Prognostic Value of HER2-low Status in ER plus Early Breast Cancer: A Systematic Review and Meta-Analysis

Background/Aim: Low human epidermal growth factor receptor 2 expression (HER2-low: 1+/2+ by immuno-histochemistry without HER2 amplification) is emerging as defining a specific breast cancer (BC) subgroup owing to its distinct biological features. However, its prognostic role has not been confirmed in clinical practice. We conducted a systematic review and meta-analysis to determine the prognostic role of HER2-low status in patients with estrogen receptor-positive (ER+) early BC. Materials and Methods: We searched PubMed, EMBASE, and the Cochrane Library for prospective or retrospective studies that reported data on overall (OS) or disease-free (DFS) survival for HER2-low compared to HER2-negative BC. Data were pooled using hazard ratios (HR) with confidence intervals (CI) for OS/DFS of HER2-low vs. HER2-negative subgroups according to the random-effects model. OS was the primary outcome measure, and DFS and pathological complete response were the secondary endpoints. Results: An analysis was made of 25 studies collected, including 34,965 patients with HER2-low BC. A HER2-low status was associated with an HR for OS of 0.83 (95% CI=0.76-0.9, p<0.0.01). Similarly, a pooled HR of 0.89 (95% CI=0.840.94, p<0.0.01) showed that patients with HER2-low BC had an increased DFS. Pathological complete response was significantly lower in HER2-low BC in 13 studies (OR=0.72, 95% CI=0.58-0.91; p<0.01). Conclusion: Based on these data, HER2-low status should be identified as a potential prognostic factor in early stage ER+ BC. This should be taken into account when considering treatment in (neo)adjuvant settings, and it should be a potential stratification factor in future investigations.