Résumé
Background: Endocrine therapy (ET) is the preferred 1st line therapy in ER+ HER2- metastatic breast cancer (MBC) patients, but not all benefit from such strategy for which predictive biomarkers are lacking. Prior studies showed that circulating tumor cells (CTC) count is the strongest prognostic factor beyond PS in that population. The STIC CTC trial (NCT01710605) assessed whether CTC count could drive the choice between frontline ET or chemotherapy (CT, with or without ET maintenance).
Methods: For this multicenter phase 3 non-inferiority trial, main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to ET or CT, informed consent. Patients were randomized 1:1 between clinically-driven choice (single agent ET if clinicallow, CT if clinicalhigh, as decided by physician based on clinical factors, blinded to CTC results) or a CTC-driven choice [ET if CTClow (<5 CTCs/7.5mL), CT if CTChigh (≥5 CTCs/7.5mL)]. The primary objective was treatment efficacy ([PFS hazard ratio (HR)], non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is <1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS.
Results: In this trial, 778 patients were randomized between both strategies. Of all patients, 71.0%, 26.6% and 2.4% were considered as endocrine-sensitive, with secondary or with primary endocrine resistance, respectively. In both arms (clinically- and CTC-driven), prognostic evaluation by physician/CTCs and allocated treatments were as follows: (i) clinicallow/CTClow 46.5% and 48.6% of patients, all treated with ET. (ii) clinicalhigh/CTChigh 14.0% and 13.0%, all treated with CT. (iii) clinicallow/CTChigh 26.1% and 24.2%, treated with ET or CT respectively. (iv) clinicalhigh/CTClow 13.4% and 14.0%, treated with CT or ET respectively. CTC-driven strategy met the primary endpoint, yielding a non-inferior PFS (median: 17 months; 95%CI [15.4-20.3] vs 18 months 95%CI[13.9-23.3]). In the 2 discordant subgroups, preplanned analyses showed the following results: in the clinicallow/CTChigh subgroup, patients treated with CT had a significantly longer PFS than those treated with ET (15.6 months, 95%CI [12.2-22.7] vs 10.5 months, 95%CI [7.3-15.4], log rank p=0.002). In the clinicalhigh/CTClow subgroup, patients treated with CT had a non-significant PFS advantage over patients treated with ET. Pooling these two subgroups of patients (N=292) with discordant treatment recommendations (depending on clinician or CTC count standpoint), an exploratory analysis showed that patients treated with CT frontline had significantly longer PFS (HR=0.66; 95%CI [0.51-0.85]) and OS (HR=0.65; 95%CI [0.43-0.98]); 2-year OS were 82.9% versus 74.7% in patients treated with CT (±maintenance ET) or ET, respectively.
Conclusion: This trial demonstrates the utility of CTC count to select 1st line therapy in ER+ HER2- MBC patients, especially in those for whom single agent ET is the recommended therapy based on clinical factors. With this modern prognostic biomarker, the STIC CTC trial is the first one to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT followed by maintenance ET than from frontline ET, challenging current standards.
Funding: French Ministry of Health (PSTIC 2011); Menarini SB; Institut Curie.
Citation Format: Francois-Clement Bidard, William Jacot, Sylvain Dureau, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Goncalves, Sylvain Ladoire, Herve Naman, Florence Dalenc, Joseph Gligorov, Marc Espie, Christelle Levy, Jean-Marc Ferrero, Delphine Loirat, Paul Cottu, Veronique Dieras, Marie-Emmanuelle Legrier, Frederique Berger, Catherine Alix-Panabieres, Jean-Yves Pierga. Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT140.