A review of trials investigating ctDNA-guided adjuvant treatment of solid tumors:The importance of trial design

Circulating tumor DNA (ctDNA) holds promise as a biomarker for guiding adjuvant treatment decisions in solid tumors. This review systematically assembles ongoing and published trials investigating ctDNA-directed adjuvant treatment strategies. A total of 57 phase II/III trials focusing on ctDNA in minimal residual disease (MRD) detection were identified, with a notable increase in initiation over recent years. Most trials target stage II or III colon/colorectal cancer, followed by breast cancer and non-small cell lung cancer. Trial methodologies vary, with some randomizing ctDNA-positive patients between standard-of-care (SoC) treatment and intensified regimens, while others aim to de-escalate therapy in ctDNA-negative patients. Challenges in trial design include the need for randomized controlled trials to establish clinical utility for ctDNA, ensuring adherence to standard treatment in control arms, and addressing the ethical dilemma of withholding treatment in high-risk ctDNA-positive patients. Longitudinal ctDNA surveillance emerges as a strategy to improve sensitivity for recurrence, particularly in less proliferative tumor types. However, ctDNA as longitudinal marker is often not validated yet. Ultimately, designing effective ctDNA interventional trials requires careful consideration of feasibility, meaningful outcomes, and potential impact on patient care.