Signatera™ MRD Test Predicts Overall Survival Benefit from Chemotherapy in Resected Metastatic Colorectal Cancer
Natera, Inc., a global leader in cell-free DNA testing and precision medicine, has announced the publication of new clinical data in JAMA Oncology demonstrating the potential value of its personalized molecular residual disease (MRD) test, Signatera®, in guiding treatment decisions for patients with resected colorectal liver metastases (CRLM). The findings were also presented as an oral presentation during the 2026 European Society for Medical Oncology Gastrointestinal (ESMO GI) Congress, highlighting the growing interest in circulating tumor DNA (ctDNA)-based technologies as tools for personalized cancer care.
The newly published study provides important evidence supporting the use of post-surgical MRD testing to identify patients who are most likely to benefit from adjuvant chemotherapy (ACT) following curative-intent surgery for colorectal liver metastases. According to Natera, this is the first large dataset to demonstrate that MRD status can predict not only disease-free survival (DFS) benefit but also an overall survival (OS) benefit from adjuvant chemotherapy in this patient population.
The findings address one of the longstanding clinical questions in colorectal cancer management—determining which patients require additional chemotherapy after surgery and which patients may safely avoid unnecessary treatment.
Addressing an Important Clinical Challenge
Colorectal cancer remains one of the most frequently diagnosed cancers worldwide and is a leading cause of cancer-related mortality. A significant proportion of patients eventually develop metastatic disease, with the liver representing the most common site of distant metastasis.
Colorectal liver metastases occur when cancer cells originating in the colon or rectum spread to the liver. For selected patients whose liver metastases can be completely removed through surgery, curative-intent resection offers the possibility of long-term survival and, in some cases, cure.
However, despite successful surgery, recurrence rates remain high because microscopic cancer cells may persist within the body even after all visible tumors have been removed.
To reduce the risk of recurrence, many patients receive adjuvant chemotherapy following surgery. Yet determining which individuals truly benefit from additional treatment has remained a subject of ongoing debate among oncologists.
While chemotherapy may eliminate remaining microscopic disease in some patients, it also carries significant toxicities and potential long-term side effects. Consequently, physicians have sought more precise tools capable of identifying patients who actually require postoperative therapy.
Molecular Residual Disease Testing
Molecular residual disease testing has emerged as one of the most promising approaches for detecting microscopic amounts of cancer that remain following curative treatment.
Unlike conventional imaging techniques, which can only identify tumors after they become large enough to visualize, MRD testing detects fragments of tumor-derived DNA circulating within the bloodstream.
Signatera is a personalized circulating tumor DNA assay that is individually designed for each patient using genomic information obtained from the patient’s tumor tissue.
The test monitors multiple tumor-specific genetic variants in blood samples collected after surgery or other treatments.
Detection of circulating tumor DNA following surgery indicates that microscopic cancer cells likely remain within the body, placing patients at increased risk of disease recurrence.
Conversely, the absence of detectable tumor DNA suggests a substantially lower likelihood of residual disease.
This personalized approach enables physicians to assess treatment response and recurrence risk with greater precision than traditional clinicopathologic factors alone.
Evaluating Patients with Colorectal Liver Metastases
The newly published study focused specifically on patients with colorectal liver metastases undergoing curative-intent surgery.
Although previous studies have demonstrated that MRD testing can predict disease recurrence and disease-free survival, evidence regarding its ability to identify patients who derive an overall survival benefit from adjuvant chemotherapy has been limited.
The current analysis addresses this knowledge gap by evaluating outcomes in a large prospective patient cohort.
Researchers analyzed data from 298 patients enrolled in the GALAXY trial, the prospective observational arm of the broader CIRCULATE-Japan clinical study.
CIRCULATE-Japan represents one of the largest prospective research programs investigating the clinical utility of circulating tumor DNA across multiple stages of colorectal cancer.
Patients included in the current analysis were followed for a median of 43 months, providing investigators with sufficient time to evaluate both disease recurrence and long-term survival outcomes.
Researchers compared outcomes according to patients’ MRD status after surgery as well as whether they received adjuvant chemotherapy.
Identifying Patients Who Benefit from Chemotherapy
One of the most significant findings from the study involved the ability of Signatera to distinguish patients who appeared to benefit from postoperative chemotherapy.
Among patients who tested positive for molecular residual disease after surgery and had not previously received neoadjuvant chemotherapy, administration of adjuvant chemotherapy was associated with meaningful improvements in both disease-free survival and overall survival compared with observation alone.
The analysis demonstrated a substantial reduction in mortality risk among MRD-positive patients receiving adjuvant chemotherapy.
Forty-eight-month overall survival reached 65.3 percent for patients receiving chemotherapy compared with 32.9 percent among those who underwent observation without additional treatment.
Similarly, disease-free survival outcomes were significantly improved in MRD-positive patients treated with adjuvant chemotherapy.
These findings suggest that postoperative MRD positivity identifies patients harboring residual microscopic disease who remain particularly likely to benefit from additional systemic treatment.
Importantly, the results indicate that molecular testing may enable clinicians to better target chemotherapy toward patients most likely to derive meaningful clinical benefit.
Limited Benefit Among MRD-Negative Patients
In contrast, patients who tested negative for molecular residual disease following surgery demonstrated favorable clinical outcomes regardless of whether they received adjuvant chemotherapy.
According to the study, no survival benefit from postoperative chemotherapy was observed among MRD-negative patients.
