Skip to main content

Advertisement

SpringerLink
Log in

Should KRAS mutation still be used as a routine predictor of response to EGFR-TKIs in advanced non-small-cell lung cancer? A revaluation based on meta-analysis

  • Review – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Regarding the controversial investigations characterizing the role of KRAS status for predicting patients’ response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC), we conducted a meta-analysis in unselected patients and a further subset analysis in EGFR wild-type advanced NSCLC to get a more accurate evaluation.

Methods

We did systematically searches following the retrieval strategies. The end points were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).

Results

Twelve prospective intervention trials comprised of 1,859 unselected advanced NSCLC patients were identified. KRAS mutation was associated with shorter OS and PFS [hazard ratio (HR) 2.09, 95 % confidence interval (CI) 1.56–2.80; HR 1.82, 95 % CI 1.50–2.20] and lower ORR (relative ratio 0.25, 95 % CI 0.11–0.59) in unselected advanced NSCLC. After subgroup analysis, the association with survival was strengthened in second- or later-line EGFR-TKIs treatment group, with an HR of 2.45 for OS (95 % CI 1.27–4.74) and 1.86 for PFS (95 % CI 1.51–2.29), while the association with response to EGFR-TKIs became nonsignificant (P = 0.153). Four retrospective studies on the role of KRAS status in EGFR wild-type advanced NSCLC were deemed eligible and presented that KRAS mutation was associated with none of the outcomes in EGFR wild-type patients treated with EGFR-TKIs.

Conclusions

In unselected advanced NSCLC patients, KRAS mutations could be used as a potential negative predictor of clinical benefit from EGFR-TKIs. However, KRAS testing is of limited value to identify patients for EGFR-TKIs when EGFR status is considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  PubMed  CAS  Google Scholar 

  • Boldrini L, Alì G, Gisfredi S et al (2009) Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. Oncol Rep 22:683–691

    PubMed  CAS  Google Scholar 

  • Brugger W, Triller N, Blasinska-Morawiec M et al (2011) Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 29:4113–4120

    Article  PubMed  CAS  Google Scholar 

  • Califano R, Landi L, Cappuzzo F (2012) Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. Drugs 72:28–36

    Article  PubMed  CAS  Google Scholar 

  • Cappuzzo F, Ligorio C, Janne PA et al (2007) Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol 25:2248–2255

    Article  PubMed  CAS  Google Scholar 

  • Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

    Article  PubMed  CAS  Google Scholar 

  • Dearden S, Stevens J, Wu YL, Blowers D (2013) Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 24:2371–2376

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  PubMed  CAS  Google Scholar 

  • Douillard JY, Shepherd FA, Hirsh V et al (2010) Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28:744–752

    Article  PubMed  CAS  Google Scholar 

  • Eberhard DA, Johnson BE, Amler LC et al (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900–5909

    Article  PubMed  CAS  Google Scholar 

  • Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ettinger DS, Akerley W, Borghaei H et al (2012) Non-small cell lung cancer. J Natl Compr Cancer Netw 10:1236–1271

    CAS  Google Scholar 

  • FDA (2007) Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. http://www.fda.gov/cber/guidelines.htm. Accessed 24 July 2014

  • Felip E, Rojo F, Reck M et al (2008) A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res 14:3867–3874

    Article  PubMed  CAS  Google Scholar 

  • Ferlay J, Soerjomataram I, Ervik M et al (2012) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon. http://globocan.iarc.fr. Accessed 12 Dec 2013

  • Gao G, Ren S, Li A et al (2012) Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. Int J Cancer 131:E822–E829

    Article  PubMed  CAS  Google Scholar 

  • Garassino MC, Martelli O, Broggini M et al (2013) Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 14:981–988

    Article  PubMed  CAS  Google Scholar 

  • Giaccone G, Gallegos Ruiz M, Le Chevalier T et al (2006) Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 12:6049–6055

    Article  PubMed  CAS  Google Scholar 

  • Guan JL, Zhong WZ, An SJ et al (2013) KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol 20:1381–1388

    Article  PubMed  Google Scholar 

  • Hirsch FR, Varella-Garcia M, Bunn PA Jr et al (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807

    Article  PubMed  CAS  Google Scholar 

  • Hirsch FR, Varella-Garcia M, Bunn PA Jr et al (2006) Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034–5042

    Article  PubMed  CAS  Google Scholar 

  • Hirsch FR, Kabbinavar F, Eisen T et al (2011) A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. J Clin Oncol 29:3567–3573

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jackman DM, Miller VA, Cioffredi LA et al (2009) Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 15:5267–5273

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Karampeazis A, Voutsina A, Souglakos J et al (2013) Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer 119:2754–2764

    Article  PubMed  CAS  Google Scholar 

  • Kerner GS, Schuuring E, Sietsma J et al (2013) Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome. PLoS ONE 8:e70346

