Clinical and pathological characteristics of HR+ breast cancer with HER2 low and HER2(0) expression: exploring endocrine therapy sensitivity

Introduction

Background

With the continuous reporting of the DESTINY-Breast04 (DB04) study results (1), human epidermal growth factor receptor 2 (HER2) low expression breast cancer has increasingly captured the attention of clinical oncologists. The findings from the DB04 study indicate that patients with HER2 low expression can benefit from trastuzumab deruxtecan (T-DXd) treatment regardless of baseline conditions (2). This raises the question of whether HER2 low expression should be recognized as a distinct subtype and separate from the HER2-negative population, which has generated considerable interest among clinicians.

Objective

To date, researchers indicate that among hormone receptor-positive (HR+) breast cancer patients, HER2 low expression is more common than either HER2 negative or HER2 high expression, with reported rates ranging from 58.1% to 90.5%. However, the clinical significance of HER2 low expression in HR+ breast cancer remains unclear. Although some studies have indicated potential prognostic differences between HER2 low and HER2 negative patients, findings have been inconsistent and largely focused on HER2-targeted therapies (3-5). Consequently, we conducted this study to explore whether there are significant clinical differences between HER2 low and HER2(0) expression in HR+ breast cancer, with a particular focus on endocrine therapy (ET) sensitivity. Meanwhile, this study introduces the Allred scoring system for estrogen receptor (ER) immunohistochemical assessment of breast cancer specimens (6), investigating the difference in ET sensitivity between the cohorts of HER2 low expression and HER2(0) expression. Our findings aim to provide a foundation for personalized treatment strategies for HR+ breast cancer patients with HER2 low and HER2(0) expression. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1013/rc).

Methods

Patients

We collected and recorded data from 390 patients who underwent radical breast cancer surgery at the First Affiliated Hospital of Bengbu Medical University between December 2014 and December 2017. All patients received standard treatment plans based on their risk of recurrence, including postoperative adjuvant chemotherapy, ET, and radiotherapy. The adjuvant chemotherapy regimen includes docetaxel + epirubicin (25 cases), epirubicin + cyclophosphamide → docetaxel (293 cases), docetaxel + cyclophosphamide (72 cases). The endocrine treatment plan includes the use of tamoxifen in premenopausal patients (205 cases) and letrozole in postmenopausal patients (185 cases). Written informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of The First Affiliated Hospital of Bengbu Medical University, Anhui, China (approval No. 2023YJS223) and written informed consent was obtained from all individual participants. This retrospective analysis of medical records summarized clinical and pathological characteristics and evaluated factors affecting patient prognosis.

The inclusion criteria for patients in this study were as follows: (I) clinically and pathologically diagnosed with primary breast cancer, (II) successful radical surgery for breast cancer, (III) no neoadjuvant therapies such as radiation or chemotherapy before surgery, and (IV) immunohistochemically confirmed ER-positive and/or progesterone receptor (PgR)-positive, HER2-negative or HER2 (+/++) with negative fluorescence in situ hybridization (FISH) results. Exclusion criteria included (I) a history of malignancies from other tissue, (II) missing or incomplete medical and treatment records, (III) rare pathological types of breast cancer other than infiltrating lobular carcinoma and infiltrating ductal carcinoma.

Clinical pathological data

We collected clinical and pathological data on the study subjects, including age at diagnosis, menstrual status, tumor size, tumor node metastasis (TNM) classification staging, pN staging, histological grading, pathological type, ER and PgR status, HER2 status, and cell proliferation index (Ki-67).

Criteria for cohort classification

HER2 judgment standard refers to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018. Tumors with a score of 0 were classified as HER2(0) expression, and those with a score of 1+ as HER2 low expression. Tumors with a score of 2+ were further subjected to FISH to assess ERBB2 gene amplification, and those with negative FISH results were also categorized as HER2 low expression. Based on these assessments, patients were classified into two cohorts: the HER2(0) cohort and the HER2-low cohort.

