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Description
The current application aims at launching EPoS IV trial. In EPoS IV we will analyze for the first time several histopathological biomarkers to predict the risk of recurrence after endoscopic treatment of malignant colorectal polyps. As part of our study, we want to assess clinical significance of poorly differentiated clusters, tumor budding, lymphovascular invasion, tumor infiltrating lymphocytes, epithelialmesenchymal transition CDX2 and ALCAM protein expression. These biomarkers will be identified during histopathological assessment using additional immunohistochemistry assays. All histopathological slides will be scanned and uploaded to digital platform, enabling blinded assessment for establishing inter- and intra-observer variability and to create future e-learning tool. All patients will undergo regular colonoscopy surveillance at 1, 3, 5 and 10 years, to detect local recurrence and metachronous lesions. The risk of metachronous lesions at 3 years follow-up will be compared between the EPoS IV trial and one of the arms of EPoS II trial. Top class European researchers from the field of gastroenterology and gastroenterological histopathology, already involved in the remaining EPoS trials, will be a warranty of high quality research standards also in the EPoS IV study. International cooperation is also necessary to shorten the recruitment time and ensure the sufficient number of participants. The risk factors for colorectal cancer recurrence after removal of early stage cancerous polyps remain poorly studied. Providing answer to this burning research question will likely change the way of histopathological assessment of malignant polyps, and help optimizing surveillance after screening colonoscopy.
Summary of project results
As stated in the proposal, the EPoS IV study has four main objectives:
Objective 1. To evaluate histopathological and immunohistochemical profiles of malignant colorectal polyps removed during colonoscopy
Objective 2. To study the performance of novel immunohistochemical biomarkers combined with standardized histopathological assessment in patients with endoscopically removed malignant colorectal polyps to predict the risk of recurrence (positive predictive value) and guide management strategy.
Objective 3. To compare of the yield of colonoscopy surveillance in patients with endoscopically removed malignant colorectal polyps (EPoS IV) and benign adenomas (EPoS II) to inform surveillance strategies. This includes risk assessment of metachronous adenomas.
Objective 4. To assess the intra- and inter-observer variability in histopathological assessment of malignant colorectal polyps and create an IT-based tool for training histopathologists.
Three out of four project objectives (1, 2, and 4) were successfully achieved.
Objectives 1 and 2 were met through completion of patient recruitment, histopathological assessment of patients´ samples and statistical analysis of risk factors. Objective 4 was completed by creation of a digital histopathology database and blinded assessment analysis. We still have to finalize calculations of intra- and inter-observer variability. Objective 3 remains under realization, and ongoing work is to achieve this final goal. The continued efforts on Objective 3 are crucial and require continuous follow up of patients included in the study cohort.
1. Completion of patient recruitment: finalized the recruitment of patients in accordance with the study''s inclusion and exclusion criteria, ensuring a representative sample size for statistical power. This deliverable was part of Work Package 1 (Task 1.2) and represented one
of the most significant undertakings of the EPOS IV project. It required a coordinated international, multicenter effort to enroll cases of patients with diagnosis of early pT1 colorectal cancer. The primary contributing countries to the cohort were Poland with 168 patients, Norway with 62 patients, and Italy with 50 patients. In total 280 patients were recruited which aligns well with around 300 pT1 cancer patients expected to be recruited in the project proposal. Up to date we identified 8 CRC recurrences so the expected number of 15
recurrences from a sample size analysis is very likely to be achieved once the full follow-up time is achieved.
