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Brain metastases (BMs) are the most common form of intracranial malignant neoplasms in adults, with a profound impact on quality of life and traditionally associated with a dismal prognosis. Lung cancer accounts for approximately 40%–50% of BM across different tumors. The process leading to BMs is complex and includes local invasion, intravasation, tumor cells circulation into the bloodstream, disruption of the blood–brain barrier, extravasation of tumor cells into the brain parenchyma, and interaction with cells of the brain microenvironment, among others. Once the tumor cells have seeded in the brain parenchyma, they encounter different glial cells of the brain, as well as immune cells. The interaction between these cells and tumor cells is complex and is associated with both antitumoral and protumoral effects. To overcome the lethal prognosis associated with BMs, different treatment strategies have been developed, such as immunotherapy with immune checkpoint inhibitors, particularly inhibitors of the PD-1/PD-L1 axis, which have demonstrated to be an effective treatment in both non-small cell lung cancer and small cell lung cancer. These antibodies have shown to be effective in the treatment of BM, alone or in combination with chemotherapy or radiotherapy. However, many unsolved questions remain to be answered, such as the sequencing of immunotherapy and radiotherapy, the optimal management in symptomatic BMs, the role of the addition of anti–CTLA-4 antibodies, and so forth. The complexity in the management of BMs in the era of immunotherapy requires a multidisciplinary approach to adequately treat this devastating event. The aim of this review is to summarize evidence regarding epidemiology of BM, its pathophysiology, current approach to treatment strategies, as well as future perspectives.

Purpose: The MammaPrint (MP) prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high-1 (MP-H1), and very high-risk high-2 (MP-H2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor-positive (HR+)/HER2-negative MP-H1, -H2, and triple-negative (TN) MP-H1 and -H2 cancers., Experimental Design: Pretreatment gene expression data from 742 HER2-negative breast cancers enrolled in the I-SPY2 neoadjuvant trial were used. Prognostic risk categories were assigned using the MP assay. Transcriptional similarities across the four receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response rates and event-free survivals by risk group., Results: Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers, whereas 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune infiltration-related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor-related gene expression. Pathologic complete response rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs. 30.5%; P = 0.11), and MP-H2 cancers with residual cancer had similarly poor event-free survival regardless of estrogen receptor status., Conclusions: In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies., (©2024 American Association for Cancer Research.)