73 The ADC Era in Breast Cancer: Contemporary Sequencing Strategies and Evidence-Based Toxicity Management

Background

By facilitating targeted cytotoxic delivery across various disease subtypes, antibody-drug conjugates (ADCs) have completely changed the landscape of breast cancer treatment. Growing indications for triple-negative, hormone receptor (HR)–positive, HER2-positive, and HER2-low breast cancers have opened new therapeutic options and necessitated the development of useful guidelines for toxicity management and sequencing techniques. Despite multiple ADC approvals, there is a lack of head-to-head sequencing trials and formal guidelines for navigating the new landscape.

Materials and Methods

Using peer-reviewed literature, important phase 2/3 studies, empirical data, the most recent regulatory revisions, and the most recent NCCN/ESMO guidelines released between 2020 and 2025, we conducted an organized narrative evaluation. In order to define current sequencing concepts, integrate clinical decision-making across subtypes of breast cancer, and incorporate guideline-based techniques for treating major toxicities associated with ADCs, evidence was collected.

Results

Across breast cancer subtypes, sequencing of ADCs incorporates disease biology, prior treatments, and clinical guidelines. Endocrine therapy with CDK4/6 inhibition is still the usual first-line treatment for HR-positive illness; ADCs are taken into consideration after the disease progresses. Clinical trials show that ADCs significantly improve survival over chemotherapy in HER2-low illness, which supports their early integration in postendocrine or postchemotherapy settings. After prior chemotherapy exposure, ADCs significantly improve triple-negative breast cancer. Sequencing choices are increasingly focused on biomarker profiles, such as HR status and HER2-low expression, even if head-to-head sequencing trials are still rare.

Toxicity management is essential for safe ADC use. To treat interstitial lung disease (ILD)/pneumonitis, early identification, drug withdrawal, and corticosteroid treatment are important. Grade 2 or higher episodes require permanent discontinuance. To treat neutropenia, regular complete blood count monitoring is used as well as granulocyte colony-stimulating factor support as needed. Dosage adjustments and guideline-based supportive care are required for nausea, fatigue, diarrhea, and cytopenia. Multidisciplinary workflows and proactive patient education improve safety and enable consistent implementation in academic and community settings.

Conclusion

ADCs represent a major therapeutic advance across breast cancer subtypes and have established a new treatment paradigm. Clinical trial data, guidelines, and patient-specific characteristics must all be integrated for effective sequencing. Evidence-based toxicity treatment is necessary to maximize outcomes with ILD, neutropenia, and gastrointestinal adverse effects. We suggest an evidence- and mechanism-based approach for ADC sequencing and toxicity management as ADC approvals increase. This framework is intended to direct clinical decision-making until comparison data are developed.