Defining HER2-Low and -Ultralow Expression: Practical Challenges and Solutions

Patient Selection and Sequencing Strategies for HER2-Low/Ultralow Disease

Treatment selection for patients with hormone receptor–positive, HER2-low/ultralow disease requires careful assessment of endocrine sensitivity and disease characteristics before considering antibody-drug conjugate (ADC) therapy. The general approach prioritizes exhausting endocrine-based treatments in patients with continued hormone responsiveness, transitioning to ADCs when endocrine resistance becomes apparent. Biomarker enrichment data consistently demonstrate improved outcomes with higher HER2 expression levels, supporting the biological rationale for HER2-targeted therapy.

Subgroup analyses from DESTINY-Breast06 reveal robust benefit across HER2 expression levels, with the ultralow disease population (approximately 150 patients) showing similar progression-free survival improvements as the intention-to-treat population. Clinical decision-making incorporates disease characteristics that include presence of visceral crisis, symptom burden, and need for rapid disease control. Alternative oral therapies such as capecitabine remain important options, offering convenience, avoiding alopecia, and eliminating concerns about interstitial lung disease or cardiotoxicity monitoring.

The selective use of first-line ADC therapy focuses on scenarios requiring immediate disease control rather than universal application. Quality-of-life considerations favor delaying ADC therapy when possible, reserving these agents for appropriate clinical contexts. Ongoing overall survival data from key trials will ultimately inform whether early ADC use provides survival advantages or whether delayed implementation achieves similar outcomes while preserving quality of life during intervening treatments.