The MRD Signal and what it means for the patients

Molecular residual disease (MRD) testing can now flag residual cancer months before a scan. The harder question is what it means for the patient in front of you; this is where blood, tissue, and genome are beginning to converge.

What about a positive result?

For a patient months past a curative-intent resection, these words are hard to decode, since the tumor DNA often starts to shed into the bloodstream long before a nodule would show on a CT scan. The oncologist now knows the certainty or likelihood of the cancer to reappear.

Several clinical and pathological factors play a collective role in predicting the aggressiveness of the disease; the role of ctDNA monitoring with serial testing becomes even more critical. Thus, more than the detection, evaluating the serial trajectory of ctDNA is crucial, which can help inform the provider to schedule an off-cycle imaging to catch recurrence early and have a plan of action with alternative intervention strategies in alignment with current guidelines.

A milestone for personalized cancer care

Signatera, Natera’s tumor-informed ctDNA-MRD test, is custom built for each patient: the tumor tissue is sequenced, somatic variants unique to that tumor are identified, and a personalized assay hunts for precisely those variants in the blood, rendering the disease as a curve rather than a coin flip.

Natera recently reached two important regulatory milestones for its ctDNA blood test, Signatera™. The test received approval from the U.S. Food and Drug Administration (FDA) as the first blood-based companion diagnostic to help doctors identify which patients with muscle-invasive bladder cancer are most likely to benefit from a specific immunotherapy after surgery. Natera also received approval from Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) for Signatera in colorectal cancer in the adjuvant setting, making it the first PMDA-approved MRD test in Japan and expanding access to this technology in a major oncology market.

These approvals highlight the growing role of blood-based testing in making cancer treatment more personalized, helping patients receive the right treatment at the right time while avoiding unnecessary therapy.

Recent evidence from ASCO and ESMO Breast 2026

At ASCO, new findings from the GALAXY study in colorectal cancer continued to demonstrate the value of Natera’s Signatera™ test in guiding treatment after surgery. Researchers found that patients whose blood test changed from ctDNA negative to positive benefited significantly from adjuvant chemotherapy, while patients who remained ctDNA-negative had excellent outcomes regardless of whether they received additional treatment.

Another analysis showed that extending chemotherapy beyond three months did not improve outcomes for patients who remained ctDNA-negative, but patients whose ctDNA levels declined during treatment benefited from continued therapy.

In addition, a large real-world meta-analysis of more than 3,000 patients across 15 cancer types confirmed that a positive Signatera result was strongly associated with a higher risk of cancer recurrence, reinforcing the test’s role in identifying patients who may benefit from earlier intervention and more personalized treatment strategies.

Other innovative data was presented at ESMO Breast on SMART Tool, which utilized a machine learning model to explore how regular monitoring with Natera’s personalized Signatera™ blood test could help predict treatment response and detect disease progression earlier in patients with metastatic breast cancer.

The study analyzed more than 3,700 sequential ctDNA samples and identified nearly 600 progression events. The model accurately predicted which patients were likely to experience disease progression within 90 days, with 87% sensitivity and 95% specificity. Patients identified as high risk needed to switch treatments much sooner than those at low risk, highlighting the potential of real-time monitoring to help doctors make more timely and informed treatment decisions.

‘These data highlight our commitment to improving outcomes and driving innovation in MRD detection,’ said Adham Jurdi, senior medical director of oncology at Natera.

Concluding Remarks – From Status to a Forecast

In January 2026, a multimodal AI risk-stratification model that takes this concept further was announced: integrating longitudinal ctDNA, clinical data, digital pathology, and tumor sequencing to extend MRD from a status into a forecast.

Trained on approximately 300,000 patients tested with Signatera, this model is designed to place a positive result on a curve, beyond that disease is present, but disease is present with this risk profile and likely this tempo. This is what ‘next generation MRD’ actually means in practice. Not a more sensitive assay – a more complete picture of the patient.

‘The next phase is understanding how molecular signals can refine the trajectory for every patient, and that depends on access to large datasets built over years of real-world clinical use,’ said Alexey Aleshin, Natera’s corporate chief medical officer and general manager of oncology.

This multimodal AI platform is currently for research use only, and not yet commercially available. However, this tells us that the foundational data to build a real trajectory forecast now exists, assembled from years of real-world clinical use at scale.

The oncology field has talked about multimodal integration for a long time. The data infrastructure to actually do it is now in place. The question the patient asks after a positive MRD result ‘what happens next?’ has never been closer to a complete answer.

Read the full OncoDaily Magazine July Issue