Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial
To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC).
Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS).
One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6–50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8–10.4) in arm A and 9.9 (95% CI 7.4–11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6–11.7) versus 8.5 (95% CI 5.8–9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS.
The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.
KeywordsMetformin Insulin resistance Advanced breast cancer HOMA index
We thank all the other investigator involved in the study: Laura Scaltriti (Ospedale di Guastalla), Gianni Michele Turolla (Ospedale Umberto I, Lugo), Claudio Dazzi (Ospedale Civile Santa Maria delle Croci), Laura Cortesi (Arcispedale S. Maria Nuova, Modena), Petros Giovanis (Ospedale S.Martino, Belluno), Silvana Saracchini (Azienda Ospedaliera Santa Maria degli Angeli, Pordenone), Mariangela Ciccarese (Presidio Ospedaliero Vito Fazzi, Lecce), Francesco Carrozza (Azienda Ospedaliera Antonio Cardarelli, Campobasso). We thank all the site personnel, in particular Antonella Spada, Erika Gervasi, Giuliana Drudi, Britt Rudnas, Silvia Coccato, Alessandra Piancastelli and Camilla Di Nunzio.
ON, DA, PB and AG designed and supervised the trial. ADC, AR, AF, AB, LG, FR, LA, LC, SS, PS, LV and DC were responsible for patient recruitment and data collection. FF, ON and PB analyzed the data. The first draft of the manuscript was written by AG, FF PB and ON, and the remaining co-authors subsequently provided valuable input. DA critically reviewed the paper for important intellectual content. All the authors read and approved the final version of the article. The corresponding author assumes responsibility for the completeness and integrity of data, the study fidelity to the protocol, and the statistical analysis. She had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The MYME study was supported by the Italian Association for Cancer Research (AIRC –IG 2009, Project Number 9239) and TEVA Pharmaceuticals.
Compliance with ethical standards
Conflict of interest
AG and DA were consultant for TEVA and DA received a funding from TEVA.
The study was approved by the Ethics Committee of each participating center and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice norms and local and national regulatory requirements.
Written informed consent was obtained from all patients included in the study.
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