A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction among Individuals with History of Colorectal Adenomas and Elevated Body Mass Index

Abstract

◥Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in Apc Min/þ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/ AMPK, decreased pmTOR/mTOR ratio, and decreased pS6 Ser235 /S6 Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6 Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI !30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6 Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6 Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P ¼ 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing

“…Zell JA et al [ 83 ] recently reported the results of a phase IIa trial of metformin for CRC risk reduction in patients with elevated BMI and positive history of colorectal adenomas. Thirty-two patients were treated, with a baseline BMI of 34.9.…”

Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data

“…A phase 3 clinical study demonstrated that significant CRA reduction was achieved by the administration of low-dose metformin in patients without diabetes (Higurashi et al, 2016). However, another phase IIa trial reported that metformin did not reduce rectal mucosa pS6 or Ki-67 levels in obese patients with adenomas (Zell et al, 2020). These seemingly contradictory results suggested the complexity of mechanisms underlying metformin treatment and prevention for CRA.…”

Metformin and Cancer, an Ambiguanidous Relationship

“…Clinical use of metformin to suppress polyp formation and proliferation in the rectal mucosa of nondiabetic, obese patients with a history of colorectal adenoma has been unsuccessful to date [ 23 ]. Furthermore, a subanalysis from the large scale Three or Six Colon Adjuvant (TOSCA) trial found that neither metformin use nor DM status were associated with survival outcomes in colorectal patients receiving adjuvant chemotherapy post-resection [ 24 ].…”