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Eur J Cancer. 2017 Jun;78:70-81. doi: 10.1016/j.ejca.2017.03.012. Epub 2017 Apr 14.

Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.

Author information

1
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy.
2
Department of Oncology, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, PSL Research University, Paris, France.
3
Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
4
Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
5
Unit of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Italy.
6
Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
7
Division of Pathological Anatomy, Papa Giovanni XXIII Hospital, Bergamo, Italy.
8
Department of Biomedicine, University Hospital of Basel, Basel, Switzerland.
9
Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mmandala@asst-pg23.it.

Abstract

BACKGROUND:

The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified.

PATIENTS AND METHODS:

Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients.

RESULTS:

We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%.

CONCLUSION:

Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.

KEYWORDS:

BRAF inhibitors; Melanoma; T lymphocytes; prognosis; β-catenin

PMID:
28412591
DOI:
10.1016/j.ejca.2017.03.012
[Indexed for MEDLINE]

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