April 23, 2024

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HER2-Low-Expressing Breast Cancer: Clinical Characteristics and Prognosis

HER2-Low-Expressing Breast Cancer: Clinical Characteristics and Prognosis

HER2-Low-Expressing Breast Cancer: Clinical Characteristics and Prognosis

Clinical Pathological Characteristics and Prognosis of Early HER2-Low-Expressing Breast Cancer: A Single-Center Retrospective Study

Clinical Issues:

Approximately 15%-20% of breast cancer patients exhibit human epidermal growth factor receptor 2 (HER2) overexpression, which is associated with poor clinical outcomes if untreated.

The introduction of patuximab and trastuzumab has significantly improved the clinical outcomes of HER2-positive breast cancer patients. However, about 40%-50% of patients with HER2-low-expressing breast cancer have negative results on in situ hybridization (ISH) but positive results on immunohistochemistry (IHC) with scores of 1+ or 2+.

Previous studies have shown that conventional anti-HER2 targeted therapy is ineffective against tumors expressing low to moderate levels of HER2. However, recent clinical trial results suggest that novel antibody-drug conjugates (ADCs) may target tumors with low HER2 expression.

The DESTINY-Breast04 phase III study demonstrated that trastuzumab deruxtecan achieved an objective response in 52.3% of patients with HER2-low-expressing metastatic breast cancer who had previously received first- or second-line chemotherapy, with a median overall survival (OS) of 23.4 months, which is encouraging.

Therefore, as a new clinical subtype, further exploration of the characteristics and prognosis of HER2-low-expressing breast cancer patients is warranted.

Although several studies have compared the outcomes of HER2-0 (HER2-IHC 0) and HER2-low-expressing breast cancer, the results are inconsistent.

A study published on March 29, 2023, in Frontiers in Endocrinology retrospectively evaluated patients with HER2-0 and HER2-low-expressing breast cancer. 

HER2-Low-Expressing Breast Cancer: Clinical Characteristics and Prognosis


Researchers collected data from the Breast Center database at Qingdao University Affiliated Hospital from January 2008 to December 2017, screening a total of 4598 patients. Among them, 2837 patients had HER2-0 tumors, and 1761 patients had HER2-low-expressing tumors.

Additionally, researchers obtained clinical pathological characteristics, survival periods, and prognosis information for these patients to compare the differences in clinical characteristics and outcomes between the HER2-0 group and the HER2-low-expressing group.


The study included 4598 patients. The study found that:

The proportion of HER2-low-expressing breast cancer patients was higher in hormone receptor (HR)-positive breast cancer patients than in HR-negative patients.

Compared to HER2-0 tumors, HER2-low-expressing tumors were associated with older median age at diagnosis, T1 stage tumors, N1 stage tumors, higher Ki-67 index at diagnosis, and lower histologic grade.

While no significant intergroup differences were observed in OS, the HER2-0 group had better disease-free survival (DFS) than the HER2-low-expressing group in the overall population (P = 0.003), lymph node-negative population (P = 0.009), and HR-positive population (P = 0.007).

Multivariate regression analysis showed that HER2-low expression was a poor prognostic factor for DFS in the HER2-negative early breast cancer population (hazard ratio 1.33, 95% confidence interval 1.06-1.66, P = 0.013).


The study results showed that the proportion of HER2-low expression in the traditional HER2-negative population was 38.2%, which is similar to previous reports indicating that approximately 40%-50% of breast cancer patients exhibit HER2-low expression. HER2-low expression may vary by HR status, with a higher proportion of HER2-low-expressing breast cancer in the HR-positive population. Additionally, HER2-low-expressing breast cancer has different clinical pathological characteristics compared to HER2-0 tumors. HER2-low-expressing tumors have a higher median age at diagnosis, are more common in postmenopausal populations, and are associated with more T1 tumors, higher N1 staging, poorer histologic grade, and higher Ki-67 index than HER2-0 tumors.

In terms of survival, regardless of HR status, there was no significant difference in OS between the HER2-low-expressing group and the HER2-0 group. However, in lymph node-negative and HR-positive populations, patients in the HER2-0 group had better 5-year DFS than those in the HER2-low-expressing group. Furthermore, Cox regression analysis showed that HER2-low expression was an independent adverse prognostic factor for DFS. The mechanism underlying the poor prognosis of HER2-low expression in early breast cancer is currently unclear but may be related to its poorer clinical pathological factors. Further research is needed to explore its more complex biological differences.