2. Histopathological assessment of patient samples: conducted thorough histopathological examinations of patient samples, adhering to standardized protocols to ensure accuracy and reproducibility of the findings. This deliverable involved conducting thorough histopathological examinations of patient samples, adhering to standardized protocols to ensure accuracy and reproducibility of the findings. As part of Work Package 1 (Task 1.3), it was the second major undertaking following patient recruitment. Samples from
previously diagnosed pT1 colorectal cancer cases were centrally assessed according to the protocol. The central histopathology assessment encompassed all morphological features listed in the European guidelines for quality assurance in colorectal cancer screening and diagnosis. Additionally, novel markers were evaluated as part of the project, including angioinvasion and lymphovascular invasion enhanced by immunohistochemistry (CD34 and D2-40, respectively), poorly differentiated clusters (PDC), desmoplastic response, inflammatory infiltrate (CD8), CDX2 in tumoral epithelial and mesenchymal cells at the invasion front, BETA-CATENIN in tumoral epithelial and mesenchymal cells at the invasion front, SMA in tumoral epithelial cells, ALFA SMA in mesenchymal cells at the invasion front, TGFβ in tumoral epithelial and mesenchymal cells at the invasion front, FAP in tumoral epithelial cells, SNAIL in tumoral epithelial and mesenchymal cells at the invasion front, and GREM1 in tumoral epithelial and mesenchymal cells. The assessment was done first using slides from a retrospective cohort of patients with pT1 cancers, recruited at the National Research Institute of Oncology, Warsaw, Poland, to ensure standardization of immunohistochemistry technique. Then the assessment of slides of patients recruited within the EPOS IV study was performed in a blinded manner, ensuring it was unbiased and not influenced by previous regional pathological reports.
3. Statistical Analysis of Risk Factors: This deliverable involved performing comprehensive statistical analyses on the identified risk factors, utilizing appropriate statistical methods to evaluate their significance and correlation with patient outcomes. This analysis constituted the final deliverable of Work Package 1. The results are pivotal to the project and will be used for further research purposes as outlined in point 4 of this report. Data from biomarker assessments (as detailed in the previous point) and clinical data from the study cohort were
analyzed to determine their potential validity for predicting cancer outcomes. Specifically, data on cancer recurrence, metastases, and clinical outcomes of the patients were used. Clinical surveillance data post-treatment was retrieved, with the primary endpoint being oncological failure, defined as colorectal cancer recurrence, and local and regional metastases. The findings from the analysis of first 75 patients who achieved at least 3 years follow up were presented at the annual congress of the European Society of Gastrointestinal Endoscopy in Berlin in April 2024. The most important findings so far are that absence of tumour infiltrating lymphocytes (TILs CD8) and positive desmoplastic reaction were associated with worse oncological outcomes of pT1 CRC. These are newly identified biomarkers which may change clinical practice if their utility is confirmed in the final analysis.
4. Creation of a Digital Histopathology Database: This deliverable involved developing a robust digital database encompassing all histopathological samples assessed during the project, providing a valuable resource for ongoing and future research. It was a cornerstone of Work Package 2, planned for the entire duration of the project. Close collaboration with histopathologists, histopathology technicians, IT specialists, and clinicians was essential to establish the final design, enabling the execution of the analyses planned in the
project. A software solution identified through an official tender process was implemented, resulting in a comprehensive web-based image and data management system, specifically designed for research settings. This central hub for the project facilitates the management of digital images and data. The software was personalized with solutions for cataloguing and preparing scans for assessment as part of EPOS IV project, ensuring high accessibility and usability. The software solution allowed not only for sharing and cataloguing the scans but also for editing, commenting and marking specific parts of the scanned slides.
5. Blinded assessment analysis: This deliverable implemented blinded assessment of histopathology slides. A sample of 105 digitalized cases, primarily assessed in a central fashion in the National Oncology Institute in Warsaw was prepared for blinded evaluation by 19 external pathologists from 3 different countries. Each of the samples was rated twice by each pathologist within a period of 4-10 weeks. This gave a total sample size of 19 raters and 210 samples. In 82 of 105 patients (78.1%) at least one discrepancy was observed between central assessment and blinded evaluation by external pathologists. Desmoplastic response showed the highest percentage of
discrepancies among pathologists (44 of 105 cases, 41.9%). Within next 6-8 weeks we plan to finalize the calculations of the intra- and inter-observer variability in histopathological assessment of malignant colorectal polyps using weighted kappa and intraclass correlation coefficient, respectively.
The project could improve patient outcomes by providing more accurate assessments and tailored treatment strategies for early-stage colorectal cancer. This can lead to cost savings for healthcare systems by reducing unnecessary surgeries and optimizing surveillance protocols. Enhanced public awareness and education efforts will contribute to early detection and prevention, ultimately reducing the incidence and burden of colorectal cancer.
Summary of bilateral results
The bilateral collaborators in the EPOS IV project resulted in the submission of an awarded project for the European Commission The HORIZON-HLTH-2024-DISEASE03.