A preoperative window study of metformin for the treatment of endometrial cancer

• Published in: Journal of clinical oncology Vol. 31; no. 15_suppl; p. 5519
• Main Authors: Schuler, Kevin M., Rambally, Brooke S., DiFurio, Megan J., Gehrig, Paola A., Bae-Jump, Victoria Lin
• Format: Journal Article
• Language: English
• Published: 20.05.2013
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.31.15_suppl.5519

Abstract only 5519 Background: Obesity and diabetes have been linked to poorer survival and increased recurrence rates in endometrial cancer. The anti-diabetic medication, metformin, has been shown to have anti-tumorigenic effects in vitro and in vivo, via AMPK activation and inhibition of the mTOR pathway. We conducted a pre-operative window clinical trial of metformin in obese endometrial cancer patients to evaluate short-term in vivo molecular changes. Methods: Women with endometrioid endometrial cancer who were obese (BMI>30) were recruited from a gynecologic oncology clinic. Once enrolled, patients had a repeat pre-treatment endometrial biopsy and then began metformin at a dose of 850 mg PO once daily for 1-4 weeks prior to hysterectomy/surgical staging. A tissue microarray, using triplicate cores from each specimen, was constructed from paired formalin-fixed, paraffin-embedded endometrial biopsy (pre-treatment) and hysterectomy (post-treatment) specimens. The expression of Ki-67, a marker of cell proliferation, was measured by immunohistochemistry. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. The Signed Rank Test was used for statistical analysis. Results: Sixteen patients have completed the protocol. The mean duration of treatment was 14.5 days. Percent Ki-67 staining decreased significantly with metformin treatment (mean of 19.5% decrease, p = 0.026). Two patients experienced grade 1 toxicities, including mild abdominal pain and loose stools. Ten of the 16 patients responded to metformin based on decreased proliferation from their pre- to post-treatment specimens. There were no differences in median age, BMI, HgbA1c, or number of doses taken between responders and non-responders to treatment. Pre-treatment Ki-67 levels were statistically higher in the women that responded to metformin treatment (52% versus 27.5%, p = 0.0067). Conclusions: Metformin significantly reduced proliferation in a pre-operative window study in obese endometrial cancer patients, providing further support for therapeutic clinical trials of metformin in this obesity-driven disease.