Previous studies have suggested that HER2-low-expressing breast cancer may be a clinically and biologically distinct subtype that could impact patient prognosis. Even in the absence of HER2 amplification, HER2-low expression can have a negative impact on early breast cancer patients. It has been reported that in HR-positive breast cancer, patients with HER2 2+ expression have lower DFS than patients with HER2 1+ or 0 expression, but there is no significant difference in breast cancer-specific survival (BCSS). Another report showed that patients aged 55 and older with HER2 2+ expression have a worse prognosis than HER2 0/1+ patients.

Moderate HER2 2+ status is defined as having 500,000 detectable HER2 receptors on the cell surface, which is crucial for driving tumor growth and invasion. Conversely, the proportion of HER2 2+ patients affected by adverse prognosis is small. These patients have lower HER2 levels, with an IHC score of 1+ or 2+ but negative FISH, suggesting that HER2 IHC 1+ may exhibit similar biological behavior to HER2 IHC 2+ and may have a detrimental effect on prognosis. HER2-low-expressing tumors may be more sensitive to different growth factors that stimulate breast cancer cells, as HER2 signaling is a key factor in breast cancer proliferation.

Furthermore, in general, the prognosis of lymph node-negative patients is better than that of lymph node-positive patients. However, in lymph node-negative patients, HER2-low expression is also an independent adverse prognostic factor for DFS. Therefore, large-scale prospective studies are needed to confirm whether HER2-low expression can serve as a reference for further intensified treatment of early breast cancer.

Recent clinical trials, such as DESTINY-Breast04, have explored novel anti-HER2 ADC drugs. Therefore, researchers have re-evaluated the diagnostic and therapeutic value of the HER2-low-expressing population. However, some studies on the HER2-low-expressing population currently yield inconsistent results. Denkt et al. analyzed the OS and DFS differences between HER2-0 and HER2-low-expressing breast cancer using data from four prospective clinical trials of neoadjuvant therapy and found that HER2-low-expressing patients showed a trend towards prolonged OS and DFS, but it was not statistically significant. Won et al. found that the breast cancer-specific survival of HER2-low-expressing breast cancer patients

was significantly better than that of HER2-0 patients. Additionally, the prognostic impact of HER2 may vary by breast cancer stage. A study based on the Chinese National Cancer Center database showed that the survival period of the HER2-low-expressing group was significantly longer than that of the HER2-0 group, but this was not the case in the HR-negative population. Recently, a study on breast cancer described the dynamic evolution characteristics of HER2-low expression, finding a significant difference in HER2-low expression levels between early and late stages, with an increase in HER2 levels in late stages. Therefore, further research is needed to explore how HER2-low expression affects differences in treatment response and prognosis. The findings of this study provide evidence that HER2-low expression is biologically different from HER2-0 expression. Researchers believe that the prognostic significance of HER2-low expression as a predictor of anti-HER2 therapy needs to be reevaluated.

Based on the HER2 status defined by the ASCO/CAP guidelines, this trial included patients who scored 1+ or 2+ in the IHC test and were negative in the ISH test. As more clinical trials on ADC drugs demonstrate their benefits in HER2-low-expressing tumors, further exploration of the algorithms currently used for HER2 diagnosis is needed to introduce more reliable HER2 quantification methods to identify more beneficiaries.

Conclusion and Outlook:

This study found that approximately 38% of early breast cancer patients exhibited HER2-low expression. The proportion of HER2-low expression was higher in HR-positive patients than in triple-negative breast cancer (TNBC) patients.

Although there was no significant difference in OS between the HER2-0 group and the HER2-low-expressing group, the former had better DFS than the latter in the HR-positive and lymph node-negative populations. Multifactorial analysis further confirmed this and suggested that HER2-low expression may be a poor prognostic factor for early breast cancer.

With the increasing number of clinical trials on HER2-low-expressing breast cancer and a deeper understanding of the concept of HER2 status, more studies are suggesting that HER2-low expression is a new biological subtype.

Therefore, larger studies are needed to clarify the prognostic impact of HER2-low expression and to explain its mechanisms at the molecular level.

HER2-Low-Expressing Breast Cancer: Clinical Characteristics and Prognosis


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