Management of brain metastases according to molecular subtypes

Abstract

The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.

Key points

  • The blood–brain, blood–tumour and blood–cerebral fluid barriers limit the effective delivery of water-soluble drugs and macromolecules, such as monoclonal antibodies, to the CNS.

  • Brain metastases from EGFR-mutant and ALK-rearranged non-small-cell lung cancer (NSCLC), HER2-positive breast cancer and BRAF-mutant melanoma can be successfully targeted with specific inhibitors.

  • Immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab and atezolizumab) have clearly improved the outcome of patients with brain metastases from melanoma and now show promising efficacy in patients with brain metastases from non-druggable subtypes of NSCLC and triple-negative breast cancer.

  • The combination of targeted agents and immune-checkpoint inhibitors with stereotactic radiosurgery might yield better results over single modalities but the risk of radionecrosis is still debated.

  • New druggable targets are being investigated in brain metastases from NSCLC (ROS1 rearrangement, NTRK fusions, BRAF and KRAS mutations), breast cancer (DNA repair, CDK4/CDK6 and ER signalling pathways) and melanoma (MEK resistance pathway).

  • Advanced neuroimaging modalities and liquid biopsy represent more precise tools than standard MRI to evaluate early response or progression following targeted therapies or immunotherapy, while phase 0 trials will give the opportunity for in vivo testing of new compounds before entering phase II or III clinical trials.

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R.S. researched data for the article, made a substantial contribution to the discussion of content, and wrote and reviewed/edited the manuscript before submission. M.A., N.U.L. and R.R. researched data for the article, made a substantial contribution to the discussion of content and wrote the manuscript.

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Correspondence to Riccardo Soffietti.

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Soffietti, R., Ahluwalia, M., Lin, N. et al. Management of brain metastases according to molecular subtypes. Nat Rev Neurol 16, 557–574 (2020). https://doi.org/10.1038/s41582-020-0391-x

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