Noninvasive MRD monitoring and profiling of clonal evolution by ctDNA in patients with advanced cancers treated within molecular tumor boards
Ranganathan, L.; Kuehn, J. C.; Klingler, C.; Pauli, T.; Metzger, P.; Bleul, S.; Philipp, U.; Hummel, F.; Weinschenk, S.; Deuter, M.; Rapp, J.; Winter, C.; Sueltmann, H.; Tinhofer, I.; Mouliere, F.; Rawluk, J.; von Bubnoff, N.; Dazert, E.; Illert, A. L.; Nieters, A.; Wehrle, J.; Peters, C.; Brummer, T.; Schultheis, A.; Lassmann, S.; Miething, C.; Becker, H.; Werner, M.; Boerries, M.; Duyster, J.; the MTB-FR Network, ; the DKTK EXLIQUID consortium, ; Scherer, F.
Show abstract
Circulating tumor DNA (ctDNA) from blood plasma has emerged as a promising biomarker for noninvasive profiling of tumor mutational landscapes and disease monitoring across cancers. In this study, we developed a targeted next-generation sequencing approach to explore the role of ctDNA for comprehensive tumor genotyping, early response prediction, and characterization of clonal heterogeneity in patients with advanced and rare cancers treated within molecular tumor boards. We applied our technology to 157 plasma specimens from 57 patients at distinct disease milestones and detected tumor variants in 96% of baseline samples, with 65% of them harboring actionable aberrations. Longitudinal monitoring of baseline mutations in on-treatment plasma revealed that ctDNA dynamics were significantly associated with clinical outcomes and enabled early prediction of disease progression. Finally, we observed substantial clonal heterogeneity over time, identifying emerging mutations in all analyzed plasma samples obtained at progression, including potentially targetable variants for subsequent personalized therapies.
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