Abstract 4771: Assessment of Ki67 proliferation index in pre-malignant colonic adenomas: Implication for new biomarker testing to predict metachronous disease (The INCISE project)
Authors: Lynch Gerard P. , Ammar Aula , Bigley Christopher , Johnstone Mark , Jawny Jakub , Morgan Hannah , Hay Jennifer , Maka Noori , McSorley Stephen , Edwards Joanne 
Published: March 2024

Abstract
Approximately 40% of patients are found to have polyps at bowel screening colonoscopy, which are associated with a higher risk of developing future polyps or colorectal cancer. The British Society of Gastroenterology 2020 (BSG20) guidelines stratify patients into high/low risk of metachronous disease, using the size, dysplasia, and number of polyps found at index colonoscopy. This study aims to explore the prognostic significance of Ki67 proliferation percentages in adenomatous polyps, with metachronous disease. Tissue microarray (TMA) was constructed from 1201 index adenomatous polyps with representative cores of basal and luminal adenomatous epithelia. 67% patients were identified as high risk at index colonoscopy. The median time to detect metachronous polyps was 55 months (range 6-72 months) with 56% of patients developing metachronous polyps by the end of follow-up. TMA was stained for Ki67 using immunohistochemistry. Ki67 proliferation percentages in adenomatous epithelia was quantified using QuPath. Data was split into training (n=830) and test (n=371) datasets. The Ki67 proliferation cutpoint was made using Survmine R package using the training dataset. X2 test was used to study associations with clinicopathological criteria and Kaplan survival analysis was used to assess Ki67 association with metachronous lesions. Ki67 percentages were higher in lumina than in basal adenomatous epithelium (median Ki67 were 63% & 48%; respectively). Total Ki67 percentages were computed by averaging luminal and basal values. Thresholds of 70%, 64% and 59% were employed to classify patients into low/high categories based on luminal, basal or total percentages; respectively. In the training cohort, high luminal, basal or total Ki67 were associated with metachronous lesions (p values 0.032, &lt;0.001 and 0.006; respectively). Other associations were significant between luminal or total Ki67 and location of index polyps (p=0.017 & p=0.044; respectively), histology (p=0.019) and advanced future lesion status (p=0.002 & p&lt;0.001; respectively). In multivariate cox regression analysis, high Ki67 was an independent prognostic factor for metachronous polyps (luminal Ki67 HR=1.28, CI: 1.052-1.560, p=0.014; basal Ki67 HR=1.639, CI: 1.313-2.046, p&lt;0.001; total Ki67 HR=1.344, CI: 1.105-1.635, p=0.003) when adjusted to number of index polyps and BSG20 risk score. BSG20 risk score stratification of patients in terms of metachronous disease was improved when combined with luminal, basal or total Ki67 in the training datasets (all p&lt;0.05). Prediction of metachronous disease by the combined groups was validated in the test cohort for luminal, basal and total Ki67 (all p&lt;0.05). High Ki67 proliferation rates in adenomatous polyps are independently associated with the development of metachronous polyps and may help improve the BSG20 criteria.
Citation Format: Gerard P. Lynch, Aula Ammar, Christopher Bigley, Mark Johnstone, Jakub Jawny, Hannah Morgan, Jennifer Hay, Noori Maka, Stephen McSorley, Joanne Edwards. Assessment of Ki67 proliferation index in pre-malignant colonic adenomas: Implication for new biomarker testing to predict metachronous disease (The INCISE project) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4771.