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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2015

Open Access 01-12-2015 | Review

Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review

Authors: James Sherwood, Simon Dearden, Marianne Ratcliffe, Jill Walker

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2015

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Abstract

Increased understanding of the genetic aetiology of advanced non-small-cell lung cancer (aNSCLC) has facilitated personalised therapies that target specific molecular aberrations associated with the disease. Biopsy samples for mutation testing may be taken from primary or metastatic sites, depending on which sample is most accessible, and upon differing diagnostic practices between territories. However, the mutation status concordance between primary tumours and corresponding metastases is the subject of debate. This review aims to ascertain whether molecular diagnostic testing of either the primary or metastatic tumours is equally suitable to determine patient eligibility for targeted therapies. A literature search was performed to identify articles reporting studies of mutations in matched primary and metastatic aNSCLC tumour samples. Clinical results of mutation status concordance between matched primary and metastatic tumour samples from patients with aNSCLC were collated. Articles included in this review (N =26) all reported mutation status data from matched primary and metastatic tumour samples obtained from adult patients with aNSCLC. Generally, substantial concordance was observed between primary and metastatic tumours in terms of EGFR, KRAS, BRAF, p16 and p53 mutations. However, some level of discordance was seen in most studies; mutation testing methodologies appeared to play a key role in this, along with underlying tumour heterogeneity. Substantial concordance in mutation status observed between primary and metastatic tumour sites suggests that diagnostic testing of either tumour type may be suitable to determine a patient’s eligibility for personalised therapies. As with all diagnostic testing, highly sensitive and appropriately validated mutation analysis methodologies are desirable to ensure accuracy. Additional work is also required to define how much discordance is clinically significant given natural tumour heterogeneity. The ability of both primary and metastatic tumour sites to accurately reflect the tumour mutation status will allow more patients to receive therapies personalised to their disease.
Literature
1.
2.
Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3:819–31.CrossRefPubMed
3.
Cortot AB, Italiano A, Burel-Vandenbos F, Martel-Planche G, Hainaut P. KRAS mutation status in primary nonsmall cell lung cancer and matched metastases. Cancer. 2010;116:2682–7.CrossRefPubMed
4.
Sun PL, Jin Y, Kim H, Lee CT, Jheon S, Chung JH. High concordance of EGFR mutation status between histologic and corresponding cytologic specimens of lung adenocarcinomas. Cancer Cytopathol. 2013;121:311–9.CrossRefPubMed
5.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–8.PubMedCentralCrossRefPubMed
6.
Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005;65:7591–5.PubMed
7.
Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24:2371–6.PubMedCentralCrossRefPubMed
8.
Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ. Lung cancer in never smokers–a review. Eur J Cancer. 2012;48:1299–311.CrossRefPubMed
9.
Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24:2899–908.CrossRefPubMed
10.
Berg M, Soreide K. EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. Discov Med. 2012;14:207–14.PubMed
11.
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802;2010:396–405.
12.
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, et al. American Society of Clinical Oncology Provisional Clinical Opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29:2121–7.CrossRefPubMed
13.
Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823–59.PubMedCentralCrossRefPubMed
14.
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, 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.PubMedCentralCrossRefPubMed
15.
Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res. 2006;12:7232–41.CrossRefPubMed
16.
Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.CrossRefPubMed
17.
Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14:38–47.CrossRefPubMed
18.
Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22:2616–24.PubMedCentralCrossRefPubMed
19.
Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–67.CrossRefPubMed
20.
21.
22.
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii56–64.CrossRefPubMed
23.
Ellison G, Zhu G, Moulis A, Dearden S, Speake G, McCormack R. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol. 2013;66:79–89.PubMedCentralCrossRefPubMed
24.
