Dear Editor,
We read with great interest the letter by Li and Che about our recently published article in “Cancer Immunology, Immunotherapy” [1]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was largely studied in the cardiovascular field [2], but less is known about its role in cancer. For this reason, we sought to investigate whether PCSK9 might predict OS in patients with advanced NSCLC treated with nivolumab. Indeed, we found that PCSK9 < 95 ng/mL at the second cycle of nivolumab treatment was associated with a better OS in elderly patients with advanced, pre-treated NSCLC [3].
We mostly agree with Li and Che that the number of patients is too small to draw definitive conclusions, as acknowledged in the limitations of the study [3]. As well, we clearly stated that this was a pilot study, whose findings need to be replicated in larger and properly designed studies aiming to confirm our preliminary findings and understand the underlying mechanisms linking PCSK9 and NSCLC growth.
With regard to covariates included in the multivariate analysis of the Cox proportional hazards model, we chose age, sex, smoking habit, and previous treatment from a mere clinical standpoint. Additionally, following an accepted statistical rule, we considered only one covariate for every 10 events. Additionally, responding to the comments by Li and Che, we herein present in detail the treatments most often administered before nivolumab, although we must acknowledge that data are missing for some patients. Carboplatin/cisplatin (33/41, 80.5%), permetrexed (27/41, 65.9%), vinorelbine (7/41, 17.1%), and gemcitabine (5/41, 12.2%) were the most used first-line treatments. Erlotinib/gefitinib/selumetinib (10/43, 23.3%) and docetaxel (6/43, 14%) were the most used second-line treatments. Erlotinib/afatinib/osimertinib (11/25, 44%) and gemcitabine (6/15, 40%) were used as third- and fourth-line treatments, respectively. Finally, only a very few number of patients was treated with further treatment lines.
Li and Che also discussed about the promising pathway involving PD-1/PD-L1 in patients with advanced NSCLC. We really thank you for the interesting remark, which allows us to provide some further information. We did not consider the expression of PD-1/PD-L1 for the analysis in our pilot study [3] as the availability of specimens for this quantification was insufficient due to previous analyses. PD-L1 and PD-1 protein expression was performed by immunohistochemistry using rabbit monoclonal anti-PD-L1 antibody (28–8 Pharm DX Dako) and rabbit polyclonal anti-PD1 antibody (Abcam) from formalin-fixed, paraffin-embedded tissue samples. Indeed, data were available only for 24 out of 44 patients, among whom 18 were found positive (75%). Considering the limited number, we decided to not consider these data for the paper since results would have been highly misleading and not conclusive at all. We are planning, however, to perform the quantification of PD-1/PD-L1, as mentioned above, in all patients enrolled in future studies to be able to add knowledge on the link between PD-L1/ PD-1 and PCSK9 in the natural history of NSCLC.
Author contribution
AB, FG, and FM equally contributed to the writing and revision of the manuscript draft and approved the final version.
Funding
This study was supported by a grant from the Italian Ministry of Health to the Italian Cardiovascular Network (#2754291) and a grant from the Fondazione CARIGE to Prof. Fabrizio Montecucco. The PD-1/PD-L1 analyses were supported by a grant from Compagnia San Paolo (SC: 2017-0529).
Compliance with ethical standards
Conflict of interest
Francesco Grossi has consulting/advisory relationship with and received honoraria from Bristol-Myers Squibb, Merck Sharp and Dohme, and Pierre Fabre and has consulting/advisory relationship with AstraZeneca and Roche. All other authors declare that there are 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.
Footnotes
Publisher's Note
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References
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