EGFR and KRAS mutation coexistence in lung adenocarcinomas

  • Vitor Manuel Leitão de Sousa 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal 2 CIMAGO – Research Center for Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3 Centre of Pulmonology, Faculty of Medicine of the University of Coimbra, Portugal 4 Service of Anatomical Pathology, University Hospital of Coimbra, Coimbra, Portugal
  • Maria Reis Silva 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal 2 CIMAGO – Research Center for Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3 Centre of Pulmonology, Faculty of Medicine of the University of Coimbra, Portugal
  • Ana Maria Alarcão 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal 2 CIMAGO – Research Center for Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3 Centre of Pulmonology, Faculty of Medicine of the University of Coimbra, Portugal
  • Maria João d’Aguiar 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal
  • Teresa Ferreira 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal
  • Lina Carvalho 1 Institute of Anatomical and Molecular Pathology, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal 2 CIMAGO – Research Center for Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3 Centre of Pulmonology, Faculty of Medicine of the University of Coimbra, Portugal 4 Service of Anatomical Pathology, University Hospital of Coimbra, Coimbra, Portugal

Abstract

Lung cancer is one of the most common causes of cancer deaths. The development of EGFR targeted therapies, including monoclonal antibodies and tyrosine kinase inhibitors have generated an interest in the molecular characterization of these tumours. KRAS mutations are associated with resistance to EGFR TKIs. EGFR and KRAS mutations have been considered as mutually exclusive.

This paper presents three bronchial-pulmonary carcinomas, two adenocarcinomas and one pleomorphic sarcomatoid carcinoma, harboring EGFR and KRAS mutations.

Case 1 corresponded to an adenocarcinoma with EGFR exon 21 mutation (L858R) and KRAS codon 12 point mutation (G12V); case 2, a  mucinous adenocarcinoma expressed coexistence of EGFR exon 21 mutation (L858R) and KRAS codon 12 point mutation (G12V); and case 3 a sarcomatoid carcinoma with EGFR exon 19 deletion – del 9bp and KRAS codon 12 point mutation (G12C - cysteine).

Based on our experience and on the literature, we conclude that EGFR and KRAS mutations can indeed coexist in the same bronchial-pulmonary carcinoma, either in the same histological type or in different patterns. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent or currently searched. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications.

