Background: Despite advances in colorectal cancer (CRC) screening, early detection, and treatment, CRC remains the 2nd most common cancer cause of death in the U.S.. Obesity is increasing in incidence in the U.S., and has been implicated in colorectal adenoma (CRA) risk, risk of CRA recurrence, and risk of CRC. Obese patients with history of CRA are a high-risk group that may benefit from novel CRC prevention strategies. There is early evidence for reduced cancer mortality among metformin users. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice, as evidenced by metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPk, decreased ratio of pmTOR/mTOR, and decreased ratio of pS6Ser235/S6Ser235 in polyp specimens. We hypothesized that metformin would affect colorectal tissue S6Ser235 similarly in humans, targeting obese patients with recent history of CRAs as a high-risk group.
Methods: A phase IIa clinical biomarker trial was conducted across 3 clinical sites via the NCI-funded Southern California Chemoprevention Program. Eligible participants included non-diabetic, obese patients (BMI >30) with history of colorectal adenoma within the past 3 years, age ≥ 35 years and ≤ 80 years. All patients received an upward titration of metformin over 3 weeks to 1000mg po bid, which was continued until the end-of-study (EOS) at 12 weeks. Rectal mucosa biopsies were obtained at baseline (BL) and at time of EOS endoscopy. Tissue S6Ser235 immunostaining was analyzed in a blinded fashion by the study pathologist using Histo Score (HScore) analysis. A paired t-test was used to examine the effect of metformin on activated S6serine235 (i.e., the ratio of pS6serine235/ S6serine235).
Results: 45 patients were consented to achieve 32 eligible subjects. 4 subjects were removed from study due to Adverse Events (1 SAE, unrelated). In order of frequency, the most common AEs were diarrhea, cramping, flatulence, nausea, stomach pain; 80% of participants had Grade 1 AE, 27% had grade 2 AE. Mean (SD) weight and body mass index at BL were 105.2 (17.42) kg and 34.9 (5.57) respectively. Weight did not significantly differ over the course of the study. Glucose levels at EOS did not significantly differ from BL. Vitamin B12 levels were significantly reduced at EOS vs. BL (-46.7 pg/mL, 95% CI -73.2 to -20.2). Comparing EOS to BL tissue S6Ser235 by IHC HScore analysis, no significant differences were observed. Mean (SD) Hscore at BL was 1.1 (0.57) and 1.1 (0.51) at EOS. Median HScore change was 0.032 (p=0.77).
Conclusions: Among obese CRA patients, 12 weeks of oral metformin 1000mg twice daily does not reduce pS6 levels in the rectal mucosa. Other potential mechanisms of action have not yet been analyzed. Data from this clinical trial indicate that metformin can be used safely in a non-diabetic population. Further research is needed to determine what effects, if any, metformin has on the target tissue of origin (colorectum) relevant to colorectal carcinogenesis if metformin is to be pursued as a CRC chemopreventive agent.
Citation Format: Jason A. Zell, Christine E. McLaren, Timothy R. Morgan, Michael J. Lawson, Sherif Rezk, Gregory C. Albers, Wen-Pin Chen, Joseph C. Carmichael, Luz Rodriguez, Eva Szabo, Leslie Ford, Michael Pollak, Frank L. Meyskens. A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A21.