EGFR Mutation Heterogeneity and the Mixed Response to EGFR Tyrosine Kinase Inhibitors of Lung Adenocarcinomas
Open accessAbstract
BACKGROUND: Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon. METHODS: We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high-resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics. RESULTS: In the study population, the discordance rate was 13.9% (25 of 180). The multiple pulmonary nodules group had the highest discordance rate of 24.4% (10 of 41; odds ratio for heterogeneity in primary lesions detected at different times, 6.37; 95% confidence interval, 1.71-23.72; p = .006). Discordance rates in the metachronous and synchronous settings were 15.7% (22 of 140) and 7.5% (three of 40), respectively. In the 34 patients who developed EGFR TKI resistance, 10 (29.4%) cases exhibited heterogeneity and five (14.7%) patients exhibited a mixed response to the drug. Three (8.8%) of the patients with a mixed response also exhibited discordant EGFR mutations. CONCLUSIONS: The overall discordance rate of EGFR mutation heterogeneity in Asian patients with pulmonary adenocarcinoma is relatively low, but the rate in patients with multiple pulmonary nodules is significantly higher. This observation may explain the mixed tumor response to EGFR TKIs.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Discordance in molecular status between primary and metastatic sites may be linked to tumor heterogeneity between sites.
“A further consideration is discordance in molecular status between primary and metastatic sites, 45,46 which could be associated with tumor heterogeneity between the different sites of involvement.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
Self-citationMitsudomi, 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 · see citing works
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002003 · Cited by 3,499 · see citing works
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904554 · Cited by 2,373 · see citing works
Sequist, L. V., Martins, R. G., Spigel, D., Grunberg, S. M., Spira, A., Jänne, P. A., Joshi, V. A., McCollum, D., Evans, T. L., Muzikansky, A., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.8494 · Cited by 820 · see citing works
United States Food and Drug Administration Drug Approval Summary
Cohen, M. H., Williams, G. A., Sridhara, R., Chen, G., McGuinn, W. D., Morse, D. E., Abraham, S., Rahman, A., Liang, C., Lostritto, R. T., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0564 · Cited by 505 · see citing works
FDA Drug Approval Summary: Erlotinib (Tarceva®) Tablets
Cohen, M. H., Johnson, J. R., Chen, Y., Sridhara, R., & Pazdur, R. (2005) · The Oncologist · doi:10.1634/theoncologist.10-7-461 · Cited by 447 · see citing works
Ono, M., & Kuwano, M. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0646 · Cited by 364 · see citing works
Oxnard, G. R., Arcila, M. E., Chmielecki, J., Ladanyi, M., Miller, V. A., & Pao, W. J. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2571 · Cited by 355 · see citing works
Krypuy, M., Newnham, G. M., Thomas, D. M., Conron, M., & Dobrovic, A. (2006) · BMC Cancer · doi:10.1186/1471-2407-6-295 · Cited by 288 · see citing works
Consensus for EGFR Mutation Testing in Non-small Cell Lung Cancer: Results from a European Workshop
Pirker, R., Herth, F. J. F., Kerr, K. M., Filipits, M., Tarón, M., Gandara, D. R., Hirsch, F. R., Grunenwald, D. H., Popper, H., Smit, E. F., et al. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181f1c8de · Cited by 283 · see citing works
Schmid, K., Oehl, N., Wrba, F., Pirker, R., Pirker, C., & Filipits, M. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0089 · Cited by 261 · see citing works
Taniguchi, K., Okami, J., Kodama, K., Higashiyama, M., & Kato, K. (2008) · Cancer Science · doi:10.1111/j.1349-7006.2008.00782.x · Cited by 251 · see citing works
Zhou, Q. H., Zhang, X., Chen, Z., Yin, X., Yang, J., Xu, C., Yan, H., Chen, H., Su, J., Zhong, W., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.3757 · Cited by 243 · see citing works
Self-citationHeterogeneous Distribution of EGFR Mutations Is Extremely Rare in Lung Adenocarcinoma
Yatabe, Y., Matsuo, K., & Mitsudomi, T. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.3906 · Cited by 222 · see citing works
Gow, C., Chang, Y., Hsu, Y.-C., Tsai, M.-F., Wu, C., Yu, C., Yang, J. C., Lee, Y., Yang, P., & Shih, J. (2008) · Annals of Oncology · doi:10.1093/annonc/mdn679 · Cited by 211 · see citing works
Self-citationKalikaki, A., Koutsopoulos, A. V., Trypaki, M., Souglakos, J., Stathopoulos, E. N., Georgoulias, V., Mavroudis, D., & Voutsina, A. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604629 · Cited by 202 · see citing works
Evidence for Common Clonal Origin of Multifocal Lung Cancers
