Scoping Review Protocol: Molecular Biomarkers in Organ Preservation Decision-Making for Rectal Cancer

Title: Molecular Biomarkers in Organ Preservation Decision-Making for Rectal Cancer: A Scoping Review Background: Organ preservation strategies following total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) have gained increasing clinical adoption. The watch-and-wait (W&W) approach offers an alternative to radical surgery for patients achieving a clinical complete response (cCR). However, accurate patient selection remains a critical challenge, as conventional response assessment methods (MRI, endoscopy, digital rectal examination) have important limitations. Molecular biomarkers — particularly circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection — have emerged as promising tools to complement conventional assessment. Additionally, immune checkpoint inhibitors have demonstrated remarkable efficacy in mismatch repair-deficient (dMMR/MSI-H) rectal cancer, while the majority of microsatellite-stable (MSS) tumors remain resistant to immunotherapy due to immunosuppressive tumor microenvironment (TME) characteristics. Objective: This scoping review aims to systematically map the scope, nature, and gaps of the available evidence regarding molecular biomarkers guiding organ preservation decisions in locally advanced rectal cancer after total neoadjuvant therapy. Research Question: What is the extent, range, and nature of evidence on molecular biomarkers (ctDNA/MRD, immunotherapy response markers, tumor microenvironment profiling) that inform organ preservation decision-making in locally advanced rectal cancer? Framework: Population-Concept-Context (PCC) Population: Adult patients with locally advanced rectal cancer (LARC) Concept: Molecular biomarkers in organ preservation decision-making (ctDNA, MRD detection, immunotherapy biomarkers, TME profiling) Context: Post-total neoadjuvant therapy watch-and-wait strategy Methods: This scoping review will be conducted in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines and the JBI methodology for scoping reviews. A systematic search will be performed in PubMed/MEDLINE, Web of Science, and Scopus databases for studies published between January 2019 and March 2026. Title/abstract screening and full-text assessment will be performed independently by two reviewers using Rayyan (rayyan.ai) with blind mode enabled. Disagreements will be resolved through discussion. Data will be extracted using a standardized charting form and synthesized using a descriptive/thematic approach. No meta-analysis is planned. Eligibility Criteria: Inclusion: Original research articles, systematic reviews, meta-analyses, and clinical guidelines focusing on rectal cancer and molecular biomarkers in organ preservation context; adult population (≥18 years); English or Turkish full text Exclusion: Case reports, conference abstracts, editorials, letters; pediatric population; studies focusing exclusively on non-rectal colorectal cancer Databases: PubMed/MEDLINE, Web of Science, Scopus Expected Outcomes: This scoping review will provide a comprehensive map of the current evidence on molecular biomarkers in organ preservation for rectal cancer, identify key knowledge gaps, and propose an integrated decision-making framework combining MRI, endoscopy, and ctDNA for personalized organ preservation strategies. The findings will inform future prospective clinical trials and guide clinical practice. Registration: This protocol is prospectively registered on OSF prior to the initiation of the systematic search.