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The mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance

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Abstract

Purpose

This study retrospectively assessed the mutations of the epidermal growth factor receptor (EGFR) and K-ras genes and their clinical significance in patients with resected stage I adenocarcinomas.

Methods

A total of 354 patients with resected lung adenocarcinomas were included, and 256 patients with stage I disease were analyzed for the prognostic and predictive value of these mutations.

Results

Mutations of EGFR and K-ras genes were detected in 149 (41.1 %) and 23 (6.4 %) of all tumors, and in 122 (47.6 %) and 14 (5.5 %) of stage I tumors, respectively. There were no significant differences in the disease-free survival (DFS) and overall survival (OS) between the EGFR-mutant and wild-type groups. However, the DFS and OS were significantly shorter in patients with K-ras mutations than in those without (5-year DFS: 50.8 vs. 76.9 %, 5-year OS: 70.0 vs. 86.6 %, p < 0.01). A multivariate analysis showed that K-ras mutations were an independent poor prognostic factor. Twenty-four of the 41 patients with recurrent disease after surgery were treated with an EGFR–TKI. Fifteen EGFR-mutant patients treated with an EGFR–TKI had a better prognosis than did the nine EGFR-wild-type patients.

Conclusion

The presence of an EGFR gene mutation was a predictive factor for the response to EGFR–TKI treatment in patients with resected stage I adenocarcinoma, but was not a prognostic factor. The presence of a K-ras gene mutation was a poor prognostic factor.

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Abbreviations

EGFR:

Epidermal growth factor receptor

TKI:

Tyrosine kinase inhibitor

DFS:

Disease-free survival

OS:

Overall survival

PFS:

Progression-free survival

NSCLC:

Non-small cell lung cancer

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Postmus PE, Brambilla E, Chansky K, Crowley J, Goldstraw P, Patz EF Jr, et al. The IASLC lung cancer staging project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol. 2007;2:686–93.

    Article  PubMed  Google Scholar 

  3. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.

    Article  CAS  PubMed  Google Scholar 

  4. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–11.

    Article  CAS  PubMed  Google Scholar 

  5. 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;350:2129–39.

    Article  CAS  PubMed  Google Scholar 

  6. Morita S, Okamoto I, Kobayashi K, Yamazaki K, Asahina H, Inoue A, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2009;15:4493–8.

    Article  CAS  PubMed  Google Scholar 

  7. Sugio K, Uramoto H, Onitsuka T, Mizukami M, Ichiki Y, Sugaya M, et al. Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations. Lung Cancer. 2009;64:314–8.

    Article  PubMed  Google Scholar 

  8. Sugio K, Uramoto H, Ono K, Oyama T, Hanagiri T, Sugaya M, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer. 2006;94:896–903.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. 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. 2010;11:121–8.

    Article  CAS  PubMed  Google Scholar 

  10. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.

    Article  CAS  PubMed  Google Scholar 

  11. Kawano D, Yano T, Shoji F, Ito K, Morodomi Y, Haro A, et al. The influence of intracellular epidermal growth factor receptor (EGFR) signal activation on the outcome of EGFR tyrosine kinase inhibitor treatment for pulmonary adenocarcinoma. Surg Today. 2011;41:818–23.

    Article  CAS  PubMed  Google Scholar 

  12. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  CAS  PubMed  Google Scholar 

  13. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.

    Article  CAS  PubMed  Google Scholar 

  14. Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, et al. 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. 2008;9:962–72.

    Article  CAS  PubMed  Google Scholar 

  15. Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323:561–5.

    Article  CAS  PubMed  Google Scholar 

  16. Sugio K, Ishida T, Yokoyama H, Inoue T, Sugimachi K, Sasazuki T. Ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res. 1992;52:2903–6.

    CAS  PubMed  Google Scholar 

  17. Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 2008;14:5731–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Fukuyama Y, Mitsudomi T, Sugio K, Ishida T, Akazawa K, Sugimachi K. K-ras and p53 mutations are an independent unfavourable prognostic indicator in patients with non-small-cell lung cancer. Br J Cancer. 1997;75:1125–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, 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;92:131–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA. 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. 2009;28:4769–77.

    Article  Google Scholar 

  21. Sugio K, Kishimoto Y, Virmani AK, Hung JY, Gazdar AF. K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res. 1994;54:5811–5.

    CAS  PubMed  Google Scholar 

  22. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 2007;98:1817–24.

    Article  CAS  PubMed  Google Scholar 

  23. Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol. 2009;4:22–9.

    Article  PubMed  Google Scholar 

  24. Hiramatsu M, Ninomiya H, Inamura K, Nomura K, Takeuchi K, Satoh Y, et al. Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. Lung Cancer. 2010;70:94–102.

