Trastuzumab Deruxtecan for HER2-Low Metastatic Breast Cancer - Practical Considerations for Medical Oncologists and Pathologists in Australia

Sep 22, 2026

Trastuzumab deruxtecan (T-DXd) is a third-generation HER2-targeting antibody-drug conjugate shown to extend overall survival versus standard chemotherapy in unresectable or metastatic HER2-low breast cancer. Eligibility includes patients previously treated in the metastatic setting or who developed recurrence during or within 6 months after adjuvant chemotherapy. The review highlights practical challenges in identifying HER2-low disease and offers guidance on managing key T-DXd toxicities including interstitial lung disease/pneumonitis, left ventricular dysfunction, and emesis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

HER2 classification in breast cancer

Practical identification of HER2-low disease

Clinical implications and management considerations

Asia-Pacific Journal of Clinical Oncology REVIEW Trastuzumab Deruxtecan for HER2-Low Metastatic Breast Cancer: Practical Considerations for Medical Oncologistsand Pathologists in Australia Andrew Redfern1, 2, 3 Elgene Lim4, 5 Sunil Lakhani6, 7 Nirmala Pathmanathan8, 9, 10 Sudarsha Selva-Nayagam11 Nicole McCarthy12, 13 Belinda Yeo14, 15 Benjamin Dessauvagie16, 17 Gelareh Farshid18, 19 1 Fiona Stanley Hospital, Murdoch, Western Australia, Australia 2University of Western Australia, Crawley, Western Australia, Australia 3 Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia 4 St Vincent’s Hospital, Sydney, New South Wales, Australia 5 Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia 6University of Queensland Centre For Clinical Research, Brisbane, Queensland, Australia 7 Pathology Queensland, Brisbane, Queensland, Australia 8Westmead Breast Cancer Institute, Westmead Hospital, Sydney, New South Wales, Australia 9 Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia 10 Douglass Hanly Moir Pathology, Macquarie Park, Sydney, New South Wales, Australia 11 Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia 12 ICON Cancer Centre Wesley, Auchenflower, Brisbane, Queensland, Australia 13University of Queensland, Brisbane, Queensland, Australia 14Austin Health, Melbourne, Victoria, Australia 15 Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia 16 Clinipath Pathology, Osborne Park, Perth, Western Australia, Australia 17UWA Medical School, University of Western Australia, Crawley, Perth, Western Australia, Australia 18 Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia 19 Directorate of Anatomical Pathology, SA Pathology, Royal Adelaide Hospital, Adelaide, South Australia, Australia Correspondence: Andrew Redfern ([Andrew.Redfern@health.wa.gov.au](Andrew.Redfern@health.wa.gov.au)) Accepted: 13 November 2025 Keywords: HER2-low | immunohistochemistry | metastatic breast cancer | T-DXd | trastuzumab deruxtecan ABSTRACT Trastuzumab deruxtecan (T-DXd) is a third-generation, HER2-targeting antibody-drug conjugate that has been shown to significantly prolong overall survival, compared with standard chemotherapy, when used to treat patients who have “HER2-low”(HER2 immunohistochemistry [IHC] score 1+; or HER2 IHC 2+ plus in situ hybridization-negative) unresectable or metastatic breast cancer and who have received prior chemotherapy in the metastatic setting or developed disease recurrence during, or within 6 months of completing, adjuvant chemotherapy. The broad aims of this paper are: (a) To draw attention to some of the challenges associated with identifying whether patients have HER2-low metastatic breast cancer (mBC), in an environment where healthcare professionals have previously only needed to determine whether mBC is HER2-positive and therefore likely to respond to traditional HER2-targeted therapies; and (b) to indicate, where possible, what might be done to help overcome specific challenges in this regard. Advice regarding the management of specific T-DXd-related side effects of interest, including interstitial lung disease and pneumonitis, left ventricular dysfunction and emesis, is also offered. 1 Introduction For more than two decades, human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) scoring and/orthe presence of HER2 (ERBB2) gene amplification have been employed to routinely classify breast cancers as either HER2-positive (HER2+; i.e. HER2 IHC 3+ or 2+/in situ hybridization [ISH]-positive) or HER2-negative (HER2−; i.e. HER2 IHC 0, 1+ or 2+/ISH-negative [ISH−]) [1–6] . This has been necessary to identify patients who have classically HER2+ disease, which is This is an open access article under the terms of the Creative Commons Attribution-

FAQs

What is HER2-low in metastatic breast cancer for the T-DXd indication?

HER2-low refers to HER2 IHC 1+ or HER2 IHC 2+/ISH-negative. The review specifies these criteria in the context of unresectable or metastatic disease.

Which patients are described as eligible for T-DXd in this review?

Patients with HER2-low unresectable or metastatic breast cancer are included when they have received prior chemotherapy in the metastatic setting or develop recurrence during, or within 6 months of completing, adjuvant chemotherapy.

What clinical challenges does the paper discuss regarding identifying HER2-low?

It addresses difficulties arising because clinicians historically only distinguished HER2-positive versus HER2-negative disease, making HER2-low identification more complex in practice.

What T-DXd-related side effects are covered with management advice?

The review provides guidance on managing interstitial lung disease and pneumonitis, left ventricular dysfunction, and emesis.

Sep 22, 2026

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