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Targeted Oncology

, Volume 13, Issue 5, pp 621–629 | Cite as

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP)

  • Alejandro Ruiz-Patiño
  • Christian David Castro
  • Luisa María Ricaurte
  • Andrés F. Cardona
  • Leonardo Rojas
  • Zyanya Lucia Zatarain-Barrón
  • Beatriz Wills
  • Noemí Reguart
  • Hernán Carranza
  • Carlos Vargas
  • Jorge Otero
  • Luis Corrales
  • Claudio Martín
  • Pilar Archila
  • July Rodriguez
  • Jenny Avila
  • Melissa Bravo
  • Luis Eduardo Pino
  • Rafael Rosell
  • Oscar Arrieta
  • On behalf of the Latin-American Consortium for the Investigation of Lung Cancer (CLICaP)
Original Research Article
  • 80 Downloads

Abstract

Background

Non-small cell lung cancer (NSCLC) has a 5-year survival of 5–16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role.

Objective

Compare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp.

Patients and Methods

Seventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status.

Results

30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3–34.6) vs. (11.0, 95% CI 8.2–16.7); p = 0.002] and OS [(37.8, 95% CI 30.9–44.7) vs. (27.1, 95% CI 12.8–41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0–44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4–42.5) (p < 0.001) and longer PFS (p = 0.043).

Conclusion

Among Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.

Notes

Acknowledgements

We are grateful for the generous contribution from the Silberman and Buendía families for altruistically promoting the development of cancer research in Colombia.

Compliance with Ethical Standards

Funding

Supported by the Foundation for Clinical and Applied Cancer Research (FICMAC, Bogotá, Colombia) research grant 017-2015.

