Precision oncology in Bulgaria: a prospective study of metastatic colorectal cancer patients

Geographic disparities in access to molecular diagnostics and targeted therapies affect the implementation of precision oncology in metastatic colorectal cancer (mCRC), particularly in Eastern Europe. This prospective study aimed to characterize the molecular landscape of advanced CRC in Bulgarian patients and evaluate associations between genomic alterations, mismatch repair (MMR) status, and stromal immune features.

Formalin-fixed paraffin-embedded tumor samples from 198 Bulgarian patients with advanced CRC were analyzed using targeted next-generation sequencing (TruSight Tumor 15, Illumina®). MMR status was assessed via immunohistochemistry using the VENTANA MMR RxDx Panel. Stromal immune reactions were histologically graded and evaluated for associations with MMR status. Statistical analyses included Chi-square tests and logistic regression.

The most frequently mutated genes were TP53 (60.6%), KRAS (37.3%), and BRAF^V600E (21.2%). Other alterations included PIK3CA (11.1%), NRAS (4.0%), and AKT1 (2.0%). No mutations were detected in EGFR, ERBB2, NTRK, or RET. Deficient MMR was observed in ∼9% of cases. Stromal reactions were significantly associated with MMR status (χ²(2) = 8.43, p = 0.015), with fibroblast-rich stroma more commonly seen in proficient MMR tumors. Logistic regression supported the results.

This study provides a regional molecular profile of advanced CRC in Bulgaria, highlighting a high prevalence of KRAS mutations and dMMR status, while underrepresentation of rare targetable alterations, likely due to limited use of broad molecular profiling. The association between stromal features and MMR status supports their potential role as surrogate markers in settings with constrained testing resources. Findings underscore the urgent need for equitable access to molecular diagnostics and targeted therapies to close the survival gap between Eastern and Western Europe.