Modulation of Response to Hormonal Therapy With Lapatinib and/or Metformin in Patients With Metastatic Breast Cancer

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Target Population: female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy. The study rationale is based on the potentiality of reversing endocrine-resistance by Lapatinib * Activity on compensatory-adaptive mechanisms of hyperactivity of signals generated by HER2 family * Modulation of energy balance and signals associated to survival through AMPK activation (via Calmodulin) Metformin * Indirect mechanism, through reduced insulin receptors and IGFR stimulation, with reduces proliferative effects downstream * Direct mechanism, through AMPK activation (via LKB1), with reduced protein synthesis (mTOR inhibition) and increased availability of intracellular energy Lapatinib and Metformin * AMPK "Double"activation, through different potentially additional mechanisms. * Inhibition of proliferative mechanisms for interference on various intracellular target * IR (A e/o B); IGFR * EGFR; HER2 Primary objectives : 1\. To assess the rate of patients free from disease progression at 3 months from randomization Secondary objectives : 1. To assess the overall response rate 2. To assess the duration of response 3. To assess 3-years overall survival rate 4. To assess tolerability of each proposed treatment Female patients with HER2-negative, ER and/or PgR positive breast cancer in progression after first-line hormonal therapy will randomized to receive: hormonal therapy + lapatinib or hormonal therapy + metformin or hormonal therapy + metformin + lapatinib with a ratio 1:1:1. For each arm of the study the following sample size is required: * First step: 23 patients, for a total of 69 patients in all 3 arms * Second step: further 33 patients, for a total of 168 patients in all 3 arms.

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