TY - JOUR
T1 - Serial next-generation sequencing of circulating cell-free DNA evaluating tumor clone response to molecularly targeted drug administration
AU - Frenel, Jean Sebastien
AU - Carreira, Suzanne
AU - Goodall, Jane
AU - Roda, Desam
AU - Perez-Lopez, Raquel
AU - Tunariu, Nina
AU - Riisnaes, Ruth
AU - Miranda, Susana
AU - Figueiredo, Ines
AU - Nava-Rodrigues, Daniel
AU - Smith, Alan
AU - Leux, Christophe
AU - Garcia-Murillas, Isaac
AU - Ferraldeschi, Roberta
AU - Lorente, David
AU - Mateo, Joaquin
AU - Ong, Michael
AU - Yap, Timothy A.
AU - Banerji, Udai
AU - Tandefelt, Delila Gasi
AU - Turner, Nick
AU - Attard, Gerhardt
AU - De Bono, Johann S.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - Purpose: We evaluated whether next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating in early-phase clinical trials of targeted drugs. Experimental Design: Plasma samples from patients with known tumor mutations who completed at least two courses of investigational targeted therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent PGM platform. Results: cfDNA was extracted from 39 patients with various tumor types. Treatments administered targeted mainly the PI3K-AKT-mTOR pathway (n = 28) or MEK (n = 7). Overall, 159 plasma samples were sequenced with a mean sequencing coverage achieved of 1,685X across experiments. At trial initiation (C1D1), 23 of 39 (59%) patients had at least one mutation identified in cfDNA (mean 2, range 1-5). Out of the 44 mutations identified at C1D1, TP53, PIK3CA and KRAS were the top 3 mutated genes identified, with 18 (41%), 9 (20%), 8 (18%) different mutations, respectively. Out of these 23 patients, 13 received a targeted drug matching their tumor profile. For the 23 patients with cfDNA mutation at C1D1, the monitoring of mutation allele frequency (AF) in consecutive plasma samples during treatment with targeted drugs demonstrated potential treatment associated clonal responses. Longitudinal monitoring of cfDNA samples with multiple mutations indicated the presence of separate clones behaving discordantly. Molecular changes at cfDNA mutation level were associated with time to disease progression by RECIST criteria. Conclusions: Targeted NGS of cfDNA has potential clinical utility to monitor the delivery of targeted therapies.
AB - Purpose: We evaluated whether next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating in early-phase clinical trials of targeted drugs. Experimental Design: Plasma samples from patients with known tumor mutations who completed at least two courses of investigational targeted therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent PGM platform. Results: cfDNA was extracted from 39 patients with various tumor types. Treatments administered targeted mainly the PI3K-AKT-mTOR pathway (n = 28) or MEK (n = 7). Overall, 159 plasma samples were sequenced with a mean sequencing coverage achieved of 1,685X across experiments. At trial initiation (C1D1), 23 of 39 (59%) patients had at least one mutation identified in cfDNA (mean 2, range 1-5). Out of the 44 mutations identified at C1D1, TP53, PIK3CA and KRAS were the top 3 mutated genes identified, with 18 (41%), 9 (20%), 8 (18%) different mutations, respectively. Out of these 23 patients, 13 received a targeted drug matching their tumor profile. For the 23 patients with cfDNA mutation at C1D1, the monitoring of mutation allele frequency (AF) in consecutive plasma samples during treatment with targeted drugs demonstrated potential treatment associated clonal responses. Longitudinal monitoring of cfDNA samples with multiple mutations indicated the presence of separate clones behaving discordantly. Molecular changes at cfDNA mutation level were associated with time to disease progression by RECIST criteria. Conclusions: Targeted NGS of cfDNA has potential clinical utility to monitor the delivery of targeted therapies.
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U2 - 10.1158/1078-0432.CCR-15-0584
DO - 10.1158/1078-0432.CCR-15-0584
M3 - Article
C2 - 26085511
AN - SCOPUS:84940095522
SN - 1078-0432
VL - 21
SP - 4586
EP - 4596
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -