The efficacy of trastuzumab-deruxtecan for the treatment of patients with advanced HER2-low breast cancer

ABSTRACT

Introduction

Until recently, the available human receptor epidermal growth factor 2 (HER2) targeted agents were ineffective for treating patients with HER2-low expressing breast cancer (defined as immunohistochemical expression of 1+ or 2+ without amplification). The development of novel and potent HER2-directed antibody-drug conjugates, affective at treating HER2-low expressing breast cancers, have changed the way we think about HER2-low expression and expanded the treatment options for many patients with advanced disease.

Areas covered

In this review, we summarize the current management of HER2-low breast cancer and commonly encountered challenges such as treatment sequencing and toxicity management.

Expert opinion

trastuzumab deruxtecan (T-DXd) is a treatment option for patients with advanced, HER2-low breast cancer, irrespective of the hormone receptor status. The current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer; however, other agents are available in this setting and risks and benefits for each should be considered in shared decision making. Up to 10–15% of patients receiving T-DXd develop interstitial lung disease. Patient and clinician education are key to safely implement T-DXd in clinical practice.

KEYWORDS:

• Breast cancer
• HER2-low
• trastuzumab-deruxtecan
• HER2

Article highlights

• Approximately half of patients with HER2-negative advanced breast cancer have tumors exhibiting low levels of HER2 expression. HER2-low is defined as a HER2 immunohistochemical expression of 1+ or 2+ without amplification by in-situ hybridization.

• HER2-low tumors do not appear to harbor unique biological or prognostic features compared to HER2-0 tumors. Therefore, HER2-low is not a distinct breast cancer subtype, but rather a target for potent, novel HER2-directed antibody-drug conjugates.

• Until recently, HER2-targeted agents were ineffective in treating patients with HER2-low disease. However, based on the findings from DESTINY-Breast 04, trastuzumab-deruxtecan recently gained FDA approval for the treatment of pretreated, advanced HER2-low breast cancer, irrespective of hormone receptor status.

• Prior to the initiation of trastuzumab-deruxtecan, patient education is required in terms of potential toxicities, including nausea and vomiting, interstitial lung disease and cardiac toxicity.

Declaration of interest

P Tarantino has received consulting fees from AstraZeneca, Daiichi Sankyo, and Lilly.

SM Tolaney has served in a consulting or advisory role for: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics; Institutional Research Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, and Seattle Genetics.

The authors have no other relevant affiliations or financial involvement with any organiza tion or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14737140.2023.2171993

Additional information

Funding

The authors have no funding to report.