Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Mok, Tony; Wu, Yi-Long; Lee, Jin Soo; Yu, Chong-Jen; Sriuranpong, Virote; Sandoval-Tan, Jennifer; Ladrera, Guia; Thongprasert, Sumitra; Srimuninnimit, Vichien; Liao, Meilin; Zhu, Yunzhong; Zhou, Caicun; Fuerte, Fatima; Margono, Benjamin; Wen, Wei; Tsai, Julie; Truman, Matt; Klughammer, Barbara; Shames, David S.; Wu, Lin

doi:10.1158/1078-0432.ccr-14-2594

Cited by 468Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Diagnosis and Treatment

The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.

Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Open access

Mok, Tony, Wu, Yi-Long, Lee, Jin Soo, Yu, Chong-Jen, Sriuranpong, Virote, Sandoval-Tan, Jennifer, Ladrera, Guia, Thongprasert, Sumitra, Srimuninnimit, Vichien, Liao, Meilin, Zhu, Yunzhong, Zhou, Caicun, Fuerte, Fatima, Margono, Benjamin, Wen, Wei, Tsai, Julie, Truman, Matt, Klughammer, Barbara, Shames, David S., Wu, Lin·2015·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-14-2594

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Purpose: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). Results: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14–0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut− cfDNA subgroup (HR, 0.83; 95% CI, 0.65–1.04, P = 0.1076). For patients with EGFR mut+ cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut+ cfDNA versus cycle 3 EGFR mut− patients, respectively (HR, 0.32; 95% CI, 0.21–0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31–0.84, P = 0.0066). Conclusions: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. Clin Cancer Res; 21(14); 3196–203. ©2015 AACR.

Integrity signals

Registry

Crossref · 10.1158/1078-0432.ccr-14-2594

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Concordance of tissue mutations detected in plasma samples can be approximately 90% in late-stage lung cancer.
“Concordance of tissue mutations detected in plasma samples can be ~90% in late-stage lung cancer71,72.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [71]
In the FAST-ACT2 study, failure to clear plasma EGFR mutations after three cycles of combined EGFR TKI and chemotherapy independently predicted shorter PFS and OS.
“the failure of clearance of plasma EGFR mutations after three cycles of combined EGFR TKI treatment and chemotherapy (the FAST-ACT2 study) was found to be an independent predictor of shorter PFS and OS.54”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [54]

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
Self-citation
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Rosell, R., Carcereny, E., Gervais, R., Vergnenegre, A., Massuti, B., Felip, E., Palmero, R., Garcia-Gomez, R., Pallares, C., Sanchez, J. M., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70393-x · Cited by 5,489
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., Tsurutani, J., Seto, T., Satouchi, M., Tada, H., Hirashima, T., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70364-x · Cited by 4,090
Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228
Self-citation
An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage
Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C. W., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3519 · Cited by 2,220
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
Wu, Y.-L., Zhou, C., Hu, C.-P., Feng, J., Lu, S., Huang, Y., Li, W., Hou, M., Shi, J. H., Lee, K. Y., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70604-1 · Cited by 1,978
Self-citation
Gefitinib Treatment in EGFR Mutated Caucasian NSCLC: Circulating-Free Tumor DNA as a Surrogate for Determination of EGFR Status
Douillard, J.-Y., Ostoros, G., Cobo, M., Ciuleanu, T., Cole, R., McWalter, G., Walker, J., Dearden, S., Webster, A., Milenkova, T., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000263 · Cited by 448

