EGFR mutations detected on cytology samples by a centralized laboratory reliably predict response to gefitinib in non–small cell lung carcinoma patientsBACKGROUND: Epidermal growth factor receptor (EGFR) mutations are reliably detected by referral laboratories, even if most lung cancer cytology specimens sent to such laboratories contain very few cells. However, EGFR mutations may be distributed heterogeneously within tumors, thereby raising concerns that mutations detected on cytology are not representative of the entire tumor and, thus, are less reliable in predicting response to tyrosine kinase inhibitor (TKI) treatment than mutations detected on histology. To address this issue, the authors reviewed their clinical practice archives and compared the outcome of TKI treatment among patients who were selected by cytology versus patients who were selected by histology. METHODS: From July 2010 to July 2012, 364 cytology samples and 318 histology samples were received. Exon 19 deletions and the L858R point mutation in exon 21, detected by fragment assay and TaqMan assay, respectively, were confirmed by direct sequencing; discrepancies were resolved by cloning polymerase chain reaction products. The response rate (RR) and progression-free survival (PFS) at 12 months (range, 3-34 months) were evaluable in 13 EGFR-mutated patients who were selected for treatment by cytology and 13 patients who were selected by histology. RESULTS: The mutation rate was similar in histology samples (8.5%) and cytology samples (8.8%). The RR (54%) and PFS (9.2 months) were similar in histologically selected patients and cytologically selected patients (RR, 62%; PFS, 8.6 months; P = .88). The disease control rate (responsive plus stable disease) was 92% in histologically selected patients and 100% in cytologically selected patients. CONCLUSIONS: EGFR mutations detected on cytology specimens by a centralized laboratory can predict TKI treatment response equally well as mutations identified on histology samples.
H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC// Marianeve Carotenuto 1,2 , Pasqualino De Antonellis 1,2 , Lucia Liguori 1,2 , Giovanna Benvenuto 3 , Daniela Magliulo 1,2 , Alessandro Alonzi 1,2 , Cecilia Turino 4 , Carmela Attanasio 1,2 , Valentina Damiani 1,2 , Anna Maria Bello 1,2 , Fabiana Vitiello 5 , Rosa Pasquinelli 6 , Luigi Terracciano 7 , Antonella Federico 8 , Alfredo Fusco 8 , Jamie Freeman 9 , Trevor C. Dale 9 , Charles Decraene 10,11 , Gennaro Chiappetta 6 , Francovito Piantedosi 5 , Cecilia Calabrese 4 and Massimo Zollo 1,2,12 1 Centro di Ingegneria Genetica e Biotecnologie Avanzate (CEINGE), Naples, Italy 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università ‘Federico II’ di Naples, Italy 3 Stazione Zoologica Anthon Dohrn, Villa Comunale, Naples, Italy 4 Dipartimento di Scienze Cardiotoraciche e Respiratorie, Clinica Seconda Università degli Studi di Napoli, Naples, Italy 5 Dipartimento di Pneumologia e Tisiologia, Day Hospital Pneumologia e Pneumoncologico, AORN Vincenzo Monaldi, Naples, Italy 6 Functional Genomic Unit, National Cancer Institute, Fondazione G. Pascale, Naples, Italy 7 Institute of Pathology, Molecular Pathology Division, University of Basel, Switzerland 8 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto Di Endocrinologia e Oncologia Sperimentale del CNR, Naples, Italy 9 School of Biosciences, Cardiff University, Museum Avenue, Cardiff, Wales, UK 10 Translational Research Dept, Institut Curie, Centre de recherche, Paris, France 11 CNRS, UMR144, Paris, France 12 Azienda Ospedaliera Federico II, DAI Medicina Trasfusionale, Naples, Italy Correspondence: Massimo Zollo1, email: // Keywords : h-Prune, lung cancer, diagnostic marker, WNT/β-catenin signalling, Gsk-3β, Wnt3a Received : June 18, 2014 Accepted : July 4, 2014 Published : July 5, 2014 Abstract H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3β). Gsk-3β is a negative regulator of canonical WNT/β-catenin signaling. Here, we investigate the role of Gsk-3β/h-Prune complex in the regulation of WNT/β-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer.
Italian Cohort of Nivolumab Expanded Access Program in Squamous Non-Small Cell Lung Cancer: Results from a Real-World PopulationAbstract Background Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients and Methods Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. Results The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. Conclusion To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Implications for Practice Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.