The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer

  • Park, Sehhoon (Department of Internal Medicine, Seoul National University Hospital) ;
  • Kim, Ji-Yeon (Department of Internal Medicine, Seoul National University Hospital) ;
  • Lee, Se-Hoon (Department of Internal Medicine, Seoul National University Hospital) ;
  • Suh, Beomseok (Department of Family Medicine and Health Promotion Center, Seoul National University Hospital) ;
  • Keam, Bhumsuk (Department of Internal Medicine, Seoul National University Hospital) ;
  • Kim, Tae Min (Department of Internal Medicine, Seoul National University Hospital) ;
  • Kim, Dong-Wan (Department of Internal Medicine, Seoul National University Hospital) ;
  • Heo, Dae Seog (Department of Internal Medicine, Seoul National University Hospital)
  • Received : 2015.09.01
  • Accepted : 2015.10.19
  • Published : 2017.05.01
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Abstract

Background/Aims: The predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment. Methods: Advanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis. KRAS mutations were observed in 45 subjects with mutation type as followed: G12C (n = 13), G12D (n = 12), G12V (n = 12), other (n = 8). Response rate (RR), progression-free survival (PFS), and overall survival (OS) of pemetrexed singlet and gemcitabine based chemotherapy were analysis. Results: Age, sex, performance status were well balanced between subjects with or without KRAS mutations. No difference was observed in RR. Hazard ratio (HR) of PFS for pemetrexed treated subjects with G12C mutation compared to subjects with KRAS wild type was 1.96 (95% confidential interval [CI], 1.01 to 3.79; p = 0.045), but other mutations failed to show clinical significance. By analysis done by PFS, compared to the subjects with transition mutation, HR was 1.48 (95% CI, 0.64 to 3.40; p = 0.360) for subjects with transversion mutation on pemetrexed treatment and 0.41 (95% CI, 0.19 to 0.87; p = 0.020) for subjects treated with gemcitabine based chemotherapy. No difference was observed in OS. Conclusions: In this study, different drug sensitivity was observed according to the type of KRAS mutation. NSCLC subpopulations with different KRAS mutation type should be considered as different subgroups and optimal chemotherapy regimens should be searched in further confirmative studies.

Keywords

Acknowledgement

Supported by : Innovative Research Institute

References

  1. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Nonsmall cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-594. https://doi.org/10.1016/S0025-6196(11)60735-0
  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. https://doi.org/10.3322/caac.20107
  3. Rosell R, Carcereny E, Gervais R, et al. 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. Lancet Oncol 2012;13:239-246. https://doi.org/10.1016/S1470-2045(11)70393-X
  4. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-2177. https://doi.org/10.1056/NEJMoa1408440
  5. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev 2010;29:49-60. https://doi.org/10.1007/s10555-010-9209-4
  6. Shankaran V, Obel J, Benson AB 3rd. Predicting response to EGFR inhibitors in metastatic colorectal cancer: current practice and future directions. Oncologist 2010;15:157-167. https://doi.org/10.1634/theoncologist.2009-0221
  7. Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2011;29:CRA7506. https://doi.org/10.1200/jco.2011.29.18_suppl.cra7506
  8. Graziano SL, Gamble GP, Newman NB, et al. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 1999;17:668-675. https://doi.org/10.1200/JCO.1999.17.2.668
  9. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with nonsmall cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010;69:272-278. https://doi.org/10.1016/j.lungcan.2009.11.020
  10. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008;14:5731-5734. https://doi.org/10.1158/1078-0432.CCR-08-0646
  11. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308. https://doi.org/10.1038/nrc2109
  12. Mascaux C, Iannino N, Martin B, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2005;92:131-139. https://doi.org/10.1038/sj.bjc.6602258
  13. Cadranel J, Mauguen A, Faller M, et al. Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project: part 2). J Thorac Oncol 2012;7:1490-1502. https://doi.org/10.1097/JTO.0b013e318265b2b5
  14. Meng D, Yuan M, Li X, et al. Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: a systematic review with meta-analysis. Lung Cancer 2013;81:1-10. https://doi.org/10.1016/j.lungcan.2013.03.019
  15. Zalcman G, Beau-Faller M, Creveuil C, et al. Use of Ras effector RASSF1A promoter gene methylation and chromosome 9p loss of heterozygosity (LOH) to predict progression-free survival (PFS) in perioperative chemotherapy (CT) phase III trial IFCT-0002 in resectable non-small cell lung cancer. J Clin Oncol 2008;26(15 Suppl):7500. https://doi.org/10.1200/jco.2008.26.15_suppl.7500
  16. D'Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 2012;7:1815-1822. https://doi.org/10.1097/JTO.0b013e31826bb7b2
  17. Loriot Y, Mordant P, Deutsch E, Olaussen KA, Soria JC. Are RAS mutations predictive markers of resistance to standard chemotherapy? Nat Rev Clin Oncol 2009;6:528-534. https://doi.org/10.1038/nrclinonc.2009.106
  18. Moran DM, Trusk PB, Pry K, Paz K, Sidransky D, Bacus SS. KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther 2014;13:1611-1624. https://doi.org/10.1158/1535-7163.MCT-13-0649
  19. Sun JM, Hwang DW, Ahn JS, Ahn MJ, Park K. Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer. PLoS One 2013;8:e64816. https://doi.org/10.1371/journal.pone.0064816
  20. Rodenhuis S, Boerrigter L, Top B, et al. Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J Clin Oncol 1997;15:285-291. https://doi.org/10.1200/JCO.1997.15.1.285
  21. Janne PA, Shaw AT, Pereira JR, et al. Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC). J Clin Oncol 2012;30:7503.
  22. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol 2011;29:3307-3315. https://doi.org/10.1200/JCO.2010.34.0570
  23. Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol 2013;31:1112-1121. https://doi.org/10.1200/JCO.2012.43.0454
  24. Lee YJ, Kim JH, Kim SK, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer 2011;72:9-15. https://doi.org/10.1016/j.lungcan.2010.12.013
  25. Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 2012;18:6169-6177. https://doi.org/10.1158/1078-0432.CCR-11-3265
  26. Andreyev HJ, Norman AR, Cunningham D, et al. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer 2001;85:692-696. https://doi.org/10.1054/bjoc.2001.1964
  27. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 2011;1:44-53. https://doi.org/10.1158/2159-8274.CD-10-0010
  28. Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 2012;104:228-239. https://doi.org/10.1093/jnci/djr523
  29. Garassino MC, Marabese M, Rusconi P, et al. Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol 2011;22:235-237. https://doi.org/10.1093/annonc/mdq680
  30. Nunez MI, Behrens C, Woods DM, et al. High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. J Thorac Oncol 2012;7:833-840. https://doi.org/10.1097/JTO.0b013e31824de09c
  31. Macerelli M, Caramella C, Faivre L, et al. Does KRAS mutational status predict chemoresistance in advanced nonsmall cell lung cancer (NSCLC)? Lung Cancer 2014;83:383-388. https://doi.org/10.1016/j.lungcan.2013.12.013
  32. Kamdar MK, Parent T, Walker PR. KRAS gene mutation status and sensitivity to pemetrexed: a retrospective analysis. J Clin Oncol 2013;31:e19154.
  33. Reck M, Popat S, Reinmuth N, et al. Metastatic nonsmall-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii27-iii39. https://doi.org/10.1093/annonc/mdu199

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