PURPOSE: Improved prognostic accuracy for treatment response and a wider understanding of drug effects in humans are crucial for enhancing the utility of sorafenib and other promising targeted therapies. We developed a strategy of global genomic investigation of sequential tumor biopsy samples at baseline and 21 days post treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumors. The objective of this study was also to validate functional parameters of DCE-US as surrogate markers to predict earlier response. EXPERIMENTAL DESIGN: Patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1,000 mg/m(2) in a 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumors. Sequential biopsy samples (baseline and day 21) were obtained from the same tumor. Changes from baseline in global gene expression (GE) measured by genomic microarrays and in tumor vascularity at baseline, D8, D21, D 42 and every 2 cycles using dynamic contrast-enhanced ultrasonography (DCE-US) were analyzed for patients with and without a clinical response to treatment at 3 months. RESULTS: Among 23 patients evaluable for treatment efficacy, 17 were eligible for gene expression and DCE-US analyses. One patient achieved a partial response; 14 exhibited stable disease. Ten patients were defined as exhibiting stable disease (SD) and 7, progressive disease (PD) at 3 months. Genomic analyses identified a 237-gene signature that distinguished SD from PD at 3 months. Of note, CDK4 overexpression and PDGFR downregulation were associated with PD. Functional parameters of DCE-US representing the blood volume at baseline, day 8, and day 21 were correlated with disease progression at 3 months. CONCLUSIONS: This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumor vascularity evaluated using DCE-US that may be predictive of clinical outcome.
PURPOSE: Improved prognostic accuracy for treatment response and a wider understanding of drug effects in humans are crucial for enhancing the utility of sorafenib and other promising targeted therapies. We developed a strategy of global genomic investigation of sequential tumor biopsy samples at baseline and 21 days post treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumors. The objective of this study was also to validate functional parameters of DCE-US as surrogate markers to predict earlier response. EXPERIMENTAL DESIGN:Patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1,000 mg/m(2) in a 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumors. Sequential biopsy samples (baseline and day 21) were obtained from the same tumor. Changes from baseline in global gene expression (GE) measured by genomic microarrays and in tumor vascularity at baseline, D8, D21, D 42 and every 2 cycles using dynamic contrast-enhanced ultrasonography (DCE-US) were analyzed for patients with and without a clinical response to treatment at 3 months. RESULTS: Among 23 patients evaluable for treatment efficacy, 17 were eligible for gene expression and DCE-US analyses. One patient achieved a partial response; 14 exhibited stable disease. Ten patients were defined as exhibiting stable disease (SD) and 7, progressive disease (PD) at 3 months. Genomic analyses identified a 237-gene signature that distinguished SD from PD at 3 months. Of note, CDK4 overexpression and PDGFR downregulation were associated with PD. Functional parameters of DCE-US representing the blood volume at baseline, day 8, and day 21 were correlated with disease progression at 3 months. CONCLUSIONS: This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumor vascularity evaluated using DCE-US that may be predictive of clinical outcome.
Authors: F Piscaglia; C Nolsøe; C F Dietrich; D O Cosgrove; O H Gilja; M Bachmann Nielsen; T Albrecht; L Barozzi; M Bertolotto; O Catalano; M Claudon; D A Clevert; J M Correas; M D'Onofrio; F M Drudi; J Eyding; M Giovannini; M Hocke; A Ignee; E M Jung; A S Klauser; N Lassau; E Leen; G Mathis; A Saftoiu; G Seidel; P S Sidhu; G ter Haar; D Timmerman; H P Weskott Journal: Ultraschall Med Date: 2011-08-26 Impact factor: 6.548
Authors: H J Mackay; R J Buckanovich; H Hirte; R Correa; P Hoskins; J Biagi; L P Martin; G F Fleming; R Morgan; L Wang; R Polintan; A M Oza Journal: Gynecol Oncol Date: 2011-12-02 Impact factor: 5.482
Authors: D Scott McMeekin; Michael W Sill; Kathleen M Darcy; Deborah J Stearns-Kurosawa; Kenneth Webster; Steven Waggoner; Doris Benbrook Journal: Gynecol Oncol Date: 2007-06-27 Impact factor: 5.482
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962