Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade

Milsch, Laura; Gesierich, Anja; Kreft, Sophia; Livingstone, Elisabeth; Zimmer, Lisa; Goebeler, Matthias; Schadendorf, Dirk; Schilling, Bastian

doi:10.1016/j.ejca.2018.05.012

Cited by 10 publications

(4 citation statements)

References 34 publications

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“…One arm of immunotherapy aims at re-activating T effector cells via immune checkpoint inhibition (Figure 2; Box 2). Indeed monoclonal antibodies, which block immune checkpoints (e.g., anti-CTLA4, anti-PD1, or anti-PDL1), demonstrate efficacy in individual BrM patients, but the overall response rates are modest, even in melanoma BrM, which is thought to be highly immunogenic (144–147). For example, a limited number of retrospective and prospective clinical trials indicate intracranial response rates of 16–25% following ipilimumab treatment in melanoma patients (148, 149) and 50–55% in trials combining ipilimumab and nivolumab (ABC trial and CheckMate 204) (150, 151).…”

Section: Introductionmentioning

confidence: 99%

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

et al. 2019

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Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.

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Section: Introductionmentioning

confidence: 99%

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

et al. 2019

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“…There was no signi cant difference in the survival of patients with and without extracranial disease activity, both in univariate and multivariate analyses. These results were unexpected given the extensive literature associating poor prognosis with systemic disease activity [18,19]. However, the two groups (extracranial disease absent v present) were signi cantly imbalanced with respect to size and censorship, making these conclusions challenging to interpret.…”

Section: Discussionmentioning

confidence: 88%

Supratentorial and infratentorial brain metastases: a single centre, retrospective cohort study

Steinruecke

Pronin

Gherman

et al. 2021

Preprint

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Purpose 15–30% of primary cancers metastasise to the brain. Of these, 10–25% involve the posterior fossa. It remains unclear whether patients undergoing resection for infratentorial brain metastases experience poorer prognosis than those with supratentorial lesions. We aim to compare the post-operative outcomes of these two groups. Methods We searched the electronic health records of all patients undergoing brain metastases resection at our regional neurosurgical centre between February 2014 and August 2019. Demographic and clinical data was collected on 85 patients (61 supratentorial, 24 infratentorial metastases). Outcome measures included survival, post-operative complications, and performance status. Patients were followed up until April 21st 2020. Results Median post-operative survival of patients with supratentorial metastases was 323 days (95% CI 235–411), compared to 277 days (95% CI 195–359) for those with infratentorial metastases. These two groups experienced comparable survival (log rank = 0.276, p = 0.60) in univariate analysis. Infratentorial metastasis location was not significantly prognostic of survival in multivariate analysis of six key clinical and demographic covariates (HR 1.51, 95% CI 0.780–2.92, p = 0.22). However, neurological and non-neurological post-operative complications were significantly more common in patients with infratentorial metastases (neurological = 21% v 13%, non-neurological = 25% v 2%, p = 0.002). Conclusions Infratentorial metastasis location alone was not associated with a significant change in survival in our patient cohort, but was linked to a higher incidence of post-operative complications. Prospective, multi-centre outcomes monitoring following brain metastasis resection is required to overcome the limitations of small sample size and evolving neurosurgical practices.

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“…However, treatment of BM in melanoma patients remains one of the major clinical challenges. Although recent data show therapeutic activity against melanoma BM by targeting the BRAF pathway or by im-mune checkpoint inhibition using inhibitors against the cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) or the Programmed cell death protein 1 (PD-1), response rates are rather limited and, overall, patients still have a poor prognosis [30,31]. Intracranial response rates for BRAF inhibitors in patients harboring mutant BRAF (V600E) have been reported in the range of 30-50%, with an increased response in asymptomatic patients and patients without previous local BM therapy [10,23,32].…”

Section: Discussionmentioning

confidence: 99%

Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Váraljai

Horn

Sucker

et al. 2021

Cancers

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Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

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Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade

Cited by 10 publications

References 34 publications

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis

Supratentorial and infratentorial brain metastases: a single centre, retrospective cohort study

Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

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