    Article  PubMed  Google Scholar 

  25. Tomizawa K, Suda K, Onozato R, Kosaka T, Endoh H, Sekido Y, et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer. 2011;74:139–44.

    Article  PubMed  Google Scholar 

  26. Sasaki H, Shimizu S, Endo K, Takada M, Kawahara M, Tanaka H, et al. EGFR and erbB2 mutation status in Japanese lung cancer patients. Int J Cancer. 2006;118:180–4.

    Article  CAS  PubMed  Google Scholar 

  27. Kakegawa S, Shimizu K, Sugano M, Miyamae Y, Kaira K, Araki T, et al. Clinicopathological features of lung adenocarcinoma with KRAS mutations. Cancer. 2011;117:4257–66.

    Article  CAS  PubMed  Google Scholar 

  28. Takano T, Fukui T, Ohe Y, Tsuta K, Yamamoto S, Nokihara H, et al. EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol. 2008;26:5589–95.

    Article  CAS  PubMed  Google Scholar 

  29. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339–46.

    Article  CAS  PubMed  Google Scholar 

  30. Yatabe Y, Koga T, Mitsudomi T, Takahashi T. CK20 expression, CDX2 expression, K-ras mutation, and goblet cell morphology in a subset of lung adenocarcinomas. J Pathol. 2004;203:645–52.

    Article  CAS  PubMed  Google Scholar 

  31. Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res. 2006;12:1647–53.

    Article  CAS  PubMed  Google Scholar 

  32. Sakuma Y, Matsukuma S, Yoshihara M, Nakamura Y, Noda K, Nakayama H, et al. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations. Am J Clin Pathol. 2007;128:100–8.

    Article  CAS  PubMed  Google Scholar 

  33. Finberg KE, Sequist LV, Joshi VA, Muzikansky A, Miller JM, Han M, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9:320–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Wislez M, Antoine M, Baudrin L, Poulot V, Neuville A, Pradere M, et al. Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib. Lung Cancer. 2010;68:185–91.

    Article  PubMed  Google Scholar 

  35. Marchetti A, Buttitta F, Pellegrini S, Chella A, Bertacca G, Filardo A, et al. Bronchioloalveolar lung carcinomas: K-ras mutations are constant events in the mucinous subtype. J Pathol. 1996;179:254–9.

    Article  CAS  PubMed  Google Scholar 

  36. Casali C, Rossi G, Marchioni A, Sartori G, Maselli F, Longo L, et al. A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice. J Thorac Oncol. 2010;5:830–6.

    Article  PubMed  Google Scholar 

  37. Marks JL, Broderick S, Zhou Q, Chitale D, Li AR, Zakowski MF, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 2008;3:111–6.

    Article  PubMed  Google Scholar 

  38. Repasky GA, Chenette EJ, Der CJ. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol. 2004;14:639–47.

    Article  CAS  PubMed  Google Scholar 

  39. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441:424–30.

    Article  CAS  PubMed  Google Scholar 

  40. Schiller JH, Adak S, Cella D, DeVore RF 3rd, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:2114–22.

    CAS  PubMed  Google Scholar 

  41. Rosell R, Gomez-Codina J, Camps C, Maestre J, Padille J, Canto A, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153–8.

    Article  CAS  PubMed  Google Scholar 

  42. Camps C, Massuti B, Jimenez A, Maestu I, Gomez RG, Isla D, et al. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial. Ann Oncol. 2006;17:467–72.

    Article  CAS  PubMed  Google Scholar 

  43. Broermann P, Junker K, Brandt BH, Heinecke A, Freitag L, Klinke F, et al. Trimodality treatment in Stage III nonsmall cell lung carcinoma: prognostic impact of K-ras mutations after neoadjuvant therapy. Cancer. 2002;94:2055–62.

    Article  CAS  PubMed  Google Scholar 

  44. Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005;23:2513–20.

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka, 811-1395, Japan

    Taro Ohba, Gouji Toyokawa, Takuro Kometani, Kaname Nosaki, Fumihiko Hirai, Masafumi Yamaguchi, Motoharu Hamatake, Takashi Seto & Kenji Sugio

  2. Clinical Research Institute, National Kyushu Cancer Center, Fukuoka, Japan

    Yukito Ichinose

  3. Department of Thoracic and Breast Surgery, Oita University, Yufu, Japan

    Kenji Sugio

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  1. Taro Ohba
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  2. Gouji Toyokawa
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Correspondence to Kenji Sugio.

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Ohba, T., Toyokawa, G., Kometani, T. et al. The mutations of the EGFR and K-ras genes in resected stage I lung adenocarcinoma and their clinical significance. Surg Today 44, 478–486 (2014). https://doi.org/10.1007/s00595-013-0589-2

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  • DOI: https://doi.org/10.1007/s00595-013-0589-2

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