Auf dem Weg zu einer individualisierten Therapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC) - Stellenwert molekularer Prädiktions- und Prognosefaktoren

S. Zirlik; S. Lampert; E. G. Hahn; G. H. Wiest; W. M. Brückl

doi:10.1055/s-2007-980130

Pneumologie 2007; 61(11): 731-738
DOI: 10.1055/s-2007-980130

Übersicht

Auf dem Weg zu einer individualisierten Therapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC) - Stellenwert molekularer Prädiktions- und Prognosefaktoren

An Approach to Individualised Therapy of Non-Small Cell Ling Carcinoma (NSCLC) - Relevance of Molecular Predictive and Prognostic FactorsS. Zirlik¹ , S. Lampert¹ , E. G. Hahn¹ , G. H. Wiest² , W. M. Brückl¹

¹Medizinische Klinik 1 (Direktor: Prof. Dr. med. E.G. Hahn) Universitätsklinikum Erlangen
²Lungenabteilung, Thoraxzentrum Hamburg (Chefarzt: PD Dr. med. G.H. Wiest) Asklepios Klinik Harburg

Abstract

Zusammenfassung

Die Therapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC) erfolgt derzeit stadienadaptiert aufgrund der Erkenntnisse aus klinischen Studien. Das Wissen über spezielle molekulare Veränderungen im Tumor wird (noch) nicht herangezogen, um eine gezielte individuelle Behandlung zu entscheiden. Durch den Einsatz moderner Hochdurchsatz-Verfahren und Analysemöglichkeiten (z. B. Gen-Chip Analysen) erfolgt derzeit in der Onkologie eine exponentielle Zunahme des Wissens über die genetischen Veränderungen in den Zellen und dem Zusammenspiel der Proteine untereinander. Hier kristallisieren sich in jüngster Zeit immer mehr molekulare Faktoren mit prädiktiver (d. h. Vorhersage des Tumoransprechens) und prognostischer (d. h. Vorhersage des Überlebens) Bedeutung beim NSCLC heraus. Zu ihnen zählen unter anderem ERCC1, RRM1 und bestimmte Rezeptor-Tyrosinkinasen. Erste prospektive Studien zeigen bereits, dass die Auswahl der Therapeutika gezielter vorgenommen werden kann, wenn molekulare Marker zuvor aus dem Tumor bestimmt werden. Dieser Übersichtsartikel soll einen Einblick geben, welchen Stellenwert molekulare Marker für die Therapieentscheidung sowohl in der adjuvanten als auch in der palliativen Situation derzeit haben und was in Zukunft möglicherweise in die klinische Praxis übernommen werden wird.

Abstract

The treatment of patients with non-small cell lung carcinoma (NSCLC) is guided by results from clinical studies. Data about molecular changes in the tumour are not used (up to now) to decide for an individualised, tumour-tailored therapy. High-throughput technologies and modern analytical methods (e. g., microarrays) lead to exponentially increasing knowledge about genetic changes in the cells and the interaction of proteins. This results in the discovery of molecular factors with high predictive (prediction of tumour response) and prognostic (prediction of survival) value in NSCLC. Among these are ERCC1, RRM1 and some receptor tyrosine kinases. Preliminary data of prospective studies have shown promising results for the selection of specific drugs, when these tumour markers were analysed. Therefore, this review focuses on the actual value of molecular markers for decision-making in the adjuvant and palliative setting and their probable future introduction into clinical practice.

