Exploration of the clonal evolution and construction of the tumor clonal evolution rate as a prognostic indicator in metastatic breast cancer

Background Tumor heterogeneity and clonal evolution are related to the treatment resistance and disease progression in metastatic breast cancer (MBC). However, the process of clonal evolution and their relationship to prognosis remain unclear. This study aimed to elucidate the evolution of MBC through circulating tumor DNA (ctDNA) analysis and to develop a novel indicator for predicting treatment efficacy and prognosis. Methods This multicenter retrospective study enrolled MBC patients who underwent next-generation sequencing between April 2016 and October 2022. The clonal evolution of tumors was inferred using PyClone and CITUP software. Results The study included 406 MBC patients. A cohort of 139 patients from the National Cancer Center served as the training cohort, while 267 patients from other centers comprised the validation cohort. In the training cohort, clonal analysis revealed that most MBCs exhibited branched clonal evolution, while a minority showed linear evolution. The branched evolution pattern was associated with slower disease progression (HR, 0.53; 95% CI, 0.32-0.87; P = 0.012). We introduced tumor clonal evolution rate (TER) as a novel concept to reflect the speed of clonal evolution. Survival analysis demonstrated that compared to the TER-high group, patients in the TER-low group had better progression-free survival (PFS) (HR, 0.62; 95% CI, 0.40-0.96; P = 0.033) and overall survival (OS) (HR, 0.45; 95% CI, 0.24-0.85; P = 0.013). Similarly, in the validation cohort, although the median OS was not reached, patients in the TER-low group had better prognosis compared to those in the TER-high group (HR, 0.41; 95% CI, 0.21-0.83; P < 0.001). Conclusions Patients with branched evolution have better treatment efficacy than those with linear evolution. The TER shows potential as a biomarker for treatment efficacy and prognosis, providing new evidence that ctDNA is a valuable molecular indicator for predicting treatment outcomes in metastatic breast cancer.