Liquid biopsy has rapidly emerged as one of the defining innovations in precision oncology. What began as a promising alternative to invasive tissue sampling is evolving into something much broader: a dynamic source of molecular insight capable of guiding treatment decisions, monitoring disease over time, and potentially reshaping how cancer care is delivered.
Discussions at the American Society of Clinical Oncology (ASCO) 2026 meeting in June reinforced just how quickly this evolution is taking place. Across studies involving circulating tumor DNA (ctDNA), minimal residual disease (MRD), and biomarker-informed treatment strategies, a common theme emerged. The next phase of precision oncology will be determined not just by our ability to detect molecular signals but also by how effectively those signals inform clinical action.
For clinical laboratory experts and pathologists, the question is no longer whether liquid biopsy works, but where and how it can deliver the greatest clinical value and improve decision-making throughout the cancer care continuum.
From static testing to ongoing monitoring
Liquid biopsy is often discussed as a technological advance, but its real value lies in what it enables.
Traditionally, molecular characterization in oncology has relied largely on tissue samples. While tissue remains the gold standard for many applications, obtaining repeat biopsies can be challenging or impossible. In metastatic disease, particularly, lesions may be difficult to access, or in patients responding well to treatment, tumor shrinkage may limit repeated sampling. Further, damaging lesions may develop and go undetected in metastatic tumors that are not biopsied.
Liquid biopsy offers a complementary approach to accessing molecular information without repeatedly sampling tumor tissue. It allows sampling throughout the course of treatment, creating opportunities for longitudinal disease monitoring that have traditionally been difficult or expensive.
This shift from episodic testing to continuous disease assessment is becoming increasingly important as oncology moves toward more personalized and adaptive treatment models. Instead of relying solely on information gathered at diagnosis, clinicians can conduct serial assessments to better understand how tumors evolve over time and monitor treatment response and recurrence risk throughout the patient journey to make informed decisions regarding continuation or modification of treatment.
MRD and the path toward surrogate endpoints
Among the many applications of liquid biopsy, few are receiving as much attention as MRD assessment. Much of the current activity in liquid biopsy is focused on determining how reliably MRD can be measured across tumor types and whether those measurements can ultimately function as meaningful surrogate endpoints in clinical development and patient care.
Several studies presented at ASCO 2026 reinforced this momentum. Prospective analyses from MONSTAR-SCREEN-3 showed that ctDNA positivity following curative-intent treatment was associated with significantly worse disease-free survival across multiple cancer types, reinforcing the prognostic value of MRD assessment. A sub-study of the PARTNER Phase 2/3 trial found that post-treatment ctDNA positivity was highly prognostic for distant recurrence and outperformed pathologic complete response as a risk stratification tool. Meanwhile, the PREDICT-RD Phase 2 study in early triple-negative breast cancer demonstrated how ctDNA-based surveillance could detect MRD before clinical or radiographic evidence of relapse, enabling earlier identification of patients at risk for recurrence.
Together, these findings strengthen the case for ctDNA as a tool for monitoring disease beyond initial diagnosis and treatment, and show the potential to enable earlier intervention than other clinical indicators can.
Looking beyond mutations alone
Today, MRD approaches often begin by sequencing a patient's tumor to identify tumor-specific mutations and then searching for those same alterations within circulating free DNA. Mutation detection has proven highly effective, but it also highlights one of the field's core challenges: sensitivity to distinguish rare tumor-derived DNA fragments from the much larger background of normal circulating DNA in the bloodstream.
To improve sensitivity and help provide valuable biological context, researchers are increasingly exploring complementary approaches. Methylation profiling evaluates cancer-associated epigenetic patterns, and fragmentomics, which analyzes length, structure, and other characteristics of circulating DNA fragments, helps distinguish tumor-derived DNA from the broader background of cell-free DNA. Advances in sequencing and analytical technologies have enabled researchers to evaluate mutations, methylation patterns, and fragmentomic signals together within a single testing strategy, instead of in isolation.
However, several key questions will likely define how this next chapter of liquid biopsy research plays out, including:
Does combining multiple approaches provide enough additional predictive power to justify increased complexity and cost?
