Chemotherapy response monitoring with DNA methylation-based ctDNA tumor fraction: Evidence from a real-world cohort of patients with advanced common solid malignancies.

Background/objectives: Chemotherapy remains standard for many cancers, but challenges remain in evaluating clinical response to therapy. Epigenomic circulating tumor DNA (ctDNA) quantification is an emerging molecular approach to tumor response assessment. Here, we examine a tissue-free, methylation-based assay to demonstrate how changes in circulating tumor fraction (TF) associate with outcomes in a real-world advanced, pan-cancer cohort treated with chemotherapy. Methods: This retrospective study evaluated patients with advanced solid tumors treated with chemotherapy and serial ctDNA testing, both pre- and post-therapy initiation. Serial samples were analyzed with an analytically validated next-generation sequencing (NGS) methylation-based ctDNA assay. The primary outcome measured was real-world time to next treatment (rwTTNT) as a surrogate for progression free survival. Secondary outcomes included real-world overall survival (rwOS) and lead time from TF increase to rwTTNT event. Results: Among 278 eligible patients, decreasing TF was associated with improved rwTTNT (aHR 0.55 [95 % CI 0.39, 0.79] p = 0.001). Patients achieving a ≥98 % decrease at any timepoint had superior outcomes (rwTTNT aHR 0.40 [95 % CI 0.28, 0.56] p < 0.005; rwOS aHR 0.54 [95 % CI 0.38, 0.79] p < 0.005). Patients with continuous TF decrease had longer rwTTNT than those with initial decrease followed by increase (aHR 0.05 [CI 0.004-0.575] p = 0.016). Increasing TF was detected in 64 patients with a median lead time to rwTTNT of 2.27 months. Conclusions: On-treatment changes in methylation-based TF in chemotherapy-treated patients are associated with long-term outcomes. CtDNA monitoring offers an opportunity to rapidly evaluate therapy efficacy, potentially improving clinical decision-making regarding benefit vs toxicity and long-term patient outcomes.