Autophagy- and Stress-Related Biomarkers in Pretreatment Rectal Adenocarcinoma Biopsies: Associations With Pathologic Response to Neoadjuvant Therapy and Survival

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal adenocarcinoma, yet therapeutic response varies widely and reliable biomarkers are lacking. This study evaluated the immunohistochemical expression of Beclin-1, LC3A, HIF-1α, Bcl-2, and eIF2α in pretreatment biopsies and explored their association with tumor regression grade (TRG) and survival. A retrospective analysis was performed on 53 patients with rectal adenocarcinoma who underwent neoadjuvant therapy and surgical resection between 2010 and 2025. Immunohistochemical expression of 5 markers was evaluated semiquantitatively and correlated with TRG (both Modified Mandard and AJCC systems) and survival outcomes. Among the evaluated markers, only Beclin-1 expression correlated significantly with poorer histopathologic response in both TRG systems (Modified Mandard: ρ =0.35, P =0.010; AJCC: ρ =0.34, P =0.012). ROC analysis confirmed its discriminatory ability (AUC=0.80), identifying high Beclin-1 as a marker of reduced nCRT sensitivity. Lymphovascular invasion (LVI) and perineural invasion (PNI) were also associated with poor response ( P =0.002 each). In multivariate analysis, PNI showed borderline significance for nonresponse (OR=4.09, P =0.050). During follow-up, overall survival was adversely affected by LVI, PNI, higher T and N stage, and metastasis ( P <0.05). Low eIF2α expression was associated with reduced overall survival ( P =0.026), while no marker correlated with disease-free survival. Beclin-1 overexpression may indicate therapy resistance through autophagy-related mechanisms, whereas eIF2α acts as a stress-response marker influencing survival. High Beclin-1 expression may serve as a predictive biomarker of poor nCRT response in rectal adenocarcinoma, while eIF2α shows prognostic significance for overall survival.