Minuti G.,Civil Hospital of Livorno |
Landi L.,Civil Hospital of Livorno
Annals of Translational Medicine | Year: 2015
Background: Mesenchymal-epithelial transition (MET) is an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). MET has a normal function in organ development during embryogenesis and in tissue homeostasis during adult life. Deregulation of HGF/MET signaling pathway is frequently observed in many cancer types, conferring invasive growth and tendency to progression. MET deregulation is due to gene amplification or increased copy number, gene mutation, receptor over-expression or ligand autocrine loops activation. These events lead to migration, invasion, proliferation, metastatic spread and neo-angiogenesis of cancer cells, suggesting that anti-HGF/MET agents may represent a potential antitumor strategy. In breast cancer (BC), preclinical and clinical data demonstrated the role of HGF/MET signalling pathway in carcinogenesis, disease progression and resistance features. Methods: For this review article, all published data on HGF/MET in BC were collected and analyzed. Results: Several evidences underline that, in early BC, MET over-expression has an independent negative prognostic significance, regardless of method used for evaluation and BC subtypes. Available data suggest that MET is a relevant target particularly in basal-like (BL) and in triple negative BC. Moreover, preclinical and retrospective data support the critical role of MET deregulation in the development of resistance to target-agents, such as anti-HER2 strategies. Conclusions: MET is a promising new target in BC. Several anti-MET agents are under investigation and ongoing clinical trials will clarify its relevance in BC treatment. © Annals of Translational Medicine.
Treatment of advanced non-small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation or ALK gene rearrangement: Results of an International expert panel meeting of the Italian association of thoracic oncology
Gridelli C.,San Giuseppe Moscati Hospital |
De Marinis F.,Italian National Cancer Institute |
Cappuzzo F.,Civil Hospital of Livorno |
Di Maio M.,Italian National Cancer Institute |
And 7 more authors.
Clinical Lung Cancer | Year: 2014
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.
Patterns of care and clinical outcomes of first-line trastuzumab-based therapy in HER2-positive metastatic breast cancer patients relapsing after (Neo)adjuvant trastuzumab: An Italian multicenter retrospective cohort study
Lambertini M.,U.O. Oncologia Medica 2 |
Ferreira A.R.,University of Lisbon |
Poggio F.,U.O. Oncologia Medica 2 |
Puglisi F.,University of Udine |
And 15 more authors.
Oncologist | Year: 2015
Background. We evaluated the patterns of care and clinical outcomes of metastatic breast cancer patients treated with first-line trastuzumab-based therapy after previous (neo)adjuvant trastuzumab. Materials and Methods. A total of 416 consecutive, HER2-positive metastatic breast cancer patients who had received first-line trastuzumab-based therapy were identified at 14 Italian centers. A total of 113 patients had presented with de novo stage IV disease and were analyzed separately. Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models. Results. In the 202 trastuzumab-naive patients and 101 patients with previous trastuzumab exposure, we observed the following outcomes, respectively: overall response rate, 69.9% versus 61.3% (adjusted odds ratio [OR], 0.62; p =.131), clinical benefit rate, 79.1% versus 72.5% (adjusted OR, 0.73; p =.370), median progression-free survival (PFS), 16.1 months versus 12.0 months (adjusted hazards ratio [HR], 1.33; p =.045), and median overall survival (OS), 52.2 months versus 48.2 months (adjusted HR, 1.18; p =.404). Patients with a trastuzumab-free interval (TFI) <6 months, visceral involvement, and hormone receptor-negative disease showed a worse OS compared with patients with aTFI of $6 months (29.5 vs. 48.3 months; p =.331), nonvisceral involvement (48.0 vs. 60.3 months;p =.270), and hormone receptor-positive disease (39.8 vs. 58.6 months; p =.003), respectively. Conclusion. Despite the inferior median PFS, trastuzumab-based therapy was an effective first-line treatment for patients relapsing after (neo)adjuvant trastuzumab. Previous trastuzumab exposure and the respective TFI, type of first site of disease relapse, and hormone receptor status should be considered in the choice of the best first-line treatment option for HER2-positive metastatic breast cancer patients. © AlphaMed Press.
Minuti G.,Civil Hospital of Livorno |
Cappuzzo F.,Civil Hospital of Livorno |
Duchnowska R.,Military Institute of Medicine |
Jassem J.,Medical University of Gdańsk |
And 14 more authors.
British Journal of Cancer | Year: 2012
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.
Proietti A.,University of Pisa |
Ali G.,Santa Chiara Hospital |
Pelliccioni S.,Santa Chiara Hospital |
Lupi C.,Santa Chiara Hospital |
And 8 more authors.
Cancer Cytopathology | Year: 2014
BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are detected in approximately 5% of cases of non-Small cell lung cancer (NSCLC). Patients who are positive for ALK rearrangements may be successfully treated with the ALK inhibitor crizotinib. Because advanced-Stage lung cancers are not suitable for surgical resection, approximately 70% of patients are diagnosed via preoperative specimens. In the current study, the authors evaluated the suitability of stained cytologic direct smears and cell blocks for fluorescence in situ hybridization (FISH) to determine ALK status compared with small biopsies. METHODS: A total of 493 consecutive patients with NSCLC were analyzed by FISH for ALK gene rearrangements. The analyzed sample comprised 180 cytological samples, 94 direct smears, 86 cell blocks, and 313 preoperative small biopsies. Moreover, in the same series, 426 patients and 369 patients, respectively, were evaluated for epidermal growth factor receptor and KRAS mutations, respectively. RESULTS: Of the total of 493 patients, 18 patients who were positive for a gene rearrangement (4.4%) demonstrated ALK FISH rearrangements, whereas 387 patients (95.6%) were negative. All other cases were classified as inadequate (7.7%) and insufficient (10.1%). A strong statistical association was found between the cytology and the small biopsy with respect to ALK rearrangements (P5.0048). Fiftythree patients (12.4%) demonstrated an epidermal growth factor receptor mutation, whereas 90 patients (24.4%) were found to have KRAS mutations. None of these patients presented with ALK gene rearrangements. CONCLUSIONS: ALK gene rearrangements may be easily detected in cytological samples and particularly in direct smears, thereby yielding important improvements in the diagnostic approach to patients with advanced NSCLC. Cytological samples may be useful for ALK analysis when insufficient material is available in cell blocks or small biopsies. © 2014 American Cancer Society.
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 | Year: 2014
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.
PubMed | Science Oncologia Medica, Regina Elena Cancer Institute, Civil Hospital of Livorno and Azienda Ospedaliera Universitaria Pisana
Type: Journal Article | Journal: Clinical colorectal cancer | Year: 2014
To investigate whether microRNAs are predictive of sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC).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 Agilents miRNA platform.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.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.