Advancing Patient Care with Antibody-Drug Conjugate Therapies in HER2-Negative and HER2-Low Metastatic Breast Cancer

A panelist discusses how differences in HER2-positive, HER2-low, and HER2-negative status impact clinical decision-making.

Panelists discuss how the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for HER2-negative breast cancer (BC) have evolved to recognize HER2-low (IHC 1+  or 2+/ISH-negative) and HER2-ultra low (IHC 0) as distinct categories. These classifications, particularly HER2-low, guide eligibility for targeted therapies such as trastuzumab deruxtecan, expanding treatment options beyond traditional chemotherapy for previously categorized HER2-negative patients.

Panelists discuss how antibody-drug conjugates (ADCs) combine monoclonal antibodies with cytotoxic payloads, enabling precise targeting of breast cancer (BC) cells through specific antigen recognition. Upon binding, the ADC-antigen complex is internalized, releasing the toxic payload inside cancer cells while largely sparing healthy tissue. This targeted approach offers improved efficacy and reduces systemic toxicity compared with traditional chemotherapy's broad cytotoxic effects.

Panelists discuss how antibody-drug conjugates (ADCs) show varying efficacy and adverse event (AE) profiles based on their payload potency, linker stability, and drug-to-antibody ratio. Cleavable linkers enable targeted drug release but may increase toxicity, while noncleavable designs offer better stability. Payload selection impacts both therapeutic index and AEs, with more potent warheads requiring careful optimization of targeting and release kinetics.

Panelists discuss how HER2 testing optimization requires multisite sampling and quantitative assessment methods to account for intratumoral heterogeneity. Beyond HER2, biomarkers such as PI3K mutations, hormone receptor status, and tumor mutational burden can guide therapy selection for metastatic breast cancer (mBC), enabling more personalized treatment approaches.