Abstract P3-13-02: Phase II randomised clinical study of first line chemotherapy plus metformin versus first line chemotherapy alone in HER2 negative, non diabetic, metastatic breast cancer patients: Final results of the MYME study
Authors: Gennari Alessandra , Nanni Oriana , DeCensi Andrea , Sarti Samanta , Freschi Andrea , Bologna Alessandra , Gianni Lorenzo , Amaducci Laura , Rosetti Francesco , Giovanardi Filippo , Fedeli Anna , Ambroggi Massimo , Bruzzi Paolo , Amadori Dino 
Published: May 2015

Abstract
Background: Epidemiological studies indicated that the presence of insulin resistance is an adverse prognostic factor in MBC. Recently increasing interest has focused on metformin, an oral insulin- sensitizing drug widely prescribed for type 2 diabetes; unexpensive and well tolerated, metformin has also been shown to have direct antiproliferative properties in breast cancer. We present here the final analysis of a phase II comparative multicentric study on the addition of metformin to first line chemotherapy in MBC non diabetic patients.
Methods:
This is a Phase II randomized study of HER-2 negative MBC patients with measurable or non-measurable disease; no prior chemotherapy for MBC was allowed. Patients were allowed to have had prior endocrine therapy for MBC and prior adjuvant chemotherapy if completed at least 1 year prior to study entry. Patients were stratified by HOMA Index (&gt;2,5 vs &lt;/= 2,5) and center. Patients were randomly assigned to Arm A, non pegylated liposomal doxorubicin 60 mg/sqm plus cyclophosphamide 600mg/sqm (AC) plus metformin (M) 1,000 mg PO QD or to AC alone. Treatment was administered for 8 3-weekly cycles in both arms, M was administered until disease progression. The primary endpoint was progression free survival (PFS). Secondary objectives included activity, safety and evaluation of metabolic profile. Correlative studies evaluated 1) circulating tumor cells and 2) modulation of insulin-related genes in mRNA isolated from CTCs. Planned sample size was 112 patients (98 events).
Results:
As of June 8th, 2014, 108 patients had been randomised. Median age was 60 yrs (range 36-77); 87% of patients were ER+, 60% had received prior adjuvant CT, with antracyclines in 51% of patients. Prior endocrine therapy for MBC was used in 39% of the patients. Measurable disease was present in 74% of the patients. 48% of the patients were insulin resistant by HOMA Index &gt;2.5 and 60% were overweight (BMI &gt; 25: 16% were obese, BMI &gt;30). At a median follow up of 16 months (range 1 – 48), median PFS (ITT) was 9 months (95% CI 8-14) with AC + M and 11 months (95% CI 7-16) with AC alone, p=.84. No significant interaction was detected between HOMA Index and treatment arm (p = 0.15). Median OS was 30 months (95% CI 14-NE) in Arm A versus 27 (95% CI 17-33) in Arm B, p = .58. The most common toxicities observed were G3/4 neutropenia in 51.5% of patients in arm A vs 69.6% in arm B, with Febrile Neutropenia observed in 2,2% and 5.4% of patients, respectively. As expected G2 diarrhea was reported by 11.1% of patients in Arm A.
Conclusions: The addition of M to AC in MBC patients receiving first line chemotherapy did not improve PFS compared with AC alone. M seems to have a protective effect on hematological toxicity. Final results including translational data will be available at SABCS 2014.
Citation Format: Alessandra Gennari, Oriana Nanni, Andrea DeCensi, Samanta Sarti, Andrea Freschi, Alessandra Bologna, Lorenzo Gianni, Laura Amaducci, Francesco Rosetti, Filippo Giovanardi, Anna Fedeli, Massimo Ambroggi, Paolo Bruzzi, Dino Amadori. Phase II randomised clinical study of first line chemotherapy plus metformin versus first line chemotherapy alone in HER2 negative, non diabetic, metastatic breast cancer patients: Final results of the MYME study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-02.