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

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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.

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References

  1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Gandini S, Ferrucci PF, Botteri E, et al. Prognostic significance of hematological profiles in melanoma patients. Int J Cancer. 2016;139(7):1618–25.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Chapman PB. Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation. Am Soc Clin Oncol Educ Book. 2013;33:e80.

    Article  Google Scholar 

  19. 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.

    Article  Google Scholar 

  20. 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.

    CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Medical Oncology of Melanoma, Sarcoma and Rare Tumors, Istituto Europeo di Oncologia IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy

    E. Cocorocchio, C. Martinoli, L. Pala, F. Conforti & P. Ferrucci

  2. Department of Experimental Oncology, Istituto Europeo di Oncologia IRCCS, Milan, Italy

    S. Gandini

  3. Clinical Research Area, Istituto Europeo di Oncologia IRCCS, Milan, Italy

    S. Stucchi

  4. Division of Pathology, Istituto Europeo di Oncologia IRCCS, Milan, Italy

    G. Mazzarol

Authors
  1. E. Cocorocchio
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  2. C. Martinoli
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  3. S. Gandini
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  4. L. Pala
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  5. F. Conforti
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  6. S. Stucchi
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  7. G. Mazzarol
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  8. P. Ferrucci
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Corresponding author

Correspondence to E. Cocorocchio.

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Conflict of interest

Dr Emilia Cocorocchio: honoraria from Roche, Novartis; Dr Pier Francesco Ferrucci: honoraria from BMS, Roche, Novartis, MSD, Piere-Fabre; the other authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with human participants or animals performed by any of the authors.

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Institutional ethical committee approved this study, and all live patients signed informed consents.

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Cocorocchio, E., Martinoli, C., Gandini, S. et al. Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors. Clin Transl Oncol 22, 1818–1824 (2020). https://doi.org/10.1007/s12094-020-02320-y

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  • DOI: https://doi.org/10.1007/s12094-020-02320-y

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