Camillo Porta1,2,3, Romano Danesi4, Marzia Del Re5, Federico Cucchiara5, Eleonora Rofi5, Lorenzo Fontanelli5, Iacopo Petrini6, Nicole Gri1, Giulia Pasquini6, Mimma Rizzo1, Michela Gabelloni7, Lorenzo Belluomini8, Stefania Crucitta5, Raffaele Ciampi9, Antonio Frassoldati8, Emanuele Neri7. 1. Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy. 2. Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. 3. Unit of Medical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari 'A. Moro', Bari, Italy. 4. Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. romano.danesi@unipi.it. 5. Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 6. General Pathology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. 7. Diagnostic and Interventional Radiology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. 8. Unit of Clinical Oncology, Specialist Medical Department, S. Anna University Hospital, Ferrara, Italy. 9. Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Abstract
BACKGROUND: It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients. METHODS: Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform. RESULTS: Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well. CONCLUSIONS: A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.
BACKGROUND: It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLCpatients. METHODS:Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform. RESULTS: Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well. CONCLUSIONS: A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.
Authors: Diego de Miguel-Perez; Alessandro Russo; Oscar Arrieta; Murat Ak; Feliciano Barron; Muthukumar Gunasekaran; Priyadarshini Mamindla; Luis Lara-Mejia; Christine B Peterson; Mehmet E Er; Vishal Peddagangireddy; Francesco Buemi; Brandon Cooper; Paolo Manca; Rena G Lapidus; Ru-Ching Hsia; Andres F Cardona; Aung Naing; Sunjay Kaushal; Fred R Hirsch; Philip C Mack; Maria Jose Serrano; Vincenzo Adamo; Rivka R Colen; Christian Rolfo Journal: J Exp Clin Cancer Res Date: 2022-06-02
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