Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy p
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RESEARCH
Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab Research
Carla Campanella1, Marcella Mottolese†2, Anna Cianciulli3, Angela Torsello1, Roberta Merola3, Isabella Sperduti4, Elisa Melucci2, Salvatore Conti2, Maria Grazia Diodoro2, Massimo Zeuli1, Giancarlo Paoletti5, Francesco Cognetti1 and Carlo Garufi*1
Abstract Background: Responsiveness to Cetuximab alone can be mediated by an increase of Epidermal Growth factor Receptor (EGFR) Gene Copy Number (GCN). Aim of this study was to assess the role of EGFR-GCN in advanced colorectal cancer (CRC) patients receiving chemotherapy plus Cetuximab. Methods: One hundred and one advanced CRC patients (43 untreated- and 58 pre-treated) were retrospectively studied by fluorescence in situ hybridization (FISH) to assess EGFR-GCN and by immunohistochemistry (IHC) to determine EGFR expression. Sixty-one out of 101 patients were evaluated also for k-ras status by direct sequencing. Clinical end-points were response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: Increased EGFR-GCN was found in 60/101 (59%) tumor samples. There was no correlation between intensity of EGFR-IHC and EGFR-GCN (p = 0.43). Patients receiving chemotherapy plus Cetuximab as first line treatment had a RR of 70% (30/43) while it was 18% (10/56) in the group with previous lines of therapy (p < 0.0001). RR was observed in 29/ 60 (48%) of patients with increased EGFR-GCN and in 6/28 (21%) in those without (p = 0.02). At multivariate analyses, number of chemotherapy lines and increased EGFR-GCN were predictive of response; EGFR-IHC score, increased EGFRGCN and number of chemotherapy lines were significantly associated with a significant better PFS. Response to therapy was the only prognostic predictive factor for OS. In the 60 patients analyzed for k-ras mutations, number of chemotherapy lines, increased EGFR-GCN and k-ras wild type status predicted a better PFS. Conclusion: In metastatic CRC patients treated with chemotherapy plus Cetuximab number of chemotherapy lines and increased EGFR-GCN were significantly associated with a better clinical outcome, independent of k-ras status. Introduction Treatment of advanced colorectal cancer (CRC) patients in the last ten years rapidly moved from a single agent 5fluorouracil (5-FU), modulated by Folinic Acid (FA), to combination chemotherapy including oxaliplatin (LOHP) and irinotecan (CPT-11). The addiction of monoclonal antibodies directed to the vascular endothelial growth factor (VEGF), or to the epidermal growth factor receptor (EGFR) to a regimen with CPT-11-FA-5-FU * Correspondence: [email protected] 1
Department of Medical Oncology, Regina Elena Institute, via E Chianesi 53, 00144 Rome, Italy † Contributed equally Full list of author information is available at the end of the article
increased progression free-survival (PFS) and overall survival (OS) in randomized phase III trials [1,2]. EGFR, whose locus is on the
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