Expert Insights: Later-Line Treatment Strategies for HER2+ Metastatic Breast Cancer
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.
EP: 1.Current Treatment Approaches in HER2+ Metastatic Breast Cancer
EP: 2.Optimizing Maintenance Therapy After First-Line Treatment in HER2+ Metastatic Breast Cancer
EP: 3.The Evolving Role of T-DXd in HER2+ Metastatic Breast Cancer
EP: 4.Strategies for Monitoring and Managing T-DXd-Related Adverse Effects
EP: 5.Patient Case Presentation: A 47-Year-Old Woman With HER2+ mBC and CNS Progression
EP: 6.Strategic Sequencing in HER2+ Breast Cancer: Optimizing Treatment in the Third Line and Beyond
EP: 7.Tucatinib Triplet Therapy: Efficacy, Safety and Clinical Decision-Making
EP: 8.Expert Insights: Later-Line Treatment Strategies for HER2+ Metastatic Breast Cancer
EP: 9.Looking Ahead in HER2+ mBC: Unmet Needs, Future Perspectives and Highlights From ASCO 2025
In advanced HER2-positive metastatic breast cancer, treatment options beyond the third line become less standardized and are often described as the “wild West” due to a lack of clear consensus. After exhausting first through third-line therapies—including combinations such as trastuzumab, pertuzumab, tucatinib, and T-DM1—clinicians often rely on a mix of agents tailored to individual patient history, prior toxicities, and preferences. The NCCN guidelines offer a broad range of fourth-line and beyond options, including monoclonal antibodies like margetuximab combined with chemotherapy, various tyrosine kinase inhibitor), and chemotherapies. Treatment choice in this space is highly individualized, focusing on balancing efficacy with adverse effect profiles, such as avoiding hair loss or severe fatigue.
Both clinicians in the discussion emphasized the importance of “dealer’s choice” at this stage, as there is no definitive fourth-line standard. Patients with long metastatic courses may cycle back through previously effective drugs, especially if tumor receptor status changes, such as from estrogen receptor positive to estrogen receptor negative. Continuing trastuzumab beyond progression remains common practice, supported by some evidence, and tucatinib is increasingly integrated into earlier lines, which influences sequencing decisions. The advent of new antibody-drug conjugates with novel linkers, bispecific antibodies, PI3K inhibitors for resistance pathways, and ongoing development of oral agents is expanding treatment possibilities, underscoring the need for innovation in the fourth-line setting.
Importantly, both experts highlighted clinical trials as an essential option for patients at this advanced stage. Trials now show response rates that can exceed standard therapies, making enrollment a key part of contemporary care rather than a last resort. With multiple novel agents emerging, including immunotherapy combinations and targeted approaches, the fourth-line and beyond setting remains a fertile ground for research and improved patient outcomes.
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