The impact of HER2 low positivity in hormone receptor-positive, HER2-negative breast cancer treated with neoadjuvant chemotherapy

Sep 22, 2026

Study aims to determine whether neoadjuvant chemotherapy efficacy differs between HER2-low and HER2-zero subgroups in hormone receptor-positive, HER2-negative breast cancer. A retrospective cohort of 61 patients receiving neoadjuvant chemotherapy from 2015–2025 was analyzed using pre-treatment core biopsy HER2 classification (HER2-low: IHC 1+ or 2+ with FISH-negative; HER2-zero: IHC 0). Pathological complete response rates were compared, showing lower pCR with HER2-low and supporting further evaluation of HER2-directed antibody–drug conjugate strategies.

LanguageEnglish

CategoryHealthcare

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Pages7

Reading Time18 min

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Abstract

Aims and background

Materials and Methods

Results

Conclusions

Introduction

Role of neoadjuvant chemotherapy

HER2 classification and HER2-low concept

Motivation for further research

Methods

Study participants

The impact of HER2 low positivityin hormone receptor-positive, HER2-negative breast cancer treated with neoadjuvant chemotherapy Mustafa Ersoy Cancer Biomarkers Vol. 43: 1–7 © The Author(s) 2026 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/18758592261427515](DOI: 10.1177/18758592261427515)[ ](DOI: 10.1177/18758592261427515)[journals.sagepub.com/home/cbm](journals.sagepub.com/home/cbm) Abstract Aims: This study aimed to investigate whether the efﬁcacy of neoadjuvant chemotherapy differs between HER2-low and HER2-zero subgroups in hormone receptor–positive, HER2-negative breast cancer. Materials and Methods: A total of 61 patients who received neoadjuvant chemotherapy between 2015 and 2025 were retrospectively analyzed. HER2 status was determined from pre-treatment core biopsy specimens and classiﬁed as HER2-low (IHC 1 + or 2 +and FISH-negative) or HER2-zero (IHC 0). The pathological complete response (pCR) rates were compared between the two groups. Results: Among 61 patients, 28 had HER2-low and 33 had HER2-zero tumors. The pCR rate was 7.1% in the HER2-low group and 27.3% in the HER2-zero group (p = 0.042). A post-hoc power analysis based on these results showed a moderate power (0.59) to detect the observed difference. Conclusions: HER2-low expression may negatively inﬂuence chemosensitivity in hormone receptor–positive breast cancer treated with neoadjuvant chemotherapy. Further studies are warranted to evaluate the potential role of trastuzumab deruxtecan (T-DXd) and other antibody–drug conjugates in this newly deﬁned subgroup. Keywords Breast cancer, drug effects, clinical trials Received: 30 June 2025; accepted: 7 February 2026 Introduction The use of neoadjuvant chemotherapy (NACT) in nonmetastatic, invasive breast cancer aims to reduce the risk of distant recurrence by eradicating micrometastatic disease at an early stage.1 This approach is also employed to downstage the extent of disease in the breast and/or regional lymph nodes, thereby providing valuable information to guide subsequent adjuvant therapies.2 Downstaging can facilitate less extensive surgical interventions, including breast-conserving procedures, thereby enhancing cosmetic outcomes and reducing postoperative complications.3 Furthermore, the extent of residual invasive disease, referred to as pathological complete response (pCR), after NACT serves as a strong prognostic factor for recurrence risk and overall survival.4 Breast cancers have traditionally been categorized as either HER2-positive or HER2-negative based on immunohistochemistry (IHC) and ﬂuorescence in situ hybridization (FISH) testing. Speciﬁcally, tumors with IHC 0 or 1 + are considered HER2-negative, and IHC 2+cases with negative FISH results are also classiﬁed as HER2-negative, whereas IHC 3+or FISH-positive tumors are deﬁned as HER2-positive. However, a distinct entity known as HER2-low breast cancer, characterized by low HER2 expression (IHC 1+or 2 +with negative FISH), has recently emerge.5 Approximately 15% of breast cancer cases are classiﬁed as HER2-positive, while 55% to 60% of all breast cancers are characterized as HER2-low.6 Among HER2-low tumors, about 80% exhibit a luminal-like molecular proﬁle and 15– 20% are triple-negative.7 This subgroup has challenged the Kütahya Health Sciences University, Faculty of Medicine, Department of Internal Medicine, Kutahya, Turkey Corresponding author: Mustafa Ersoy, Kütahya University of Health Sciences, Alipaşa District, Fatih Sultan Mehmet Boulevard No:22 Center, Kütahya, 43020. [Email: mustafa.ersoy@ksbu.edu.tr](Email: mustafa.ersoy@ksbu.edu.tr) Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution NonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permit

FAQs

What was the primary goal of this study?

To assess whether neoadjuvant chemotherapy efficacy differs between HER2-low and HER2-zero subgroups in hormone receptor-positive, HER2-negative breast cancer.

How were tumors classified as HER2-low or HER2-zero?

HER2-low was defined as IHC 1+ or 2+ with FISH-negative, while HER2-zero was defined as IHC 0, based on pre-treatment core biopsy specimens.

What did the study find about pathological complete response (pCR) rates?

pCR was 7.1% in the HER2-low group versus 27.3% in the HER2-zero group, with p = 0.042, indicating a lower chemosensitivity signal for HER2-low.

Sep 22, 2026

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