HER2-Low Breast Cancer: a New Subtype?

Area of Science:

• Oncology, Breast Cancer Research, Targeted Therapy

Background:

• Traditional breast cancer (BC) classification includes HR-positive HER2-negative, HER2-positive, and triple-negative BC (TNBC).
• HER2-targeted therapies historically required HER2 overexpression (IHC 3+) or amplification for efficacy.
• Emerging data redefines HER2-low BC, encompassing tumors with some HER2 expression, previously considered HER2-negative.

Purpose of the Study:

• To evaluate the clinical significance of the HER2-low BC subtype in light of new antibody-drug conjugate (ADC) therapies.
• To discuss the implications of trastuzumab deruxtecan (T-DXd) efficacy in HER2-low breast cancer populations.
• To provide guidance on treatment selection for HER2-low BC, including HR-positive and HR-negative subtypes.

Main Methods:

• Analysis of clinical trial data, specifically the DESTINY-Breast04 trial for T-DXd in HER2-low BC.
• Review of existing approvals and evidence for ADCs like sacituzumab govitecan in TNBC.
• Comparative assessment of treatment outcomes and cross-resistance potential between different ADCs.

Main Results:

• Trastuzumab deruxtecan (T-DXd) demonstrated clinical benefit in HER2-low breast cancer patients, including a subset of HR-negative/HER2-low (TNBC) and HR-positive/HER2-low tumors.
• The DESTINY-Breast04 trial showed efficacy of T-DXd in previously treated HER2-low metastatic breast cancer.
• Sacituzumab govitecan is approved for pretreated TNBC, highlighting the growing role of ADCs in this setting.

Conclusions:

• The HER2-low classification is critical for identifying patients who may benefit from novel ADC therapies.
• T-DXd shows promise for HR-negative HER2-low (TNBC) and HR-positive HER2-low breast cancer, warranting its use based on available evidence and approvals.
• Treatment decisions for HER2-low BC require careful consideration of ADC efficacy, regulatory approvals, and potential cross-resistance.