National Clinical Study

Refining Post-Surgical Management in CRC: A National Study on Prognostic Accuracy of UICC TNM classification, ctDNA analyses, and digital pathology assessment

Colorectal cancer (CRC) is the third most common cancer globally, with approximately 25% of patients experiencing relapse despite receiving curative intended surgery. Currently, selection of high-risk patients for adjuvant chemotherapy (ACT) is guided by the Union for Internation Cancer Control (UICC) Tumor-Node-Metastasis (TNM) system, which remains limited in its ability to accurately identify patients at high risk of recurrence. In consequence, between 60-70% of the patients receiving ACT are overtreated, as they were already cured by surgery. Therefore, there is a need for new and better tools for assessing prognosis and selecting patients for ACT.

The project received funding in 2024.

Abstract

Colorectal cancer (CRC) is the third most common cancer globally, with approximately 25% of patients experiencing relapse despite receiving curative intended surgery. Currently, selection of high-risk patients for adjuvant chemotherapy (ACT) is guided by the Union for Internation Cancer Control (UICC) Tumor-Node-Metastasis (TNM) system, which remains limited in its ability to accurately identify patients at high risk of recurrence. In consequence, between 60-70% of the patients receiving ACT are overtreated, as they were already cured by surgery. Therefore, there is a need for new and better tools for assessing prognosis and selecting patients for ACT. Postoperative circulating tumor DNA (ctDNA) assessment is one such promising novel prognostic tool. Another more recently developed tool is Histotype Px (DoMore Diagnostics, Norway), a digital pathology approach using a machine learning based algorithm for automated analysis of digitalized Hematoxylin and Eosin tumor sections (H&E). In studies published in Lancet and Lancet Oncology the digital pathology approach was shown to outperform the prognostic assessment of the UICC TNM system. At present it is debated whether prognostic precision of digital pathology will be suffi cient for guiding ACT decisions, or whether there is a continued need for implementing ctDNA?

To assess this, we need a head-to-head comparison assessing the sensitivity, specifi city, positive and negative predictive values, and the health economic consequences. The assessment should be made in a rigorous and blinded setting and on a cohort suffi ciently large to be conclusive.

With the present study, we aim to perform this assessment. We will also explore whether combining the tools off ers further improvements in prognostic accuracy.

The design is a nested case control study within the Danish IMPROVE trial (NCT03637686) i.e. the study is based on 1,290 already recruited stage II and III CRC patients for which the median follow up is 47 months (interquartile range 31-63 months). The cohort includes 186 recurrence cases. Blood samples of 1210 of the patients were prospectively analyzed for ctDNA in the IMPROVE study, using a tumor-informed digital PCR approach or panel sequencing. The remainder (n=80) will have their blood samples analyzed, with the same ctDNA approach, in Q1 of 2025. The Histotype Px algorithm will be applied to digitalized H&E tumor sections in the fi rst half 2025. This will be conducted in collaboration with the company DoMore Diagnostics. The health economic assessment will be conducted by Danish Center for Health Economics at the University of Southern Denmark.

Improved risk stratifi cation using ctDNA analysis and/or digital pathology algorithms have paradigm changing potential for the postoperative management of colorectal cancer. It has potential to reduce treatment-related morbidity, mortality, and healthcare expenses and at the same time improve patient quality of life. Moreover, these approaches are not limited to colorectal cancer but could be broadly applicable in the management of nearly all solid cancer types.

If successful, this project will provide further evidence and motivation to change clinical practice and introduce new technologies in the routine postoperative management of CRC, ultimately enhancing patient outcomes.

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