to destroy any remaining cancer cells, has long been a blunt instrument in colon cancer. For decades, treatment intensity has been assigned largely on the basis of anatomical staging, the depth of tumor invasion through the bowel wall and the number of lymph nodes involved. Patients deemed high risk by these pathological criteria have typically received combination chemotherapy regimens, while those considered lower risk have received single-agent treatment or, in some cases, observation alone. This one-size-fits-many approach inevitably overtreats some patients, exposing them to toxicities such as peripheral neuropathy, diarrhea, fatigue and long-term nerve damage without any proven benefit, and undertreats others whose residual disease goes undetected until it reappears as metastatic recurrence.

Circulating tumor DNA offers a fundamentally different lens. Tumors continuously shed fragments of their DNA into the bloodstream, and highly sensitive assays can detect these fragments by looking for tumor-specific mutations or abnormal methylation patterns. In the context of colon cancer, the presence of detectable ctDNA after surgery is one of the most powerful predictors of eventual recurrence yet identified, outperforming conventional imaging and standard tumor markers. A positive postoperative ctDNA result indicates that microscopic disease almost certainly persists somewhere in the body, while a negative result suggests, with a high degree of confidence, that no measurable residual disease remains. The logical corollary is that patients with persistent ctDNA might benefit from more aggressive therapy, whereas those who clear their ctDNA might be spared unnecessary treatment.

Translating that logic into practice, however, has proven difficult. Most ctDNA studies to date have been observational, measuring the marker and correlating it with outcomes without letting it dictate treatment. The few interventional trials that have used ctDNA to assign therapy have generally done so in a static way, taking a single postoperative measurement and using it once. PEGASUS was designed to go further by making ctDNA a dynamic, longitudinal guide. In the trial, patients with microsatellite-stable, high-risk stage II or III colon cancer underwent serial blood testing, and the results were used to direct both the initial choice of adjuvant chemotherapy and subsequent decisions about whether to continue, de-escalate, or escalate treatment after the standard adjuvant period had ended.

The population studied was deliberately chosen to be clinically challenging. Microsatellite-stable tumors, which constitute the majority of colon cancers, do not respond to immune checkpoint inhibitors and carry a worse prognosis than their microsatellite-instability-high counterparts. High-risk stage II disease, defined by features such as bowel obstruction or perforation, poorly differentiated histology, lymphovascular invasion or inadequate lymph node sampling, sits in a particularly gray zone of practice, where the benefit of adding oxaliplatin to fluoropyrimidine chemotherapy is debated and treatment decisions vary widely between centers. Stage III disease, with its proven lymph node involvement, carries a substantial recurrence risk even after apparently complete resection. For all of these patients, the trade-off between the toxicity of intensive chemotherapy and the danger of undertreating occult disease is acute and personal.

The feasibility question that PEGASUS addressed is not trivial. A ctDNA-guided strategy demands that blood samples be drawn, processed and analyzed on a tight timeline so that results arrive in time to inform treatment decisions. It requires laboratories to maintain consistent assay sensitivity across repeated measurements for the same patient, because a test that flickers between positive and negative near its detection limit creates clinical ambiguity. It requires oncologists to accept a new kind of evidence, a molecular measurement, as the basis for withholding or adding cytotoxic drugs, and it requires patients to understand that a negative blood test does not guarantee cure but may justify a lighter treatment burden. Any one of these links could break the chain, and the trial was structured to determine whether the whole chain could hold together in practice.

De-escalation is the arm of the strategy with the greatest potential to change daily practice. If serial ctDNA testing shows that a patient has no detectable residual disease after surgery, or that ctDNA clears rapidly once chemotherapy begins, the rationale for continuing full-intensity combination chemotherapy weakens considerably. Oxaliplatin, the component of standard regimens most associated with permanent peripheral neuropathy, is the natural target of such de-escalation. Avoiding even a fraction of unnecessary oxaliplatin exposure across the large population of high-risk colon cancer survivors would represent a meaningful quality-of-life gain, sparing patients years of numbness, cold sensitivity and functional impairment, while reducing healthcare costs associated with managing chemotherapy toxicities.

Escalation, conversely, addresses the patients whom standard staging fails. A patient whose ctDNA remains detectable despite completing a full course of adjuvant chemotherapy is, by the logic of the biomarker, harboring active microscopic disease that current treatment has not eradicated. In conventional practice such a patient would simply be monitored, with treatment resuming only once relapse became visible on scans, often at a point when cure is no longer possible. A ctDNA-guided postadjuvant strategy opens a window in which additional or alternative therapy can be considered while the disease burden is still molecular rather than radiographic. Whether such escalation improves survival is a question that feasibility trials like PEGASUS set the stage for but cannot fully answer; establishing that the strategy can be delivered consistently is the necessary first step.

The significance of the trial extends beyond colon cancer. The concept of minimal residual disease guidance, in which molecular testing determines treatment intensity, is being pursued in breast cancer, pancreatic cancer, gastric cancer and a range of other tumor types, and the operational lessons from PEGASUS are likely to inform all of these efforts. The trial also contributes to a broader rethinking of how adjuvant therapy decisions are made, moving the field away from population averages and toward individualized risk. As ctDNA assays become more standardized and more affordable, the barrier to adopting such strategies shifts from technology to clinical governance: which laboratories, which thresholds, which timelines, and who bears responsibility for acting on a positive result.

What PEGASUS ultimately demonstrates, within the limits of a phase 2 design, is that the vision of blood-test-guided cancer treatment can be operationalized for one of the most common malignancies worldwide. Colon cancer affects well over a million people each year globally, and a substantial fraction undergo surgery with curative intent followed by adjuvant chemotherapy whose value in any individual case is uncertain. If serial ctDNA monitoring can reliably sort these patients into those who need maximal therapy and those who do not, the result would be a rare win on both fronts of oncology: better outcomes for patients with hidden residual disease and fewer toxic treatments for those already cured by surgery. The trial’s findings now form part of the growing evidence base that will determine whether molecular residual disease testing becomes a routine companion to the surgeon’s knife and the oncologist’s infusion chair, transforming follow-up after colon cancer surgery from a period of anxious waiting into a period of active, data-driven decision-making.

Subject of Research: Circulating tumor DNA-guided adjuvant and postadjuvant treatment in resected high-risk stage II and III microsatellite-stable colon cancer

Article Title: Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial

Article References: Marsoni, S., Montagut, C., Pietrantonio, F., Sartore-Bianchi, A., Lazzari, L., Bergamo, F., Zampino, M. G., Tarazona, N., Mandalà, M., Tamberi, S., Elez, E., Santos Vivas, C., Luraghi, P., Prisciandaro, M., Tosi, F., Ciardiello, D., Vidal, J., Seguì, V., Palazzo, M., … Lonardi, S. (2026). Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial. Nature Cancer. https://doi.org/10.1038/s43018-026-01237-9

Image Credits: AI Generated

DOI: 10.1038/s43018-026-01237-9

Keywords: circulating tumor DNA, colon cancer, adjuvant chemotherapy, PEGASUS trial, de-escalation, escalation, microsatellite stability, minimal residual disease, stage III colon cancer, precision oncology, oxaliplatin, biomarker-guided therapy