Choi YL, Sun JM, Cho J, Rampal S, Han J, Parasuraman B, et al. EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital. PLoS ONE. 2013;8:e56011.PubMedCentralCrossRefPubMed
25.
26.
Marchetti A, Normanno N. Recommendations for mutational analysis of EGFR in lung carcinoma. Pathologica. 2010;102:119–26.PubMed
27.
Chen ZY, Zhong WZ, Zhang XC, Su J, Yang XN, Chen ZH, et al. EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist. 2012;17:978–85.PubMedCentralCrossRefPubMed
28.
Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol. 2009;20:696–702.CrossRefPubMed
29.
Han HS, Eom DW, Kim JH, Kim KH, Shin HM, An JY, et al. EGFR mutation status in primary lung adenocarcinomas and corresponding metastatic lesions: discordance in pleural metastases. Clin Lung Cancer. 2011;12:380–6.CrossRefPubMed
30.
Mansuet-Lupo A, Zouiti F, Alifano M, Tallet A, Charpentier MC, Ducruit V, et al. Intratumoral distribution of EGFR mutations and copy number in metastatic lung cancer, what impact on the initial molecular diagnosis? J Transl Med. 2014;12:131.PubMedCentralCrossRefPubMed
31.
Park S, Holmes-Tisch AJ, Cho EY, Shim YM, Kim J, Kim HS, et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J Thorac Oncol. 2009;4:809–15.CrossRefPubMed
32.
Sun L, Zhang Q, Luan H, Zhan Z, Wang C, Sun B. Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice. J Exp Clin Cancer Res. 2011;30:30.PubMedCentralCrossRefPubMed
33.
Wang F, Fang P, Hou DY, Leng ZJ, Cao LJ. Comparison of epidermal growth factor receptor mutations between primary tumors and lymph nodes in non-small cell lung cancer: a review and meta-analysis of published data. Asian Pac J Cancer Prev. 2014;15:4493–7.CrossRefPubMed
34.
Liu X, Lu Y, Zhu G, Lei Y, Zheng L, Qin H, et al. The diagnostic accuracy of pleural effusion and plasma samples versus tumour tissue for detection of EGFR mutation in patients with advanced non-small cell lung cancer: comparison of methodologies. J Clin Pathol. 2013;66:1065–9.PubMedCentralCrossRefPubMed
35.
Hasanovic A, Ang D, Moreira AL, Zakowski MF. Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma. Lung Cancer. 2012;77:299–305.CrossRefPubMed
36.
Wu SG, Chang YL, Lin JW, Wu CT, Chen HY, Tsai MF, et al. Including total EGFR staining in scoring improves EGFR mutations detection by mutation-specific antibodies and EGFR TKIs response prediction. PLoS ONE. 2011;6:e23303.PubMedCentralCrossRefPubMed
37.
Angulo B, Conde E, Suárez-Gauthier A, Plaza C, Martinez R, Redondo P, et al. A comparison of EGFR mutation testing methods in lung carcinoma: direct sequencing, real-time PCR and immunohistochemistry. PLoS ONE. 2012;7:e43842.PubMedCentralCrossRefPubMed
38.
Goto K, Satouchi M, Ishii G, Nishio K, Hagiwara K, Mitsudomi T, et al. An evaluation study of EGFR mutation tests utilized for non-small-cell lung cancer in the diagnostic setting. Ann Oncol. 2012;23:2914–9.CrossRefPubMed
39.
Tsai T-H, Wu S-G, Chang Y-L, Wu C-T, Tsai M-F, Wei P-F, et al. Effusion immunocytochemistry as an alternative approach for the selection of first-line targeted therapy in advanced lung adenocarcinoma. J Thorac Oncol. 2012;7:993–1000.CrossRefPubMed
40.
Ilie MI, Hofman V, Bonnetaud C, Havet K, Lespinet-Fabre V, Coëlle C, et al. Usefulness of tissue microarrays for assessment of protein expression, gene copy number and mutational status of EGFR in lung adenocarcinoma. Virchows Arch. 2010;457:483–95.CrossRefPubMed
41.
Kozu Y, Tsuta K, Kohno T, Sekine I, Yoshida A, Watanabe S, et al. The usefulness of mutation-specific antibodies in detecting epidermal growth factor receptor mutations and in predicting response to tyrosine kinase inhibitor therapy in lung adenocarcinoma. Lung Cancer. 2011;73:45–50.CrossRefPubMed
42.
Li J, Wang L, Mamon H, Kulke MH, Berbeco R, Makrigiorgos GM. Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing. Nat Med. 2008;14:579–84.CrossRefPubMed
43.
Ogino S, Kawasaki T, Brahmandam M, Yan L, Cantor M, Namgyal C, et al. Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. J Mol Diagn. 2005;7:413–21.PubMedCentralCrossRefPubMed
44.
Reichel MB, Ohgaki H, Petersen I, Kleihues P. p53 mutations in primary human lung tumors and their metastases. Mol Carcinog. 1994;9:105–9.CrossRefPubMed
45.
Matsuzoe D, Hideshima T, Ohshima K, Kawahara K, Shirakusa T, Kimura A. Discrimination of double primary lung cancer from intrapulmonary metastasis by p53 gene mutation. Br J Cancer. 1999;79:1549–52.PubMedCentralCrossRefPubMed
46.
Kalikaki A, Koutsopoulos A, Trypaki M, Souglakos J, Stathopoulos E, Georgoulias V, 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.PubMedCentralCrossRefPubMed
47.
Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009;15:4554–60.CrossRefPubMed
48.
Munfus-McCray D, Harada S, Adams C, Askin F, Clark D, Gabrielson E, et al. EGFR and KRAS mutations in metastatic lung adenocarcinomas. Hum Pathol. 2011;42:1447–53.CrossRefPubMed
49.
