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Livorno, Italy

Gridelli C.,San Giuseppe Moscati Hospital | De Marinis F.,Italian National Cancer Institute | Cappuzzo F.,Civil Hospital of Livorno | Di Maio M.,Clinical Trials Unit | And 7 more authors.
Clinical Lung Cancer

The availability of targeted drugs has made the assessment of the EGFR mutation and ALK rearrangement critical in choosing the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC). In May 2013, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting to review strengths and limitations of the available evidence for the diagnosis and treatment of advanced NSCLC with EGFR or anaplastic lymphoma kinase (ALK) alterations and to discuss implications for clinical practice and future clinical research. All patients with advanced NSCLC, with the exclusion of pure squamous cell carcinoma in former or current smokers, should be tested for EGFR mutations and ALK rearrangements before decisions are made on first-line treatment. First-line treatment of EGFR-mutated cases should be with an EGFR tyrosine kinase inhibitor (TKI). Any available agent (gefitinib, erlotinib, or afatinib) can be used, until further data from comparative studies may better guide TKI selection. As general rule, and when clinically feasible, results of EGFR mutational status should be awaited before starting first-line treatment. Panelists agreed that the use of crizotinib is justified in any line of treatment. Although solid evidence supporting the continuation of EGFR TKIs or crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified. Experimental strategies to target tumor heterogeneity and to treat patients after failure of EGFR TKIs or crizotinib are considered high-priority areas of research. A number of relevant research priorities were identified to optimize available treatment options. ©2014 Elsevier Inc. All rights reserved. Source

Minuti G.,Civil Hospital of Livorno | Cappuzzo F.,Civil Hospital of Livorno | Duchnowska R.,Military Institute of Medicine | Jassem J.,Medical University of Gdansk | And 14 more authors.
British Journal of Cancer

Background:To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC).Methods:We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN.Results:MET FISH-positive cases (N=36, mean ≥3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN ≥3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately.Conclusion:High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC. © 2012 Cancer Research UK. Source

Minuti G.,Civil Hospital of Livorno | D'Incecco A.,Civil Hospital of Livorno | Cappuzzo F.,Civil Hospital of Livorno
Expert Opinion on Biological Therapy

Introduction: Activating mutations of the epidermal growth factor receptor (EGFR) gene and rearrangement of anaplastic lymphoma kinase (ALK) gene best illustrate the therapeutic relevance of molecular characterization in non-small cell lung cancer (NSCLC) patients. Several genetic aberrations with a potential prognostic or predictive role have been identified, mainly in adenocarcinoma subtype, including ROS1, RET, MET, HER2, BRAF and KRAS. More recently oncogenic drivers, such as DDR2, FGFR1 and PI3KCA, have been characterized in squamous cell lung carcinoma (SCC) and target agents are currently under evaluation. The aim of this review is to summarize the growing scenario of new targetable oncogenes in NSCLC. Areas covered: For this review article all published data on NSCLC genomic alterations, including the techniques employed for oncogenic drivers identification, the prevalence of each one in lung cancer subtypes, the preclinical data corroborating their role in tumorigenesis and the potential biological tailored agents tested and under evaluation were collected and analyzed using PubMed. Expert opinion: Oncogenic products represent reliable targets for drug therapy and the expanding knowledge of molecular pathways involved in lung tumorigenesis is resulting in a dramatic change of treatment strategies leading to an improvement in disease and symptom control, extending life duration and improving quality of life. © 2013 Informa UK, Ltd. Source

Cappuzzo F.,Civil Hospital of Livorno | Sacconi A.,Regina Elena Cancer Institute | Landi L.,Civil Hospital of Livorno | Ludovini V.,Science Oncologia Medica | And 10 more authors.
Clinical Colorectal Cancer

Background To investigate whether microRNAs are predictive of sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). Methods A total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform. Results The study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P =.02) and longer overall survival (OS) (29.8 vs. 7.0 mo, P =.08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P =.02; OS 12.8 vs. 7.5 mo, P =.02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P =.016) and longer OS (16.1 vs. 10.9 mo, P =.09) than low-signature individuals, with no difference in KRAS mutated patients. Conclusion The MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy. © 2014 Elsevier Inc. All rights reserved. Source

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