Is HER2-Low Breast Cancer a Distinct Prognostic Entity? Real-World Survival Outcomes from a Cohort in Colombia

Background/Objectives: The HER2-low classification has redefined therapeutic strategies, but its prognostic significance remains uncertain. We compared overall survival (OS) and progression-free survival (PFS) across HER2 categories (HER2-low, HER2-negative, HER2-positive) in a real-world cohort. Methods: This was a single-center retrospective cohort study conducted at a high-complexity cancer center in Colombia; it included 373 patients with invasive breast cancer classified as HER2-positive (IHC 3+ or ISH+), HER2-low (IHC 1+ or 2+/ISH−), or HER2-negative (IHC 0). Survival was estimated by Kaplan–Meier. Multivariable Cox models were adjusted for age, clinical stage, histological grade, and hormone receptor status, and PFS was additionally analyzed separately in stage I–III and stage IV disease. Results: The cohort included HER2-low (38.3%), HER2-negative (39.7%), and HER2-positive (22.0%) tumors. HER2-low tumors showed lower grade and higher hormone receptor expression (p < 0.001), without better survival. Three-year OS (81.8%, 76.5%, 62.8%; p = 0.178) and PFS (p = 0.227) did not differ. Advanced stage remained the main determinant of mortality, whereas the association with high grade was attenuated. HER2-low was not independently associated with OS (HR 0.67; 95% CI 0.31–1.45) or PFS (HR 0.77; 95% CI 0.40–1.49). Hormone receptor positivity was associated with lower mortality (HR 0.43; 95% CI 0.21–0.88). PFS did not differ across HER2 categories in stage I–III (p = 0.307) or stage IV disease (p = 0.068). Conclusions: HER2-low status was not independently associated with survival. Its more favorable clinicopathological profile was largely explained by higher hormone receptor expression, which was itself associated with survival once included in the models.