The advent of targeted HER2 antibody drugs in patients with metastatic HER2-low breast cancer disease has challenged the dichotomous classification of HER2-positive and HER2-negative disease [13, 23]. The advent of new ADC drugs makes it possible for HER2-low breast cancer patients, to benefit from HER2 therapy [11]. Several recent studies have identified differences between HER2-low and HER2-0 disease [24, 25], suggesting that among HER2 negative diseases (including HER2-0, HER2-1+, HER2-2 + and ISH-), HER2-low (HER2-1+, HER2-2 + and ISH-) tumors represent a specific classification. In this work, we conducted an ambidirectional cohort study on the molecular characterization of primary HER2-low level BC in four tertiary care hospitals across China and performed a comprehensive analysis of its prognosis.
Our study provided valuable baseline characteristics of HER2-low breast cancers from real-world cases. The prevalence of hormone receptors in tumors with HER2-low is consistent with previous data from the literature [16, 17, 26–29]. We observed that patients with HER2-low breast cancer had a higher percentage of ER, PR and HR positivity and lower Ki-67 levels compared to patients with HER2-0 breast cancer. A retrospective examination of 281 cases revealed that HER2-low breast cancers had considerably lower Ki-67 and higher ER-positive than HER2-0 breast cancers [30]. The study by Alves, F. R. showed [31] that these two subgroups differed significantly in hormone receptor status and proliferation grade (Ki67), with statistically significant differences in hormone and progesterone receptors. The Korean Breast Cancer Association conducted a nationwide investigation revealed that breast cancer with low HER2 was significantly associated with a lower Ki-67 marker index [18]. These data suggested that HER2-low tumors can be identified as a more distinct clinical entity from HER2-0 tumors. However, regarding menopausal state, fertility, lymph node invasion, TNM stage, and surgical strategy, there were no differences between patients with HER2-0 and HER2-low breast cancer in the present research.
Previous study [32] reported that HER2 levels were significantly higher in women with a family history of cancer. Family history of cancer was significantly associated with elevated HER2 levels in tumors. Another study [33] used enzyme-linked immunosorbent assay (ELISA)6 to detect HER2 protein in tumors and showed that HER2 concentrations were significantly higher in women with a family history of cancer. We observed that a higher proportion of patients with low HER2 breast cancer had a family history of cancer compared to those with HER2-0 breast cancer, in line with the above-mentioned study. The HER 2 gene is located on the long arm of chromosome 17 and encodes a protein with growth factor receptor characteristics. It has been reported [34] that heterozygous deletion of chromosome 17p is associated with HER-2 amplification in breast cancer. The clinical challenge in treating breast cancer with low levels of HER2 is the lack of actionable drug targets. Due to the low levels of the HER2 protein on the surface of cancer cells, HER2-targeted therapies are often clinically ineffective for this disease. Li, Y.’ study [35] demonstrated that α-amanitin-conjugated trastuzumab (T-Ama) enhances HER2-targeted therapy and showed superior efficacy in the treatment of 17p-deficient HER2-low-grade breast cancer. The correlation between HER2-low expression breast cancer and family history of cancer and the strong association of HER2 with chromosome 17 suggested the potential value of drug development targeting chromosome 17 for the treatment of HER2-low expression breast cancer.
Recently, several retrospective studies exploring the prognostic significance of HER2-0 and HER2-low breast cancers in the context of neoadjuvant therapy have reported conflicting results. According to Shao, Y’ study [36], there is no discernible difference in prognosis between breast tumors with HER2-0 and those with HER2-low. However, other studies have shown that BC cases with low HER2 have higher 5-year overall survival (OS) and disease-free survival (DFS) rates [29]. In addition, it had also been demonstrated that there is no difference in DFS between the two groups, but the prognosis tends to be worse in hormone receptor (HR)-negative/HER2- low cases compared to HR-negative/HER2-0 [26]. Additionally, studies on pCR in breast cancers with low HER2 yielded mixed findings. Several studies have shown that pCR was significantly lower in HER2-low tumors compared to HER2-0 tumors after neoadjuvant therapy [20, 27]. More patients in the HER2-0 group achieved a pathological complete response [29]. However, some studies have shown no statistical difference in HER2-low tumor pCR compared to HER2-0 tumors. The study by Alves, F. R. concluded [31] that the subgroup with low HER2 achieved a lower pCR rate, but this difference was not statistically significant. de Moura Leite, L.'s study [37] reported no difference in the pCR rate between the two groups either. In our research, differences in rwOS, bpCR and ORR were not observed between HER2-low breast cancer patients and HER2-0 breast cancer patients. An important explanation may lie in the limited reproducibility of HER2 scores. It is well known that the reproducibility of HER2 scores is far from perfect, especially when differentiating between score 0 and score 1+ [38]. Another important explanation is the dynamic evolution of HER2 expression from early to advanced breast cancer, where HER2 expression status is not invariant and increases in advanced stages [39]. Overall, our current findings do not support the prognostic significance of survival analysis of HER2-low breast cancer versus HER2-0 breast cancer in patients receiving neoadjuvant chemotherapy. However, considering that the prognostic impact of HER2-low status on BC remains controversial, further studies are needed.
There are certain limitations of our study. There is a potential survivor bias in this study, as patients who died before they could participate were no included in our study. Meanwhile, inverse probability weighting method was used to balance the confounders between the two groups but unobserved confounders might still affect the results and interpretations. HER2 type IHC2 + breast cancer patients without available FISH results were excluded from the study, which might affect the representativeness. Finally, it is difficult to completely distinguish HER2 0 tumors from HER2 IHC 1 + tumors using current detection techniques [40].
In conclusion, we report the clinicopathological characteristics and survival outcomes of HER2-low entities. Our analysis showed no difference in survival between HER2-low and HER2-0 breast tumors, and some pathological features of the two were significantly different. Although defining HER2-low as a specific biological subtype remains difficult, the therapeutic value shown by the novel ADC trastuzumab derutecan (T-DXd) in patients with advanced breast cancer with low HER2 expression suggests the need to further deepen our research and understanding of HER2-low breast cancer.