Will different cancer types benefit equally from multimodal analysis?
Can these approaches be implemented across clinical laboratories with consistency and quality?
Challenging traditional oncology diagnostic models
Emerging therapies are also forcing the industry to rethink some long-standing assumptions about companion diagnostics.
Historically, precision oncology has often followed a relatively linear path from mutation to targeted therapy to companion diagnostic. For example, epidermal growth factor receptor (EGFR)-targeted therapies in non-small cell lung cancer are prescribed based on the presence of specific EGFR mutations, illustrating the traditional relationship between a genetic alteration, a targeted therapy, and companion diagnostic testing.
However, recent developments involving KRAS-directed therapies show how this model is evolving. At ASCO 2026, results from the RASolute 302 Phase III study of daraxonrasib, a RAS(ON) multi-selective inhibitor, for previously treated metastatic pancreatic cancer, demonstrated activity across bothKRAS-mutant and non-mutant populations. This suggests that clinical benefit may not always be limited to a single genetic alteration. As emerging therapies are increasingly designed to target broader biological pathways and differing routes of pathway activation, the question may shift from whether a specific mutation is present to whether a pathway is active.
This shift has important implications for diagnostic strategies employed by pathologists. As future therapies target broader pathway activation in place of a specific lesion that drives activation, diagnostic approaches must also evolve. Rather than focusing on mutation status alone, laboratories will need to characterize pathway activity, biological function, and other indicators of tumor biology.
Clinical research defining future approaches
The gray areas for liquid biopsy are unlikely to be resolved in routine clinical practice alone. Instead, they are being actively explored within oncology clinical trials, where sponsors have greater flexibility to evaluate competing methodologies and emerging technologies.
This distinction is particularly important because liquid biopsy often serves different purposes in clinical research and routine care. Clinical trials remain the proving ground for emerging approaches, and sponsors may frequently evaluate multiple MRD methodologies to compare analytical strategies and determine which technologies are best suited to different disease settings.
Also, not all cancers behave similarly. Tumor-derived DNA enters the circulation at different rates depending on disease biology, and ctDNA detectability varies substantially across tumor types. Colorectal and bladder cancers are often considered favorable settings for ctDNA-based MRD assessment because of their relatively robust shedding characteristics. Lower shedding tumors, such as prostate cancer, may require greater analytical sensitivity or alternative approaches. These biological differences suggest that a single MRD strategy may not be equally effective across all cancers.
As a result, clinical laboratories supporting oncology development are increasingly involved in evaluating a range of liquid biopsy methodologies. Because questions remain regarding assay design, performance, and clinical utility, trial sponsors often seek to compare multiple approaches rather than adopting a single strategy at the outset. Determining which technologies are best suited to specific disease settings and whether gains in sensitivity or discriminatory power justify additional cost and complexity will be key to shaping future applications of liquid biopsy.
Executing innovation
Scientific progress alone will not determine the future of liquid biopsy. Operational execution always plays an important role.
Preanalytical variables, such as sample collection, stabilization, transport, and storage, remain critical determinants of assay quality. Circulating biomarkers are inherently fragile, and preserving analyte integrity is essential for obtaining reliable results. Seemingly routine considerations, including collection tube selection and sample preservation protocols, can have significant implications for assay performance.
The challenge becomes even greater as assays evolve toward multimodal designs. Future tests may need to simultaneously support mutation analysis, methylation profiling, fragmentomics, and other assessments, potentially introducing competing requirements for sample preservation and workflow design.
This tells pathologists that the next major advances in liquid biopsy may depend as much on standardization, scalability, and implementation as they do on scientific discovery.
From molecular signal to clinical standard
As discussions emerging from ASCO 2026 suggest, liquid biopsy is entering a pivotal new phase. Advanced solutions clearly generate meaningful molecular information. Now the aperture widens to determining how that information can be translated into clinically relevant decisions that are both actionable and scalable.
As biomarkers become more dynamic, assays become more multimodal, and cancer care becomes increasingly personalized, clinical lab scientists will help expand its application from what can be measured to what should be measured and why.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
