Abstract
ABSTRACT
Background
Homologous recombination deficiency (HRD) has been reported to be associated with increased sensitivity to platinum‐based treatment and radiotherapy in some solid tumors.
Aim
This study investigated the correlation between HRD score and treatment response to neoadjuvant short‐course radiotherapy combined with sequential chemotherapy and tislelizumab in mismatch repair‐proficient (pMMR) locally advanced rectal cancer (LARC).
Methods and Results
Thirty‐two pMMR LARC patients from clinical trial NCT05515796 were enrolled. Pretreatment biopsy samples were analyzed for HRD scores and tumor immune microenvironment (TIME) gene expression profiles. Using receiver operating characteristic (ROC) analysis, patients were stratified into low (0–8), intermediate (9–37), and high (> 37) HRD score groups to compare pathological complete response (pCR) rates. Abundance of immune cells and immune‐related pathways were assessed with MCPcounter and single sample gene set enrichment analysis (ssGSEA) respectively and compared among the three HRD score groups. The entire cohort demonstrated pCR rate of 40.62% (13/32) with a median HRD score of 9 (range: 0–70). ROC analysis showed that HRD score as a continuous variable did not reach statistical significance in distinguishing pCR patients from non‐pCR patients, nor did TMB and HR mutation. However, the proportion of categorized HRD score was significantly different between pCR and non‐pCR groups (low, intermediate, high HRD score: 61.54%, 23.08%, 15.38% vs. 31.58%, 68.42%, 0%,
p
= 0.017). High‐HRD tumors exhibited the highest CD8+ T‐cell abundance followed by low‐HRD and intermediate‐HRD groups.
Conclusion
HRD score may be associated with efficacy of neoadjuvant radioimmunotherapy in pMMR LARC patients, potentially mediated through enhanced CD8+ T‐cell recruitment. These findings support precision patient selection, though mechanistic validation is required.