The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600

D. Massi, D. Brusa, B. Merelli, C. Falcone, G. Xue, A. Carobbio, R. Nassini, G. Baroni, E. Tamborini, L. Cattaneo, V. Audrito, S. Deaglio, Mario Mandalà

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Abstract

Background: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. Methods: PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAFV600-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. Results: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P <0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P <0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P <0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P <0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P <0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P <0.002) were independent prognostic factors for melanoma-specific survival. Conclusion: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAFV600-mutated MMP treated with BRAFi.

Original languageEnglish
Article numbermdv255
Pages (from-to)1980-1987
Number of pages8
JournalAnnals of Oncology
Volume26
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

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Melanoma
Ligands
Confidence Intervals
Neoplasms
Disease-Free Survival
Survival
Odds Ratio
Staining and Labeling
Hematoxylin
Eosine Yellowish-(YS)
Drug Resistance
Paraffin
Formaldehyde
Multivariate Analysis
Cell Count
Immunohistochemistry
Antibodies

Keywords

  • BRAF inhibitors
  • Immune cell infiltration
  • Melanoma
  • PD-L1
  • Prognosis
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. / Massi, D.; Brusa, D.; Merelli, B.; Falcone, C.; Xue, G.; Carobbio, A.; Nassini, R.; Baroni, G.; Tamborini, E.; Cattaneo, L.; Audrito, V.; Deaglio, S.; Mandalà, Mario.

In: Annals of Oncology, Vol. 26, No. 9, mdv255, 01.09.2015, p. 1980-1987.

Research output: Contribution to journalArticle

Massi, D, Brusa, D, Merelli, B, Falcone, C, Xue, G, Carobbio, A, Nassini, R, Baroni, G, Tamborini, E, Cattaneo, L, Audrito, V, Deaglio, S & Mandalà, M 2015, 'The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600', Annals of Oncology, vol. 26, no. 9, mdv255, pp. 1980-1987. https://doi.org/10.1093/annonc/mdv255
Massi, D. ; Brusa, D. ; Merelli, B. ; Falcone, C. ; Xue, G. ; Carobbio, A. ; Nassini, R. ; Baroni, G. ; Tamborini, E. ; Cattaneo, L. ; Audrito, V. ; Deaglio, S. ; Mandalà, Mario. / The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. In: Annals of Oncology. 2015 ; Vol. 26, No. 9. pp. 1980-1987.
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abstract = "Background: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. Methods: PD-L1 expression (cutoff 5{\%}) was analyzed by immunohistochemistry with two different antibodies in BRAFV600-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. Results: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35{\%}) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95{\%} confidence interval (CI) 2.7-43.3, P <0.001] and the presence of TIMC (OR 6.5, 95{\%} CI 1.7-24.3, P <0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95{\%} CI 2.1-8.7, P <0.0001] and absence of TIMC (HR 2.5, 95{\%} CI 1.4-4.7, P <0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95{\%} CI 2.8-14.2, P <0.0001) and absence of TIMC (HR 3.1, 95{\%} CI 1.5-6.5, P <0.002) were independent prognostic factors for melanoma-specific survival. Conclusion: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAFV600-mutated MMP treated with BRAFi.",
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T1 - The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600

AU - Massi, D.

AU - Brusa, D.

AU - Merelli, B.

AU - Falcone, C.

AU - Xue, G.

AU - Carobbio, A.

AU - Nassini, R.

AU - Baroni, G.

AU - Tamborini, E.

AU - Cattaneo, L.

AU - Audrito, V.

AU - Deaglio, S.

AU - Mandalà, Mario

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. Methods: PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAFV600-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. Results: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P <0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P <0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P <0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P <0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P <0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P <0.002) were independent prognostic factors for melanoma-specific survival. Conclusion: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAFV600-mutated MMP treated with BRAFi.

AB - Background: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. Methods: PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAFV600-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. Results: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P <0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P <0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P <0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P <0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P <0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P <0.002) were independent prognostic factors for melanoma-specific survival. Conclusion: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAFV600-mutated MMP treated with BRAFi.

KW - BRAF inhibitors

KW - Immune cell infiltration

KW - Melanoma

KW - PD-L1

KW - Prognosis

KW - Resistance

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