CDK 4/6i + ET combination therapy is the standard treatment regimen used in HR + /HER2-negative mBC, both in first-line and later-line settings. Low expression of HER2 is observed at a rate of ~ 60% among all BC patients [7]. In recent years, there has been data supporting the evaluation of HER2-low disease as a different entity [7, 20,21,22]. In a study by Schettini et al. evaluating 3689 patients, it was observed that low HER2 expression was more frequent in HR-positive disease than in triple-negative breast cancer (TNBC) (65.4% vs 36.5%, p < 0.001), and HER2-low patients were significantly associated with more nodal involvement and a larger primary tumor diameter compared to HER2-zero [5]. In another analysis of 523 patients analyzing genomic data, significant differences were observed between gene mutations seen in HER2-low and zero disease [23]. In this study, patients with low HER2 expression were more frequent in the HR-positive subgroup and had lower Ki67 expression levels than HER2-zero. In the same study, it was shown that PI3K-Akt signal pathway mutations were more frequent in the HER2-low group, and checkpoint factors, Fanconi anemia, p53 signaling, and cell cycle pathway mutations were more frequent in the HER2-zero group. After the use of antibody–drug conjugates such as trastuzumab deruxtecan in HER2-positive patients and the demonstration of its efficacy in HER2-low patients, interest in this subgroup has increased.

It has been observed that HER2-low disease is detected more frequently in HR-positive breast cancer patients than in the HR-negative group [20, 24]. Data have been published showing that low HER2 expression is associated with both lower pathological complete response rates (pCR) and worse survival in HR + BC patients receiving neoadjuvant chemotherapy. In a pooled analysis of four neoadjuvant chemotherapy trials involving a total of 2310 patients, it was observed that pCR rates were significantly lower in patients with HER2 low expression in the HR-positive subgroup compared to HER2-zero (17.5% vs 23.6%, p = 0.024), while there was no significant difference between the two groups in the HR-negative subgroup [20]. There are data supporting the existence of bidirectional crosstalk between HER2 and HR pathways as a potential mechanism of hormonal resistance and unfavorable outcomes on survival [18].

In our study, there were 36.3% of patients with low HER2 expression. Compared to previous studies [25,26,27,28], this rate was lower in our research. There could be several factors leading to this occurrence. One of them is the absence of a centralized pathology assessment. A recent study shows the lack of concordance between pathologists in distinguishing tumors with a HER2 score of 0 and those with a score of 1 + [29]. Another possible factor is that not all recurrent metastatic patients undergo a re-biopsy.

We investigated the effects of first-line ET in combination with CDK 4/6i treatment on OS and PFS in HER2-low and zero groups in patients with metastatic HR + /HER2-negative BC and we found no significant difference between the two groups in both OS and PFS. The literature has discrepancies in the findings of retrospective studies on this issue. Similar to the results in our study, Yildirim et al. conducted a multicenter retrospective analysis with 204 patients, and they found no significant impact of low HER2 expression on survival [30]. In another study conducted with a small group of patients, no significant difference was observed between objective response rates (ORR) in the HER2-low and zero patient groups [31].

Zattarin et al. [27] retrospectively evaluated 436 patients who received CDK 4/6i in the first line of the metastatic disease. In this study, it was observed that low HER2 expression was associated with poor OS and PFS, independent of other risk factors. In a retrospective analysis of 106 patients by Bao et al. [25], 77.3% of patients had HER2 low expression, and this subgroup had a shorter PFS (8.9 vs 18.8 months, p = 0.01) compared to HER2-zero patients. In this study, most patients (84.9%) were treated with palbociclib, and only half of the patients received first-line CDK 4/6 inhibitors.

It's not yet clear what the prognostic value of HER2 expression status is in HR + /HER2-negative mBC that is treated by CDK 4/6i plus ET. Studies on this subject in the literature are limited to retrospective analyses. Various factors might be responsible for the disparities shown in the findings of the studies. The assessment of HER2 status using different methodologies may be the most crucial among these factors. Another possible reason for the observed disparities among studies might originate from alterations to the patient group, including disparities in tumor-related parameters. A recent review evaluated nine retrospective analyses encompassing 2705 individuals [32]. The findings revealed a statistically significant increase in the risk of disease progression and death among patients with mBC who had low expression of HER2 and were treated with CDK 4/6 inhibitors.

Our study has several limitations that result from its retrospective design, which encompasses selection bias. Another limitation of our study is the short follow-up time for an optimal evaluation of survival outcomes. We consider the absence of centralization in the HER2 expression evaluation to constitute a significant limitation of our study that may have contributed to discrepancies in the results. According to the latest ASCO/CAP guideline, cases with tumor cell staining between 1 and 10% should be classified as ER-low positive [33]. However, in our country, insurance coverage for CDK 4/6 inhibitors is limited to patients with ER levels exceeding 10%. Therefore, patients classified as ER-low were not included in our study. Approximately 2 − 3% of breast cancers have been reported to be ER-low and there is limited data on the overall benefit of endocrine therapy in these patients [34]. Consequently, we suspect the exclusion of this patient subgroup from our study may have influenced our results.

In conclusion, our multicenter research suggests that low HER2 expression does not significantly affect survival outcomes in HR + mBC patients treated with first-line ET plus CDK4/6 inhibitors. Prospective analyses are needed to more accurately evaluate the effects of HER2 expression levels on treatment responses and survival in mBC patients treated with CDK 4/6 inhibitors.