Prospective study of oncogenic mutations in circulating cell-free DNA (cfDNA) using a multiplex sequencing platform for patient (pt) allocation to phase I clinical trials

Autor: Kirsty Moran, Amy Mulick Cassidy, Stanley B. Kaye, Timothy A. Yap, Jen Kate Lewis, Ruth Riisnaes, Géraldine Perkins, Jesus Corral Jaime, Sadiya Saeed, Michael Ong, Helen Nicole Toloui, L Rhoda Molife, Khin Thway, Lorna Pope, Udai Banerji, Joaquin Mateo, K. A. Denholm, Andrea Biondo, Penelope Flohr, Johann S. de Bono
Rok vydání: 2012
Předmět:
Zdroj: Journal of Clinical Oncology. 30:10525-10525
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2012.30.15_suppl.10525
Popis: 10525 Background: Studies suggest that tumoral cfDNA can be isolated from plasma and used as a biomarker. Methods: We conducted a prospective study in adult pts with advanced cancer referred for phase I clinical trials Sep09-Dec10 (A: Pilot Phase n=104) and Jan11-Sep11 (B: Expansion Phase n=176). cfDNA and tumor DNA from formalin-fixed paraffin-embedded (FFPE) tissue were isolated, quantified, and analyzed for 238 mutations in 19 oncogenes by the Sequenom OncoCarta Panel 1.0. Mutation data were used for trial allocation when available. Pt data and outcomes were collected. Statistical inferences used Wilcoxon rank-sum and Pearson’s Chi-squared. Results: 280 pts enrolled including breast (60), colorectal (42), ovarian (37), lung (31), and prostate (20); median age 60yrs [23-81]; 93% ECOG PS 0-1. cfDNA in 95% and FFPE in 60% were analyzed. Median time to cfDNA result, trial allocation and consent were 7 [5-14], 6 and 23 d. Median cancer pt cfDNA concentration (ng/ml) (A: 18 [1-1600]; B: 34 [16-1657]) was higher than 20 healthy volunteers (6 [5-13] A: p=0.0001) and higher in metastatic vs locally advanced cancer (A: 21 vs 4 p=0.0006; B: 42 vs 24 p=0.066). Pts with higher than median [cfDNA] had shorter median survival (MST) than below (A: 217 vs 274 d, HR 1.72 95% CI 1.07-2.65, p=0.025; B: MST not reached yet). Mutations were found in 89 pts (32%), including KRAS (11%), PIK3CA (5%), MET (5%), BRAF (4%), and AKT (2%). cfDNA mutations (57 pts, 21.5%) were mainly found above the median [cfDNA] (A: 41 vs 17% χ2=6.9, p=0.009; B: 24 vs 11% χ2=5.0, p=0.025). Of 155 pts with both cfDNA and FFPE available, 68 had mutations detected: 30 identical in cfDNA and FFPE; 28 in FFPE alone and 10 in cfDNA alone. Overall, 153 pts were treated on a phase I trial; 23 pts had relevant mutation data and received a trial targeting the PI3-Akt-mTOR axis. Conclusions: Higher cfDNA is associated with greater disease burden, worse prognosis, and higher mutation detection rate, suggesting cfDNA is tumorally derived. Moreover, cfDNA can be analyzed for oncogenic mutations in a time-frame suitable for clinical decision making, making it a potentially useful non-invasive adjunct to tumour DNA analysis.
Databáze: OpenAIRE
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