Conflict of Interest

Andrés F. Cardona declares consulting fees or honorarium, support for travel to meetings for the study, manuscript preparation or other purposes, payment for lectures including service on speakers’ bureaus for Roche, Pfizer, Bristol-Myers Squibb, Merck, MSD, and AstraZeneca. Noemí Reguart declares advisory roles for Boehringer Ingelheim, Roche, AstraZeneca, Bristol Myers, and Pfizer, lectures and speaker bureaus for Boehringer Ingelheim, Roche, AstraZeneca, Bristol Myers, and Pfizer, and expert testimony for Boehringer Ingelheim, Roche, AstraZeneca, Bristol-Myers, and Pfizer. Luis Corrales declares that he has participated in advisory boards organized by AstraZeneca and received honoraria from AstraZeneca for lectures in scientific meetings. Oscar Arrieta declares advisory role, lectures, and speaker bureaus and expert testimony for Boehringer Ingelheim, Roche, AstraZeneca, and Lilly. Alejandro Ruiz-Patiño, Christian David Castro, Luisa María Ricaurte, Leonardo Rojas, Zyanya Lucia Zatarain-Barrón, Beatriz Wills, Hernán Carranza, Carlos Vargas, Jorge Otero, Claudio Martín, Pilar Archila, July Rodriguez, Jenny Avila, Melissa Bravo, Luis Eduardo Pino, and Rafael Rosell declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Fidler MM, Bray F, Soerjomataram I. The global cancer burden and human development: a review. Scand J Public Health. 2018;46(1):27–36.CrossRefGoogle Scholar
  2. 2.
    Barrón F, Zatarain-Barrón ZL, Cardona AF, Arrieta O. Extending the curve: survival of EGFR-mutated lung cancer patients in the 21st century. J Thorac Dis. 2018;10(3):1265–8.CrossRefGoogle Scholar
  3. 3.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.CrossRefGoogle Scholar
  4. 4.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123–32.CrossRefGoogle Scholar
  5. 5.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133–44.CrossRefGoogle Scholar
  6. 6.
    Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005;23(4):857–65.CrossRefGoogle Scholar
  7. 7.
    Huang SF, Liu HP, Li LH, Ku YC, Fu YN, Tsai HY, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004;10(24):8195–203.CrossRefGoogle Scholar
  8. 8.
    Arrieta O, Cardona AF, Martín C, Más-López L, Corrales-Rodríguez L, Bramuglia G, et al. Updated frequency of EGFR and KRAS mutations in nonsmall-cell lung cancer in Latin America: the Latin-American Consortium for the Investigation of Lung Cancer (CLICaP). J Thorac Oncol. 2015;10(5):838–43.CrossRefGoogle Scholar
  9. 9.
    Arrieta O, Cardona AF, Federico Bramuglia G, Gallo A, Campos-Parra AD, Serrano S, et al. Genotyping non-small cell lung cancer (NSCLC) in Latin America. J Thorac Oncol. 2011;6(11):1955–9.CrossRefGoogle Scholar
  10. 10.
    Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 2005;11(3):1167–73.PubMedGoogle Scholar
  11. 11.
    Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527–37.CrossRefGoogle Scholar
  12. 12.
    Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290(16):2149–58.CrossRefGoogle Scholar
  13. 13.
    Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21(12):2237–46.CrossRefGoogle Scholar
  14. 14.
    Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22(16):3238–47.CrossRefGoogle Scholar
  15. 15.
    Santarpia M, Altavilla G, Salazar MF, Magri I, Pettineo G, Benecchi S, et al. Tyrosine kinase inhibitors for non-small-cell lung cancer: finding patients who will be responsive. Expert Rev Respir Med. 2011;5(3):413–24.CrossRefGoogle Scholar
  16. 16.
    Zhang X, Zhang Y, Tang H, He J. EGFR gene copy number as a predictive/biomarker for patients with non-small-cell lung cancer receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis. J Investig Med. 2017;65(1):72–81.CrossRefGoogle Scholar
  17. 17.
    Taniguchi K, Okami J, Kodama K, Higashiyama M, Kato K. Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib. Cancer Sci. 2008;99(5):929–35.CrossRefGoogle Scholar
  18. 18.
    Bai H, Wang Z, Wang Y, Zhuo M, Zhou Q, Duan J, et al. Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One. 2013;8(2):e54170.CrossRefGoogle Scholar
  19. 19.
    Zhou Q, Zhang XC, Chen ZH, Yin XL, Yang JJ, Xu CR, et al. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(24):3316–21.CrossRefGoogle Scholar
  20. 20.
    Chang JW, Liu HP, Hsieh MH, Fang YF, Hsieh MS, Hsieh JJ, et al. Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients. Lung Cancer. 2008;61(3):328–39.CrossRefGoogle Scholar
  21. 21.
    Zhong WZ, Zhou Q, Wu YL. The resistance mechanisms and treatment strategies for EGFR-mutant advanced non-small-cell lung cancer. Oncotarget. 2017;8(41):71358–70.CrossRefGoogle Scholar
  22. 22.
    Gandhi J, Zhang J, Xie Y, Soh J, Shigematsu H, Zhang W, et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One. 2009;4(2):e4576.CrossRefGoogle Scholar
  23. 23.
    Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, et al. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One. 2009;4(10):e7464.CrossRefGoogle Scholar
  24. 24.
    Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94.CrossRefGoogle Scholar
  25. 25.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643–55.CrossRefGoogle Scholar
  26. 26.
    Dahabreh IJ, Linardou H, Kosmidis P, Bafaloukos D, Murray S. EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol. 2011;22(3):545–52.CrossRefGoogle Scholar
  27. 27.
    Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a southwest oncology group study. J Clin Oncol. 2005;23(28):6838–45.CrossRefGoogle Scholar
  28. 28.
    Hsu WH, Yang JC, Mok TS, Loong HH. Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol. 2018;29(suppl_1):i3–9.CrossRefGoogle Scholar
  29. 29.
    Shan L, Wang Z, Guo L, Sun H, Qiu T, Ling Y, et al. Concurrence of EGFR amplification and sensitizing mutations indicate a better survival benefit from EGFR-TKI therapy in lung adenocarcinoma patients. Lung Cancer. 2015;89(3):337–42.CrossRefGoogle Scholar
  30. 30.
    Zhao ZR, Wang JF, Lin YB, Wang F, Fu S, Zhang SL, et al. Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministration in non-small-cell lung cancer with acquired resistance. Med Oncol. 2014;31(1):810.CrossRefGoogle Scholar
  31. 31.
    Lee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol. 2015;33(17):1958–65.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Alejandro Ruiz-Patiño
    • 1
  • Christian David Castro
    • 1
  • Luisa María Ricaurte
    • 1
  • Andrés F. Cardona
    • 1
    • 2
    • 3
  • Leonardo Rojas
    • 2
    • 4
  • Zyanya Lucia Zatarain-Barrón
    • 5
  • Beatriz Wills
    • 6
  • Noemí Reguart
    • 7
  • Hernán Carranza
    • 1
    • 2
  • Carlos Vargas
    • 1
    • 2
  • Jorge Otero
    • 1
    • 2
  • Luis Corrales
    • 8
  • Claudio Martín
    • 9
  • Pilar Archila
    • 1
  • July Rodriguez
    • 1
  • Jenny Avila
    • 1
  • Melissa Bravo
    • 1
  • Luis Eduardo Pino
    • 10
  • Rafael Rosell
    • 11
  • Oscar Arrieta
    • 5
  • On behalf of the Latin-American Consortium for the Investigation of Lung Cancer (CLICaP)
  1. 1.Foundation for Clinical and Applied Cancer Research (FICMAC)BogotáColombia
  2. 2.Clinical and Translational Oncology Group, Institute of OncologyClínica del CountryBogotáColombia
  3. 3.Molecular Oncology and Biology Systems Research Group (FOX-G)Universidad El BosqueBogotáColombia
  4. 4.Clinical Oncology DepartmentClínica ColsanitasBogotáColombia
  5. 5.Thoracic Oncology Unit and Laboratory of Personalized MedicineInstituto Nacional de Cancerología (INCan)Mexico CityMexico
  6. 6.Internal Medicine DepartmentJohns Hopkins UniversityBaltimoreUSA
  7. 7.Medical Oncology DepartmentHospital ClinicBarcelonaSpain
  8. 8.Clinical Oncology DepartmentHospital San Juan de DiosSan JoséCosta Rica
  9. 9.Thoracic Oncology UnitAlexander Fleming InstituteBuenos AiresArgentina
  10. 10.Medical Oncology GroupFundación Santa Fe de BogotáBogotáColombia
  11. 11.Cancer Biology and Precision Medicine Program, Catalan Institute of OncologyHospital Germans Trias i PujolBadalona, BarcelonaSpain

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