This finding has important clinical implications because it raises the possibility that certain patients with no detectable residual disease may safely avoid unnecessary chemotherapy and its associated toxicities.
Although treatment decisions must always consider multiple clinical factors, personalized MRD testing may provide additional information that supports more individualized therapeutic strategies.
Reducing unnecessary chemotherapy could improve quality of life while minimizing treatment-related complications and healthcare costs.
Strong Prognostic Value of Post-Surgical MRD
Beyond predicting treatment benefit, the study also demonstrated the powerful prognostic significance of postoperative MRD testing.
Patients who remained MRD-positive between two and ten weeks after surgery experienced substantially worse clinical outcomes compared with MRD-negative individuals.
This association remained consistent regardless of whether patients had received neoadjuvant chemotherapy before surgery.
Among patients treated with neoadjuvant therapy prior to surgical resection, MRD positivity was associated with markedly increased risks of disease recurrence and mortality.
Similarly, patients who underwent surgery without preceding neoadjuvant treatment also experienced significantly poorer disease-free and overall survival when postoperative MRD remained detectable.
These findings reinforce the concept that persistent circulating tumor DNA following surgery represents a strong indicator of residual cancer burden and future recurrence risk.
The ability to identify high-risk patients shortly after surgery may allow clinicians to intervene earlier with additional therapeutic strategies.
Importance of the GALAXY Trial
The current analysis was derived from the GALAXY study, which forms part of the larger CIRCULATE-Japan research initiative.
GALAXY is a prospective observational trial designed to evaluate the clinical utility of personalized circulating tumor DNA testing across multiple stages of colorectal cancer management.
Prospective studies such as GALAXY provide particularly valuable evidence because patients are enrolled and followed according to predefined protocols before clinical outcomes occur.
This design minimizes many of the biases associated with retrospective analyses while providing more reliable evidence regarding the relationship between MRD status and patient outcomes.
The availability of long-term follow-up extending beyond three years strengthens confidence in the study’s findings and provides important information regarding overall survival.
Expert Perspective on Clinical Impact
Kozo Kataoka, M.D., Ph.D., of the Division of Lower Gastrointestinal Surgery within the Department of Gastroenterological Surgery at Hyogo Medical University and senior author of the study, emphasized the importance of the findings.
According to Dr. Kataoka, uncertainty has persisted regarding the role of adjuvant chemotherapy following curative-intent surgery for colorectal liver metastases.
He explained that the newly published analysis represents the largest evaluation demonstrating that postoperative MRD status may help identify patients who derive meaningful benefit from adjuvant chemotherapy after upfront surgical treatment.
The ability to personalize postoperative treatment based on molecular evidence rather than relying solely on traditional clinical factors could represent an important advancement in colorectal cancer management.
Natera Highlights Personalized Treatment Potential
Adham Jurdi, M.D., Senior Medical Director of Oncology at Natera, noted that clinicians have historically had limited tools for determining which patients with resected colorectal liver metastases should receive postoperative chemotherapy.
He explained that the newly reported overall survival findings strengthen the growing body of evidence supporting personalized MRD testing as a means of tailoring treatment according to each patient’s individual disease biology.
Rather than treating all patients similarly following surgery, Signatera may enable more individualized therapeutic decisions by identifying those at greatest risk of recurrence while potentially sparing lower-risk patients from unnecessary treatment.
The approach aligns with the broader goals of precision oncology, which seeks to customize cancer care using molecular information unique to each patient.
Advancing Precision Oncology
The publication of these findings reflects the continuing evolution of precision medicine in oncology.
Historically, treatment decisions after cancer surgery have relied primarily on pathological staging, imaging results, and clinicopathologic risk factors.
While these variables remain important, they often cannot determine with certainty whether microscopic disease persists after apparently curative treatment.
Personalized molecular residual disease testing offers an additional layer of biological information capable of identifying residual cancer at levels undetectable by conventional imaging.
As evidence supporting ctDNA-guided treatment strategies continues to accumulate across multiple tumor types, MRD testing may become an increasingly important component of routine cancer management.
The publication of the GALAXY trial analysis in JAMA Oncology represents a significant milestone in the development of personalized molecular residual disease testing for colorectal cancer. By demonstrating that Signatera can identify patients with resected colorectal liver metastases who are most likely to benefit from adjuvant chemotherapy—including improvements in overall survival—the study addresses an important unmet need in postoperative treatment planning.
The findings suggest that MRD-guided therapy has the potential to improve patient outcomes by directing chemotherapy toward individuals with detectable residual disease while helping others avoid unnecessary treatment. As additional prospective clinical trials continue evaluating ctDNA-guided treatment strategies, molecular residual disease testing may play an increasingly central role in precision oncology.
For patients with colorectal liver metastases, where recurrence remains a major clinical challenge despite successful surgery, personalized MRD assessment offers a promising approach to refining therapeutic decisions and advancing more individualized, evidence-based cancer care.
About Natera
Natera™ is a global leader in cell-free DNA and precision medicine, dedicated to oncology, women’s health, and organ health. We aim to make personalized genetic testing and diagnostics part of the standard-of-care to protect health and inform earlier, more targeted interventions that help lead to longer, healthier lives. Natera’s tests are supported by more than 400 peer-reviewed publications that demonstrate excellent performance.
Natera operates ISO 13485-certified and CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in Austin, Texas, and San Carlos, California, and through Foresight Diagnostics, its subsidiary, operates an ISO 27001-certified and CAP-accredited laboratory certified under CLIA in Boulder, Colorado.