Clinical bottom line
Circulating tumor DNA (ctDNA) analysis is emerging as a promising tool to guide treatment adaptation in advanced gastric cancer, particularly in HER2-positive and other molecularly defined subgroups. Early evidence suggests that ctDNA profiling can detect actionable genomic alterations such as TP53 mutations and MET amplifications, which may predict disease progression and resistance to standard therapies. While ctDNA-guided treatment strategies remain investigational, they hold potential to personalize therapy, monitor response dynamically, and identify early relapse, thereby informing timely therapeutic modifications. However, clinical implementation requires further validation in prospective trials to establish standardized assays, optimal timing, and impact on patient outcomes.
What the evidence shows
Recent studies have demonstrated the clinical relevance of ctDNA in advanced gastric cancer, highlighting its potential as a minimally invasive biomarker for treatment guidance. Osumi et al. (2025) reported that in HER2-positive advanced gastric cancer, ctDNA analysis identified genomic alterations correlating with treatment response and resistance, suggesting utility in monitoring HER2-targeted therapies. Specifically, detection of emerging mutations in ctDNA preceded radiographic progression, offering a window for early intervention.
Additional work has focused on the prognostic value of specific alterations detected in ctDNA. Peer reviews of studies analyzing TP53 mutations and MET amplifications in ctDNA indicate these alterations may serve as predictors of disease progression in advanced gastric cancer (Peer Review #2, 2021). These findings imply that ctDNA profiling could stratify patients at higher risk of progression who might benefit from treatment intensification or alternative regimens.
Chakrabarti et al. (2023) extended these observations by demonstrating that ctDNA-guided recurrence risk assessment in esophageal and gastric cancers can refine post-treatment surveillance strategies. Their data suggest that patients with detectable ctDNA post-therapy have a higher likelihood of relapse, supporting ctDNA as a marker for minimal residual disease and a trigger for therapeutic adaptation.
While much of the evidence derives from observational cohorts and retrospective analyses, the collective data underscore the feasibility and potential clinical value of ctDNA-guided treatment adaptation in advanced gastric cancer.
Caveats and uncertainty
Despite promising findings, several limitations temper enthusiasm for routine clinical use of ctDNA-guided treatment adaptation in advanced gastric cancer. First, assay variability and lack of standardized ctDNA testing platforms complicate interpretation and cross-study comparisons. Sensitivity and specificity can vary depending on the technology and timing of sample collection.
Second, the heterogeneity of gastric cancer and the dynamic nature of tumor evolution mean that ctDNA may not capture all relevant resistance mechanisms or tumor clones, potentially leading to underestimation of disease burden or missed targets.
Third, most evidence to date is hypothesis-generating, derived from small cohorts or peer-reviewed analyses of preliminary data rather than large, prospective randomized trials. The clinical benefit of changing therapy based on ctDNA findings alone remains unproven.
Finally, the optimal thresholds for ctDNA positivity, timing of serial sampling, and integration with imaging and clinical parameters require further elucidation before widespread adoption.
How this may change practice
If validated in prospective clinical trials, ctDNA-guided treatment adaptation could transform management of advanced gastric cancer by enabling more precise, real-time monitoring of tumor genomics and dynamics. This approach may allow oncologists to:
- Detect emerging resistance mutations earlier than conventional imaging, prompting timely switches to alternative therapies or enrollment in clinical trials.
- Stratify patients by molecular risk to tailor intensity and duration of systemic treatments.
- Monitor minimal residual disease post-treatment to guide surveillance intensity and adjuvant therapy decisions.
- Reduce reliance on invasive tissue biopsies, improving patient comfort and feasibility of serial monitoring.
Incorporation of ctDNA analysis into multidisciplinary care pathways would require education on assay interpretation, development of standardized protocols, and integration with existing clinical and radiologic assessments.