Flagged first, then by citations

Research works printed but not linked: 19

Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study, Lancet Oncol, 12, 735, 10.1016/S1470-2045(11)70184-X · DOI · Paper page
Han, 2012, First-SIGNAL: First-line single-agent Iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung, J Clin Oncol, 30, 1122, 10.1200/JCO.2011.36.8456 · DOI · Paper page
Paz-Ares, 2014, Pooled analysis of clinical outcomes for EGFR TKI-treated patients with EGFR mutation-positive NSCLC, J Cell Mol Med, 18, 1519, 10.1111/jcmm.12278 · DOI
Xue, 2012, National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China, Lung Cancer, 77, 371, 10.1016/j.lungcan.2012.04.014 · DOI
Xu, 2012, Can EGFR TKIs be used in first-line treatment for advanced non-small cell lung cancer based on selection according to clinical factors? A literature-based meta-analysis, J Haematol Oncol, 5, 62, 10.1186/1756-8722-5-62 · DOI
Bai, 2009, Epidermal growth factor receptor mutations in plasma DNA samples predict tumour response in Chinese patients with stages IIIB to IV non-small-cell lung cancer, J Clin Oncol, 27, 2653, 10.1200/JCO.2008.17.3930 · DOI
Kimura, 2007, Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA), Br J Cancer, 97, 778, 10.1038/sj.bjc.6603949 · DOI
Goto, 2012, Epidermal growth factor receptor mutation status in circulating free DNA in serum, J Thorac Oncol, 7, 115, 10.1097/JTO.0b013e3182307f98 · DOI
Kim, 2013, Detection of EGFR mutations in circulating free DNA by PNA-mediated PCR clamping, J Exp Clin Cancer Res, 32, 50, 10.1186/1756-9966-32-50 · DOI
Courard, 2014, Non invasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never-smokers: a proof-of-concept study from BioCAST/IFCT-1002, Clin Cancer Res, 20, 4613, 10.1158/1078-0432.CCR-13-3063 · DOI · Paper page
Oxnard, 2014, Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA, Clin Cancer Res, 20, 1698, 10.1158/1078-0432.CCR-13-2482 · DOI · Paper page
Mok, 2009, Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer, J Clin Oncol, 27, 5080, 10.1200/JCO.2008.21.5541 · DOI
Wu, 2013, Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial, Lancet Oncol, 14, 777, 10.1016/S1470-2045(13)70254-7 · DOI
Weber, 2014, Detection of EGFR mutations in plasma and biopsies from non-small-cell lung cancer patients by allele-specific PCR assays, BMC Cancer, 14, 294, 10.1186/1471-2407-14-294 · DOI
An, 2012, Identification of enriched driver gene alterations in subgroups of non-small-cell lung cancer patients based on histology and smoking status, PLoS ONE, 7, e40109, 10.1371/journal.pone.0040109 · DOI
Kamat, 2006, Circulating cell-free DNA: a novel biomarker for response to therapy in ovarian carcinoma, Cancer Biol Ther, 5, 1369, 10.4161/cbt.5.10.3240 · DOI
Ng, 2012, A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer, Nat Med, 18, 521, 10.1038/nm.2713 · DOI · Paper page
Bottcher, 2012, Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial, J Clin Oncol, 30, 980, 10.1200/JCO.2011.36.9348 · DOI
Leduc, 2014, Tumour burden and tyrosine kinase inhibitors (TKI) benefit in advanced non-small-cell lung cancer (NSCLC) patients with EGFR sensitizing mutations (mEGFR) and ALK rearrangement (ALK+) [abstract 92O], J Thorac Oncol, 9, S37