Full Text

References

Literatur

1 Nakamura H, Saji H, Ogata A. et al . cDNA microarray analysis of gene expression in pathologic Stage IA nonsmall cell lung carcinomas. Cancer. 2003; 97 2798-2805
2 Jackman D M, Johnson B E. Small-cell lung cancer. Lancet. 2005; 366 1385-1396
3 Brambilla E, Travis W D, Colby T V. et al . The new World Health Organization classification of lung tumours. Eur Respir J. 2001; 18 1059-1068
4 Tomida S, Koshikawa K, Yatabe Y. et al . Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients. Oncogene. 2004; 23 5360-5370
5 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
6 Douillard J Y, Rosell R, De Lena M. et al . Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006; 7 719-727
7 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
8 Breathnach O S, Freidlin B, Conley B. et al . Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol. 2001; 19 1734-1742
9 Quackenbush J. Microarray analysis and tumor classification. N Engl J Med. 2006; 354 2463-2472
10 Croner R S, Foertsch T, Siebenhaar R. et al . Tissue preparation for gene expression profiling of colorectal carcinoma: Three alternatives to laser microdissection with preamplification. J Lab Clin Med. 2004; 143 344-351
11 Hofmann W-K OOG, Hoelzer D. Globale Genexpressionsanalyse mit Microarrays. Deutsches Ärzteblatt. 2003; 5 243-246
12 Veer L J van't, Dai H, Vijver M J van de. et al . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415 530-536
13 Ramaswamy S, Ross K N, Lander E S. et al . A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003; 33 49-54
14 Golub T R, Slonim D K, Tamayo P. et al . Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999; 286 531-537
15 Croner R S, Foertsch T, Brueckl W M. et al . Common denominator genes that distinguish colorectal carcinoma from normal mucosa. Int J Colorectal Dis. 2005; 20 353-362
16 Alizadeh A A, Eisen M B, Davis R E. et al . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403 503-511
17 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
18 Hermanek P, Mansmann U. Criteria for evaluating prognostic factors. Chirurg. 2001; 72 474-480
19 Hayes D F, Trock B, Harris A L. Assessing the clinical impact of prognostic factors: when is „statistically significant” clinically useful?. Breast Cancer Res Treat. 1998; 52 305-319
20 Adler A S, Chang H Y. From description to causality: mechanisms of gene expression signatures in cancer. Cell Cycle. 2006; 5 1148-1151
21 Garber M E, Troyanskaya O G, Schluens K. et al . Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A. 2001; 98 13 784-13 789
22 Nacht M, Dracheva T, Gao Y. et al . Molecular characteristics of non-small cell lung cancer. Proc Natl Acad Sci U S A. 2001; 98 15 203-15 208
23 Virtanen C, Ishikawa Y, Honjoh D. et al . Integrated classification of lung tumors and cell lines by expression profiling. Proc Natl Acad Sci U S A. 2002; 99 12 357-12 362
24 Borczuk A C, Gorenstein L, Walter K L. et al . Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol. 2003; 163 1949-1960
25 Tsao M S, Sakurada A, Cutz J C. et al . Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005; 353 133-144
26 Cohen M H, Gootenberg J, Keegan P. et al . FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007; 12 713-718
27 Sandler A, Gray R, Perry M C. et al . Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355 2542-2550
28 Sandler A B. Advanced non-small-cell lung cancer: new data, therapy choices, and challenging decisions. Oncology. 2006; 20 626-628
29 Johnson D H, Fehrenbacher L, Novotny W F. et al . Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004; 22 2184-2191
30 Mountain C F. Revisions in the International System for Staging Lung Cancer. Chest. 1997; 111 1710-1717
31 Bolliger C T, Perruchoud A P. Functional evaluation of the lung resection candidate. Eur Respir J. 1998; 11 198-212
32 Chen H Y, Yu S L, Chen C H. et al . A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med. 2007; 356 11-20
33 Kassam F, Shepherd F A, Johnston M. et al . Referral patterns for adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. J Thorac Oncol. 2007; 2 39-43
34 Pignon J P, Tribodet H, Scagliotti G V. et al . Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of five randomized clicial trials including 4,584 patients. Proc Am Soc Clin Oncol. 2006; 24 366s
35 Wakelee H, Dubey S, Gandara D. Optimal adjuvant therapy for non-small cell lung cancer - how to handle stage I disease. Oncologist. 2007; 12 331-337
