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Current Oncology Reports
Published in: Current Oncology Reports 5/2010

01-09-2010

Molecular Testing in Lung Cancer: The Time Is Now

Authors: Haiying Cheng, Xunhai Xu, Daniel B. Costa, Charles A. Powell, Balazs Halmos

Published in: Current Oncology Reports | Issue 5/2010

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Abstract

In the past few years, we have witnessed a revolution in the molecular understanding of non-small cell lung cancer. Major progress has also been made in the clinic, with the introduction of EGFR-targeted and anti-angiogenic therapies. These advances have led to the development of a multitude of commercially available prognostic and predictive biomarkers. In particular, EGFR mutation and EML4/ALK testing have reached clinical validation and are incorporated into current treatment paradigms. This overview will present the scientific background of the biology of the relevant biomarkers and the studies conducted for their clinical validation. The technical challenges and shortcomings of these assays are also discussed. Furthermore, ongoing biomarker-driven clinical studies and the appropriate clinical use of available tests will be reviewed to assist the clinician with the proper incorporation of molecular testing into the routine care of patients with non-small cell lung cancer.
Literature
1.
Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004, 350:351–360.CrossRefPubMed
2.
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, 352:2589–2597.CrossRefPubMed
3.
Slebos RJ, Kibbelaar RE, Dalesio O, et al.: K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 1990, 323:561–565.PubMed
4.
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.CrossRefPubMed
5.
Butts CA, Ding K, Seymour L, et al.: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010, 28:29–34.CrossRefPubMed
6.
Horio Y, Takahashi T, Kuroishi T, et al.: Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 1993, 53:1–4.PubMed
7.
Cheng L, Spitz MR, Hong WK, Wei Q: Reduced expression levels of nucleotide excision repair genes in lung cancer: a case-control analysis. Carcinogenesis 2000, 21:1527–1530.CrossRefPubMed
8.
Simon GR, Sharma S, Cantor A, et al.: ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest 2005, 127:978–983.CrossRefPubMed
9.
Olaussen KA, Dunant A, Fouret P, et al.: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006, 355:983–991.CrossRefPubMed
10.
Zheng Z, Chen T, Li X, et al.: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 2007, 356:800–808.CrossRefPubMed
11.
Bepler G, Sharma S, Cantor A, et al.: RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol 2004, 22:1878–1885.CrossRefPubMed
12.
13.
Potti A, Mukherjee S, Petersen R, et al.: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006, 355:570–580.CrossRefPubMed
14.
Shedden K, Taylor JM, Enkemann SA, et al.: Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 2008, 14:822–827.CrossRefPubMed
15.
• Scagliotti GV, Parikh P, von Pawel J, et al.: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008, 26:3543–3551. This phase 3 study demonstrated that in patients with adenocarcinoma and large cell histology, overall survival was superior for cisplatin/pemetrexed versus cisplatin/gemcitabine compared to patients with squamous cell histology, for whom the opposite results were seen.CrossRefPubMed
16.
Scagliotti G, Hanna N, Fossella F, et al.: The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 2009, 14:253–263.CrossRefPubMed
17.
Ciuleanu T, Brodowicz T, Zielinski C, et al.: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009, 374:1432–1440.CrossRefPubMed
18.
Takenaka T, Yoshino I, Kouso H, et al.: Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer. Int J Cancer 2007, 121:895–900.CrossRefPubMed
19.
Azuma K, Sasada T, Kawahara A, et al.: Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with carboplatin and paclitaxel. Lung Cancer 2009, 64:326–333.CrossRefPubMed
20.
Lord RV, Brabender J, Gandara D, et al.: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002, 8:2286–2291.PubMed
21.
Cobo M, Isla D, Massuti B, et al.: Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol 2007, 25:2747–2754.CrossRefPubMed
22.
Bepler G, Kusmartseva I, Sharma S, et al.: RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 2006, 24:4731–4737.CrossRefPubMed
23.
Rosell R, Danenberg KD, Alberola V, et al.: Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 2004, 10:1318–1325.CrossRefPubMed
24.
