Skip to main content
Erschienen in: Clinical and Translational Oncology 10/2020

27.02.2020 | Research Article

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors

verfasst von: E. Cocorocchio, C. Martinoli, S. Gandini, L. Pala, F. Conforti, S. Stucchi, G. Mazzarol, P. Ferrucci

Erschienen in: Clinical and Translational Oncology | Ausgabe 10/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS).

Methods

We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites.

Results

The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28–0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23–0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13–0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10–0.55; p = 0.001).

Conclusions

These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.PubMedCrossRef Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.PubMedCrossRef
2.
Zurück zum Zitat Pratilas CA, Taylor BS, Ye Q, Viale A, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009;106(11):4519–24.PubMedPubMedCentralCrossRef Pratilas CA, Taylor BS, Ye Q, Viale A, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009;106(11):4519–24.PubMedPubMedCentralCrossRef
3.
Zurück zum Zitat Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedPubMedCentralCrossRef Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedPubMedCentralCrossRef
4.
Zurück zum Zitat McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.PubMedPubMedCentralCrossRef McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.PubMedPubMedCentralCrossRef
5.
Zurück zum Zitat Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.PubMedCrossRef Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.PubMedCrossRef
6.
Zurück zum Zitat Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.PubMedCrossRef Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.PubMedCrossRef
7.
Zurück zum Zitat Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.PubMedCrossRef Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.PubMedCrossRef
8.
Zurück zum Zitat Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.PubMedCrossRef Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.PubMedCrossRef
9.
Zurück zum Zitat Gandini S, Ferrucci PF, Botteri E, et al. Prognostic significance of hematological profiles in melanoma patients. Int J Cancer. 2016;139(7):1618–25.PubMedCrossRef Gandini S, Ferrucci PF, Botteri E, et al. Prognostic significance of hematological profiles in melanoma patients. Int J Cancer. 2016;139(7):1618–25.PubMedCrossRef
10.
Zurück zum Zitat Ferrucci PF, Gandini S, Battaglia A, et al. Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer. 2015;112(12):1904–10.PubMedPubMedCentralCrossRef Ferrucci PF, Gandini S, Battaglia A, et al. Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer. 2015;112(12):1904–10.PubMedPubMedCentralCrossRef
11.
Zurück zum Zitat Ferrucci PF, Ascierto PA, Pigozzo J, et al. Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol. 2016;27(4):732–8.PubMedCrossRef Ferrucci PF, Ascierto PA, Pigozzo J, et al. Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol. 2016;27(4):732–8.PubMedCrossRef
12.
Zurück zum Zitat Zaragoza J, Caille A, Beneton N, et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol. 2016;174(1):146–51.PubMedCrossRef Zaragoza J, Caille A, Beneton N, et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol. 2016;174(1):146–51.PubMedCrossRef
13.
Zurück zum Zitat Weide B, Martens A, Hassel JC, et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. 2016;22(22):5487–96.PubMedPubMedCentralCrossRef Weide B, Martens A, Hassel JC, et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. 2016;22(22):5487–96.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Martens A, Wistuba-Hamprecht K, Geukes Foppen M, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(12):2908–18.PubMedPubMedCentralCrossRef Martens A, Wistuba-Hamprecht K, Geukes Foppen M, et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 2016;22(12):2908–18.PubMedPubMedCentralCrossRef
15.
Zurück zum Zitat Nakamura Y, Kitano S, Takahashi A, et al. Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 2016;7(47):77404–15.PubMedPubMedCentralCrossRef Nakamura Y, Kitano S, Takahashi A, et al. Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 2016;7(47):77404–15.PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–46.PubMedCrossRef Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–46.PubMedCrossRef
17.
Zurück zum Zitat Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626–36.PubMedCrossRef Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626–36.PubMedCrossRef
18.
Zurück zum Zitat Chapman PB. Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation. Am Soc Clin Oncol Educ Book. 2013;33:e80.CrossRef Chapman PB. Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation. Am Soc Clin Oncol Educ Book. 2013;33:e80.CrossRef
19.
Zurück zum Zitat Hi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93.CrossRef Hi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93.CrossRef
20.
Zurück zum Zitat Teterycz P, Jagodzińska-Mucha P, Cybulska-Stopa B, et al. High baseline neutrophil-to-lymphocyte ratio predicts worse outcome in patients with metastatic BRAF-positive melanoma treated with BRAF and MEK inhibitors. Melanoma Res. 2018;28(5):435–41.PubMed Teterycz P, Jagodzińska-Mucha P, Cybulska-Stopa B, et al. High baseline neutrophil-to-lymphocyte ratio predicts worse outcome in patients with metastatic BRAF-positive melanoma treated with BRAF and MEK inhibitors. Melanoma Res. 2018;28(5):435–41.PubMed
21.
Zurück zum Zitat Khalili JS, Liu S, Rodríguez-Cruz TG, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012;18(19):5329–40.PubMedPubMedCentralCrossRef Khalili JS, Liu S, Rodríguez-Cruz TG, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012;18(19):5329–40.PubMedPubMedCentralCrossRef
22.
Zurück zum Zitat Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213–9.PubMedCrossRef Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213–9.PubMedCrossRef
Metadaten
Titel
Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors
verfasst von
E. Cocorocchio
C. Martinoli
S. Gandini
L. Pala
F. Conforti
S. Stucchi
G. Mazzarol
P. Ferrucci
Publikationsdatum
27.02.2020
Verlag
Springer International Publishing
Erschienen in
Clinical and Translational Oncology / Ausgabe 10/2020
Print ISSN: 1699-048X
Elektronische ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-020-02320-y

Weitere Artikel der Ausgabe 10/2020

Clinical and Translational Oncology 10/2020 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.