odels. Clinical responses were observed in a recent 200 patient phase II study of AZD6244 vs temozolomide in patients with advanced melanoma. Six patients randomised to AZD6244 had a confirmed partial response, of whom five had BRAFt tumours. Nine patients randomised to temozolomide had a confirmed partial response, three of whom had BRAFt tumours. Tandutinib FLT inhibitor In subsequent clinical trials of this drug, patients will be screened and selected on the basis of the mutational status of their tumour. In particular, future clinical trials of AZD6244 in advanced melanoma will evaluate patient selection on the basis of tumour mutation status. Mutation status is traditionally assessed by analysis of DNA extracted from archival tumour tissue samples. However, biopsy material is not always readily available, even in patients with metastatic melanoma.
Furthermore, limited and degraded amounts of DNA extracted from tumour biopsies and formalin fixed paraffin embedded tissues present an inherent technical challenge in mutation detection. If the response to a therapeutic agent depends on the presence or absence of a particular DNA mutation, Nutlin-3 548472-68-0 then the availability of tumour derived DNA for mutation analysis becomes critically important. An alternative source of tumour derived DNA is cell free or circulating free DNA. This can be extracted from plasma and serum, providing an opportunity to develop a less invasive Received 16 July 2009, revised 14 September 2009, accepted 17 September 2009, published online 27 October 2009 Correspondence: Professor A Hughes, Journal of Cancer 101, 1724 1730& 2009 Cancer Research UK All rights reserved 0007 0920/09 $32.
00 www.bjcancer.com Molecular Diagnostics and more accessible source of tumour DNA for mutation detection. Previous studies have demonstrated the feasibility of detecting tumour specific mutations in cfDNA from patients with cancer, including detection of epidermal growth factor receptor mutations in patients with non small cell lung cancer and KRAS mutations in patients with pancreatic and colorectal cancers. More recently, BRAF mutations have been detected in cfDNA of patients with melanoma. However, these initial studies included a small number of patients with only limited numbers of matched tumour samples.
In this study, we investigated the potential utility of cfDNA for the detection of BRAF mutation status in a large group of patients enrolled into the AZD6244 advanced melanoma phase II study to determine whether cfDNA mutations could be used for patient selection as an alternative to tissue biopsies. MATERIALS AND METHODS Patients and samples A total of 200 patients with advanced melanoma were enrolled into study D1532C00003. The study was conducted according to Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent before participation in the main study. Consent for analysis of tumour biopsy material was obtained from all patients enrolled in the study and additional voluntary consent for collection of serum samples for genetic analysis was given by 126 patients. Blood processing for cfDNA extraction At the time of enrolment, 8.5 ml of peripheral blood was taken in a Becton Dickinson Vacutainer Serum Collection Tube and gently inverted for a minimum of five times to ensure a thorough mixing of the sample. The blood was allowed to clot for 30 min and was centrifuged at 2000 g for 10 min. The resultant serum supernatan
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