Circulating Tumor DNA (ctDNA) Testing to Predict Response in Solid Tumors

Characterizing molecular material from solid tumors using body fluids, such as blood, urine, and cerebrospinal fluid, rather than invasive biopsies, represents a major advancement in oncology.¹ One of the most widely studied forms of liquid biopsy utilizes circulating tumor DNA (ctDNA), which consists of DNA fragments released into the bloodstream when tumor cells die.²

Initially developed to identify pharmacologically actionable genes, ctDNA analysis is being explored to monitor treatment response, modify treatment courses, detect the emergence of resistance mutations, and refine prognosis. This article summarizes current data supporting ctDNA as a predictor of response, delving into key studies, remaining challenges, and future research directions.

ctDNA in Advanced Disease: Monitoring Response

CtDNA provides a real-time measure of tumor burden and response to systemic therapy in metastatic and unresectable cancers. The ARTEMIS-PC trial (NCT06043921)³ in unresectable pancreatic cancer demonstrated that ctDNA clearance correlated with higher response rates, prolonged progression-free survival (PFS; 9.0 vs 3.5 months), and earlier relapse detection compared with imaging. Notably, ctDNA changes often preceded radiographic progression by approximately 3 months, suggesting that ctDNA may serve as an early, more sensitive indicator of treatment efficacy.^4,5
Similar observations are reported across other solid tumors, including non–small cell lung cancer (NSCLC), where the time between ctDNA positivity and radiologic progression ranges from 2.8 to 12.6 months.⁶ However, there are currently no prospective studies confirming that switching therapy solely based on a lack of ctDNA response, without evidence of radiologic progression, improves patient outcomes. Because treatment options are often limited in advanced disease, premature therapy changes risk depleting effective lines of treatment without proven survival benefit. Defining optimal thresholds and timing for ctDNA-based intervention remains an unmet need.

Adaptive Study Designs and ctDNA-Guided Therapy

Adaptive clinical trial designs incorporating ctDNA response are 1 approach to evaluating the effects of ctDNA-guided treatment decisions. These study designs allow for real-time modification of treatment arms based on molecular response data. In a recent trial in NSCLC, ctDNA-guided therapy adaptation significantly improved PFS and reduced platinum-based chemotherapy exposure compared with PD-L1 tumor proportion score-informed treatment.^7,8 These findings highlight the potential utility of ctDNA as a biomarker to individualize therapy intensity and sequence. Future ctDNA-adaptive trials may help clarify whether early treatment modifications guided by molecular response can enhance survival while sparing additional treatment for some patients with advanced disease.

Detection of Resistance Mutations

Another clinical application of ctDNA lies in the detection of emergent resistance mutations, enabling therapy adjustments before clinical progression. Early studies demonstrated that ctDNA assays can detect resistance mutations before clinical or radiographic progression.⁶

In estrogen receptor-positive/HER2-negative breast cancer, the PADA-1 and SERENA-6 trials (NCT03079011; NCT04964934)^9,10 demonstrated that serial ctDNA testing can identify ESR1 mutations that develop with resistance to aromatase inhibitors. Switching therapy to a selective estrogen receptor degrader upon ctDNA mutation detection significantly improved PFS compared with waiting until radiographic progression.^11,12 These results provide compelling evidence that early ctDNA-guided therapeutic intervention may improve outcomes in selected malignancies and support the integration of serial ctDNA monitoring into clinical trial design.

Detecting Molecular Residual Disease (MRD)

In early-stage solid tumors, ctDNA-based tests are being used to detect MRD following curative-intent surgery or definitive radiation. Two main ctDNA assay approaches exist: tumor agnostic and tumor informed.

Tumor-agnostic assays employ predefined gene panels specific to each cancer type. They are advantageous for their rapid turnaround and ability to capture tumor heterogeneity, but they offer lower sensitivity and specificity because they are not tailored to individual mutational profiles.