The Allred scoring system was introduced to evaluate the ER immunohistochemical scores in breast cancer specimens (7). This system quantifies both the proportion of positively stained tumor cells and the intensity of staining on slides. The proportion scored as follows: 0 (none), 1 (1/100), 2 (1/100 to 1/10), 3 (1/10 to 1/3), 4 (1/3 to 2/3), and 5 (2/3 or more). The intensity scored as 0 (none), 1 (weak), 2 (moderate), and 3 (strong). The combined scores provide a total score ranging from 0 to 8. Patients were then divided into cohorts based on their ER scores, using a cutoff value derived from receiver operating characteristic (ROC) curve analysis: those with ER scores ≤ the cutoff value and ER scores > the cutoff value.

Statistical analysis

Statistical analyses were performed using Spss26.0 and GraphPad prism9.5 software. Categorical variables, expressed as percentages (%), were compared between cohorts using the Chi-squared test. The primary endpoints were disease-free survival (DFS) and overall survival (OS). DFS was defined as the time from initial diagnosis to disease recurrence or death of any cause, whereas OS was defined as the time from initial diagnosis to death of any cause or the last follow-up. The Kaplan-Meier method was used to generate survival curves. Both univariate and multivariate Cox proportional hazards models were utilized to identify prognostic factors, with a significance level set at α=0.05.

Additionally, the ROC curve analysis was employed to evaluate the prognostic utility of the immunohistochemistry (IHC) score in predicting the prognosis for ER-positive breast cancer and to determine the optimal threshold for this score. Based on the derived threshold, patients were stratified into two cohorts: those with ER scores above the threshold, indicating higher sensitivity to ET, and those below, suggesting lower sensitivity. Kaplan-Meier survival curves were then plotted for each cohort to assess the significance of differences in survival outcomes, which could inform the tailoring of ET based on ER status.

Results

Comparison of clinical and pathological characteristics between the HER2(0) and HER2-low cohorts

This study included 390 breast cancer patients identified as HR-positive, of whom 263 (67.4%) exhibited HER2 low expression and 127 (32.6%) had HER2(0) expression (Figure 1A). Statistically significant differences were observed in histological grading (P=0.03) and pN staging (P<0.001) between the two cohorts. There were no differences observed in T staging, TNM staging, ER status, proliferation index (measured by Ki-67), menopausal status, age beyond 60 years, or pathological type (Table 1).

Figure 1 HER2 expression, ER IHC score and survival outcomes. (A) Pie chart displaying the percentage distribution of patients with low HER2 expression and HER2(0) expression. (B) ROC curve for ER IHC score. (C) Kaplan-Meier curve illustrating DFS in patients with low HER2 expression versus patients with HER2(0) expression. (D) Kaplan-Meier curve showing OS in patients with low HER2 expression and patients with HER2(0) expression. HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; IHC, immunohistochemistry; ROC, receiver operating characteristic; DFS, disease-free survival; OS, overall survival.

Determination of the ER-positive IHC score threshold

To establish a clinically significant threshold for ER-positive tumors, we analyzed the prognosis and IHC score of 390 patients. The ROC curve analysis (Figure 1B) indicated a threshold value of 4.5. However, as the Allred scoring system requires integer values, we adjusted the threshold to 4. Subsequently, patients were stratified into five cohorts based on their IHC scores and HER2 expression: Cohort 1 included 93 patients with an IHC score ≤4 and 297 patients with an IHC score >4; Cohort 2 comprised 35 patients with HER2(0) expression and an IHC score ≤4 alongside 58 with low HER2 expression; Cohort 3 included 92 patients with HER2(0) expression and an IHC score >4, and 205 with low HER2 expression; Cohort 4 grouped 35 patients with HER2(0) expression and an IHC score ≤4 and 92 with an IHC score >4; finally, Cohort 5 had 58 patients with low HER2 expression and an IHC score ≤4, and 205 with an IHC score >4 (Table 2). This stratification allows for a detailed comparison of outcomes based on ER positivity and HER2 expression status, aiding in the evaluation of prognosis related to different levels of ER expression in breast cancer.

Comparison of clinical and pathological characteristics between the IHC score >4 and IHC score ≤4 cohorts

Of the 390 patients included in this study, 93 patients were found to have an IHC score ≤4, while 297 patients had an IHC score >4. Our analyses revealed no statistically significant differences between these two cohorts in terms of histological grade (P=0.41), pN stage (P=0.16), T stage (P=0.74), TNM stage (P=0.45), menopausal status (P=0.86), age over 60 years (P=0.68), or pathological type (P=0.63) (Table 3).

