Cancer is quite good at hiding, making it a persistent threat. Even after waves of treatments, microscopic cancer reservoirs, called molecular residual disease (MRD), often remain, waiting for the right moment to grow again. In many ways, MRD is synonymous with relapse. 

While imaging has been incredibly helpful to initially diagnose cancer, it is virtually useless when searching for MRD, the cell numbers are just too small¹. As a result, scientists worldwide have been investigating how liquid biopsies can leverage circulating tumor DNA (ctDNA) to detect these tiny pockets of cancer.

Researchers believe more sensitive ctDNA diagnostics could better detect MRD, predicting each individual’s risk of recurrence to get those patients the most effective treatments. But before that can happen, labs must gather the most effective molecular tools to help them find the smallest tumors.

How ctDNA analysis is being used in MRD research

Identifying the most valuable variants

On paper, liquid biopsies are a relatively simple process. A sample is collected and concentrated, and the DNA is extracted and sequenced. The tricky part is identifying the variants with the most prognostic value, and there are two primary approaches: tumor-informed and tumor-naïve.

Tumor-informed tests are personalized to each individual cancer. Labs use the genomic data from primary tumor sequencing to model which MRD variants they are most likely to find in ctDNA. From there, they must acquire and develop the most suitable DNA probes to detect those variants. Because tumor-informed assays key on specific tumor traits, they have great potential to increase MRD sensitivity².

Tumor-naïve MRD assays use broad, off-the-shelf, sequencing panels to identify relevant mutations. This fixed approach is both faster and less expensive than the tumor-informed tests; however, it sacrifices personalization. As a result, only a relatively small subset of the variants in the tumor-naïve panel will be relevant to any given sample, potentially trading sensitivity for ease of use.

Comparing tumor-informed and tumor-naïve MRD approaches

Hybridization capture vs amplicon sequencing

The two primary MRD assay development approaches are hybridization capture and amplicon (PCR-based) sequencing. 

Hybridization uses genomic probes that complement tumor variants, binding directly to them. 

Amplicon sequencing uses PCR primers to bind target flanking regions. This can be the better choice when the target list is relatively small; however, amplicon and primer design can be challenging to scale. 

Because hybridization capture probes can bind specific variants, a large number of targets can be designed for each sample to potentially monitor thousands of variants. As a result, hybrid capture lends itself to personalized panel design³.

Comparing hybrid capture and amplicon approaches for MRD research

Separating signal from noise

Unfortunately, tumor mutations aren’t the only genomic variations in liquid biopsy samples.  Somatic mutations accumulate in hematopoietic stem cells (clonal hematopoiesis), and that can be a major confounding factor in ctDNA analyses. 

To contend with the molecular background noise from clonal hematopoiesis, and perhaps other sources, increasing the number of variants boosts panel breadth and gives the assay more opportunities to capture relevant signals⁴. A panel with sufficient coverage increases variant sensitivity, reducing the LoD and increasing opportunities to detect MRD⁵.

Contending with LoD

The time factor

MRD research is often conducted longitudinally, closely following ctDNA variants to better understand treatment responses and disease recurrence. Scientists want to identify the adjuvant therapy window, the period when follow-up treatments can most effectively kill residual cancer cells. These results are incredibly time sensitive. Cancers move fast and late results may not keep up with that progression to inform future treatments⁶. 

In other words, speed is an essential part of the research equation. Before a lab can translate their research workflows into clinical protocols, they must show timely results that can positively impact patient care. 

This is particularly relevant when working on tumor-informed liquid biopsies. Researchers need a steady, reliable DNA supply to rapidly personalize panels and get results before the adjuvant therapy window expires. 

Explore why speed, sensitivity, target count, and chemistry all matter in MRD research 

See how MRD Express is designed to shorten the path from personalized panel design to sequencing

Next steps for MRD liquid biopsies

We’ve learned a lot about how cancer persists in the body, even after waves of treatments. We know that disease leaves a molecular footprint that can be detected long before residual tumors become visible. We’ve also found that personalized variant targets can make that footprint easier to find, and broader panels can better detect those extremely rare signals. In addition, it was no surprise that speed is essential to keep up with cancer.

At this point, the ability to translate lab findings into clinical care may lie less in deeper sequencing and more in optimizing personalized MRD workflows. They need to be faster, scalable and, most importantly, easily adoptable in the clinic.

The science and technology behind MRD research

Personalized MRD panels

References

1. Pulumati A, Pulumati A, Dwarakanath BS, Verma A, Papineni RVL. Technological advancements in cancer diagnostics: Improvements and limitations. Cancer Reports. 2023; 6(2):e1764. doi:10.1002/cnr2.1764
2. Bekaii-Saab TS, Schoen RE. The promise of molecular residual disease (MRD) testing for patients with colorectal cancer. Clin Adv Hematol Oncol. 2025 Jun;23 Suppl 7(4):1-11. PMID: 40590865. 
3. Singh RR. Target Enrichment Approaches for Next-Generation Sequencing Applications in Oncology. Diagnostics. 2022; 12(7):1539. doi:10.3390/diagnostics12071539 
4. Based on Muzzey, D. Ultra-sensitive molecular residual disease detection with Myriad’s Precise MRD test. Sponsored Industry Expert Theater presentation, ASCO Annual Meeting, Chicago, Illinois, USA (2026). Used with permission. 
5. Chan HT, Chin YM, Nakamura Y, Low SK. Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications. Cancers (Basel). 2020;12(8):2277. Published 2020 Aug 14. doi:10.3390/cancers12082277
6. Gillis R, Zahavi T, Peled N, Yaacov A, Afifi B, Salim J, Basheer R, Asna N, Makori A, Peer M, et al. The Impact of Minimal Residual Disease (MRD) Testing on the Decision-Making Process in Non-Small-Cell Lung Cancer (NSCLC). Cancers. 2026; 18(8):1246. https://doi.org/10.3390/cancers18081246 

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