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Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases

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Opinion Statement

In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs’ inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.

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Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, 30 Duke Medicine Circle Drive, Box 3841, Durham, NC, 27710, USA

    Ryan K. Rader MD & Carey K. Anders MD

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Yawkey 1250, Boston, MA, 02215, USA

    Nancy U. Lin MD & Sarah L. Sammons MD

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Correspondence to Sarah L. Sammons MD.

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Conflict of Interest

Ryan Rader has no conflicts of interest.

Sarah Sammons declares research funding from Astra Zeneca, Lilly, Seagen, and Sermonix, and consulting fees from AstraZeneca, Daichii Sankyo, Foundation Medicine, Gilead, Novartis, Pfizer, Seagen, and Sermonix.

Carey Anders declares research funding from PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, and Pfizer; consulting fees from Genentech, Eisai, IPSEN, Seattle Genetics; Astra Zeneca, Novartis, Immunomedics, Elucida, and Athenex; and royalties from UpToDate and Jones and Bartlett.

Nancy Lin declares research funding from Genentech, Seattle Genetics, Merck, and Pfizer and consulting fees from Daichii Sankyo, AstraZeneca, Seattle Genetics, Prelude Therapeutics, Denali Therapeutics, and California Institute for Regenerative Medicine.

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Rader, R.K., Anders, C.K., Lin, N.U. et al. Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases. Curr. Treat. Options in Oncol. 24, 611–627 (2023). https://doi.org/10.1007/s11864-023-01086-z

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