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Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study

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A Letter to the Editors to this article was published on 05 December 2019

Abstract

Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32–169.89) ng/mL and 117.17 (80.46–147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan–Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.

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Abbreviations

AUC:

Area under the curve

CI:

Confidence interval

ECOG PS:

Eastern Cooperative Oncology Group scale of Performance Status

HR:

Hazard ratio

KO:

Knock-out

LRP-1:

Lipoprotein receptor-related protein-1

NLR:

Neutrophil-to-lymphocyte ratio

PC:

Proprotein convertase

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PLR:

Platelet-to-lymphocyte ratio

ROC:

Receiver operating characteristic

(si)RNA:

Small interfering RNA

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Funding

This study was supported by a grant from the Italian Ministry of Health to the Italian Cardiovascular Network and a grant from the Fondazione CARIGE to Prof. Fabrizio Montecucco.

Author information

Author notes

  1. Aldo Bonaventura and Francesco Grossi equally contributed as first authors.

  2. Carlo Genova and Fabrizio Montecucco equally contributed as last authors.

Authors and Affiliations

  1. Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132, Genoa, Italy

    Aldo Bonaventura, Federico Carbone, Alessandra Vecchié, Silvia Minetti, Nicholas Bardi, Edoardo Elia, Anna Maria Ansaldo, Daniele Ferrara & Franco Dallegri

  2. Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, 1200 East Marshall Street, Richmond, VA, 23298, USA

    Aldo Bonaventura & Alessandra Vecchié

  3. Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Francesco Grossi

  4. IRCCS Ospedale Policlinico San Martino Genova, Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy

    Federico Carbone, Franco Dallegri & Fabrizio Montecucco

  5. UOS Tumori Polmonari, IRCCS Ospedale Policlinico San Martino Genova, Largo R. Benzi 10, 16132, Genoa, Italy

    Erika Rijavec, Maria Giovanna Dal Bello, Giovanni Rossi, Marco Tagliamento, Angela Alama, Simona Coco & Carlo Genova

  6. Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy

    Federica Biello

  7. Cardiovascular Diseases Unit, IRCCS Ospedale Policlinico San Martino Genova, Italian Cardiovascular Network, Largo R. Benzi 10, 16132, Genoa, Italy

    Paolo Spallarossa

  8. Department of Internal Medicine, First Clinic of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 6, 16132, Genoa, Italy

    Fabrizio Montecucco

Authors
  1. Aldo Bonaventura
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  2. Francesco Grossi
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  3. Federico Carbone
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  4. Alessandra Vecchié
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  5. Silvia Minetti
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  6. Nicholas Bardi
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  7. Edoardo Elia
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  8. Anna Maria Ansaldo
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  9. Daniele Ferrara
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  10. Erika Rijavec
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  11. Maria Giovanna Dal Bello
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  12. Giovanni Rossi
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  13. Federica Biello
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  14. Marco Tagliamento
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  15. Angela Alama
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  16. Simona Coco
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  17. Paolo Spallarossa
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  18. Franco Dallegri
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  19. Carlo Genova
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  20. Fabrizio Montecucco
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Contributions

CG, MGB, ER, GR, FB, MT, and FG recruited patients and collected clinical data. AA and SC stored samples and provided aliquots for the measurement of PCSK9. AB, FC, AV, SM, NB, EE, AMA, and DF analyzed samples by ELISA technique. AB performed the statistical analysis and wrote the first manuscript draft. FD, FG, PS, and FM critically read the manuscript and suggested changes for improvement. All authors approved the final version of the revised manuscript.

Corresponding author

Correspondence to Aldo Bonaventura.

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Conflict of interest

Francesco Grossi has consulting/advisory relationship with and received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre and has consulting/advisory relationship with AstraZeneca and Roche. Carlo Genova received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Merck Sharp & Dohme, and Roche. Erika Rijavec received honoraria from Bristol-Myers Squibb. Paolo Spallarossa has consulting/advisory relationship with Incyte, Teva, Bristol-Myers Squibb and received honoraria from Incyte, Teva, and Servier. All other authors declare no conflicts of interest.

Ethical approval

The study was approved by the Institutional Review Board of IRCCS Ospedale Policlinico San Martino, Genoa, Italy (registry number: P.R. 191REG2015). The study was conducted in accordance with the Declaration of Helsinki and consistent with International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice.

Informed consent

Prior to inclusion in the study, all patients gave written, informed consent to the use of their samples and data for research and scientific publications.

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Bonaventura, A., Grossi, F., Carbone, F. et al. Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study. Cancer Immunol Immunother 68, 1351–1358 (2019). https://doi.org/10.1007/s00262-019-02367-z

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  • DOI: https://doi.org/10.1007/s00262-019-02367-z

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