NeoProspect HER2-low: Response and Prognosis After Neoadjuvant Treatment in Patients with HER2-low Breast Cancer

The majority of breast cancers (BCs) are classified as human epidermal growth factor receptor 2 (HER2)-negative. Within this group, more than half show low levels of HER2 expression, defined as an immunohistochemistry (IHC) score of 1+ or 2+ with a negative result on reflex in situ hybridization. The clinical and biological relevance of this HER2-low category remains under investigation, particularly regarding response to systemic therapy.

A national, multicentric, prospective, and observational study was conducted to evaluate the value of HER2-low as a predictive marker of pathological complete response (pCR) to neoadjuvant treatment in BC. Patients with HER2-low or HER2-zero (IHC 0), diagnosed at clinical stage I-III, were identified and followed throughout neoadjuvant treatment, consisting of chemotherapy ± immune checkpoint inhibitors, and subsequent surgery. Differences in subgroups and pCR were assessed using appropriate statistical tests.

A total of 128 patients were included, of which 46% were HER2-low and 54% were HER2-zero, with a median age of 54 years and a median follow-up of 12 months. Within the HER2-low group, 68% patients were HER2-low 1+ and 32% were HER2-low 2+. In the HER2-low group, 71% of tumours were hormone receptor (HR) positive, and in the HER2-zero group, 67% were triple negative (TN). Tumours in the HER2-low group were more often HR-positive, postmenopausal, and had lower Ki67, while tumours in the HER2-zero group were more frequently TN, grade 3, and node-positive. Immunotherapy use was lower in HER2-low patients. Overall pCR rates were 20% in HER2-low, and 32% in HER2-zero (p=0.14), and pCR rates were lower in HR-positive compared with HR-negative tumours (12% vs. 41%). Among HER2-zero tumours, pCR was significantly lower in HR-positive than in HR-negative (9% vs. 43%; p=0.005). In HER2-low HR-positive, pCR was also lower than in the HER2-low HR-negative (14% vs. 35%; p=0.085). Within HER2-low, 23% of HER2 1+ and 16% of HER2 2+ obtained pCR. Pathological nodal response was more frequent in HER2-zero tumours (70% vs. 39%, p=0.009). Treatment was generally well tolerated, with grade ≥3 haematological toxicity being the most frequent one, without differences between the two groups.

This prospective real-world study suggests a trend toward lower pCR in HER2-low compared with HER2-zero tumours, although not statistically significant. The lower use of immunotherapy among HER2-low patients may have influenced these results and should be considered when interpreting comparative efficacy. The significantly reduced pCR in HR-positive compared with HR-negative disease within HER2-low tumours underscores the influence of HR status and highlights the need for careful pre-therapeutic stratification and larger, long-term studies.