Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

Eiji Iwama, Kazuko Sakai, Noriko Hidaka, Koji Inoue, Akiko Fujii, Noriaki Nakagaki, Keiichi Ota, Ryo Toyozawa, Koichi Azuma, Keita Nakatomi, Taishi Harada, Junko Hisasue, Shinya Sakata, Takayuki Shimose, Junji Kishimoto, Yoichi Nakanishi, Kazuto Nishio, Isamu Okamoto

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Abstract

Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods: Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI–naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P <.001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P <.001) for EGFR-TKI–naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.

Original languageEnglish
JournalCancer
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Epidermal Growth Factor Receptor
Epidermal Growth Factor
Phosphotransferases
DNA
Protein-Tyrosine Kinases
Mutation
Therapeutics
Disease Progression
Clonal Evolution
Biopsy
Non-Small Cell Lung Carcinoma
Disease-Free Survival
Alleles
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors. / Iwama, Eiji; Sakai, Kazuko; Hidaka, Noriko; Inoue, Koji; Fujii, Akiko; Nakagaki, Noriaki; Ota, Keiichi; Toyozawa, Ryo; Azuma, Koichi; Nakatomi, Keita; Harada, Taishi; Hisasue, Junko; Sakata, Shinya; Shimose, Takayuki; Kishimoto, Junji; Nakanishi, Yoichi; Nishio, Kazuto; Okamoto, Isamu.

In: Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Iwama, E, Sakai, K, Hidaka, N, Inoue, K, Fujii, A, Nakagaki, N, Ota, K, Toyozawa, R, Azuma, K, Nakatomi, K, Harada, T, Hisasue, J, Sakata, S, Shimose, T, Kishimoto, J, Nakanishi, Y, Nishio, K & Okamoto, I 2019, 'Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors', Cancer. https://doi.org/10.1002/cncr.32481
Iwama, Eiji ; Sakai, Kazuko ; Hidaka, Noriko ; Inoue, Koji ; Fujii, Akiko ; Nakagaki, Noriaki ; Ota, Keiichi ; Toyozawa, Ryo ; Azuma, Koichi ; Nakatomi, Keita ; Harada, Taishi ; Hisasue, Junko ; Sakata, Shinya ; Shimose, Takayuki ; Kishimoto, Junji ; Nakanishi, Yoichi ; Nishio, Kazuto ; Okamoto, Isamu. / Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors. In: Cancer. 2019.
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abstract = "Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods: Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. Results: One hundred patients, including 87 who were EGFR-TKI na{\"i}ve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI–na{\"i}ve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P <.001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95{\%} CI, 2.07-10.79; P <.001) for EGFR-TKI–na{\"i}ve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.",
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T1 - Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

AU - Iwama, Eiji

AU - Sakai, Kazuko

AU - Hidaka, Noriko

AU - Inoue, Koji

AU - Fujii, Akiko

AU - Nakagaki, Noriaki

AU - Ota, Keiichi

AU - Toyozawa, Ryo

AU - Azuma, Koichi

AU - Nakatomi, Keita

AU - Harada, Taishi

AU - Hisasue, Junko

AU - Sakata, Shinya

AU - Shimose, Takayuki

AU - Kishimoto, Junji

AU - Nakanishi, Yoichi

AU - Nishio, Kazuto

AU - Okamoto, Isamu

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods: Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI–naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P <.001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P <.001) for EGFR-TKI–naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.

AB - Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment. Methods: Plasma samples were prospectively collected from non–small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing. Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI–naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P <.001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P <.001) for EGFR-TKI–naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04). Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.

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