Strategic Sequencing and Treatment Tailoring in Later-Line HER2+ mBC: Combination vs Monotherapy, CNS Considerations, and Sequencing

Later-Line Treatment Considerations

Fourth-line and beyond treatment decisions require careful consideration of patient-specific factors including cumulative toxicities, performance status, and treatment goals. Patients often have long treatment histories with persistent toxicities like neuropathy from prior taxane therapy. The extensive NCCN guideline options for later lines necessitate individualized discussions about adverse effects, administration schedules, and patient preferences.

Available agents include trastuzumab with various chemotherapy combinations, margetuximab (though rarely used in practice), and multiple tyrosine kinase inhibitors. T-DM1 has moved to later-line positioning but remains valuable as the first solid tumor antibody-drug conjugate with established efficacy and excellent tolerability. Quality-of-life considerations become paramount as patients often prefer less-intensive regimens after years of treatment.

The concept of escalation versus de-escalation in later lines mirrors discussions in hormone receptor–positive, HER2-negative disease. Monotherapy versus combination approaches depend on disease characteristics, patient preferences, and prior treatment tolerance. The goal shifts toward maintaining disease control while preserving quality of life, with treatment intensity guided by disease pace and patient goals rather than maximum efficacy pursuit.