Sorted by citations

Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review
Merker, J. D., Oxnard, G. R., Compton, C., Diehn, M., Hurley, P., Lazar, A. J., Lindeman, N., Lockwood, C. M., Rai, A. J., Schilsky, R. L., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.76.8671 · Cited by 959
ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: A report from the ESMO Precision Medicine Working Group
Pascual, J., Attard, G., Bidard, F.-C., Curigliano, G., De Mattos-Arruda, L., Diehn, M., Italiano, A., Lindberg, J., Merker, J. D., Montagut, C., et al. (2022) · Annals of Oncology · doi:10.1016/j.annonc.2022.05.520 · Cited by 783
Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses
Sundaresan, T. K., Sequist, L. V., Heymach, J. V., Riely, G. J., Jänne, P. A., Koch, W. H., Sullivan, J. P., Fox, D. B., Maher, R., Muzikansky, A., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1031 · Cited by 347
A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma
Reckamp, K. L., Melnikova, V. O., Karlovich, C., Sequist, L. V., Camidge, D. R., Wakelee, H., Perol, M., Oxnard, G. R., Kosco, K., Croucher, P., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.05.035 · Cited by 287
The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016
Tan, D. S. W., Yom, S. S., Tsao, M. S., Pass, H. I., Kelly, K., Peled, N., Yung, R. C., Wistuba, I. I., Yatabe, Y., Unger, M., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.05.008 · Cited by 201
Self-citation
Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA
Chae, Y. K., Davis, A. A., Carneiro, B. A., Chandra, S., Mohindra, N., Kalyan, A., Kaplan, J., Matsangou, M., Pai, S., Costa, R., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11692 · Cited by 110
Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer
Tan, C.-S., Cho, B.-C., & Soo, R. A. (2016) · Lung Cancer · doi:10.1016/j.lungcan.2016.01.003 · Cited by 105
Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes
Palma, G., Khurshid, F., Lu, K., Woodward, B., & Husain, H. (2021) · npj Precision Oncology · doi:10.1038/s41698-021-00237-5 · Cited by 72
Dynamic monitoring of EGFR mutations in circulating cell-free DNA for EGFR-mutant metastatic patients with lung cancer: Early detection of drug resistance and prognostic significance
Ni, J., Weng, L., Liu, Y., Sun, Z., Bai, C., & Wang, Y. (2017) · Oncology Letters · doi:10.3892/ol.2017.6022 · Cited by 23

Authors: Mok, T., Wu, Y.-L., Lee, J. S., Yu, C.-J., Sriuranpong, V., Sandoval-Tan, J., Ladrera, G., Thongprasert, S., Srimuninnimit, V., Liao, M., Zhu, Y., Zhou, C., Fuerte, F., Margono, B., Wen, W., Tsai, J., Truman, M., Klughammer, B., Shames, D. S., & Wu, L.
Affiliations: Chinese University of Hong Kong (HK)
Guangdong General Hospital (CN)
National Cancer Center (KR)
National Taiwan University Hospital (TW)
Chulalongkorn University (TH)
Philippine General Hospital (PH)
Lung Center of the Philippines (PH)
Chiang Mai University (TH)
Siriraj Hospital (TH)
Shanghai Chest Hospital (CN)
Beijing Chest Hospital (CN)
Tongji University (CN)
13Rizal Medical Center, Pasig City, Philippines.
Rumah Sakit Dokter Soetomo (ID)
15Roche Molecular Systems, Inc., Pleasanton, California.
16Roche Products Ltd, Dee Why, Australia.
F. Hoffmann-La Roche AG (CH)
Genentech (US)
ORCID: Mok, Tony
Wu, Yi-Long
Lee, Jin Soo
Yu, Chong-Jen
Sriuranpong, Virote
Zhou, Caicun
Klughammer, Barbara
Shames, David S.
Wu, Lin
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2015-07-14
Volume: 21
Issue: 14
Pages: 3196-3203
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-14-2594
OpenAlex: W2070059866
Cited by: 468
References: 8
Citations by year: 2026: 4 · 2025: 10 · 2024: 28 · 2023: 23 · 2022: 42 · 2021: 49 · 2020: 46 · 2019: 64 · 2018: 66 · 2017: 72 · 2016: 49 · 2015: 15
FWCI: 53.26
Type: journal article
Language: en
Open access: green
doi.org
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Greater South Information System
Funders: F. Hoffmann-La Roche
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: EGFR mutation, circulating tumor DNA, non-small cell lung cancer, erlotinib, first-line therapy, liquid biopsy, progression-free survival, overall survival, treatment response prediction
MeSH terms: Erlotinib Hydrochloride, Gemcitabine, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Deoxycytidine, DNA Mutational Analysis, DNA, Neoplasm, Double-Blind Method, Female, Humans, Intercalating Agents, Lung Neoplasms, Male, Middle Aged, Mutation, Treatment Outcome, Platinum Compounds, Disease-Free Survival, Genes, erbB-1, Kaplan-Meier Estimate

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Metadata

Record

About these checks