Survival analysis

Univariate analysis of prognostic factors

The results from the univariate analysis indicated significant correlations between several clinical and pathological characteristics and DFS in breast cancer. Specifically, the T stage, pN stage, histological grade, HER2 expression level, and IHC score all demonstrated significant associations with DFS (P<0.001). However, the significance of histological grade in univariate analysis was not maintained in the subsequent multivariate analysis (P=0.42) (Table 4).

Survival curve analysis

Survival curve analysis of all breast cancer patients in the study showed that the HER2-low cohort had improved OS and DFS compared with the HER2(0) cohort, demonstrating that low HER2 expression was an independent predictor of favorable survival outcomes (DFS, P=0.002; OS, P<0.001; Figure 1C,1D). Stratified analysis by pN stage revealed that the prognosis for patients worsened with advancing pN stages (P=0.003, Figure 2A). Within the same pN stages (pN0–pN2), significant survival differences were found between the HER2-low and HER2(0) cohorts, indicating superior outcomes for patients with low HER2 expression (pN0, P=0.002; pN1, P=0.047; pN2, P=0.04; Figure 2B-2D). Despite these findings, no significant differences in DFS and OS were observed between the HER2-low and HER2(0) cohorts at pN3 staging (P=0.78) (Figure 2B-2E).

Figure 2 DFS by pN stage. (A) DFS across all patients stratified by pN stage. (B) DFS in patients with low HER2 expression and HER2(0) expression at pN0 stage. (C) DFS in patients with low HER2 expression and HER2(0) expression in pN1 stage. (D) DFS in patients with low HER2 expression and HER2(0) expression at pN2 stage. (E) DFS in patients with low HER2 expression and HER2(0) expression at pN3 stage. HER2, human epidermal growth factor receptor 2; HR, hazard ratio; CI, confidence interval; DFS, disease-free survival; pN stage, pathologic node stage.

In addition, survival analysis based on the ER-positive IHC score threshold revealed that patients with an IHC score >4 had significantly better OS and DFS compared to those with an IHC score ≤4 (DFS, P=0.003; OS, P<0.001; Figure 3A,3B). Moreover, multivariate analysis further supported this result, showing that an IHC score ≤4 was independently associated with poorer prognosis. Specifically, within subgroup analyses, there were no statistically significant differences in OS or DFS between the HER2-low and HER2(0) cohorts among patients with an IHC score ≤4 (OS, P=0.37; DFS, P=0.22; Figure 4A,4B). For patients with an IHC score >4, both OS and DFS were superior in the HER2-low cohort compared to the HER2(0) cohort (OS, P<0.001; DFS, P=0.01; Figure 4C,4D). Among patients with HER2(0) expression, those with an IHC score >4 also showed better OS and DFS than those with an IHC score ≤4 (DFS, P=0.005; OS, P=0.02; Figure 5A,5B). Similarly, in the HER2-low cohort, patients with an IHC score >4 had better survival outcomes than those with an IHC score ≤4 (P<0.001; Figure 5C,5D).

Figure 3 Impact of ER IHC score on survival outcomes. (A) DFS of patients with ER IHC score ≤4 and ER IHC score >4 in the overall population. (B) OS of patients with ER IHC score ≤4 and ER IHC score >4 in the overall population. IHC, immunohistochemistry; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; DFS, disease-free survival; OS, overall survival.

Figure 4 Survival analysis of cohorts 2 and 3 by HER2 expression and IHC score. (A) OS in patients with low HER2 expression and HER2(0) expression in cohort 2 with IHC score ≤4. (B) DFS in patients with low HER2 expression and HER2(0) expression with IHC score ≤4 in cohort 2. (C) OS in patients with low HER2 expression and HER2(0) expression with IHC score >4 in cohort 3. (D) DFS in patients with low HER2 expression and HER2(0) expression with IHC score >4 in cohort 3. HER2, human epidermal growth factor receptor 2; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor; IHC, immunohistochemistry; DFS, disease-free survival; OS, overall survival.