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kris M, Johnson B, Kwiatkowski D et al (2011) 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 29(Suppl 18). Abstract CRA7506

  • Lee JK, Hahn S, Kim DW et al (2014) Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor. JAMA 311:1430–1437

    Article  PubMed  Google Scholar 

  • Linardou H, Dahabreh IJ, Kanaloupiti D et al (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 9:962–972

    Article  PubMed  CAS  Google Scholar 

  • Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  PubMed  CAS  Google Scholar 

  • Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    PubMed  CAS  Google Scholar 

  • Mao C, Qiu LX, Liao RY et al (2010) KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 69:272–278

    Article  PubMed  Google Scholar 

  • Maruyama R, Nishiwaki Y, Tamura T et al (2008) Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol 26:4244–4252

    Article  PubMed  CAS  Google Scholar 

  • Mascaux C, Iannino N, Martin B et al (2005) The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 92:131–139

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Metro G, Chiari R, Duranti S et al (2012) Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer 78:81–86

    Article  PubMed  Google Scholar 

  • Milella M, Nuzzo C, Bria E et al (2012) EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. J Thorac Oncol 7:672–680

    Article  PubMed  CAS  Google Scholar 

  • Miller VA, Riely GJ, Zakowski MF et al (2008) Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 26:1472–1478

    Article  PubMed  CAS  Google Scholar 

  • Mitsudomi T, Morita S, Yatabe Y et al (2010) 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. Lancet Oncol 11:121–128

    Article  PubMed  CAS  Google Scholar 

  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): non-small cell lung cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed 23 March 2014

  • Ohashi K, Sequist LV, Arcila ME et al (2013) Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res 19:2584–2591

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Oxnard GR, Janne PA (2012) KRAS wild-type lung cancer: a moving target in an era of genotype migration. J Clin Oncol 30:3322–3324

    Article  PubMed  CAS  Google Scholar 

  • Pao W, Wang TY, Riely GJ et al (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17

    Article  PubMed  PubMed Central  Google Scholar 

  • Pirker R, Pereira JR, von Pawel J (2012) EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 13:33–42

    Article  PubMed  CAS  Google Scholar 

  • Ramalingam SS, Spigel DR, Chen D et al (2011) Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J Clin Oncol 29:4574–4580

    Article  PubMed  CAS  Google Scholar 

  • Riely GJ, Marks J, Pao W (2009) KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc 6:201–205

    Article  PubMed  CAS  Google Scholar 

  • Roberts PJ, Stinchcombe TE (2013) KRAS mutation: should we test for it, and does it matter? J Clin Oncol 31:1112–1121

    Article  PubMed  CAS  Google Scholar 

  • Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA (2010) Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 28:4769–4777

    Article  PubMed  CAS  Google Scholar 

  • Rosell R, Carcereny E, Gervais R et al (2012) 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 13:239–246

    Article  PubMed  CAS  Google Scholar 

  • Schneider CP, Heigener D, Schott-von-Römer K et al (2008) Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J Thorac Oncol 3:1446–1453

    Article  PubMed  Google Scholar 

  • Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS (2014) Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. doi:10.1093/annonc/mdu378

    PubMed  Google Scholar 

  • Sun JM, Hwang DW, Ahn JS, Ahn MJ, Park K (2013) Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer. PLoS ONE 8:e64816

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  • Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang J, Dong Y, Cai Y et al (2014) Clinicopathologic characteristics of ALK rearrangements in primary lung adenocarcinoma with identified EGFR and KRAS status. J Cancer Res Clin Oncol 140:453–460

    Article  PubMed  CAS  Google Scholar 

  • Zhu CQ, da Cunha Santos G, Ding K et al (2008) Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR. 21. J Clin Oncol 26:4268–4275

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from National Natural Science Foundation of China (No. 81001047/H1615), Excellent Young Teachers Program of Higher Education of Guangdong Province (Yq2013040), and Research Fund for the Science and technology Star of Zhujiang of Guangzhou City (2014J2200031).

Conflict of interest

No potential conflict of interest to disclose.

Ethical standard

The manuscript does not contain clinical studies or patient data.

Author information

Author notes

    Authors and Affiliations

    1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China

      Min Ying, Xiaoxia Zhu, Zhou Sha & Longhua Chen

    2. The First Clinical Medical College, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China

      Kexu Chen

    Authors
    1. Min Ying
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiaoxia Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Kexu Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zhou Sha
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Longhua Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Xiaoxia Zhu.

    Additional information

    Min Ying, Xiaoxia Zhu, and Kexu Chen have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ying, M., Zhu, X., Chen, K. et al. Should KRAS mutation still be used as a routine predictor of response to EGFR-TKIs in advanced non-small-cell lung cancer? A revaluation based on meta-analysis. J Cancer Res Clin Oncol 141, 1427–1439 (2015). https://doi.org/10.1007/s00432-015-1910-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00432-015-1910-9

    Keywords

    Search

    Navigation