Early evaluation of risk stratification and clinical outcomes for patients with advanced breast cancer through combined monitoring of baseline circulating tumor cells and DNA.

Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced BCa in the clinic. Here we introduce the value of baseline CTCs and ctDNA to early differentiate clinical stages, tumor heterogeneity, and prognosis. We enrolled 254 stage IV and 38 stage III BCa patients and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies. Outcome including PFS, and OS were evaluated. The baseline CTCs for stage IV patients were approximately 9.5 times higher than those detected in stage III patients. Baseline CTC counts with a cutoff of 5 were significantly associated with prognosis. Within each stage, patients with <5 CTCs had longer PFS. Stage III patients with no CTCs exhibited the longest survival compared to patients with ≥1 CTC. CTC-clusters were only found in stage IV patients, among whom 15 stage IV patients with ≥5 CTC-clusters had the worst PFS compared to the 239 stage IV patients with <5 CTC-clusters. Similar outcomes were observed in 28 out of 254 stage IV patients who had at least 1 CTC-cluster detected, as these patients had shorter PFS. The major differences in ctDNA mutations between stage III and stage IV BCa were in PIK3CA and ESR1, which were associated with specific organ metastasis and worse outcomes. Assessing the baseline levels of CTCs, CTC-clusters, and mutational ctDNA profile could reliably aid in differentiation of clinical stage and early prediction of metastasis and outcomes in advanced BCa.