Wang, X., Wang, M., MacLennan, G. T., Abdul‐Karim, F. W., Eble, J. N., Jones, T. D., Olobatuyi, F. A., Eisenberg, R., Cummings, O. W., Zhang, S., et al. (2009) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djp054 · Cited by 162 · see citing works
Park, S. E., Tisch, A. H., Cho, E. Y., Shim, Y. M., Kim, J., Kim, H. S., Lee, J., Park, Y. H., Ahn, J. S., Park, K., et al. (2009) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181a94af4 · Cited by 145 · see citing works
Chung, J.-H., Choe, G., Jheon, S., Sung, S. W., Kim, T. J., Lee, K. W., Lee, J. H., & Lee, C. (2009) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181bc9731 · Cited by 121 · see citing works
Chang, Y., Wu, C., Lin, S., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1743 · Cited by 113 · see citing works
Girard, N., Deshpande, C. G., Azzoli, C. G., Rusch, V. W., Travis, W. D., Ladanyi, M., & Pao, W. J. (2009) · CHEST Journal · doi:10.1378/chest.09-0325 · Cited by 99 · see citing works
Jiang, S., Yamashita, K., Yamamoto, M., Chun-ji, P., Umezawa, A., Saegusa, M., Yoshida, T., Katagiri, M., Masuda, N., Hayakawa, K., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.23868 · Cited by 75 · see citing works
Chang, Y., Wu, C., Shih, J., & Lee, Y.-C. (2010) · Annals of Surgical Oncology · doi:10.1245/s10434-010-1295-6 · Cited by 56 · see citing works
Nakano, H., Soda, H., Takasu, M., Tomonaga, N., Yamaguchi, H., Nakatomi, K., Fujino, S., Hayashi, T., Nakamura, Y., Tsukamoto, K., et al. (2007) · Lung Cancer · doi:10.1016/j.lungcan.2007.08.021 · Cited by 44 · see citing works
Cheng, H., An, S., Dong, S., Yi-fang, Z., Zhang, X., Chen, Z., Jian-Su, & Wu, Y.-L. L. C. (2011) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-4-5 · Cited by 32 · see citing works
Self-citationSynchronous multiple primary lung cancers with different response to gefitinib
Ryoo, B., Na, I. I., Yang, S. H., et al. (2006) · Lung Cancer · doi:10.1016/j.lungcan.2006.05.010 · Cited by 17 · see citing works
Zhong, W., Wu, Y.-L. L. C., Yang, X.-N., et al. (2010) · Clinical Lung Cancer · doi:10.3816/clc.2010.n.020 · Cited by 7 · see citing works
Self-citationSynchronous Primary Lung Cancer and Epidermal Growth Factor Receptor Mutation
Ma, E. S. K., Cheng, P., Wong, C. L. P., et al. (2010) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2010.06.042 · Cited by 6 · see citing works
Two Lung Masses with Different Responses to Pemetrexed
Park, K. Y., Jung, J. W., Nam, S. B., et al. (2010) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2010.25.2.213 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
McGranahan, N., & Swanton, C. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.12.001 · Cited by 1,077 · see citing works
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 · see citing works
Self-citationTargeting EGFR in Lung Cancer: Current Standards and Developments
Díaz-Serrano, A., Gella, P., Jiménez, E., Zugazagoitia, J., & Paz-Ares Rodríguez, L. (2018) · Drugs · doi:10.1007/s40265-018-0916-4 · Cited by 108 · see citing works
Reguart, N., & Remon, J. (2015) · Future Oncology · doi:10.2217/fon.15.15 · Cited by 91 · see citing works
- Authors
- Chen, Z.-Y., Zhong, W.-Z., Zhang, X.-C., Su, J., Yang, X.-N., Chen, Z.-H., Yang, J.-J., Zhou, Q., Yan, H.-H., An, S.-J., Chen, H.-J., Jiang, B.-Y., Mok, T. S., & Wu, Y.-L.
- Affiliations
- Guangdong General Hospital (CN)
- a Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, China;
- Chinese University of Hong Kong (HK)
- Corresponding author
- Mok, Tony S.
- Wu, Yi-Long
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-06
- Volume
- 17
- Issue
- 7
- Pages
- 978-985
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC3399655
- OpenAlex
- W2118320591
- Cited by
- 165
- References
- 30
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 13 · 2020: 6 · 2019: 15 · 2018: 15 · 2017: 12 · 2016: 13 · 2015: 21 · 2014: 19 · 2013: 23 · 2012: 5
- FWCI
- 17.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81001031, 30772531)
- Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002)
- Natural Science Foundation of Guangdong (8151008004000015)
- Medical Research and Science Technology Foundation of Guangdong Province (A20100011)
- Chinese Lung Cancer Research Foundation
- 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 › Oncology › HER2/EGFR in Cancer Research
- Keywords
- EGFR mutation, intertumoral heterogeneity, lung adenocarcinoma, EGFR tyrosine kinase inhibitors, metachronous tumors, synchronous tumors, multiple pulmonary nodules, metastatic lymph nodes, EGFR tyrosine kinase inhibitor resistance
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Adult, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Genetic Heterogeneity, Protein Kinase Inhibitors, ErbB Receptors
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
