PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability

// Enrico Munari 1, 2 , Giuseppe Zamboni 1 , Marcella Marconi 1 , Marco Sommaggio 1 , Matteo Brunelli 2 , Guido Martignoni 2, 3 , George J. Netto 4 , Francesca Moretta 5 , Maria Cristina Mingari 6 , Matteo Salgarello 7 , Alberto Terzi 8 , Vincenzo Picece 9 , Carlo Pomari 10 , Gianluigi Lunardi 9 , Alberto Cavazza 11 , Giulio Rossi 12 , Lorenzo Moretta 13 and Giuseppe Bogina 1 1 Department of Pathology, Sacro Cuore Don Calabria Hospital, Negrar, Italy 2 Department of Pathology AOUI, University of Verona, Verona, Italy 3 Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy 4 Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA 5 Department of Laboratory Medicine, Sacro Cuore Don Calabria Hospital, Negrar, Italy 6 Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy 7 Department of Nuclear Medicine, Sacro Cuore Don Calabria Hospital, Negrar, Italy 8 Department of Thoracic Surgery, Sacro Cuore Don Calabria Hospital, Negrar, Italy 9 Department of Oncology, Sacro Cuore Don Calabria Hospital, Negrar, Italy 10 Department of Pulmonology, Sacro Cuore Don Calabria Hospital, Negrar, Italy 11 Department of Pathology, Arcispedale S. Maria Nuova/IRCCS, Reggio Emilia, Italy 12 Department of Pathology, Azienda USL Valle d'Aosta, Aosta, Italy 13 Immunology Research Area, IRCCS Bambino Gesu Pediatric Hospital, Rome, Italy Correspondence to: Enrico Munari, email: enrico.munari@sacrocuore.it Keywords: PD-L1, lung cancer, immunotherapy, SP263, pembrolizumab Received: July 12, 2017      Accepted: August 27, 2017      Published: October 04, 2017 ABSTRACT Immunotherapy with checkpoint inhibitors, allowing recovery of effector cells function, has demonstrated to be highly effective in many tumor types and represents a true revolution in oncology. Recently, the anti-PD1 agent pembrolizumab was granted FDA approval for the first line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors show PD-L1 expression in ≥ 50% of neoplastic cells and as a second line treatment for patients with NSCLC expressing PD-L1 in ≥1% of neoplastic cells, evaluated with a validated assay. For the large majority of patients such evaluation is made on small biopsies. However, small tissue samples such as core biopsies might not be representative of tumors and may show divergent results given the possible heterogeneous immunoexpression of the biomarker. We therefore sought to evaluate PD-L1 expression concordance in a cohort of 239 patients using tissue microarrays (TMA) as surrogates of biopsies stained with a validated PD-L1 immunohistochemical assay (SP263) and report the degree of discordance among tissue cores in order to understand how such heterogeneity could affect decisions regarding therapy. We observed a discordance rate of 20% and 7.9% and a Cohen’s κ value of 0.53 (moderate) and 0,48 (moderate) for ≥ 1% and ≥ 50% cutoffs, respectively. Our results suggest that caution must be taken when evaluating single biopsies from patients with advanced NSCLC eligible for immunotherapy; moreover, at least 4 biopsies are necessary in order to minimize the risk of tumor misclassification.