Clinical Evaluation of HHLA2 in Hormone Receptor-Positive Breast Cancer: Expression Patterns and Prognostic Implications

Background: HHLA2 (human endogenous retrovirus-H long terminal repeat-associating protein 2) is a B7 family immune checkpoint molecule that delivers costimulatory or coinhibitory signals depending on the receptor engaged. Although it has been implicated in various cancers, its clinical significance in hormone receptor (HR)-positive breast cancer remains unclear. Methods: Ninety-three patients with HR-positive breast cancer who underwent surgical resection were analyzed using tissue microarrays. HHLA2 expression was assessed by immunohistochemistry using a combined intensity and proportion score (0–8), analyzed as a continuous variable by Cox regression, with dichotomized comparisons (score >5 vs. ≤5) as sensitivity analyses. Associations with clinicopathologic variables were evaluated using Fisher’s exact test and Spearman correlation. A complementary analysis was performed using RNA-sequencing data from the TCGA-BRCA cohort. Results: HHLA2 immunoreactivity was detected in 86 tumors (92.5%). No significant associations were identified between HHLA2 expression and age, tumor size, nodal status, grade, or HER2 status. The HHLA2 score was not associated with overall, disease-specific, or relapse-free survival (hazard ratio per 1-point increase 1.17, 1.86, and 1.19, respectively; all p > 0.1), and no cutoff reached significance after correction for multiple comparisons. In TCGA-BRCA, HHLA2 transcript levels were low overall and higher in triple-negative than in HR-positive tumors (p < 0.001), but were not associated with survival in either group. Conclusions: HHLA2 immunoreactivity was detected in most HR-positive breast cancers, but no association with clinicopathologic features or survival was detected in this small exploratory cohort. Larger studies are needed to exclude modest prognostic effects.