With T-DXd showing significant anti-tumor activity against HER2-low breast cancer in the DB-04 trial, the indications and beneficiaries of anti-HER2 therapy have been further expanded (Modi et.al 2022; Wu et.al 2023). The results of this study showed that HER2 low breast cancer accounted for about 28.3% of patients with breast invasive ductal carcinoma, lower than 45% ∼55% reported in previous studies (Tarantino et.al 2020). This difference may be related to the platform used in HER2 detection in different studies, whether the test results are reviewed, histological classification, pathological stage, and many other factors. Despite this difference, the population of breast cancer patients with low HER2 expression is still very large, which is an attractive area of opportunity for HER2 targeted therapy.
The emergence of novel ADC drugs has provided a promising therapeutic approach for the treatment of HER2-low breast cancer patients, but also brings new challenges in the accurate detection and interpretation of HER2 expression levels, particularly in distinguishing HER2-zero and HER2-low subgroups. Notably, several studies have assessed the interpretation consistency of HER2 immunohistochemistry results among different laboratories and pathologists. A two-year survey conducted by the American College of Pathologists (CAP) involving 1391 ~ 1452 laboratories worldwide revealed a high interpretation consistency rate (≥ 90%) for HER2-IHC 0 and 3 + results across different laboratories. However, the interpretation consistency rate for HER2-IHC 0 and 1 + cases was found to be the lowest at less than 70%. Similarly, a study conducted at Yale University involving 18 pathologists from 15 institutions reported only 26% concordance rate in the interpretation of HER2-IHC 0 and 1+ (Fernandez et.al 2022). These findings demonstrate that conventional immunohistochemical techniques still have limitations in accurately detecting low levels of HER2 expression, and there is a need to explore more reliable methods to achieve accurate interpretation of HER2 expression levels in order to identify breast cancer patients suitable for T-Dxd treatment (Fernandez et.al 2022; Viale et.al 2023).
This study found that compared with HER2-zero breast cancer, HR positive patients in HER2-low breast cancer are more common, and the molecular classification is mainly Luminal B type, which is consistent with previous studies (Schettini et.al 2021; Horisawa et.al 2022), and such differences may be due to changes in gene expression. Schettini et al. (2021) evaluated the gene expression data of 1320 patients with HER2-negative breast cancer and found that compared with HER2-zero breast cancer, the expression of Luminal related genes (such as ESR1, FOXA1, AR, BCL2) in HER2-low breast cancer was significantly up-regulated, while the expression of proliferation related genes (MKI67, CCNB1, MYBL2, CCNE1) was relatively down-regulated, resulting in a higher proportion of HR positive tumors in HER2-low breast cancer. The study also identified associations between HER2-low breast cancer and older age, male gender, larger primary tumor volumes, and higher axillary lymph node involvement [14]. Horisawa et. al (2022) retrospectively analyzed the biological data of 4918 patients with primary breast cancer and showed that, regardless of HR status, HER2-low breast cancer had a smaller primary tumor volume, a lower proportion of histological grade 3 and fewer adverse prognostic factors than HER2-zero breast cancer. The results of this study showed that HER2-low breast cancer had higher N stage and TNM stage than HER2-zero breast cancer. Further analyses revealed that the clinicopathological features of HER2-low breast cancer may differ according to HR status. In the HR-positive subgroup, HER2-low breast cancer was more common in younger patients and was associated with more axillary lymph node involvement and higher TNM stage. Conversely, in the HR-negative subgroup, HER2-low breast cancer was more prevalent among older patients and correlated with lower histological grade and Ki-67 proliferation index. These findings are consistent with a study conducted by Zhu et al. (2023) in China, involving a cohort of 969 cases of primary non-metastatic HER2-negative breast cancer. However, in a retrospective study of 30491 cases of HER2-negative early breast cancer in South Korea (Won et.al 2022) reported that HR+/HER2-low breast cancer had fewer axillary lymph node metastasis compared to HER2-zero breast cancer, whereas HR-/HER2-low breast cancer had more axillary lymph node metastasis and a higher lymph node metastasis rate, which contradicts the results of this study. It can be seen that not all studies on the characteristics of HER2-low breast cancer can reach consistent results. In the analysis of clinicopathological characteristics of HER2-low breast cancer based on HR status, a mixed result of favorable and unfavorable prognostic factors was found. Among them, high N stage and TNM stage were unfavorable prognostic factors, and low histological grade and Ki-67 proliferation index were favorable prognostic factors. The reason for these differences remain unclear and may be related to the existence of differences in intrinsic molecular subtypes (Won et.al 2022), necessitating further in-depth investigation.
Regarding the effect of HER2 low expression on survival outcomes in breast cancer patients, the results of this study were similar to those previously reported by Horisawa and Agostinetto et al (Horisawa et.al 2022; Agostinetto et.al 2021). In multivariate analysis, regardless of HR status, no significant difference was observed in DFS and BCSS between the HER2-low and HER2-zero groups, that is, the survival prognosis of HER2-low breast cancer was not related to the intrinsic difference of its biological characteristics (Peiffer et.al 2023), which is different from the research results reported by Denkert et al. (Denkert et.al 2021). They found that in the overall population and TNBC patients, the DFS and OS of HER2-low breast cancer were significantly longer than HER2-zero breast cancer. A meta-analysis (Yang et.al 2023) of 39,831 patients with early breast cancer also showed that the survival outcome of HER2-low patients was better than that of HER2-zero patients, including recurrence-free survival (RFS) time and overall survival (OS) time, and this survival difference was not related to HR status. In contrast, a retrospective study of 91 patients with axillary lymph node-positive breast cancer conducted by Michael Z et al. (2009) showed that low HER2 expression was significantly associated with decreased local recurrence-free survival (LRFS), disease-specific survival (DSS), and OS in breast cancer patients, and this association was stronger in HR-positive subgroups. Moderate HER2 expression (2+) was also identified as a poor prognostic factor for DFS in HR-positive breast cancer patients in a German study including 5907 breast cancer patients (Eggemann et.al 2015). Based on these conflicting results, it is impossible to draw a clear conclusion about the prognostic significance of HER2-low breast cancer. Possible reasons for these differences include: (1) there were differences in patient population, study design, study endpoint and follow-up time between different studies; (2) treatment regimen as an important prognostic factor was not reported in most studies; (3) HER2-low breast cancer may have a high degree of heterogeneity, which affects the accurate interpretation of HER2 expression levels by pathologists.
This study is a single-center retrospective analysis, which carries the risk of potential confounding bias. The sample size is relatively limited, and the follow-up time is relatively short. To gain a more comprehensive understanding and to mitigate these limitations, further investigation through a larger-scale, multi-center, and scientifically designed prospective study is warranted. This would enable a more rigorous exploration of the clinicopathological characteristics and prognosis of HER2-low breast cancer.