Molecular and clinical traits of HER2-low breast cancer patients and their relationship with neoadjuvant treatment effectiveness.

Background: We aimed to investigate the clinical and molecular characteristics of different degrees of human epidermal growth factor receptor 2 (HER2) protein expression in HER2-negative breast cancer and the related factors affecting the efficacy of neoadjuvant chemotherapy in HER2-low breast cancer patients.

Methods: The study endpoint was pathological complete remission (PCR). Blood specimens and fresh cancer tissue samples were collected before neoadjuvant chemotherapy for whole-exon sequencing (WES) and RNA sequencing (RNA-seq), and patients were divided into a human epidermal growth factor receptor 2 (HER2)-low group and a HER2-0 group according to their HER2 expression status via bioinformatics analysis.

Results: A total of 409 HER2-negative breast cancer patients were included in the analysis, and HER2 status (HER2-0 vs. HER2-low) was significantly different between hormone receptor status, the Ki-67 index, and the PCR rate. A total of 18 patients who underwent WES and RNA testing were included, and the WES results suggested that the HER2-low group had a significantly higher rate of PIK3CA mutations and a greater frequency of PI3K pathway variants than the other groups and the HER2-low group had a greater number of concomitant mutations and reached statistical significance ( P  = 0.03). In terms of expression profiles, HER2-low and HER2-0 patients had different expression profiles. Overall, suggesting that the low PCR rate in the HER2-low group may also be related to chemoresistance.

Conclusion: Our investigation highlights the possibility that HER2-low breast cancer may indicate a unique clinical and biological phenomenon.