According to previous studies, between 40% and 50% of patients with breast cancer have tumors with low HER2 expression [15-17]. Here we observed a slightly higher proportion of HER-low cases (64% of all breast cancers). The reason for the differences in frequency are currently unclear. However, one explanation is that there may be differences in the methods of quality control for the HER2 test, as we describe below. We also found that the overall incidences of HR-positive/HER2-low and HR-negative/HER2-low cases were 58.1% and 6.3%, respectively.
There have been several reports regarding the prognosis of breast cancer patients with low HER2 expression. Ignatov et al. reported that patients with an intermediate HER2 score (defined as IHC 2+ and ISH-negative) had a worse prognosis than HER2-negative patients (defined as IHC 0 or 1+) breast cancer [18]. However, their study did not further stratify the patients based on HR status, which is an important parameter in the clinic. Francesco et al. were the first to compare the prognosis of HER2-low and HER2-0 by HR status, and found no statistically significant differences these two groups, regardless of HR status [16]. We suggest that it is more important to determine whether HER2-low or HER2-0 status is associated with a poorer prognosis in luminal or triple negative breast cancer. Our current study was designed to address this question, and the results suggest that HER2-low patients did not have a significantly different prognosis than HER2-0 patients, which is consistent with Francesco et al. However, we did find that the HER2-low group tended to have a better prognosis than the HER2-0 group regardless of HR status, although the differences were not statistically significant. We infer that this is because patients in the HER2-0 group tended to have more factors associated with poor prognosis than those in the HER2-low group. Further studies are required to fully understand the prognostic significance of different levels of HER2 expression in breast cancer.
There are currently no approved guidelines that recommend anti-HER2 therapy for breast cancers with low HER2 expression. However, several studies have assessed anti-HER2 therapy in HER2-low breast cancer patients. The use of trastuzumab as adjuvant therapy in this setting did not improve DFS [19], nor did trastuzumab emtansine (T-DM1) improve DFS in metastatic breast cancer with low HER2 expression [20]. On the other hand, T-DXd may be effective for the treatment of breast cancer patients with low HER2 expression. T-DXd is a novel, HER2targeted ADC that is composed of a humanized monoclonal antibody attached by a cleavable peptide-based linker to a potent topoisomerase I inhibitor payload [21]. In the DESTINY-Breast 01 phaseⅡstudy, T-DXd seemed to be effective in 44% patients with metastatic disease and low HER2 expression [21]. These results lead to the DESTINY-Breast04 phase III randomized trial, which is currently evaluating T-DXd for the treatment of HER2-low metastatic or advanced breast cancer (ClinicalTrials.gov identifier: NCT03734029). In our current study, there was no statistical difference between HER2-0 and HER2-low patients with regard to prognosis, irrespective of HR status. However, if T-DXd and other anti-HER2 therapies are demonstrated to be effective in patients with HER2-low breast cancer, this should improve their overall prognosis. In particular, the prognosis of HR-negative/HER2-low breast cancer is poor, and novel therapeutic agents to treat patients in this group are clearly needed. HER2-low status may eventually be used as a predictive factor of the efficacy of novel therapeutics in early breast cancer, in much the same way that HER2-positive status is now used to stratify patients for T-DXd treatment.
The limitations of our current study are that it was carried out at a single institution, was retrospective and relied on inconsistent evaluation of HER2 scores. Moreover, different types of formalin solution can lead to different HER2 scores, which could contribute to inter-institutional discrepancies [22, 23]. In addition, the HER2 scoring scale was different in each study due to the continual updating of ASCO/CAP guidelines. However, our study is one of only a few that have determined the frequency and prognostic value of low HER2 expression in breast cancer in the context of of HR status.