Comparison of Stromal Tumor-Infiltrating Lymphocyte (sTIL) Levels and Clinicopathological Features in Neoadjuvant-Naive HER2-Low and HER2-Negative Primary Breast Cancers

Sep 22, 2026

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Clinical success of novel antibody–drug conjugates has enabled recognition of a breast cancer subgroup within traditionally HER2-negative disease, termed HER2-low. This neoadjuvant-naive study compared clinicopathological differences between HER2-low and HER2-negative primary tumors, focusing on stromal tumor-infiltrating lymphocyte (sTIL) density. Among 731 patients, HER2-low showed higher histological grade and sTIL density, with stepwise increases across HER2 IHC scores. HER2-low/HR-negative displayed the highest sTIL levels, while overall and disease-free survival remained comparable. Findings support an immunogenic tumor microenvironment that may reconcile grade differences and rationalize combining ADCs with immune checkpoint inhibition.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Background and Objective

Materials and Methods

Results

Conclusions

Introduction

HER2 classification and clinical relevance

Emergence of the HER2-low category

Prior evidence and remaining uncertainties

Role of stromal tumor-infiltrating lymphocytes (sTILs)

Article Comparison of Stromal Tumor-Infiltrating Lymphocyte (sTIL) Levels and Clinicopathological Features in Neoadjuvant-Naive HER2-Low and HER2-Negative Primary Breast Cancers Mümin Emiro ˘glu 1, *, Esra Canan Kelten Talu 2, Cem Karaali 3, Olçun Ümit Ünal 4 and Mihriban Erdo ˘gan 5 Academic Editor: Dinesh K. Thekkinkattil Received: 24 March 2026 Revised: 15 April 2026 Accepted: 23 April 2026 Published: 27 April 2026 Copyright: © 2026 by the authors. Published by MDPI on behalf of the Lithuanian University of Health Sciences. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Pathology, Elazı ˘g Fethi Sekin City Hospital, Elazı ˘g 23100, Turkey 2 Department of Pathology, UHS Izmir Faculty of Medicine, Izmir Tepecik Education and Research Hospital, Izmir 35020, Turkey; [ecanankelten@gmail.com](ecanankelten@gmail.com) 3 Department of General Surgery, UHS Izmir Faculty of Medicine, Izmir Tepecik Education and Research Hospital, Izmir 35020, Turkey; [cemkaraali@gmail.com](cemkaraali@gmail.com) 4 Department of Medical Oncology, UHS Faculty of Medicine, Izmir City Hospital, Izmir 35540, Turkey; [drolcun@hotmail.com](drolcun@hotmail.com) 5 Department of Radiation Oncology, UHS Faculty of Medicine, Izmir City Hospital, Izmir 35540, Turkey; [mihribankocak@hotmail.com](mihribankocak@hotmail.com) * [Correspondence: muminemiroglu93@gmail.com](Correspondence: muminemiroglu93@gmail.com); Tel.: +90-537-383-26-15 Abstract Background and Objective: The clinical success of novel antibody-drug conjugates has led to the identification of a new subgroup within traditionally HER2-negative breast cancers, termed ‘HER2-low.’ The aim of this study was to investigate the clinicopathological differences between HER2-low and HER2-negative groups in neoadjuvant-naive primary breast cancer patients, with a specific focus on stromal tumor-infiltrating lymphocyte (sTIL) density. Materials and Methods: The study included 731 neoadjuvant-naive invasive breast cancer patients. Tumors were classified as HER2-negative (IHC 0) and HER2-low (IHC 1+ or 2+/ISH-negative) . sTIL levels were evaluated following the International TILs Working Group guidelines. Results: The HER2-low group (38.7%) demonstrated significantly higher histological grade (p = 0.033) and higher sTIL density (p = 0.006) compared to the HER2-negative group. A stepwise increase in sTIL rates was observed parallel to the HER2 immunohistochemical score (0 → 1+ → 2+) (p = 0.015) . The HER2-low/hormone receptor (HR)-negative subgroup exhibited the highest sTIL density (median 35%) . No statistically significant difference in overall or disease-free survival was found between the groups. Conclusions: HER2-low breast cancers were associated with a more immunogenic tumor microenvironment compared to HER2-negative tumors. This robust immune infiltration may offset the higher histological grade observed in the HER2-low cohort, potentially explaining the comparable survival outcomes. These findings provide a biological rationale for exploring the synergy between novel antibody–drug conjugates and immune checkpoint inhibitors, particularly in the highly immunogenic HER2-low/HR-negative subgroup. Keywords: breast cancer; HER2-low; stromal tumor-infiltrating lymphocytes; prognosis; tumor microenvironment; antibody-drug conjugates 1. Introduction Breast cancer is a highly heterogeneous group of diseases in terms of biological behavior and treatment responses, and it is traditionally classified based on hormone receptor (HR) and Human Epidermal Growth Factor Receptor 2 (HER2) status [1] . In clinical practice, HER2 status is determined according to guidelines from the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP); tumors with an immunohistochemistry (IHC) score of 3+ or showing gene amplificatio

FAQs

How were HER2-low and HER2-negative tumors defined in this study?

HER2-negative tumors were classified as IHC 0. HER2-low included IHC 1+ or 2+/ISH-negative, following standard definitions.

What were the main differences in sTIL density between HER2-low and HER2-negative groups?

The HER2-low group showed significantly higher sTIL density than the HER2-negative group, and sTIL rates increased stepwise with higher HER2 IHC scores.

Did HER2-low status translate into different overall or disease-free survival?

No statistically significant differences in overall survival or disease-free survival were found between the groups.

Sep 22, 2026

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