Pathologic and gene expression features of metastatic melanomas to the brain

Hamilton, Ronald L.; Krauze, Michal T.; Romkes, Marjorie; Omolo, Bernard; Konstantinopoulos, Panagiotis A.; Reinhart, Todd A.; Harasymczuk, Malgorzata; Wang, Yangyang; Lin, Yan; Ferrone, Soldano; Whiteside, Theresa L.; Bortoluzzi, Stephanie; Werley, Jonette; Nukui, Tomoko; Fallert-Junecko, Beth; Kondziolka, Douglas; Ibrahim, Joseph G.; Becker, Dorothea; Kirkwood, John M.; Moschos, Stergios J.

doi:10.1002/cncr.28029

Cited by 46 publications

(44 citation statements)

References 26 publications

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“…The risk of BM remains a concern and in fact occurs with a higher incidence as patients with extracranial metastases achieve increasingly longer survival. However, the similar biology of extracranial and brain metastases and equivalent responses following MAPKi have lessened the apparent significance of when metastases involve the brain [26, 34,35]. Patients may also benefit from other mechanisms of MAPKi therapy even after their disease has progressed [36], and ongoing work is elucidating complementary approaches to MAPKi resistance, including co-targeting of the PI3K/AKT signaling pathway [37,38].…”

Section: Discussionmentioning

confidence: 99%

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era

et al. 2015

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Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi). Among patients with brain metastases (BM), however, the clinical course of MAPKi-treated patients is not well described. We therefore explored these patients' survival patterns compared to contemporary patients not treated with MAPKi. We analyzed 106 patients who developed melanoma BM between 2007 and 2013. Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease, which preceded BM in 49%. Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi. We evaluated the potential influence of patient characteristics, systemic therapies, and BM-directed treatments on time to appearance of new BM and overall survival. With a median follow-up of 8.0 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7.0 months, P = 0.03, adjusted hazard ratio 0.39). This survival advantage was driven by the 16.6-month median survival of patients who initiated MAPKi after BM were diagnosed, versus 5.6 months if initiated prior to BM development (P = 0.03). Median survival from the onset of any systemic metastases was 22 months regardless of the timing of MAPKi relative to BM appearance. Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement. These findings are consistent with potential MAPKi activity in intracranial melanoma.

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Section: Discussionmentioning

confidence: 99%

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era

et al. 2015

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“…Good ( Jung et al, 2013;Wansom et al, 2012) Poor Wolf et al, 2015) Poor Good ( Interestingly, some studies have assessed this correlation also in the metastatic sites and have consistently found that increased CD8 + T-cell densities correlated with prolonged OS in CRC liver (Brunner et al, 2014;Katz et al, 2013;Liu et al, 2012;Yoon et al, 2012), lung metastases (Remark et al, 2013), and CNS melanoma metastases (Hamilton et al, 2013;Kluger et al, 2015) (Table 1 and (Table 1 and Fig. 2).…”

Section: )mentioning

confidence: 96%

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Becht¹,

Giraldo²,

Germain³

et al. 2016

Advances in Immunology

181

136

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“…For example, Hamilton et al studied 26 matched brain and extra-cerebral metastases for gene expression profiling and found differences in pathways associated with T cell activity (16). …”

Section: Introductionmentioning

confidence: 99%

Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites

Kluger

Zito

Barr

et al. 2015

Clinical Cancer Research

189

134

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Purpose Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. Experimental Design We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome and anatomic site of disease. We assessed PD-L1 expression and tumor infiltrating lymphocytes (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. Results High PD-L1 expression was associated with improved survival (P=0.02) and higher T cell content (P=0.0005). Higher T cell content (total and CD8 cells) were independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extra-cerebral metastases was associated with increased time to developing brain metastases (P=0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P=0.01). Conclusions T cell infiltrated melanomas, particularly those with high CD8 T cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites.

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Pathologic and gene expression features of metastatic melanomas to the brain

Cited by 46 publications

References 26 publications

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites

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