Survival in Patients With Low Expression of Wild-Type Homologous Recombination Genes: Refining the Homologous Recombination Paradigm in Colorectal Cancer.

[PURPOSE] Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy.

[METHODS] A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability-high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data.

[RESULTS] In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically (43.0 36.3 months; < .005) and (42.9 34.2 months; < .005). Similar associations were observed for (28.1 22.9 months; = .02) and (29.1 23.2 months; < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low expression was associated with improved OS (41.5 22.4 months; HR = 0.52; = .002), whereas showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden.

[CONCLUSION] Low RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.