Introduction Metformin may provide a therapeutic benefit in different types of malignancy. Purpose We aimed at evaluating the effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women. Methods Seventy-five postmenopausal stages II–III breast cancer female patients were assessed for eligibility in an open-labeled parallel pilot study. Forty-five patients met the inclusion criteria and were assigned into three arms: the lean arm (n = 15) women who received letrozole 2.5 mg/day, the control arm (n = 15) overweight/obese women who received letrozole 2.5 mg/day, and the metformin arm (n = 15) overweight/obese women who received letrozole 2.5 mg/day plus metformin (2000 ± 500 mg/day). The intervention duration was 6 months. Blood samples were obtained at baseline and 6 months after intervention for the measurement of serum estradiol, leptin, osteocalcin levels, fasting blood glucose concentration, and serum insulin. Results After the intervention and as compared to the control arm, the metformin arm showed a significantly lower ratio to the baseline (significant reduction) for estradiol (p = 0.0433), leptin (p < 0.0001), fasting blood glucose (p = 0.0128), insulin (p = 0.0360), osteocalcin serum levels (p < 0.0001), and the homeostatic model assessment of insulin resistance “HOMA-IR” value (p = 0.0145). There was a non-significant variation in the lactate ratio to the baseline among the three study arms (p = 0.5298). Conclusion Metformin may exert anti-cancer activity by decreasing the circulating estradiol, leptin, and insulin. Metformin might represent a safe and promising adjuvant therapy to letrozole in overweight/obese postmenopausal women with breast cancer. Trial registration ClinicalTrials.gov Identifier: NCT05053841/Registered September 23, 2021 - Retrospectively.

Introduction: Metformin may provide therapeutic benefits to patients with various types of malignancy. Through its insulin-sensitizing effect, metformin can also reduce weight in non-diabetic populations.Purpose: Our research aimed at evaluating the effect of metformin as an adjuvant therapy to aromatase inhibitor (letrozole) on estradiol and other biomarkers serum levels in postmenopausal obese breast cancer women.Patients and methods: This controlled study involved 45 postmenopausal breast cancer females who were assigned into three arms: the control arm (arm 1; n= 15 obese women) which received letrozole only (2.5 mg/day); the metformin arm (arm 2; n= 15 obese women) which provided a similar letrozole dosage in addition to metformin (2000 ± 500 mg/day); and the lean arm (arm 3; n= 15) which received letrozole. The intervention duration was 6 months. Blood samples were obtained at zero time and six months later for the measurement of serum estradiol, osteocalcin, insulin, leptin, lactate, and fasting blood glucose. Results: After the intervention, the metformin arm had significantly lower osteocalcin and fasting blood glucose levels than both the control and the lean arms (p<0.0001, p<0.0001, respectively). The metformin and lean arms had significantly lower fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), estradiol, and leptin concentrations than the control arm (p = 0.0064, p = 0.0020, p<0.0001, and p<0.0001, respectively). We observed non-significant variation in serum lactate levels among the three study arms.Conclusion: Metformin might represent a promising adjuvant therapy to letrozole in postmenopausal women with breast cancer.ClinicalTrials.gov Identifier: NCT05053841/Registered September 23, 2021 - Retrospectively