Evaluation of Prognostic Factors, New Predictive Biomarkers, and Organ-Sparing Strategy for Rectal Cancer after Combined Neoadjuvant Therapy. Summary of the Doctoral Thesis

Relevance. Colorectal cancer is one of the most common types of tumors in Latvia and Europe. Standard treatment for stage II and III rectal cancer includes neoadjuvant therapy (NAT) (radiotherapy and chemotherapy or radiotherapy alone), followed by surgical treatment – low rectal resection or abdominoperineal excision. The tumor’s response to NAT varies from complete tumor remission to resistance to therapy, which determines subsequent treatment strategies, the patient’s oncological prognosis, and quality of life. Studying prognostic factors of tumor behavior is essential for personalized treatment planning. Objective. To identify the clinical and molecular-biological prognostic factors of locally advanced rectal cancer and to evaluate disease-free survival and overall survival rates depending on the tumor’s response to NAT (tumor pathomorphosis) and molecular-biological parameters. Methods. The study included patients with stage II and III anorectal adenocarcinoma (C20 and C21 according to ICD-10) who received NAT at the Oncology Clinic of P. Stradiņš Clinical University Hospital (PSCUH), followed by radical surgical treatment at the Surgery Clinic of PSCUH, from January 1, 2016, to January 1, 2022 (6 years). The study comprises three parts. The first part analyzed 10 cases in which complete clinical remission of the tumor was achieved after NAT, and a "Watch and Wait" (“W&W”) strategy was applied. The outcomes of the organ-preserving strategy were evaluated. The second part involved retrospective analysis of 82 patients who underwent radical surgical treatment after NAT, divided into four groups based on tumor post-therapy pathomorphosis (using the Dworak classification). Clinical prognostic factors and the relationship between tumor post-therapy pathomorphosis and survival rates were analyzed. The third part involved tissue sample analysis from selected patient groups (17 patients with poor and 23 with good response to NAT). MicroRNA (miRNA) extraction was performed from tumor and resection margin tissues, and miRNA identification was carried out. Potentially clinically significant miRNAs were selected, and survival rates were analyzed depending on their expression levels. Results. The disease-free survival and overall survival rates for patients who received NAT and subsequently underwent the “W&W” strategy in this study are comparable to published global data. The systematic application of the “W&W” strategy was implemented at PSCUH during this study. Evaluation of clinical prognostic parameters before treatment showed that a smaller rectal tumor circumference on pre-treatment pelvic magnetic resonance imaging (MRI) was associated with more significant tumor regression on post-treatment MRI. The mrTRG classification, based on post-treatment pelvic MRI findings, reliably predicts tumor pathomorphosis in surgical specimens according to the Dworak classification. Tumor pathomorphosis according to Dworak, pT stage, and mucinous component of the tumor are prognostic indicators for the risk of local recurrence after surgical treatment, and pT stage is a prognostic indicator of distant metastases. A total of 752 miRNAs were analyzed in tumor and resection line tissues, with 48 showing expression levels at least twice as high or low as than the established standard when comparing tumor tissue with resection line tissues, and reaching p < 0.05. . Three miRNAs were considered clinically significant: miR-99a-3p in the good response group, and miR-142-5p and miR-182-3p in the poor response group to NAT. A statistical trend towards better survival rates was observed with higher expression of miR-142-5p and miR-99a, and lower expression of miR-182-3p. Conclusions. Pre-treatment radiological parameters and post-treatment tumor pathomorphosis have prognostic significance in rectal cancer. Tumor miRNAs might be used as additional biological markers to predict the response of rectal cancer to NAT and to anticipate long-term oncological outcomes. The Doctoral Thesis was developed at the Surgery Clinic of Pauls Stradiņš Clinical University Hospital and at the Institute of Oncology and Molecular Genetics of Rīga Stradiņš University, Latvia. Defence of the Doctoral Thesis will take place at the public session of the Promotion Council of Clinical Medicine on 14 January 2026 at 13.00 in the Senate Hall, 16 Dzirciema Street, Rīga Stradiņš University. 3.2. Clinical Medicine; Sub-Sector – Surgery. Keywords: Locally advanced rectal cancer; neoadjuvant therapy; complete clinical response; “Watch and Wait” strategy; prognostic factors; Dworak pathomorphosis; microRNA; survival.