Dataset Information

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/+ 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 = 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.

SUBMITTER: Zell JA

PROVIDER: S-EPMC8025666 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Zell Jason A JA McLaren Christine E CE Morgan Timothy R TR Lawson Michael J MJ Rezk Sherif S Albers C Gregory CG Chen Wen-Pin WP Carmichael Joseph C JC Chung Jinah J Richmond Ellen E Rodriguez L M LM Szabo Eva E Ford Leslie G LG Pollak Michael N MN Meyskens Frank L FL

Cancer prevention research (Philadelphia, Pa.) 20191209 2

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 ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with rece ...[more]

PMID: 31818851

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Project description:ObjectiveFamilial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma.DesignTissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC.ResultsInherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of "genomic scars") was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion.ConclusionWe identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.

Project description:ImportancePostpolypectomy surveillance is a common colonoscopy indication in older adults; however, guidelines provide little direction on when to stop surveillance in this population.ObjectiveTo estimate surveillance colonoscopy yields in older adults.Design, setting, and participantsThis population-based cross-sectional study included individuals 70 to 85 years of age who received surveillance colonoscopy at a large, community-based US health care system between January 1, 2017, and December 31, 2019; had an adenoma detected 12 or more months previously; and had at least 1 year of health plan enrollment before surveillance. Individuals were excluded due to prior colorectal cancer (CRC), hereditary CRC syndrome, inflammatory bowel disease, or prior colectomy or if the surveillance colonoscopy had an inadequate bowel preparation or was incomplete. Data were analyzed from September 1, 2022, to February 22, 2024.ExposuresAge (70-74, 75-79, or 80-85 years) at surveillance colonoscopy and prior adenoma finding (ie, advanced adenoma vs nonadvanced adenoma).Main outcomes and measuresThe main outcomes were yields of CRC, advanced adenoma, and advanced neoplasia overall (all ages) by age group and by both age group and prior adenoma finding. Multivariable logistic regression was used to identify factors associated with advanced neoplasia detection at surveillance.ResultsOf 9740 surveillance colonoscopies among 9601 patients, 5895 (60.5%) were in men, and 5738 (58.9%), 3225 (33.1%), and 777 (8.0%) were performed in those aged 70-74, 75-79, and 80-85 years, respectively. Overall, CRC yields were found in 28 procedures (0.3%), advanced adenoma in 1141 (11.7%), and advanced neoplasia in 1169 (12.0%); yields did not differ significantly across age groups. Overall, CRC yields were higher for colonoscopies among patients with a prior advanced adenoma vs nonadvanced adenoma (12 of 2305 [0.5%] vs 16 of 7435 [0.2%]; P = .02), and the same was observed for advanced neoplasia (380 of 2305 [16.5%] vs 789 of 7435 [10.6%]; P < .001). Factors associated with advanced neoplasia at surveillance were prior advanced adenoma (adjusted odds ratio [AOR], 1.65; 95% CI, 1.44-1.88), body mass index of 30 or greater vs less than 25 (AOR, 1.21; 95% CI, 1.03-1.44), and having ever smoked tobacco (AOR, 1.14; 95% CI, 1.01-1.30). Asian or Pacific Islander race was inversely associated with advanced neoplasia (AOR, 0.81; 95% CI, 0.67-0.99).Conclusions and relevanceIn this cross-sectional study of surveillance colonoscopy yield in older adults, CRC detection was rare regardless of prior adenoma finding, whereas the advanced neoplasia yield was 12.0% overall. Yields were higher among those with a prior advanced adenoma than among those with prior nonadvanced adenoma and did not increase significantly with age. These findings can help inform whether to continue surveillance colonoscopy in older adults.

Dataset Information

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

Publications

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

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