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

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.

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.

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.

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.