Giovannetti E, Mey V, Nannizzi S, et al.: Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 2005, 68:110–118.PubMed
25.
Bepler G, Sommers KE, Cantor A, et al.: Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer. J Thorac Oncol 2008, 3:1112–1118.CrossRefPubMed
26.
Simon G, Sharma A, Li X, et al.: Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007, 25:2741–2746.CrossRefPubMed
27.
Hirsch FR, Varella-Garcia M, Cappuzzo F: Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene 2009, 28(Suppl 1): S32–S37.CrossRefPubMed
28.
John T, Liu G, Tsao MS: Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. Oncogene 2009, 28(Suppl 1): S14–S23.CrossRefPubMed
29.
Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004, 22:1103–1109.CrossRefPubMed
30.
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, 350:2129–2139.CrossRefPubMed
31.
Paez JG, Janne PA, Lee JC, et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004, 304:1497–1500.CrossRefPubMed
32.
Tokumo M, Toyooka S, Kiura K, et al.: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 2005, 11:1167–1173.PubMed
33.
Leidner RS, Fu P, Clifford B, et al.: Genetic abnormalities of the EGFR pathway in African American patients with non-small-cell lung cancer. J Clin Oncol 2009, 27:5620–5626.CrossRefPubMed
34.
Sharma SV, Bell DW, Settleman J, Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007, 7:169–181.CrossRefPubMed
35.
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, 23:5900–5909.CrossRefPubMed
36.
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, 26:4268–4275.CrossRefPubMed
37.
Dahabreh IJ, Linardou H, Siannis F, et al.: Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2010, 16:291–303.CrossRefPubMed
38.
•• Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009, 361:947–957. The I-PASS study showed that gefitinib is superior to carboplatin-paclitaxel as first-line treatment in Asian patients with advanced lung adenocarcinoma and no/limited smoking history. PFS was significantly longer for EGFR-mutant tumors when treated with gefitinib versus chemotherapy, while the opposite held true for EGFR wild-type tumors.CrossRefPubMed
39.
Mitsudomi T, Morita S, Yatabe Y, 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, 11:121–128.CrossRefPubMed
40.
•Douillard JY, Shepherd FA, Hirsh V, et al.: 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 2010, 28:744–752. The INTEREST trial showed that patients with EGFR-mutated tumors had longer PFS with gefitinib versus docetaxel in the second-line setting.CrossRefPubMed
41.
• Cappuzzo TC, Stelmakh L, Cicenas S, et al.: SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol 2009, 27(15s): abstract 8001. In the phase 3 SATURN trial, erlotinib was shown to produce prolonged PFS and overall survival when compared with placebo in the maintenance setting after first-line chemotherapy. The benefit was modest overall but very striking in patients with EGFR-mutant tumors.
42.
Khambata-Ford S, Harbison CT, Hart LL, et al.: Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010, 28:918–927.CrossRefPubMed
43.
Kobayashi S, Boggon TJ, Dayaram T, et al.: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005, 352:786–792.CrossRefPubMed
44.
Pao W, Miller VA, Politi KA, et al.: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005, 2:e73.CrossRefPubMed
45.
Hammerman PS, Janne PA, Johnson BE: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2009, 15:7502–7509.CrossRefPubMed
46.
Zhou W, Ercan D, Chen L, et al.: Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009, 462:1070–1074.CrossRefPubMed
47.
Maheswaran S, Sequist LV, Nagrath S, et al.: Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008, 359:366–377.CrossRefPubMed
48.
Coate LE, John T, Tsao MS, Shepherd FA: Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol 2009, 10:1001–1010.CrossRefPubMed
49.
Cappuzzo F, Hirsch FR, Rossi E, et al.: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005, 97:643–655.CrossRefPubMed
50.
Pirker R, Pereira JR, Szczesna A, et al.: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009, 373:1525–1531.CrossRefPubMed
51.
Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006, 24:5034–5042.CrossRefPubMed
52.
Eberhard DA, Giaccone G, Johnson BE: Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 2008, 26:983–994.CrossRefPubMed
53.
54.
Taguchi F, Solomon B, Gregorc V, et al.: Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 2007, 99:838–846.CrossRefPubMed
55.
