Breast Cancer Research and Treatment (2019) 174:433–442 https://doi.org/10.1007/s10549-018-05070-2 CLINICAL TRIAL Metformin plus chemotherapy versus chemotherapy alone in the first- line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial O. Nanni1 · D. Amadori2 · A. De Censi3 · A. Rocca2 · A. Freschi4 · A. Bologna5 · L. Gianni6 · F. Rosetti7 · L. Amaducci8 · L. Cavanna9 · F. Foca1 · S. Sarti2 · P. Serra1 · L. Valmorri1 · P. Bruzzi10 · D. Corradengo3 · A. Gennari11 on behalf of MYME investigators Received: 20 November 2018 / Accepted: 23 November 2018 / Published online: 7 December 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). Methods 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). Results 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 neu- tropenia 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. Conclusions 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. Keywords Metformin · Insulin resistance · Advanced breast cancer · HOMA index Introduction DNA synthesis and cell proliferation [2]. This effect may also be attributable to the cross-activation of the insulin-like growth There is increasing evidence that the insulin pathway is factor (IGF) receptor family. Insulin-like growth factors (IGFs) involved in the development and prognosis of a variety of are endocrine mediators of growth hormones that also act in human neoplasms, including breast cancer (BC) [1]. This a paracrine and autocrine manner to regulate cell growth, dif- association is biologically plausible as hyperinsulinemia ferentiation, apoptosis, and transformation in numerous tissues induces proliferative tissue abnormalities due to the strong including the breast [3]. The downstream pathway of the insu- anabolic effect of insulin, resulting in the enhancement of lin/IGF system is well defined: IGF-I and insulin activate the tyrosine kinase growth receptor pathway, i.e., insulin, IGF-I, and hybrid IGF-I/insulin receptors, all of which are overex- The members of the MYME investigators study group are listed in pressed in breast cancer cells. Activation of these receptors the acknowledgments. results in the upregulation of the insulin receptor-substrate-2 * O. Nanni (IRS2), leading to the downstream activation of the MAPKi- [email protected] nase and PI3K-Akt pathways [4]. It has also been shown that Extended author information available on the last page of the article stimulation of the insulin receptor by insulin or IGFs enhances Vol.:(0123456789)1 3 434 Breast Cancer Research and Treatment (2019) 174:433–442 cancer cell proliferation. These findings suggest that the insu- assessing whether the addition of M to first-line chemo- lin/IGF pathway may be involved in tumor development and therapy in HER2-negative MBC is associated with a clini- progression, and might thus represent a novel therapeutic tar- cal effect, thus warranting further research. The study was get [5]. Furthermore, in patients with BC, higher circulating approved by the Ethics Committee of each participating insulin levels have been found to be associated with adverse center and was conducted in accordance with the Declara- outcome, while IGF1 levels do not appear to have such an tion of Helsinki, Good Clinical Practice norms and local impact [6, 7] . and national regulatory requirements. Written informed Within this context, it has been suggested that metformin consent was obtained from all patients before study entry. (M), the most widely prescribed anti-diabetic drug for the The study is registered in Clinicaltrials.gov (NCT01885013) treatment of hyperglycaemia and hyperinsulinemia [8], may and in European Clinical Trials Database (EudraCT No. improve prognosis in BC patients [9]. M is an oral biguanide 2009-014662-26). that inhibits hepatic gluconeogenesis and sensitizes insulin Women were eligible if they met the following criteria: action at the peripheral level. It is also widely prescribed for stage IV histologically or cytologically confirmed MBC, the treatment of type 2 diabetes [10] because of its good toler- HER2-negative disease (determined by immunohistochem- ability, and is approved by FDA for the prevention of diabetes istry [IHC] or fluorescence in situ hybridization [FISH]); in healthy at-risk subjects [11]. Pre-clinical data have shown non endocrine-responsive disease (negative hormonal sta- that the key mechanism of action of M is the through activa- tus or failure of endocrine therapy in metastatic disease); tion of the AMPK pathway, resulting in a regulation of cellular measurable and/or non-measurable disease according to energy homeostasis and an improvement in insulin sensitivity RECIST Criteria (Version 1.1) [18]; availability of HOMA [12]. Epidemiological studies on diabetic patients indicate an index calculated according to Matthews’ formula [19]; association between the use of M and reduced BC incidence prior endocrine therapy was allowed in the adjuvant and/or and mortality with respect to other antidiabetic drugs, espe- metastatic setting; prior chemotherapy was allowed in the cially in overweight/insulin-resistant women [13]. It can there- adjuvant setting providing patients had completed it at least fore be hypothesized that the potential antineoplastic effect 12 months before study entry; adjuvant anthracyclines were of M in vivo is related either to its direct effect on cancer cell allowed if prior cumulative dose did not exceed 360 mg/ metabolism or to its indirect effect through the reduction of m2 for epirubicin and 280 mg/m2 for doxorubicin; adjuvant systemic insulin levels and hyperglycaemia, especially in taxanes; age 18 to 75 years; Eastern Cooperative Oncology insulin-resistant patients. Group performance status (ECOG PS) ≤ 2; normal organ and There are little clinical data on the effect of M as an anti- bone marrow functions; and left ventricular ejection fraction cancer agent. In a large observational study of BC patients (LVEF) > 50%. Patients with known diabetes (type 1 or 2) treated with pre-operative chemotherapy, the proportion of were excluded. M-treated diabetic patients achieving a pathological com- plete response was significantly higher than that of diabetic Randomization patients treated with other antidiabetic drugs and of non- diabetic BC patients [14]. More recently, in a window of Patients were randomly assigned (1:1) with a centralized opportunity, double-blind, randomized study in early BC procedure to one of two treatment groups: first-line chemo- patients, the administration of M for 4 weeks before surgery therapy alone or chemotherapy plus M. Randomization was did not impact tumor proliferation, compared to baseline lev- performed using a computer-generated list and permuted els, in the overall patient population. However, a significant blocks within strata. Randomization was stratified by center effect of M on Ki-67 was seen in insulin-resistant patients and HOMA index (< 2.5 vs ≥ 2.5). Investigators and patients [15]. A large adjuvant trial on non-diabetic women with were not masked to treatment assignment. early BC comparing M with matching placebo in terms of disease-free survival (DFS) is currently ongoing [16, 17]. Treatment and procedures The present clinical trial evaluated the anticancer effect of M used in association with first-line chemotherapy in MBC. Eligible patients were allocated to arm A (non pegylated liposomal doxorubicin (NPLD) 60 mg/m2 intravenously (i.v.) plus cyclophosphamide (C) 600 mg/m2 i.v plus M Methods 1000 mg twice daily) or arm B (NPLD 60 mg/m2 i.v. plus C 600 mg/m2 i.v.). Chemotherapy cycles were administered Study design and participants every 21 days for a maximum of 8 cycles. M was admin- istered until disease progression. Staging procedures were The MYME (Myocet® - Metformin) trial was a phase II, performed at baseline a maximum of 28 days before ran- open-label, multicenter, randomized clinical trial aimed at domization and consisted in contrast-enhanced chest and 1 3 Breast Cancer Research and Treatment (2019) 174:433–442 435 abdominopelvic CT scan. Other tests for tumor assessment 112 patients was planned over a period of 24 months with a were performed as clinically indicated. Disease status was further follow-up of 12 months. monitored every 2 cycles (8 weeks) with the same radiologi- The primary analysis was performed on the intention- cal exams used at baseline. to-treat (ITT) population, defined as the population of Anthropometric evaluation and biochemical and hemato- randomized patients who received at least one dose of logical laboratory tests were performed at baseline (within the assigned study treatment.