What Is Minimal Residual Disease in Cancer? Why It Matters and How Liquid Biopsy Detects It

What Is Minimal Residual Disease (MRD)?

Minimal residual disease (MRD) refers to what remains in a patient after surgery or chemotherapy and cannot be detected by conventional imaging, namely tumor remnants left behind after treatment.

MRD, an important indicator of success in cancer treatment, includes disease that carries a risk of spread, often metastasis, arising from a microscopic tumor burden. Detecting MRD is critical to understanding whether the disease has been brought under control before recurrence and to providing patient-specific treatments.

The Biology of Minimal Residual Disease

Figure Explanation:

The biology of MRD in patients with solid tumors removed by surgery: Different sources of tumor DNA in the bloodstream play an important role in evaluating minimal residual disease (MRD) in patients with cancer. MRD is also known as measurable or molecular residual disease. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may originate from a primary tumor or precancerous lesions before surgery. However, because ctDNA has a short half-life measured in minutes, ctDNA detected in the first days after surgery cannot originate from the primary lesion.

The release of ctDNA and the biology of MRD in this setting are not fully understood. The primary lesion may have had CTCs before treatment, may not have been completely removed, or may not have achieved complete remission after neoadjuvant therapy. This can lead to the spread of residual tumor cells (DTCs: disseminated tumor cells). In the figure, MRD is represented as individual dormant DTCs. These DTCs may contribute ctDNA to the bloodstream not only through developing micrometastases but also through an increase in the number of dying tumor cells.

Micrometastases may actively release tumor cells into the bloodstream. These cells may die within minutes, producing ctDNA. Individual DTCs may also migrate into the bloodstream, appear as CTCs, and become a new source of ctDNA. Finally, DTCs with stem-cell characteristics that reach the bloodstream may acquire metastatic abilities. This aggressive CTC subgroup may reach distant organs such as the bone marrow, liver, and lungs, establish new metastases there, and spread to other sites.

Why Minimal Residual Disease Matters

Conventional imaging technologies are not sensitive enough to detect MRD. This highlights the need for more sensitive, innovative tests that enable early intervention against cancer. Early detection of MRD is key to preventing metastasis and achieving complete disease control.

In this context, liquid biopsy is an innovative method that enables MRD detection by analyzing tumor-derived DNA (ctDNA), circulating tumor cells (CTCs), or other biomarkers in blood or other body fluids collected from the patient. It has already entered clinical practice in hematological cancers, such as leukemia and lymphoma arising in blood and bone marrow, and could also revolutionize the treatment of solid tumors arising in organs and tissues, such as lung, colon, and breast cancers.

A Recent Nature Review

Nature Reviews Clinical Oncology published on 28 November 2024 the article "Minimal residual disease as a target for liquid biopsy in patients with solid tumours", which provides a comprehensive assessment of minimal residual disease. Here, we summarize its most important points for our readers.

Key Points of the Article:

• Sensitive blood tests enable the detection of circulating tumor DNA (ctDNA) at very low concentrations (<10 ppm). <10 ppm: Fewer than 10 parts per million. In other words, in a solution or environment containing 1 million parts, the amount of tumor-related material is less than 10 parts.
• MRD detection can be associated with progression-free survival (PFS) and overall survival, among other clinical outcomes.
• ctDNA-based MRD detection can identify cancer recurrence before it is detected by imaging, potentially months earlier. This interval depends on the tumor type and stage.
• Progression from ctDNA-detected MRD to overt metastasis may depend on the remaining tumor burden and the host response, such as the antitumor immune response.
• Interventional clinical trials are needed to identify treatments that can eliminate MRD in patients with solid tumors who test positive for MRD.

Main Findings of the Article

1. MRD Detection Using ctDNA

ctDNA consists of DNA fragments released into the bloodstream by tumor cells through apoptosis, necrosis, or active release. These DNA fragments are crucial to understanding the biological state of tumors and the presence of residual tumor. ctDNA concentrations used to detect MRD are generally at the parts-per-million (ppm) level, indicating the need for extremely sensitive tests.

Studies suggest that ctDNA-based MRD detection can signal the risk of recurrence months in advance. For example, a study in patients with colorectal cancer showed that an increase in ctDNA levels enabled detection 9.8 months before recurrence was identified by imaging and that this detection influenced clinical decisions.

2. Current Clinical Applications

Liquid biopsy for MRD detection is currently being investigated extensively in both observational and interventional clinical trials. Although ctDNA tests vary across cancer types, they show promise particularly in colorectal cancer and early-stage lung cancer.

Notable findings from clinical trials:

• Colorectal Cancer: The DYNAMIC study showed that MRD detection could optimize decisions about adjuvant chemotherapy. Patients testing negative for ctDNA had similar survival rates even without chemotherapy.