Tumor-informed assays are patient specific and are designed using mutations identified from a tumor tissue sample. These tests achieve higher sensitivity but require sufficient tumor tissue, longer assay development times, and may miss relapse driven by new clonal genotypes.¹³

Prognostic Value of MRD Detection

ctDNA-based MRD testing has demonstrated prognostic value across multiple solid tumors. Persistent ctDNA-positivity following surgery or definitive radiation is consistently associated with shorter disease-free survival (DFS) and overall survival (OS).¹⁴ A meta-analysis of stage 2 colorectal cancer (CRC) showed that postoperative ctDNA positivity conferred an approximate 3.7-fold higher recurrence risk. In the absence of adjuvant chemotherapy, ctDNA-positive patients had an approximate 5.6-fold higher recurrence risk.¹⁵ Dynamic changes in ctDNA levels correlate with tumor volume reduction and disease recurrence, supporting its use as a real-time biomarker of treatment efficacy.¹⁶

However, optimal clinical management for patients who are ctDNA-positive following definitive therapy remains undefined. Whether therapy intensification or alteration in response to ctDNA persistence can improve outcomes is an active and critical area for future studies.

MRD and Systemic Therapy Decisions

Several recent studies explored whether ctDNA positivity after surgery can identify patients who benefit from adjuvant systemic therapy. The GALAXY study (UMIN000039205)¹⁷ in CRC and IMvigor010 (NCT02450331)¹⁸ in urothelial cancer found that patients with ctDNA positivity experienced improved DFS and OS, respectively, with adjuvant therapy, whereas those with ctDNA negativity did not derive benefit from its addition.^19,20

In contrast, the DYNAMIC-III trial (ACTRN12617001566325)²¹ in colon cancer prospectively assigned treatment based on ctDNA status in 1 group, while other participants received standard management. Although this ctDNA-guided, treatment-escalation approach did not improve DFS among ctDNA-positive patients, it safely spared ctDNA-negative patients from additional chemotherapy.²²

These studies suggest that ctDNA may serve as a biomarker to tailor the intensity of adjuvant therapy. Still, integration of ctDNA testing into clinical guidelines remains cautious. Current National Comprehensive Cancer Network guidelines for bladder and colon cancer state that while ctDNA is prognostic, it is not yet predictive, and routine use of ctDNA assays for surveillance or therapeutic decision-making outside clinical trials is not recommended.^23,24

Challenges and Limitations

Despite its promise, several challenges impede the widespread adoption of ctDNA testing. A significant limitation is the lack of standardized thresholds for defining molecular response. Assay heterogeneity further complicates interpretation, as differences in sensitivity, specificity, and limit of detection can yield different results across different studies.²⁵ Existing data have limited generalizability as they are primarily derived from retrospective and/or small cohort studies. The optimal frequency and timing of ctDNA testing have not been established, and cost-effectiveness remains uncertain, particularly for serial monitoring. Clinical benefit from treatment modification based solely on ctDNA findings has yet to be demonstrated in large, randomized trials. Addressing these gaps requires harmonizing assay methodologies, establishing clinically meaningful ctDNA cutoffs, and rigorously evaluating in prospective, interventional studies whether ctDNA-guided management can translate into improved patient outcomes.

Looking Forward

Future research should focus on refining ctDNA quantification and clinical workflow integration. Defining validated thresholds for ctDNA and optimal sampling intervals is critical to standardizing interpretation. Parallel cost-effectiveness analyses are necessary to support reimbursement and clinical adoption. As sequencing technologies continue to evolve, ctDNA may improve the assessment of therapy response and identification of emerging resistance mutations, facilitating earlier therapeutic interventions. Ultimately, improvements in assay sensitivity (which have improved over the past few years), and workflow integration will enhance ctDNA’s precision, reliability, and clinical utility. This will position ctDNA as a vital component of precision oncology, bridging molecular profiling with dynamic disease monitoring.²⁵

Conclusion

ctDNA analysis is a transformative step in personalized oncology care. Beyond identifying actionable mutations, ctDNA may also predict therapeutic response, detect resistance, and detect MRD. While integration into standard practice depends on validation from ongoing and future studies, accumulating evidence supports ctDNA’s potential to refine prognosis, individualize treatment plans, and reduce chemotherapy exposure in some patient groups. ctDNA-guided adaptive trials will be critical in determining its role in clinical decision-making and solidifying liquid biopsy as a cornerstone of modern oncology.

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