Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

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Metastatic melanoma patients are at high risk of brain metastases (BM). Although intracranial control is a prognostic factor for survival, impact of local (intracranial) treatment (LT), surgery and/or radiotherapy (stereotactic or whole brain) in the era of novel therapies remains unknown. We evaluated BM incidence in melanoma patients receiving immune checkpoint inhibitors (ICI) or anti-BRAF therapy and identified prognostic factors for overall survival (OS). Clinical data and treatment patterns were retrospectively collected from all patients treated for newly diagnosed locally advanced or metastatic melanoma between May 2014 and December 2017 with available BRAF mutation status and receiving systemic therapy. Prognostic factors for OS were analyzed with univariable and multivariable survival analyses. BMs occurred in 106 of 250 eligible patients (42.4%), 64 of whom received LT. Median OS in patients with BM was 7.8 months (95% CI [5.4–10.4]). In multivariable analyses, LT was significantly correlated with improved OS (HR 0.21, p < 0.01). Median OS was 17.3 months (95% CI [8.3–22.3]) versus 3.6 months (95% CI [1.4–4.8]) in patients with or without LT. LT correlates with improved OS in melanoma patients with BM in the era of ICI and anti-BRAF therapy. The use of LT should be addressed at diagnosis of BM while introducing systemic treatment.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017 (Toulouse, N = 202; Limoges, N = 91). Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group [95% confidence interval (CI) 9.14–19.36] and 27.26% in the other group (95% CI 19.38–35.71), P = 0.004. The cumulative incidence was 9.49% in the anti-PD-1 group (95% CI 5.43–14.90) vs 30.11% in the other group (95% CI 22.59–37.97), P < 0.0001. In multivariable analysis (model with 277 patients), anti-PD-1 reduced the risk of brain metastases by almost 70% (hazard ratio = 0.29, 95% CI 0.15–0.56, P < 0.0001). The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

While immunotherapies and targeted therapies such as BRAF inhibitors have improved the prognosis, BM is still associated with poor outcome and a short survival. Metastatic melanoma patients are a heterogeneous subgroup with variable prognosis. As several prospective clinical trials have addressed the question of optimal therapy for these patients, an accurate validated selection tool is needed. Melanoma molecular graded prognostic assessment (Melanoma-molGPA) is a new prognostic score for BM melanoma patients. We decided to perform an external validation of this score. All consecutive patients treated between May 2014 and December 2017 for a newly diagnosed locally advanced or metastatic melanoma with available status for BRAF mutation were identified. Melanoma mol-GPA was applied in each patient with BM and correlated to overall survival. One hundred patients were included. Median follow-up was 27.8 months. Distribution for the Melanoma-molGPA groups GPA 0–1, GPA 1.5–2, GPA 2.5–3 and GPA 3.5–4 were as follows: 23, 51, 24 and 2.0%, respectively. Subgroups GPA 2.5–3 and 3.5–4 were combined. Median overall survival for groups GPA 0–1, 1.5–2 and 2.5–4.0 was 4.2, 6.9 and 18.4 months, respectively, P = 0.0032. Our study is the most recent, and with the largest cohort, to validate the Melanoma-molGPA score as an accurate and reproducible score for estimating overall survival. As several prospective clinical trials are addressing the issue of optimal therapy including the impact of local treatment for these patients, the Melanoma-molGPA is a useful tool in BM melanoma patients.