Exploring the clinicopathological parameters of HER2 low breast cancers: insights from a retrospective cohort study

Article information

Korean Journal of Clinical Oncology. 2024;20(2):79-83

Publication date (electronic) : 2024 December 31

doi : https://doi.org/10.14216/kjco.24011

Sana Ahuja, Adil Aziz Khan, Kiruthikasri G, Sufian Zaheer

Department of Pathology, Safdarjung Hospital, Vardhman Mahavir Medical College, New Delhi, India

Correspondence to: Sufian Zaheer, Department of Pathology, Safdarjung Hospital, Vardhman Mahavir Medical College, Ansari Nagar, New Delhi 110029, India, Tel: +91-9650594818, Fax: +91-9958188632, E-mail: sufianzaheer@gmail.com

Received 2024 June 23; Revised 2024 September 23; Accepted 2024 September 24.

Abstract

INTRODUCTION

In the intricate landscape of breast cancer subtypes, the role of human epidermal growth factor receptor 2 (HER2) has long been a focal point. Traditionally, tumors either exhibit overexpression or amplification of HER2, defining them as HER2-positive, or they lack such aberrations, categorizing them as HER2-negative. Assessing HER2 expression in both early and advanced breast cancer cases holds significant clinical importance, as HER2-targeted therapies have substantially improved the prognosis of patients diagnosed with HER2-positive disease. The evaluation of HER2 expression typically involves immunohistochemistry (IHC) and in-situ hybridization (ISH) techniques. According to prevailing guidelines, tumors are considered HER2-positive if they exhibit IHC 3+ for HER2 or IHC 2+ with a HER2/CEP17 (chromosome enumeration probe 17) ratio ≥2 and/or a HER2 copy number ≥6 signals/cell by ISH. However, despite these stringent criteria capturing approximately 15% of tumors, a considerable proportion of tumors traditionally classified as “HER2-negative” manifest low levels of HER2 expression, even in the absence of gene amplification. This subgroup of tumors, now identified as HER2-low breast cancer, is characterized by IHC 1–2+ staining without amplification on ISH. Notably, this sizable cohort of patients presents an intriguing opportunity for exploration and intervention with HER2-targeted therapies [1,2].

However, within this dichotomy lies a subgroup with a less defined identity: HER2 low breast tumors. These tumors exhibit low levels of HER2 expression, distinguishing them from both HER2-positive and HER2-negative counterparts. Nonetheless, two antibody-drug conjugates (ADCs) targeting HER2, namely trastuzumab deruxtecan (T-DXd) and trastuzumab duocarmazine (SYD985), have demonstrated highly encouraging therapeutic efficacy in individuals diagnosed with HER2-low breast cancer [3]. Yet, their clinicopathological features and therapeutic implications remain less understood compared to their more characterized counterparts. The present study aims to evaluate the clinicopathological parameters of the HER2 low breast cancers.

METHODS

Patients

This was a retrospective cohort study which included all histologically proven cases of breast cancer in the 2 years from January 2022 to December 2023 at a tertiary care center. It was conducted after informed patient consent and ethical approval from the Institutional Ethics Committee (IEC/VMMC/SJH/Thesis/06/2022/CC-229).

This study was performed in line with STROCSS criteria [4]. The following clinicopathological data was retrieved from the histopathological records–age, tumor size, nodal involvement, lymphovascular/perineural invasion, and Bloom Richardson grading.

Routine histopathological processing was done followed by immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER2, Ki-67, and androgen receptor (AR). All the cases were categorized into luminal A, B, HER2 enriched, and triple-negative breast cancer based on the surrogate molecular classification. Further, all the cases were categorized into HER2 negative (no staining or incomplete weak membrane staining in ≤10% tumor cells), HER2 3+ (complete membranous staining), and HER2 low (1–2+ staining without amplification on ISH) based on consensus of two pathology consultants (SA and SZ) (Fig. 1).

Fig. 1

Flowchart depicting the distribution of cases. HER2, human epidermal growth factor receptor 2.

RESULTS

There were a total of 70 cases of breast cancer which ranged from 26 years to 75 years with a mean age of 45.6 years. All cases were female patients. Based on tumor size, there were 16 (22.8%), 14 (20%), 22 (31.4%), and 18 (25.7%) cases belonging to T1, T2, T3, and T4, respectively. Twenty-five cases (35.7%) exhibited no nodal involvement, while there were 13 (18.6%), 17 (24.3%), and 15 (21.4%) cases of N1, N2, and N3, respectively. There were 14 (20%) cases of grade 1, 36 (51.4%) cases of grade 2, and 20 (28.6%) cases of grade 3 breast carcinoma. Histologically, all cases were of invasive ductal carcinoma. There was no case of invasive lobular carcinoma. According to the surrogate molecular classification, there were 32 (45.7%) cases of luminal A/B, 24 (34.3%) cases of triple negative, and 14 (20%) cases of HER2 enriched breast cancer. The higher percentage on triple-negative breast cancer could be explained by ethnic differences and the percentage of triple-negative breast cancer being higher in the Indian population.

On re-evaluation of HER2 IHC, there were 28 (40%) cases of HER2 low and 24 (34.3%) cases of HER2-negative breast cancer.

The HER2 low tumors showed a significant association with higher tumor stage, nodal involvement, lymphovascular invasion, positive androgen expression and luminal type of surrogate classification. No association was seen with grade, age, perineural invasion and Ki-67 index (Table 1).

Table 1

Association of clinicopathological parameters with HER2 expression

The HER2 low breast cancers were further categorized as HER2 low hormone receptor-positive (n=22, 78.6%) and HER2 low triple-negative (n=6, 21.4%). The HER2 low hormone receptor-positive cases exhibited a significant association with higher tumor stage, nodal involvement, lower grade and positive androgen expression (Table 2).