Amann JM, Lee JW, Roder H, et al.: Genetic and proteomic features associated with survival after treatment with erlotinib in first-line therapy of non-small cell lung cancer in Eastern Cooperative Oncology Group 3503. J Thorac Oncol 2010, 5:169–178.CrossRefPubMed
56.
Carbone DP, Salmon JS, Billheimer D, et al.: VeriStrat® classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab. Lung Cancer 2009 Dec 24 (Epub ahead of print).
57.
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.CrossRefPubMed
58.
Linardou H, Dahabreh IJ, Kanaloupiti D, 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, 9:962–972.CrossRefPubMed
59.
•• Soda M, Choi YL, Enomoto M, et al.: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448:561–566. This study identified the most recent oncogene found in NSCLC, EML4-ALK fusion gene.CrossRefPubMed
60.
Rikova K, Guo A, Zeng Q, et al.: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007, 131:1190–1203.CrossRefPubMed
61.
Takeuchi K, Choi YL, Togashi Y, et al.: KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009, 15:3143–3149.CrossRefPubMed
62.
Choi YL, Takeuchi K, Soda M, et al.: Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008, 68:4971–4976.CrossRefPubMed
63.
Soda M, Takada S, Takeuchi K, et al.: A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 2008, 105:19893–19897.CrossRefPubMed
64.
Horn L, Pao W: EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009, 27:4232–4235.CrossRefPubMed
65.
Inamura K, Takeuchi K, Togashi Y, et al.: EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 2008, 3:13–17.CrossRefPubMed
66.
Rodig SJ, Mino-Kenudson M, Dacic S, et al.: Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009, 15:5216–5223.CrossRefPubMed
67.
Shaw AT, Yeap BY, Mino-Kenudson M, et al.: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009, 27:4247–4253.CrossRefPubMed
68.
Koivunen JP, Mermel C, Zejnullahu K, et al.: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008, 14:4275–4283.CrossRefPubMed
69.
McDermott U, Iafrate AJ, Gray NS, et al.: Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008, 68:3389–3395.CrossRefPubMed
70.
Shaw AT CD, Iafrate AJ, Dezube BJ, et al.: Clinical activity of the oral ALK and MET inhibitor PF-02341066 in non-small lung cancer (NSCLC) with EML4-ALK translocations. J Thorac Oncol 2009, 4:S305–S306.
71.
Toschi L, Janne PA: Single-agent and combination therapeutic strategies to inhibit hepatocyte growth factor/MET signaling in cancer. Clin Cancer Res 2008, 14:5941–5946.CrossRefPubMed
72.
Faoro L, Cervantes GM, El-Hashani E, Salgia R: MET receptor tyrosine kinase. J Thorac Oncol 2009, 4:S1064–S1065.CrossRefPubMed
73.
Cappuzzo F, Marchetti A, Skokan M, et al.: Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009, 27:1667–1674.CrossRefPubMed
74.
Cappuzzo F, Janne PA, Skokan M, et al.: MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 2009, 20:298–304.CrossRefPubMed
75.
Engelman JA, Zejnullahu K, Mitsudomi T, et al.: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007, 316:1039–1043.CrossRefPubMed
76.
Turke AB, Zejnullahu K, Wu YL, et al.: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010, 17:77–88.CrossRefPubMed
77.
Nguyen KS, Kobayashi S, Costa DB: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 2009, 10:281–289.CrossRefPubMed
78.
79.
Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355:2542–2550.CrossRefPubMed
80.
Reck M, von Pawel J, Zatloukal P, et al.: Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010 Feb 11 (Epub ahead of print).
81.
Dowlati A, Gray R, Sandler AB, et al.: Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res 2008, 14:1407–1412.CrossRefPubMed
82.
Murukesh N, Dive C, Jayson GC: Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 2010, 102:8–18.CrossRefPubMed
83.
Dahlberg SE, Sandler AB, Brahmer JR, et al.: Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 2010, 28:949–954.CrossRefPubMed
84.
BATTLE Trial Personalizes Lung Cancer Therapy [AACR press release]. April 18, 2010.
85.
Travis WD, Rekhtman N, Riley GJ, et al.: Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift. J Thorac Oncol 2010, 5:411–414.CrossRefPubMed
86.
Marchetti A, Milella M, Felicioni L, et al.: Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones. Neoplasia 2009, 11:1084–1092.PubMed
Metadata
Title
Molecular Testing in Lung Cancer: The Time Is Now
Authors
Haiying Cheng
Xunhai Xu
Daniel B. Costa
Charles A. Powell
Balazs Halmos
Publication date
01-09-2010
Publisher
Current Science Inc.
Published in
Current Oncology Reports / Issue 5/2010
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-010-0118-z

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