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.
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.
Prolaris in Practice: Guiding ADT Benefits, Clinical Application, and Expert Insights From ACRO 2025
April 15th 2025Steven E. Finkelstein, MD, DABR, FACRO discuses how Prolaris distinguishes itself from other genomic biomarker platforms by providing uniquely actionable clinical information that quantifies the absolute benefit of androgen deprivation therapy when added to radiation therapy, offering clinicians a more precise tool for personalizing prostate cancer treatment strategies.
Recap: Recent Advances in the Treatment of Metastatic Castration-Sensitive Prostate Cancer
September 18th 2022Expert oncologists review key studies in the metastatic castration-resistant prostate cancer treatment landscape and discuss how evidence can be applied to clinical practice to improve patient outcomes.
CCR Scores and Beyond: Precision Strategies for Treatment Intensification in Prostate Cancer
April 15th 2025Alvaro Martinez, MD discusses how emerging genomic risk stratification tools such as the clinical cell-cycle risk (CCR) score are transforming personalized prostate cancer treatment by enabling more nuanced assessments of metastasis risk and treatment intensification strategies beyond traditional NCCN risk groupings.
Recap: Updates in Treatment of HER2-Positive Breast Cancer and Brain Metastases
July 16th 2022Sara A. Hurvitz, MD; Stefania Maraka, MD; and Ruta Rao, MD, discuss the evolving landscape of metastatic HER2+ breast cancer, highlighting recent clinical trials and the management of patients with brain metastases.
Recap: Emory Experts Review Treatment Strategies for Transplant-Ineligible Multiple Myeloma
June 20th 2022A panel of experts from Emory University review several key data updates in multiple myeloma from recent meetings and discuss how the data can be applied to clinical practice to improve patient outcomes.