Figure 5 Survival analysis of cohorts 4 and 5 by HER2 expression and IHC score. (A) DFS in patients with IHC score ≤4 and IHC score >4 with HER2(0) expression in cohort 4. (B) OS in patients with IHC score ≤4 and IHC score >4 with HER2(0) expression in cohort 4. (C) DFS in patients with IHC score ≤4 group and IHC score >4 with low HER2 expression in cohort 5. (D) OS in patients with IHC score ≤4 group and IHC score >4 with low HER2 expression in cohort 5. IHC, immunohistochemistry; HR, hazard ratio; CI, confidence interval; HER2, human epidermal growth factor receptor 2; DFS, disease-free survival; OS, overall survival.

Discussion

The molecular classification of breast cancer in clinical practice primarily relies on ER, PR, HER2, and Ki-67. These biomarkers define subtypes such as luminal A, luminal B, HER2 positive, and triple negative, which guide clinical treatment decisions (8). The prognostic implications of these molecular subtypes have been well-documented, with luminal subtypes generally showing better prognosis, while triple-negative and HER2-positive subtypes often exhibiting poorer prognosis.

ET remains the backbone of treatment for patients with luminal subtypes of breast cancer. In recent years, with the continuous advancement in drug development, particularly the emergence of third-generation antibody-drug conjugates (ADCs) represented by T-DXd, breast cancer treatment has been significantly impacted (9-11). The DB04 study series, especially the recent findings of DB04 in the treatment of HER2 low expression population, has highlighted the clinical relevance of this subgroup. In the 2024 ASCO conference report, we saw DESTINY-Beast06 indicating that T-DXd is an effective new treatment option for HR+, HER2 low, and HER2 ultra low metastatic breast cancer patients who have progressed to ≥1-line endocrine based therapy. Relevant studies focusing on the HER2 low expression population have been reported, demonstrating slight variations in findings (12-14). It is generally accepted that HER2 low expression is predominantly observed in the HR-positive population than in the triple-negative population. With the latest results from the DB04 study, it has been shown that patients with advanced HER2 low expression benefit from ADCs, leading to superior treatment outcomes.

The question of whether HER2 low expression should be considered an independent clinical subtype warranting specific therapeutic strategies remains a topic of intense research. In fact, there is currently no consensus on the definition of HER2 low status. The ASCO/CAP guidelines primarily define HER2 status to identify tumors with HER2 overexpression, and they provide limited reference value for other levels of HER2 expression (15). The effectiveness of anti-HER2 therapies in patients with HER2 low expression also remains unclear. While some phase III studies have shown that patients with HER2 low expression (IHC 1+ or 2+ with FISH-negative) benefit minimally from trastuzumab (16), the DESTINY-Breast04 study demonstrated that HER2-targeted therapy with T-DXd could reduce progression risk in patients with an IHC score of 1+ (1). In addition, reports on the biological characteristics of patients between HER2 low and HER(0) expression are variable (15,16). Although HER2 low disease accounts for approximately 60% of all HR+ breast cancer cases—consistent with our findings of 67.4% HER2 low expression in the HR+ cohort—relatively few studies have focused on this subgroup (17). Our data also indicate significant differences in pN stage and histological grade between HER2 low and HER2(0) patients. In terms of survival outcomes, both DFS and OS are better in the HER2 low expression cohort compared to the HER2(0) expression cohort within the HR-positive population, suggesting a more favorable prognosis for patients with HER2 low expression. To our knowledge, this is the first study to report on survival outcomes in HR+ patients with ranging low levels of HER2 expression (18), offering insights that could inform future research on tailored ET and personalized treatment strategies for this distinct patient subgroup.

Currently, there are no research reports that specifically address differences in ET outcomes between HR-positive patients with HER2 low expression and those with HER2(0) expression. To explore this issue, we conducted an exploratory analysis using the Allred scoring system to quantitatively assess ER status through IHC. By establishing a threshold with a statistical model and constructing an ROC curve, we discovered that patients with an IHC score ≤4 had a significantly increased risk of mortality, poorer response to ET, and tended to be a negative ER status. In contrast, patients with an IHC score >4 demonstrated a clearly benefit from ET. Patients were then stratified into two cohorts according to the IHC score threshold of 4, and the survival analysis revealed a significant statistical difference between the two cohorts. Both univariate and multivariate analyses identified IHC score ≤4 as an independent risk factor associated with worse prognosis.