Table 2

Association of clinicopathological parameters with HER2 low hormone receptor-positive and HER2 low triple-negative

DISCUSSION

The intricate landscape of breast cancer subtypes is further complicated by the emergence of HER2 low breast cancers, a subgroup that challenges traditional classifications and treatment paradigms. Our retrospective study delves into the clinicopathological parameters of HER2 low breast cancers, offering valuable insights into their distinct characteristics and implications for clinical management.

One of the notable findings of our study is the significant heterogeneity observed within HER2 low breast cancers. While traditionally grouped under the umbrella of HER2 low expression, these tumors exhibited diverse clinicopathological features that defy simplistic categorization. Our analysis revealed distinct associations between HER2 low breast cancers and clinicopathological parameters such as tumor stage, nodal involvement, histological grade, and molecular subtype. Notably, HER2 low hormone receptor-positive cases demonstrated unique characteristics compared to HER2 low triple-negative cases, highlighting the complex interplay between HER2 expression and hormonal status in breast cancer biology.

Beyond clinicopathological differences, the biology of HER2-low breast cancer represents a distinctive molecular entity. Unlike HER2-positive cancers, which are driven by the overexpression or amplification of the HER2 gene, HER2-low tumors have low but detectable HER2 expression without amplification. This suggests that HER2-low cancers may not be primarily driven by HER2-related signaling pathways, but rather, they possess a unique molecular profile. Research has shown that HER2-low breast cancers often exhibit gene expression patterns resembling HER2-negative tumors, particularly in the hormone receptor-positive subtype. The limited HER2 expression in these tumors may activate alternative pathways, such as the PI3K/AKT pathway or other compensatory growth signals, contributing to their progression and therapeutic resistance. Furthermore, the interplay between HER2 and ER signaling could play a role in the biology of HER2-low, hormone receptor-positive tumors, creating opportunities for combination therapies targeting both pathways.

Previously very few studies have been done which illustrate the clinicopathological features of HER2 low breast cancers. Schettini et al. [5] demonstrated a significant association of HER2 low cancers with more frequent hormonal receptor positivity in comparison to triple-negative cases. Besides, they also observed an association between HER2 low cases and larger T stage, greater nodal involvement and older mean age at diagnosis. No association could be exhibited with grade and Ki-67 index. Yang et al. [6] observed a significant association with greater ER, PR, AR expression, lower histological grade and no association with age, lymphovascular invasion and TNM staging. Baez-Navarro et al. [7] demonstrated a significant association between HER2 tumors with older patients, lower histological grade, higher ER, PR expression and a lower Ki-67 index. Shao et al. [8] demonstrated a significant association with nodal involvement, hormone receptor positivity and Ki-67 proliferation index. In the study by Li et al. on the Chinese population [9], HER2 low cancers were positively associated with ER, AR expression and negatively with Ki-67 index. Further the HER2 low luminal cancers were associated with younger age, larger tumors while HER2 low triple-negative cancers were associated with older age, smaller tumors and nodal involvement. Van den Ende et al. [10] evaluated HER2 status with various clinicopathologic characteristics and survival outcomes, stratified by ER status. Among the ER+ subgroup, no significant correlations were observed between the HER2 groups and clinicopathologic features. In ER– cases (n=224), HER2 low status was significantly linked to higher nodal positivity and decreased protein expression of Ki-67 and EGFR compared to HER2 negative cases. Won et al. in their study on the Korean population [11] observed a significant association of HER2-low breast cancer with hormone receptor-positive breast cancer than with triple-negative breast cancer. Among patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. Among cases with triple-negative breast cancer, HER2-low breast cancer was associated with a positive lymphatic invasion. Further, HER2-low breast cancer was significantly associated with a lower Ki-67 labelling index [11].

The present study observed a significant association of HER2 low tumors with higher tumor stage, nodal involvement, positive androgen expression and luminal type of surrogate classification similar to Schettini et al. [5]. The HER2 low hormone receptor-positive cases exhibited a significant association with higher tumor stage similar to the findings of Li et al. [9].

The clinical implications of our findings extend beyond mere classification, offering valuable insights for tailored therapeutic strategies. HER2 low breast cancers, despite their lower expression levels, exhibited aggressive features such as higher tumor stage and nodal involvement, suggesting the need for vigilant clinical monitoring and aggressive treatment approaches. However, owing to the small sample size, this needs to be further validated in larger studies. The association of HER2 low breast cancers with positive AR expression underscores the potential for hormone receptor-targeted therapies in this subgroup, presenting new avenues for personalized treatment strategies.

Despite advancements in HER2-targeted therapies, HER2 low breast cancers pose unique challenges due to their less-defined identity and limited therapeutic options. While ADCs targeting HER2 have shown promising efficacy in HER2 low breast cancer, further research is needed to elucidate their optimal use and identify predictive biomarkers for treatment response. Additionally, the molecular mechanisms underlying HER2 low breast cancer remain incompletely understood, highlighting the need for continued research efforts to unravel the complexities of this subtype and identify novel therapeutic targets.

The limitations of this study include being a single-center retrospective study with a small sample size and lack of survival analysis.

In conclusion, the present study contributes to the evolving understanding of HER2 low breast cancers, shedding light on their heterogeneity and clinical implications. By unravelling the complexities of HER2 low breast cancers, we pave the way for personalized treatment approaches tailored to the unique characteristics of this subtype. Continued research efforts are essential to optimize clinical management and improve outcomes for patients with HER2 low breast cancer.

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