Efficacy and Safety of Metformin Compared with Watchful Observation for Breast Fibroadenomas: A Randomized Controlled Assessor-Blinded Study from India.

introductionBreast fibroadenoma (FA) is the most common benign, painless, and solid mass in women of reproductive age and presents as a single or multiple masses located in the same or both breasts. No drug is approved for the treatment of breast FA as yet. Because of the estrogen-dependent and proliferative features of FA and the anti-proliferative and sex hormone-suppressing characteristics of metformin, we aimed to assess metformin for its clinical effectiveness in the treatment of breast FA. The primary objective was to evaluate the efficacy of metformin in comparison with watchful observation in reducing the number and size of breast lumps among patients of breast FA, whereas the secondary objective was to evaluate the safety of metformin used for the treatment of breast FA.

methodsThis was a hospital-based, prospective, two-arm, parallel design, assessor-blinded, randomized controlled trial. Pre-menopausal women aged 18-50 years and diagnosed with breast FA with a lump size < 5 cm were included in the study. Assessment of lump size was done under two categories: smaller mass (<2 cm) and larger mass (≥ 2 cm). One hundred and sixty-eight women were randomized into two groups in a 1:1 ratio to receive either 1000 mg of metformin daily or be put on watchful observation for 12 weeks. The study participants were followed for 24 weeks. Primary outcomes were mean change from baseline in size of the smallest and largest masses and in number of masses at 12 and 24 weeks, as well as proportion of women showing complete regression of masses at 12 and 24 weeks. Descriptive and inferential analyses were performed. Both intention-to-treat (ITT) and per protocol (PP) analyses were performed.

resultsResults of both ITT and PP analyses showed a significant difference between the two groups for mean change from baseline in size of smallest and largest masses as well as in number of masses at 12 and 24 weeks. In ITT analysis, mean change from baseline in size of largest masses, in size of smallest mass, and in number at 12 weeks were, respectively, -6.18 (±3.88), -2.10 (±2.36), and -0.70 (±1.03) in the metformin group as compared to, respectively, -3.24 (±3.40), -0.57 (±1.81), and -0.18 (±1.29) in the watchful observation group, and differences were statistically significant (p < 0.001, < 0.001, and 0.004, respectively). The same changes at 24 weeks were, respectively, -7.18 (±4.24), -2.16 (±2.53), and -1.07 (±1.10) in the metformin group as compared to -4.08 (±4.36), -1.21 (±1.64), and -0.28 (±1.49) in the watchful observation group, and the differences were statistically significant (p=0.002, 0.017, and <0.001, respectively).

conclusionTreatment with metformin (1000 mg twice daily) for 12 weeks resulted in a reduction in both the size and the number of breast FAs measuring < 5 cm. At 24 weeks, the effect of metformin in reducing the size and number of breast masses was carried forward post treatment.