Han CB, Ma JT, Li F, Zhao JZ, Jing W, Zhou Y, et al. EGFR and KRAS mutations and altered c-Met gene copy numbers in primary non-small cell lung cancer and associated stage N2 lymph node-metastasis. Cancer Lett. 2012;314:63–72.CrossRefPubMed
50.
Wei B, Yang K, Zhao J, Chang Y, Ma Z, Dong B, et al. Quantification of EGFR mutations in primary and metastatic tumors in non-small cell lung cancer. J Exp Clin Cancer Res. 2014;33:5.PubMedCentralCrossRefPubMed
51.
Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J Clin Oncol. 2011;29:2972–7.CrossRefPubMed
52.
Shimizu K, Yukawa T, Hirami Y, Okita R, Saisho S, Maeda A, et al. Heterogeneity of the EGFR mutation status between the primary tumor and metastatic lymph node and the sensitivity to EGFR tyrosine kinase inhibitor in non-small cell lung cancer. Target Oncol. 2013;8:237–42.CrossRefPubMed
53.
Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer. 2006;119:1491–4.CrossRefPubMed
54.
Luo D, Ye X, Hu Z, Peng K, Song Y, Yin X, et al. EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumour Biol. 2014;35:2437–44.CrossRefPubMed
55.
Alsdorf WH, Clauditz TS, Hoenig T, Quaas A, Sirma H, Koenig AM, et al. Intratumoral heterogeneity of KRAS mutation is rare in non-small-cell lung cancer. Exp Mol Pathol. 2013;94:155–9.CrossRefPubMed
56.
Li S, Rosell R, Urban A, Font A, Ariza A, Armengol P, et al. K-ras gene point mutation: a stable tumor marker in non-small cell lung carcinoma. Lung Cancer. 1994;11:19–27.CrossRefPubMed
57.
Badalian G, Barbai T, Rásó E, Derecskei K, Szendrôi M, Tímár J. Phenotype of bone metastases of non-small cell lung cancer: epidermal growth factor receptor expression and K-RAS mutational status. Pathol Oncol Res. 2007;13:99–104.CrossRefPubMed
58.
Holst VA, Finkelstein S, Yousem SA. Bronchioloalveolar adenocarcinoma of lung: monoclonal origin for multifocal disease. Am J Surg Pathol. 1998;22:1343–50.CrossRefPubMed
59.
Marchetti A, Buttitta F, Pellegrini S, Bertacca G, Chella A, Carnicelli V, et al. Alterations of P16 (MTS1) in node-positive non-small cell lung carcinomas. J Pathol. 1997;181:178–82.CrossRefPubMed
60.
Tang X, Varella-Garcia M, Xavier AC, Massarelli E, Ozburn N, Moran C, et al. Epidermal growth factor receptor abnormalities in the pathogenesis and progression of lung adenocarcinomas. Cancer Prev Res (Phila). 2008;1:192–200.CrossRef
61.
Takahashi K, Kohno T, Matsumoto S, Nakanishi Y, Arai Y, Yamamoto S, et al. Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells. Clin Cancer Res. 2007;13:111–20.CrossRefPubMed
62.
Vignot S, Frampton GM, Soria JC, Yelensky R, Commo F, Brambilla C, et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. 2013;31:2167–72.CrossRefPubMed
63.
Ellison G, Donald E, McWalter G, Knight L, Fletcher L, Sherwood J, et al. A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples. J Exp Clin Cancer Res. 2010;29:132.PubMedCentralCrossRefPubMed
64.
Han B, Zhou X, Zhang RX, Zang WF, Chen ZY, Song HD, et al. Mutations of the epidermal growth factor receptor gene in NSCLC patients. Oncol Lett. 2011;2:1233–7.PubMedCentralPubMed
65.
Jancik S, Drabek J, Berkovcova J, Xu YZ, Stankova M, Klein J, et al. A comparison of Direct sequencing, Pyrosequencing, High resolution melting analysis, TheraScreen DxS, and the K-ras StripAssay for detecting KRAS mutations in non small cell lung carcinomas. J Exp Clin Cancer Res. 2012;31:79.PubMedCentralCrossRefPubMed
66.
Dufort S, Richard MJ, Lantuejoul S. de FF. Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC. J Exp Clin Cancer Res. 2011;30:57.PubMedCentralCrossRefPubMed
67.
Espina V, Wulfkuhle JD, Calvert VS, VanMeter A, Zhou W, Coukos G, et al. Laser-capture microdissection. Nat Protoc. 2006;1:586–603.CrossRefPubMed
68.
Jakobsen JN, Sørensen JB. Intratumor heterogeneity and chemotherapy-induced changes in EGFR status in non-small cell lung cancer. Cancer Chemother Pharmacol. 2012;69:289–99.CrossRefPubMed
69.
da Cunha SG, Saieg MA, Geddie W, Leighl N. EGFR gene status in cytological samples of nonsmall cell lung carcinoma: controversies and opportunities. Cancer Cytopathol. 2011;119:80–91.CrossRef
70.
Pirker R, Herth FJ, Kerr KM, Filipits M, Taron M, Gandara D, et al. Consensus for EGFR mutation testing in non-small cell lung cancer: results from a European workshop. J Thorac Oncol. 2010;5:1706–13.CrossRefPubMed
71.
Tartarone A, Lazzari C, Lerose R, Conteduca V, Improta G, Zupa A, et al. Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib. Lung Cancer. 2013;81:328–36.CrossRefPubMed
72.
D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112:95–102.CrossRefPubMed
Metadata
Title
Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review
Authors
James Sherwood
Simon Dearden
Marianne Ratcliffe
Jill Walker
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2015
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-015-0207-9

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