5 results on '"Kopetz, E. S."'
Search Results
2. Impact of multimodal therapy in locally recurrent rectal cancer
- Author
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You, Y. N., Skibber, J. M., Hu, C.-Y., Crane, C. H., Das, P., Kopetz, E. S., Eng, C., Feig, B. W., Rodriguez-Bigas, M. A., and Chang, G. J.
- Published
- 2016
- Full Text
- View/download PDF
3. Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction.
- Author
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Janku, F., Huang, H. J., Fujii, T., Shelton, D. N., Madwani, K., Fu, S., Tsimberidou, A. M., Piha-Paul, S. A., Wheler, J. J., Zinner, R. G., Naing, A., Hong, D. S., Karp, D. D., Cabrilo, G., Kopetz, E. S., Subbiah, V., Luthra, R., Kee, B. K., Eng, C., and Morris, V. K.
- Subjects
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ELECTRON-transfer catalysis , *GENES , *BIOMOLECULES , *CANCER invasiveness , *POLYMERASE chain reaction - Abstract
Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy. Patients and methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRAS G12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care. Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of≥6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P=0.001). Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
4. PIK3CA mutations in plasma circulating tumor DNA predict survival and treatment outcomes in patients with advanced cancers.
- Author
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Dumbrava EE, Call SG, Huang HJ, Stuckett AL, Madwani K, Adat A, Hong DS, Piha-Paul SA, Subbiah V, Karp DD, Fu S, Naing A, Tsimberidou AM, Moulder SL, Koenig KH, Barcenas CH, Kee BK, Fogelman DR, Kopetz ES, Meric-Bernstam F, and Janku F
- Subjects
- Biomarkers, Tumor genetics, Class I Phosphatidylinositol 3-Kinases genetics, Female, Humans, Mutation, Phosphatidylinositol 3-Kinases genetics, Treatment Outcome, Breast Neoplasms, Circulating Tumor DNA genetics
- Abstract
Background: Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations., Patients and Methods: We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes., Results: Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048)., Conclusions: Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF., Competing Interests: Disclosure FJ has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, PIQUR, Symphogen, Bristol-Myers Squibb, Asana, and Upsher-Smith Laboratories; is or has been on the Scientific Advisory Boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Cardiff Oncology and ImmunoMet; and has ownership interests in Cardiff Oncology. MF reports grants and personal consulting fees through 06/04/18 from Seattle Genetics and salary and stocks from 10/01/18 following the start of her employment with Seattle Genetics; grants and personal fees from Takeda, Celgene, BMS, and Merck through 06/04/18; grants from ADC Therapeutics, Molecular Templates, MedImmune, Gilead, and Genentech through 06/04/18; and personal fees from Bayer and Spectrum through 06/04/18. VS has research funding/grant support for clinical trials (to institution) from Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning point therapeutics, and Boston Pharmaceuticals; travel funding from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte; and serves on the advisory board of Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, Astra-Zeneca/Medimmune, Novartis, Signant Health. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
- Full Text
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5. Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification.
- Author
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Liu L, Toung JM, Jassowicz AF, Vijayaraghavan R, Kang H, Zhang R, Kruglyak KM, Huang HJ, Hinoue T, Shen H, Salathia NS, Hong DS, Naing A, Subbiah V, Piha-Paul SA, Bibikova M, Granger G, Barnes B, Shen R, Gutekunst K, Fu S, Tsimberidou AM, Lu C, Eng C, Moulder SL, Kopetz ES, Amaria RN, Meric-Bernstam F, Laird PW, Fan JB, and Janku F
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- Adolescent, Adult, Aged, Biomarkers, Tumor blood, Case-Control Studies, Cell-Free Nucleic Acids blood, Combined Modality Therapy, DNA, Neoplasm blood, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms blood, Neoplasms therapy, Prognosis, Survival Rate, Young Adult, Biomarkers, Tumor genetics, Cell-Free Nucleic Acids genetics, DNA Methylation, DNA, Neoplasm genetics, Neoplasms classification, Neoplasms genetics
- Abstract
Background: Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis., Patients and Methods: We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes., Results: Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016)., Conclusions: Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.
- Published
- 2018
- Full Text
- View/download PDF
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