Navigating HER2+ Breast Cancer Treatment: Expert Perspectives on Patient Selection and Treatment Sequencing

Panelists discussed how evolving strategies in HER2-positive metastatic breast cancer are shifting toward more personalized maintenance approaches, including the integration of CDK4/6 inhibitors and endocrine therapy, with growing interest in chemotherapy-free options for select patients.

Panelists discussed how maintenance therapy in HER2-positive metastatic breast cancer is evolving beyond traditional dual antibody approaches, with emerging strategies incorporating targeted agents like tucatinib and endocrine therapy to personalize care and potentially delay central nervous system progression.

Panelists discussed how DESTINY-Breast03 firmly established trastuzumab deruxtecan (T-DXd) as the second-line standard in HER2-positive metastatic breast cancer, while early DESTINY-Breast09 data suggest that T-DXd combined with pertuzumab may challenge the CLEOPATRA regimen in the frontline setting, though questions remain about global applicability.

Panelists discussed the persistent risk of interstitial lung disease with trastuzumab deruxtecan, emphasizing the need for early detection through routine imaging, rapid intervention to prevent severe toxicity, and cautious retreatment in select cases where interstitial lung disease was mild and well managed.

Panelists discussed a complex case of a 47-year-old woman with metastatic HER2-positive breast cancer, emphasizing the importance of continuous systemic therapy despite treatment interruptions, the critical role of multidisciplinary care for central nervous system involvement, and the need to balance efficacy with quality of life as patients navigate prolonged disease courses and evolving treatment strategies.

Panelists emphasized that for a patient with metastatic HER2-positive breast cancer and active brain metastases, selecting a treatment with proven intracranial activity is critical, while carefully considering prior therapy tolerability, radiation history, and the balance between treatment efficacy and patient convenience to optimize both disease control and quality of life.

Panelists highlighted that the HER2CLIMB study showed adding tucatinib to trastuzumab and capecitabine provides a meaningful progression-free survival benefit in HER2-positive metastatic breast cancer with brain metastases, balancing improved intracranial control against manageable toxicities like diarrhea and hand-foot syndrome, and underscored the importance of patient education and dose management to maintain adherence and quality of life.

Panelists agreed that beyond third-line therapy for HER2-positive metastatic breast cancer, treatment becomes highly individualized—often described as the “wild West”—with options including various monoclonal antibodies, tyrosine kinase inhibitors, chemotherapy, and emerging agents; decisions are largely based on prior toxicities, patient preferences, and disease biology, with clinical trials playing a crucial role in offering promising new therapies that may outperform standard care.

Panelists highlighted the impressive central nervous system activity of trastuzumab deruxtecan demonstrated in the DX12 trial, underscoring the need for multidisciplinary collaboration to optimize treatment of brain metastases and reduce reliance on whole-brain radiation, while acknowledging ongoing challenges in sequencing and patient selection amid evolving therapies.