Personalized ctDNA monitoring in metastatic HR+/HER2− breast cancer patients during endocrine and CDK4/6 inhibitor therapy
Jesús Fuentes‐Antrás, Mitchell J. Elliott, Sasha Main, Philippe Echelard, Aaron Dou, Philippe L. Bédard, Eitan Amir, Michelle B. Nadler, Nicholas Meti, Nancy Gregorio, Elizabeth Shah, Emily Van de Laar, Celeste Yu, Yangqing Deng, Lisa Gates, Clodagh Murray, Christopher G. Smith, A. Chevalier, Scott V. Bratman, Lillian L. Siu, Hal K. Berman, David W. Cescon
Abstract
Improved methods to monitor treatment response may enhance patient management and clinical outcomes. This study assessed the feasibility and performance of a tumor-informed circulating tumor DNA (ctDNA) assay in metastatic HR+/HER2- breast cancer patients receiving endocrine and CDK4/6 inhibitor therapy. By conducting whole exome sequencing on archival tumors, highly sensitive personalized ctDNA panels were designed for blood monitoring. The assay showed high detection sensitivity (91% baseline, 70% all timepoints) and associations between higher baseline estimated variant allele fractions, liver metastases, and shorter time to treatment failure (TTF) and overall survival (OS). Complete molecular response, defined as ctDNA clearance, was observed in 28% of patients and correlated with improved TTF (HR 0.07) and OS (HR 0.07). The last cleared timepoint predated treatment failure by a median 14.3 months. ctDNA rises or limited decreases preceded radiographic progression. Molecular metrics may facilitate plasma-first monitoring and innovative strategies for clinical practice and trial design.