Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-line chemotherapy

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. Methods: Serial CTC data from 469 patients (2,202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs (bCTC), combined CTC status at baseline to the end of cycle 1 (cCTC), and tCTC. Akaike Information Criterion (AIC) was used to select the model that best predicted PFS and OS. Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (tCTCneg, 56.9% ), low (tCTClo, 23.7%), intermediate (tCTCmid, 14.5%), or high (tCTChi, 4.9%). Patients with tCTClo, tCTCmid and tCTChi patterns had statistically significant inferior PFS and OS compared to those with tCTCneg (P<.001). AIC indicated that the tCTC model best predicted PFS and OS when compared to bCTC and cCTC models. Validation studies in an independent cohort of 1,856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. Conclusions: We identified four novel prognostic groups in MBC based on similarities in CTC trajectory patterns during chemotherapy. Prognostic groups included patients with very poor outcome (tCTCmid+tCTChi, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be utilized for fine-tuning of CTC-based risk-stratification strategies to guide future prospective clinical trials in MBC.