June 13, 2024

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Characteristics of HER2 Low Protein Expression in Luminal and Triple-Negative Breast Cancer

Characteristics of HER2 Low Protein Expression in Luminal and Triple-Negative Breast Cancer

Characteristics of HER2 Low Protein Expression in Luminal and Triple-Negative Breast Cancer

Breast cancer (BC) can be classified based on the human epidermal growth factor receptor-2 (HER2) status into HER2-positive (HER2+) tumors and HER2-negative (HER2-) tumors.

HER2+ tumors either exhibit HER2 protein overexpression in immunohistochemistry (IHC) or show critical IHC expression with evidence of HER2 gene amplification.

With the introduction of antibody-drug conjugates (ADCs) targeting HER2 protein, the clinical relevance of traditional HER2 classification is evolving.

Patients with low HER2 expression (HER2 Low), defined as IHC score 1+ or lack of evidence of HER2 gene amplification in IHC 2+, have been shown to benefit from these new treatment approaches.

Given that the HER2-Low category accounts for 45%-55% of BC cases, accurate identification of this patient group is crucial for clinical management and further understanding the biology and behavior of HER2-Low BC.

The interaction between estrogen receptor (ER) and the HER2 signaling pathway has garnered significant attention.

In tumors expressing HER2 Low, it is currently unclear whether ER or the HER2 signaling pathway is the dominant pathway.

Triple-negative breast cancer (TNBC) is a highly diverse and heterogeneous tumor type associated with a higher risk of local and distant recurrence and poorer patient survival rates. Chemotherapy is the main treatment option for TNBC patients, with personalized therapies also being applied.

However, the response of TNBC to these drugs is unstable, prompting researchers to further explore the immune phenotype and gene profiling of tumor-infiltrating lymphocytes (TILs) in TNBC.

A study published on October 7, 2023, in The European Journal of Cancer aimed to delve into the characteristics of HER2-Low BC, focusing on the clinical and pathological features, immune phenotypes, and molecular features in hormone receptor-positive and TNBC subtypes.

The following is a summary of the key findings from this research.

Characteristics of HER2 Low Protein Expression in Luminal and Triple-Negative Breast Cancer


The study included two distinct and independent BC cohorts: the Nottingham cohort (A) with n = 5744 and the Cancer Genome Atlas (TCGA) BC cohort (B) with n = 854.

Researchers conducted a study of clinical, molecular, biological, and immunological features of HER2 Low BC. For the TCGA BC cohort, transcriptomic and pathway enrichment analyses were performed, and the findings were validated through next-generation sequencing in the Nottingham cohort subgroups.


The study results revealed:

– 90% of HER2-Low tumors are hormone receptor-positive (HR+), and these tumors enrich the luminal intrinsic molecular subtype. Compared to HER2-negative (HER2-) BC, these tumors lack significant expression of HER2 oncogenic signaling genes and exhibit favorable clinical behavior.

– In HR+ BC, no significant prognosis difference was observed between HER2 Low and HER2 tumors. However, in HR- BC, HER2 Low tumors showed lower invasiveness and longer patient survival.

– Transcriptomic data showed that most HR-/HER2 Low tumors belong to the luminal androgen receptor (LAR) intrinsic subtype, enriching for helper T lymphocytes, activated dendritic cells, and tumor-associated neutrophils. In contrast, most HR-/HER2- tumors belong to the basal subtype, enriching for tumor-associated macrophages.


In this study, HER2 Low tumors accounted for 43% of the entire study tumor population, with 90% being HR+. Similar to observations in previous studies, HER2 Low tumors had higher ER H-scores than HER2- and HER2+ tumors.

The study results suggest that, compared to HER2- tumors, HER2 Low tumors may extend the survival of unselected patients and HR- BC subgroup patients.

These findings align with previous research. However, after adjusting for HR+ tumors, this trend was not sustained, and HER2 Low tumors lost prognostic significance in clinical-pathological parameters or patient prognosis. Some scholars have also confirmed these results.

These study results indicate that prognostic significance is lacking for HER2 Low tumors in HR+ BC and that the association between HER2 Low and luminal phenotype in HR- BC subgroups suggests that the favorable prognosis of HER2 Low tumors depends on HR activity.

Therefore, the conclusion is drawn that while HER2 Low tumors represent a unique category in BC treatment, eligible for specific HER2-targeted ADC therapy, they are not a distinct BC category in terms of biology or prognosis.

Regarding the molecular differences between HER2 Low and HER2- BC in HR- tumors, our study suggests that HER2 Low tumors exhibit unique molecular features.

Differential gene expression and pathway enrichment analysis indicate that HR-/HER2 Low tumors primarily belong to the LAR subtype, with upregulation of luminal androgen receptor pathway genes, especially AR. AR is one of the top 10 PPI hub genes and is associated with enrichment in fatty acid and steroid hormone metabolism pathways, as reported in the LAR TNBC subtype.

This aligns with the experiences of other researchers who observed distinct molecular characteristics in HER2- and HER2 Low BC.

Our study results indicate that high expression of AR protein is significantly associated with HR-/HER2 Low tumors and serves as an independent predictor of poor prognosis, consistent with previous research indicating more common AR expression in HER2 Low-expressing BCs than in HER2 BCs.

These findings support the hypothesis that HER2 Low tumors are associated with luminal differentiation in TNBC, consistent with the conclusion of Zhang et al., who also suggested that HER2 Low tumors are unlikely to be basal-type TNBC subtypes. The role of AR inhibitors in treating AR+ BC has been studied, but these inhibitors have not yet been used as therapeutic targets.

Based on our research results, the association between AR and HER2 Low warrants further investigation to assess the combined use of AR inhibitors and novel anti-HER2 ADC targeted therapies.

Considering the heterogeneity and low expression levels of tumors, the dynamics of HER2 expression are an important issue.

Recent research results indicate an increase in late-stage HER2 Low tumors, with correlations found between these changes and factors such as recurrence time.

Bar and colleagues emphasized the issue of HER2 heterogeneity in repeat biopsies of TNBC patients, concluding that repeat biopsies during disease progression can increase the likelihood of obtaining HER2 Low results, especially in patients included in the Destiny-breast04 clinical trial, even if other samples are negative.

Conclusion and Outlook

HER2 Low tumors are mostly hormone receptor-positive (HR+), and compared to HR+/HER2- tumors, HR+/HER2 Low tumors show no significant differences in tumor behavior and patient outcomes. In hormone receptor-negative (HR-) BC, the prognosis of HER2 Low tumors improves, but their response to neoadjuvant chemotherapy appears to be less favorable.

Additionally, HR-/HER2- tumors enrich unique immune phenotypes associated with invasive tumor behavior.

The high expression of androgen receptor (AR) in HER2 Low TNBC patients predicts an adverse prognosis, making it a potential therapeutic target.

Article Source:

Alsaleem M, Rutland CS, Allegrucci C, Mongan NP, Rakha E. Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression. Eur J Cancer. 2023 Oct 7;195:113371. doi: 10.1016/j.ejca.2023.113371. Epub ahead of print. PMID: 37897865.

Characteristics of HER2 Low Protein Expression in Luminal and Triple-Negative Breast Cancer


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