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References

References
1. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001;37 Suppl 8:S4-66.
2. Riely GJ. Lung cancer in 'Never-smokers': molecular factors trump risk factors. Oncology (Williston Park) 2010;24:38, 40.
3. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
4. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.
5. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-81.
6. Travis W.D. BE, Müller-Hermelink H.K., Harris C.C. Pathology Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press, 2004.
7. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85.
8. Fukuoka M, Yano S, Giaccone G, 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;21:2237-46.
9. Kris MG, Natale RB, Herbst RS, 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;290:2149-58.
10. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol 2004;22:3238-47.
11. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
12. Thatcher N, Chang A, Parikh P, 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;366:1527-37.
13. Cortes-Funes H, Gomez C, Rosell R, et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 2005;16:1081-6.
14. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493-501.
15. Lynch TJ. Predictive tests for EGFR inhibitors. Clin Adv Hematol Oncol 2005;3:678-9.
16. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.
17. Taron M, Ichinose Y, Rosell R, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005;11:5878-85.
18. Massarelli E, Varella-Garcia M, Tang X, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 2007;13:2890-6.
19. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.
20. Janne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 2005;23:3227-34.
21. Shigematsu H, Lin L, Takahashi T, 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.
22. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006;24:3340-6.
23. Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol 2007;2:22-8.
24. Blons H, Cote JF, Le Corre D, et al. Epidermal growth factor receptor mutation in lung cancer are linked to bronchioloalveolar differentiation. Am J Surg Pathol 2006;30:1309-15.
25. Haneda H, Sasaki H, Lindeman N, et al. A correlation between EGFR gene mutation status and bronchioloalveolar carcinoma features in Japanese patients with adenocarcinoma. Jpn J Clin Oncol 2006;36:69-75.
26. Zakowski MF, Hussain S, Pao W, et al. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med 2009;133:470-7.
27. Motoi N, Szoke J, Riely GJ, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol 2008;32:810-27.
28. Ninomiya H, Hiramatsu M, Inamura K, et al. Correlation between morphology and EGFR mutations in lung adenocarcinomas Significance of the micropapillary pattern and the hobnail cell type. Lung Cancer 2009;63:235-40.
29. Dacic S, Shuai Y, Yousem S, et al. Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas. Mod Pathol 2010;23:159-68.
30. Bai H, Wang Z, Chen K, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077-83.
31. Ferte C, Besse B, Dansin E, et al. Durable responses to Erlotinib despite KRAS mutations in two patients with metastatic lung adenocarcinoma. Ann Oncol 2010;21:1385-7.
32. Finberg KE, Sequist LV, Joshi VA, 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.
33. Sakuma Y, Matsukuma S, Yoshihara M, 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.
34. Kobayashi T, Tsuda H, Noguchi M, et al. Association of point mutation in c-Ki-ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes. Cancer 1990;66:289-94.
35. Marchetti A, Buttitta F, Pellegrini S, et al. Bronchioloalveolar lung carcinomas: K-ras mutations are constant events in the mucinous subtype. J Pathol 1996;179:254-9.
36. Tsuchiya E, Furuta R, Wada N, et al. High K-ras mutation rates in goblet-cell-type adenocarcinomas of the lungs. J Cancer Res Clin Oncol 1995;121:577-81.
37. Yatabe Y, Koga T, Mitsudomi T, et al. CK20 expression, CDX2 expression, K-ras mutation, and goblet cell morphology in a subset of lung adenocarcinomas. J Pathol 2004;203:645-52.
38. Mitsudomi T, Viallet J, Mulshine JL, et al. Mutations of ras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines. Oncogene 1991;6:1353-62.
39. Shibata T, Hanada S, Kokubu A, et al. Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma. Cancer Sci 2007;98:985-91.
40. Eberhard DA, Johnson BE, Amler LC, et al. 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 2005;23:5900-9.
41. Jackman DM, Miller VA, Cioffredi LA, et al. 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 2009;15:5267-73.
42. Wu YL, Chu DT, Han B, et al. Phase III, randomized, open-label, first-line study in Asia of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer: evaluation of patients recruited from mainland China. Asia Pac J Clin Oncol 2012;8:232-43.
43. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:2866-74.
44. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-37.
45. Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003;22:2812-22.
46. She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res 2003;9:4340-6.
47. Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol 2007;25:5240-7.
48. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-97.
49. Lynch TJ, Bell DW, Sordella R, 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.
50. Pao W, Miller V, Zakowski M, 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 U S A 2004;101:13306-11.
51. Kalikaki A, Koutsopoulos A, Trypaki M, et al. Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. Br J Cancer 2008;99:923-9.
52. Lynch TJ, Patel t., Dreisbach l., McCleod M., Heim W.J., Robert H., et al. A randomized multicenter phase III study of cetuximab in combination with taxane/carboplatin versus taxane/carboplatin alone as first-line treatment for patients with advanced/metastatic non-small cell lung cancer. J Thorac Oncol 2007;2.
53. O'Byrne KJ BI, Barrios C, Eschbach C, Martens U, Hotko Y et al. Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study. J Clin Oncol 2009;27:(suppl; abstr 8007).
54. 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.
55. Zhu CQ, da Cunha Santos G, Ding K, et al. 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 2008;26:4268-75.
56. Gumerlock P.H. HWS, Chen H., et al. Mutational analysis of K-RAS and EGFR implicates K-RAS as a resitance marker in the Southwest Oncology Group (SWOG) trial S0126 of bronchioalveolar carcinoma (BAC) patients (pts) treated with gefitinib. J Clin Oncol 2005;23:623s (suppl; abstr 7008).
57. Singh A, Greninger P, Rhodes D, et al. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 2009;15:489-500.
58. Han SW, Kim TY, Jeon YK, et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538-44.
59. Italiano A, Cortot AB, Ilie M, et al. EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy. Int J Cancer 2009;125:2479-82.
Published
2015-04-27
How to Cite
SOUSA, Vitor Manuel Leitão de et al. EGFR and KRAS mutation coexistence in lung adenocarcinomas. Diagnostic Pathology, [S.l.], apr. 2015. ISSN 2364-4893. Available at: <http://www.diagnosticpathology.eu/content/index.php/dpath/article/view/13>. Date accessed: 29 mar. 2024. doi: https://doi.org/10.17629/www.diagnosticpathology.eu-2015-1:13.
Issue
Section
Research

Keywords

KRAS; EGFR; Bronchial-pulmonary carcinomas.