• Lung Cancer: The TRACERx study showed that ctDNA levels are an effective marker for predicting metastatic spread and assessing treatment response.

Finally, monitoring MRD with ctDNA is a critical step not only toward preventing recurrence but also toward sparing patients the risk of unnecessary treatment. This could accelerate the shift toward personalized medicine in cancer treatment.

Liquid Biopsy and MRD

Technological Methods and Innovations

Recent advances have brought liquid biopsy technology to a critical turning point in cancer detection and monitoring. Newly developed next-generation sequencing (NGS) methods go far beyond conventional techniques by detecting ctDNA at extremely low concentrations for MRD assessment. Methylation-based analyses also enable more precise detection by revealing tumor-type-specific characteristics of ctDNA.

Pioneering methods such as MAESTRO can also track low-frequency mutations with up to 100 times fewer sequencing reads, increasing the speed and accuracy of MRD detection.

Managing Different Cancer Types with ctDNA

• Colorectal Cancer: ctDNA provides substantial support for MRD detection and treatment decisions in colorectal cancer. Large clinical trials such as DYNAMIC and CIRCULATE-Japan have demonstrated that ctDNA positivity is highly valuable for predicting recurrence risk.

• Breast Cancer: Triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer are settings in which ctDNA detection is used to monitor treatment response and help prevent early recurrence. For example, ChemoNEAR showed that ultrasensitive ctDNA tests are highly effective in measuring treatment efficacy.

• Lung Cancer: Studies such as TRACERx and IMpower010 have shown that ctDNA is a critical biomarker for detecting early recurrence and evaluating the effectiveness of treatments such as immune checkpoint inhibitors.

Overall, ctDNA-based liquid biopsies continue to play a transformative role in oncology through their potential to detect MRD and guide treatment across different cancer types.

Clinical Trials and Results

Clinical Trials Testing ctDNA-Based MRD Monitoring

Many clinical trials are investigating ctDNA-based MRD detection. Studies such as DYNAMIC and CIRCULATE-Japan have demonstrated that ctDNA can be used to predict recurrence risk and guide adjuvant treatment. In CIRCULATE-Japan, postoperative ctDNA positivity increased recurrence risk by up to 10 times (HR 10.0), while being associated with a better response to adjuvant treatment.

DYNAMIC showed that adjuvant chemotherapy was unnecessary in patients with stage II colon cancer who tested negative for ctDNA. These patients showed no significant difference in 5-year survival rates even without treatment. This finding could improve quality of life by sparing patients unnecessary treatment.

Potential to Guide Adjuvant Treatment

Adjuvant treatment strategies could be redesigned around MRD detection. More aggressive treatments, such as targeted therapies or immune checkpoint inhibitors, could be used in ctDNA-positive patients, while treatment de-escalation may become possible in ctDNA-negative patients. This approach could offer substantial benefits to both patients and healthcare systems.

Overall, the growing body of clinical trial data demonstrates that ctDNA is a versatile biomarker for MRD detection and management. These findings could reshape the future of cancer treatment.

Future Directions: Multiomic Approaches

Liquid biopsy approaches for diagnosing and monitoring minimal residual disease (MRD) are becoming more powerful through multiomic data analysis.

Multiomic assessment enables genetic, epigenetic, protein, and metabolite levels to be examined using a single blood sample.

This approach aims to better understand the biological diversity of MRD and analyze the dynamics of the tumor microenvironment (TME). For example, DNA methylation analyses and fragmentomic methods have increased liquid biopsy sensitivity. Integrating multiomics into routine clinical practice is expected to guide diagnostic and treatment decisions more accurately in the future.

MRD Control and Treatment Strategies

Controlling MRD requires early detection, targeted therapies, and an effective monitoring strategy. Although liquid biopsy-based approaches are effective in assessing minimal tumor burden, developing treatments that stop MRD progression remains challenging. Therapies directed at MRD include immune checkpoint inhibitors, cancer vaccines, and molecularly targeted agents. In addition to eliminating MRD completely, keeping residual tumor cells dormant is also being considered as a strategy.

Conclusions and Recommendations: The Potential of MRD in Future Oncology Practice

Sensitive MRD detection with liquid biopsy could bring a paradigm shift in cancer management. Detecting MRD early could optimize the timing of interventions aimed at stopping disease progression. Integrating liquid biopsy results into routine clinical practice may improve treatment outcomes, particularly in tumors with a high risk of MRD, such as colon and breast cancers.

Early MRD detection may increase overall survival rates by reducing the risk of cancer recurrence. For example, better identification of patients who will benefit from adjuvant chemotherapy enables treatment intensity to be individualized. Monitoring MRD with liquid biopsy also allows recurrent disease to be recognized months before radiological imaging detects it. This could improve quality of life by enabling earlier intervention and less toxic treatment options.