First-Line Doublet Chemotherapy for Metastatic Triple-Negative Breast Cancer: Circulating Tumor Cell Analysis of the tnAcity Trial

Abstract

Purpose: Circulating tumor cells (CTCs) are prognostic biomarkers in metastatic breast cancer, but their role in predicting treatment outcomes in metastatic triple-negative breast cancer (mTNBC) is less clear. The tnAcity trial demonstrated a significant progression-free survival (PFS) benefit with nab-paclitaxel (nab-P)/carboplatin (C) over nab-P/gemcitabine (G) or G/C in patients with mTNBC. We assessed the correlation between CTC dynamics and clinical benefit in all patients and by treatment arm.

Methods: CTC enumeration, performed using CELLSEARCH technology (Menarini Silicon Biosystems, Huntingdon Valley, PA, USA), was a prespecified exploratory endpoint in the tnAcity trial. Patients with TNBC were categorized based on pre- and post-treatment CTC levels: Group 1 (+ + +; elevated CTCs at baseline and postbaseline), Group 2 (+ ± ±; CTCs elevated at baseline and cleared postbaseline [cycle 3 and/or cycle 5]), or Group 3 (-; no CTCs detected at baseline). The baseline cutoff was ≥1 CTC/7.5 mL for the main analysis; cutoffs of ≥2 and ≥5 CTCs were used for supporting analyses.

Results: The main analysis included 126 patients (Group 1, n = 24; Group 2, n = 54; and Group 3, n = 48). The median PFS was longer in Group 2 vs Group 1 (8.5 vs 4.7 months; HR, 0.30 [95% CI, 0.17-0.54]). These results were supported by the ≥2- and ≥5-CTC cutoff analyses. The median overall survival rates were 17.8, 16.0, and 9.8 months in Groups 2, 3, and 1, respectively. The overall response rates were 79.6%, 43.8%, and 29.2%, respectively. A numerically higher percentage of patients had CTC clearance during nab-P/C treatment vs nab-P/G or G/C.

Conclusion: Efficacy outcomes trended positively with chemotherapy-induced elimination of CTCs, suggesting that CTC clearance may predict the chemosensitivity of mTNBC tumors.

Trial registration: EudraCT Number: 2013-000113-20; ClinicalTrials.gov number: NCT01881230.

Keywords: chemotherapy; circulating tumor cells; metastatic triple-negative breast cancer; nab-paclitaxel; prognosis.

Conflict of interest statement

Dr Liu reports nonfinancial support from MediTech Media during the conduct of the study, her institution received funding from Celgene to conduct the trial. Dr Liu had received clinical trial support from Eisai, Genentech, GRAIL, Janssen, Merck, Novartis, Seattle Genetics and Tesaro. Dr Liu also received nonfinancial support from Ionis, nonfinancial support from Pfizer, nonfinancial support from Syndax, nonfinancial support from Agena, nonfinancial support from Cynvenio, and nonfinancial support from Menarini Silicon Biosystems outside the submitted work. Dr Janni reports grants from Celgene during the conduct of the study. Dr Yardley reports grants from Novartis during the conduct of the study. Sarah Cannon, the institution for which Dr Yardley serves as a research leader, has been paid for consulting/advisory roles from the following companies: Abraxis, Amgen, Alexion, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisai, Lilly, Roche/Genentech, Gilead, GlaxoSmithKline, Janssen, Luitpold, Medivation, Novartis, Otsuka, Pfizer, ProStrakan, Spectrum, Janssen, Ipsen, Novartis, R-Pharm US, Millennium, Seattle Genetics, Sanofi, Merck, Merrimack, AbbVie, Incyte, Concordia, Genzyme, Exelixis, Nippon Kayaku, Odonate, ELM Medical, Biotheranostics, and Hengrui; and funding for the conduct of research projects has been provided by the following companies: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BioMarin, Bristol-Myers Squibb, Celgene, Concordia, Eisai, Exelixis, Genentech, Genzyme, GlaxoSmithKline, ImClone, Incyte, Ipsen, Janssen, Lilly, MedImmune, Medivation, Merck, Merrimack, Novartis, Pfizer, Roche, Sanofi, Spectrum, and Tesaro. Dr Harbeck reports personal fees from Celgene during the conduct of the study. Mr McGovern, Mr Beck and Dr Wei reports employment and stock options from Celgene during the conduct of the study. The authors report no other conflicts of interest in this work.

© 2019 Liu et al.

Figures

Figure 1

Efficacy outcomes by change in circulating tumor cell levels from baseline. Kaplan–Meier plots of (A) PFS and (B) OS. Notes: Group 1 (+ + +), elevated at baseline and elevated postbaseline; Group 2 (+ ± ±), elevated at baseline and cleared postbaseline (cycle 3 and/or cycle 5); Group 3 (−), no CTCs detected at baseline. a vs Group 1. Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Figure 2

Efficacy outcomes by the absence or presence of circulating tumor cells at baseline. Kaplan–Meier plots of (A) PFS and (B) OS. Abbreviations: CTC, circulating tumor cell; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.