Clinicopathological Landscape and Survival Outcomes of HER2-Low Breast Cancer in a Large Arab Cohort.

[BACKGROUND] HER2-low breast cancer (BC) has recently emerged as a therapeutically targetable entity, yet its biological and clinical relevance remains debatable. Limited data are available about HER2-low from non-Western populations, particularly the Middle East, where distinct tumor biology may influence phenotype and treatment response.

[METHODS] We retrospectively analyzed 1097 Saudi breast cancer patients for HER2 status by immunohistochemistry (IHC), classifying tumors as HER2-zero (IHC 0) or HER2-low (IHC 1+/2+ and FISH-negative). Clinicopathological characteristics, biomarker profiles (ER, PR, Ki-67), molecular alterations (PIK3CA, TP53, BRCA) and survival outcomes (overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and distant disease-free survival (DDFS)) were compared.

[RESULTS] HER2-low tumors comprised 34.5% (n = 378) of the cohort and were significantly associated with ER (p < 0.0001) and PR (p = 0.0226) positivity, lower triple-negative phenotype (p < 0.0001), and reduced Ki-67 proliferation index (p = 0.0136) compared to HER2-zero tumors. Trends toward higher PIK3CA mutation (p = 0.0875) and lower BRCA mutation (p = 0.0892) rates were observed in HER2-low tumors, though not statistically significant. Despite these favorable biological features, survival analyses revealed no significant differences between HER2-low and HER2-zero subtypes with regards to OS, CSS, DFS, and DDFS.

[CONCLUSION] In this large, ethnically homogenous Saudi cohort, HER2-low breast cancer represents a distinct molecular and clinicopathological subtype with luminal like features, yet no prognostic advantage. These findings reinforce the therapeutic, rather than prognostic, significance of HER2-low status, highlighting its relevance in targeted antibody-drug conjugate-based therapies rather than influencing baseline risk stratification.