The Expanding Role of Liquid Biopsy in Oncology

Dr. Heidi Ko is a board-certified medical oncologist and hematologist, currently serving as the medical director of medical affairs at Labcorp Oncology. She leads clinical, educational, and research initiatives to advance oncology diagnostics for healthcare providers and biopharmaceutical partners. Before joining Labcorp, Dr. Ko was an assistant professor at UT Health San Antonio, specializing in breast oncology. She also served as site principal investigator for the Academic Breast Cancer Consortium and participated in the experimental and developmental therapeutics and protocol review committees.

Dr. Ko earned her medical degree from the Rowan University School of Osteopathic Medicine, followed by a residency in internal medicine at UT Health/McGovern Medical School in Houston and a fellowship in hematology and oncology at Albert Einstein College of Medicine/Montefiore Medical Center. She is also an active member of the American Society of Clinical Oncology. Today’s Clinical Lab recently spoke with Dr. Ko.

Q: How is liquid biopsy being utilized in clinical practice?

A: To begin, it’s important to distinguish between solid tumors, such as breast or colon cancer, and hematologic malignancies like leukemia or lymphoma. In blood cancers, molecular testing has traditionally relied on blood-based assays to evaluate the biological and genetic features of malignant cells, so the concept of using a blood test to understand a cancer’s molecular profile isn’t new in this context.

However, when we talk about liquid biopsy in solid tumors, we’re referring to a newer application of this approach. I find it helpful to think about its clinical utility in two main categories. First, circulating tumor DNA (ctDNA) analysis for molecular profiling has an established role in identifying actionable mutations—for example, ESR1 mutations that may inform the use of oral selective estrogen receptor degraders (SERDs), or PIK3CA mutations that guide PI3K/AKT-targeted therapies.

The second category is the use of ctDNA for assessing molecular residual disease (MRD). This is an emerging area. While we know MRD positivity has prognostic significance, meaning it’s associated with worse outcomes, we don’t yet have definitive evidence that it has predictive value. In other words, we’re still learning whether MRD results can be used to guide treatment changes in early-stage or metastatic settings.

Q: In what clinical scenarios does liquid biopsy offer an advantage over tissue biopsy?

A: When it comes to molecular profiling, using liquid biopsy or ctDNA testing can be particularly advantageous in situations where tissue biopsy is difficult, risky, or not feasible. This includes patients with tumors in anatomically challenging locations, those with poor performance status, or when tissue is limited, such as in non-small cell lung cancer (NSCLC), upper GI malignancies, or pancreatic cancer.

Liquid biopsy is also highly valuable in the metastatic setting, particularly at the time of disease progression or relapse on treatment, when there is a need to assess tumor evolution or detect resistance mutations that could inform the next line of therapy. Another benefit is the relatively rapid turnaround time, which can be critical for timely treatment decisions.

That said, one important caveat is that a negative ctDNA result, meaning no genomic alterations are detected, does not rule out the presence of clinically actionable biomarkers. In such cases, confirmatory tissue testing should be considered to ensure that key molecular targets are not missed.

Q: With that important limitation in mind, what are the other limitations of liquid biopsy compared to tissue biopsy?

A: Liquid biopsy has several other important limitations. Unlike tissue biopsy, it does not provide histopathological context, meaning it cannot determine tumor grade, stage, or architecture, all of which are essential for many diagnostic and prognostic decisions.

Another key limitation is sensitivity. In early-stage cancers, especially when the tumor has been surgically removed or treated with systemic therapy, or in low-shedding tumors like gliomas, the amount of ctDNA may be too low for detection, increasing the risk of false-negative results, as I previously mentioned. 

Additionally, liquid biopsy analyzes cell-free DNA (cfDNA) from both healthy and cancerous cells. Mutations that arise from clonal hematopoiesis of indeterminate potential (CHIP), a common age-related phenomenon, can be misinterpreted as tumor-derived mutations. This is especially relevant in cancers like prostate cancer, where CHIP-related mutations may be clinically significant. Many commercial assays now incorporate strategies to filter out CHIP-associated mutations; however, this remains an area of ongoing refinement to reduce the risk of false positives and improve result interpretation.

Q: How does liquid biopsy complement tissue biopsy, and when should they be used together?

A: Liquid biopsy and tissue biopsy serve complementary roles in cancer care. Tissue biopsy remains the gold standard for initial diagnosis, providing critical histologic information such as tumor type, grade, and morphology. However, liquid biopsy offers a less invasive way to monitor molecular changes over time, making it a valuable adjunct, particularly in dynamic clinical scenarios.

This combined approach is especially useful in cancers like NSCLC, where “tissue is the issue.” Limited or inaccessible biopsy samples can prevent comprehensive molecular profiling, yet identifying actionable biomarkers, such as EGFR mutations, is essential for selecting first-line targeted therapies, which are now the standard of care in many cases of NSCLC.

Complementary testing could also help detect acquired resistance mutations. For example, in hormone receptor-positive breast cancer, ESR1 mutations, which can emerge after aromatase inhibitor therapy, are more reliably detected via liquid biopsy. In these cases, ctDNA analysis can inform timely treatment adjustments, such as initiating an oral SERD.

Q: How are reimbursement policies and clinical guidelines limiting the use of liquid biopsy testing for certain mutations or cancer types?

A: Reimbursement remains one of the key barriers to the broader adoption of liquid biopsy. Expanded coverage is likely to depend on continued demonstration of clinical utility and incorporation into national guidelines. As noted earlier, the strongest clinical utility of liquid biopsy today is molecular profiling or genotyping in advanced or metastatic disease. This is particularly useful when molecular profiling can identify actionable targets that inform therapy selection, either concurrently or as an alternative solution in scenarios where tissue is limited or unsafe to obtain. It’s also well-established for detecting acquired resistance mutations during or after systemic therapy.

In contrast, the use of liquid biopsy for assessing MRD is still an emerging area. While we know that MRD positivity is prognostic, associated with a higher risk of recurrence, the predictive value is not yet fully established. That is, we don’t yet have definitive evidence that detecting ctDNA should drive changes in therapy to improve outcomes. This is why ongoing clinical trials aimed at evaluating the role of ctDNA in guiding treatment decisions are so important for moving the field forward.

Q: Which applications of liquid biopsy show the greatest promise for improving patient care?

A: One of the most promising applications of liquid biopsy continues to be in monitoring treatment response and detecting MRD after curative therapy and/or in metastatic disease. Here, early detection of recurrence or molecular relapse could enable earlier intervention before radiographic or clinical relapse occurs, which is what our hematology colleagues have already been doing. 

A compelling example of this was presented at ASCO 2025 with the results from the SERENA-6 trial. This study evaluated the strategy of early intervention, specifically switching to an oral SERD, in patients with metastatic hormone receptor–positive breast cancer who were receiving an aromatase inhibitor upon detection of an ESR1 mutation via serial ctDNA testing. While we’re still awaiting long-term data such as overall survival, the trial met its primary endpoint: switching therapy at the time of molecular progression improved progression-free survival.

That said, many important questions remain, such as the optimal frequency and duration of serial ctDNA monitoring, the overall cost-effectiveness of this approach, and whether we’re meaningfully extending survival or simply delaying disease progression. I’m hopeful that ongoing and future trials will provide clarity on these points.

As technology continues to evolve and as evidence supporting predictive utility grows, I believe liquid biopsy will become an even more powerful tool for longitudinal disease monitoring and truly personalized cancer care.