Development and Validation of a Collagen Nomogram for Pretreatment Prediction of Pathological Complete Response in Rectal Cancer Patients

Background: Collagen in the tumour microenvironment is recognized as a potential biomarker for predicting treatment response. This study investigated whether the collagen features are associated with pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) and develop and validate a prediction model for individualized prediction of pCR. Methods: The prediction model was developed in a primary cohort (353 consecutive patients). In total, 142 collagen features were extracted from the multiphoton image of pretreatment biopsy, and the least absolute shrinkage and selection operator (Lasso) regression was applied for feature selection and collagen signature building. A nomogram was developed by multivariable analysis. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical utility. An independent cohort (153 consecutive patients) was used to validate the model. Findings: The collagen signature comprised 4 collagen features significantly associated with pCR both in the two cohorts (P<0·0001). Predictors in the individualized prediction nomogram included the collagen signature and clinicopathological predictors. The nomogram showed good discrimination with AUC of 0·89 in the primary cohort and good calibration. Good discrimination (AUC = 0·91) and favourable calibration of the nomogram were also confirmed in the validation cohort. Decision curve analysis confirmed the clinical utility of the nomogram. Interpretation: The collagen signature in the tumour microenvironment of pretreatment biopsy is significantly associated with pCR. The nomogram based on the collagen signature and clinicopathological predictors could be used for individualized prediction of pCR in LARC patients before nCRT. Funding Information: This work was supported by grants from the National Natural Science Foundation of China (81773117, 81771881, and 82103041), the State’s Key Project of Research and Development Plan (2019YFE0113700), the Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer (2020B121201004), the Guangdong Provincial Major Talents Project (No.2019JC05Y361), the China Postdoctoral Science Foundation (2020M682789), the Natural Science Foundation of Fujian Province (2018J07004), the Joint Funds of Fujian Provincial Health and Education Research (2019-WJ-21), the Science and Technology Program of Fujian Province (2018Y2003, 2019L3018 and 2019YZ016006), the Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY010), the Clinical Research Project of Nanfang Hospital (2018CR034, 2020CR001, and 2020CR011), the President Foundation of Nanfang Hospital, Southern Medical University (2019Z023), and the Training Program for Undergraduate Innovation and Entrepreneurship (201912121008, 202012121091 and 202012121277). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: This study was approved by the Institutional Review Board at Nanfang Hospital of Southern Medical University, Sun Yat-sen University Cancer Center, and Fujian Province Tumor Hospital. Written informed consent was obtained from all participants. The study was conducted in compliance with the Declaration of Helsinki.