In further analysis, we examined the differences between patients with IHC score ≤4 and those with IHC score >4, separately within the subcohorts of HR-positive HER2 low expression and HER2(0) expression breast cancers. Consistent with the trends observed in the overall population, both subcohorts demonstrated that patients with the IHC score >4 experienced significantly better OS (P<0.001) and DFS (P=0.003) compared to those with the IHC score ≤4. This indicates that patients with a lower IHC score may have a worse response to ET. Further research is needed to investigate whether adjustments in the duration or intensity of ET could potentially benefit patients with lower IHC scores. Moreover, further stratified analysis within the subcohorts with the IHC score >4, which is characterized by relatively favorable outcomes to ET, revealed that the prognosis for patients with HER2 low expression was superior to those with HER2(0) expression. This distinction underscores the potential impact of HER2 low expression on the efficacy of ET, and highlights the necessity for individualized clinical endocrine treatment strategies. In addition to ET, current studies suggest that HR-positive/HER2-low breast cancer patients may benefit from combination treatments with CDK4/6 or PIK3 inhibitors (19-21). For patients with germline BRCA mutations, PARP inhibitors are also a viable option (22). However, these treatments rely on ET sensitivity, and therapeutic options become very limited once resistance develops. To date, only the HER2-targeted ADC T-DXd and the TROP2-targeted ADC sacituzumab govitecan have shown some efficacy in ET-resistant cases (23). For this patient population, ongoing efforts are essential not only to develop new treatment options but also to explore strategies for overcoming ET resistance.

In addition to the recognized prognostic markers of molecular subtypes and lymph node metastasis status in breast cancer, numerous studies have documented the relationship between lymph node metastasis and breast cancer subtypes (24-26). However, reports on the association between lymph node metastasis and HER2 low expression are limited. Our research has contributed to this area by demonstrating that the prognosis of patients worsens with advancing pN staging in HER2 low expression and HER2(0) expression breast cancer. Specifically, we stratified patients according to pN staging and observed significant differences in survival outcomes between these subcohorts at lower pN stages (pN0–pN2). Notably, these differences disappear at the highest pN stage (pN3). These results demonstrate the significant impact of advanced nodal disease on prognosis, showing that patients with pN3 disease have worse survival outcomes regardless of HER2 status. Our study provides further insight into HR-positive breast cancer with low HER2 expression.

In conclusion, our study provides evidence that HR+ breast cancer patients with HER2 low expression exhibit distinct clinical characteristics and a more favorable prognosis compared to those with HER2(0) expression, particularly in terms of ET sensitivity. However, this study is limited by its single-center, retrospective design, which may impact the generalizability and robustness of the findings. Furthermore, the lack of molecular insights into HER2 low expression restricts a deeper understanding of the underlying mechanisms that differentiate HER2 low from HER2(0) subtypes. Prospective, multi-center studies are warranted to validate these findings, along with biomarker research to better predict ET responses in these patients. Additionally, as HER2 low expression continues to gain recognition as a potential therapeutic target, further exploration of its implications for personalized treatment and the efficacy of advanced ADCs in this subgroup will be critical to enhancing outcomes for HR+ breast cancer patients.

Conclusions

Among HR-positive HER2-negative breast cancer patients, a significant proportion have low HER2 expression as evidenced by weak IHC or FISH signal. These low HER2 patients have distinct clinical characteristics compared to those with HER2(0) expression. Furthermore, patients with HER2 low expression have a better prognosis than those with HER2(0) expression. Among people with ER IHC Score scores greater than 4 points, the prognosis of HER2 expresses the population is different from HER2(0) the prognosis of the crowd. It is reminded that the formulation of ET strategies of these people requires more individualization.

Acknowledgments

Funding: This work was supported by the Key Projects of the Department of Education of Anhui Province (No. 2023AH051980, No. 2022AH051479); Clinical Research Special Fund of WU JIEPING Medical Foundation (No. 320.6750.2022-19-79); and Open Project of Anhui Province Key Laboratory of Cancer Translational Medicine (No. KFDX202203).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1013/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1013/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1013/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1013/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of The First Affiliated Hospital of Bengbu Medical University, Anhui, China (approval No. 2023YJS223) and written informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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