36 Gail M H. A placebo-controlled randomized double-blind study of adjuvant intrapleural BCG in patients with resected T1N0, T1N1, or T2N0 squamous cell carcinoma, adenocarcinoma, or large cell carcinoma of the lung. LCSG Protocol 771. Chest. 1994; 106 287S-292S
37 Naruke T. Surgery in locally advanced non-small cell lung cancer. Lung Cancer. 2003; 42 Suppl 2 S11-15
38 Serke M. Pharmacologic treatment of bronchial cancer. Part 1: Standards. Pneumologie. 2006; 60 493-508
39 Cecere F, Bria E, Rosell R. DNA repair by ERCC1 in non-small-cell lung cancer. N Engl J Med. 2006; 355 2590-2591 author reply 2591
40 Grenader T, Shavit L. DNA repair by ERCC1 in non-small-cell lung cancer. N Engl J Med. 2006; 355 2591
41 Reed E. ERCC1 and clinical resistance to platinum-based therapy. Clin Cancer Res. 2005; 11 6100-6102
42 Metzger R, Leichman C G, Danenberg K D. et al . ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol. 1998; 16 309-316
43 Dabholkar M, Vionnet J, Bostick-Bruton F. et al . Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest. 1994; 94 703-708
44 Lord R V, 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
45 Olaussen K A, 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
46 Olaussen K A, Mountzios G, Soria J C. ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer. Curr Opin Pulm Med. 2007; 13 284-289
47 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
48 Bepler G. Using translational research to tailor the use of chemotherapy in the treatment of NSCLC. Lung Cancer. 2005; 50 Suppl 1 S13-34
49 Chou T Y, Chiu C H, Li L H. et al . Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res. 2005; 11 3750-3757
50 Non-small Cell Lung Cancer Collaborative Group . Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Bmj. 1995; 311 899-909
51 Huber R M. Lung cancer. Internist. 2006; 47 611-620 quiz 621
52 Ramalingam S, Belani C P. State-of-the-art chemotherapy for advanced non-small cell lung cancer. Semin Oncol. 2004; 31 68-74
53 Shepherd F A, Dancey J, Ramlau R. et al . Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000; 18 2095-2103
54 Shepherd F A, Rodrigues P ereira, Ciuleanu T. et al . Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353 123-132
55 Hanna N, Shepherd F A, Fossella F V. et al . Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22 1589-1597
56 Grunwald V, Hidalgo M. Development of the epidermal growth factor receptor inhibitor OSI-774. Semin Oncol. 2003; 30 23-31
57 Moyer J D, Barbacci E G, Iwata K K. et al . Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 1997; 57 4838-4848
58 Pollack V A, Savage D M, Baker D A. et al . Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther. 1999; 291 739-748
59 Wells A. EGF receptor. Int J Biochem Cell Biol. 1999; 31 637-643
60 Gamou S, Hunts J, Harigai H. et al . Molecular evidence for the lack of epidermal growth factor receptor gene expression in small cell lung carcinoma cells. Cancer Res. 1987; 47 2668-2673
61 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; 97 339-346
62 Zhou W, Gurubhagavatula S, Liu G. et al . Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2004; 10 4939-4943
63 Marchetti A, Martella C, Felicioni L. et al . EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005; 23 857-865
64 Mitsudomi T, Kosaka T, Endoh H. 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 2513-2520
65 Kosaka T, Yatabe Y, Endoh H. et al . Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 2004; 64 8919-8923
66 Jackman D M, Yeap B Y, Sequist L V. et al . Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006; 12 3908-3914
67 Riely G J, Pao W. Combining EGFR targeted therapy with chemotherapy in pancreatic cancer: is timing important?. Cancer Biol Ther. 2005; 4 1096-1097
68 Cappuzzo F, Hirsch F R, 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
69 Han S W, Kim T Y, Hwang P G. 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 2493-2501
70 Takano T, Ohe Y, Sakamoto H. et al . Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23 6829-6837
71 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 5878-5885
72 Zhang X T, Li L Y, Mu X L. et al . The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol. 2005; 16 1334-1342
73 Cortese J F, Gowda A L, Wali A. et al . Common EGFR mutations conferring sensitivity to gefitinib in lung adenocarcinoma are not prevalent in human malignant mesothelioma. Int J Cancer. 2006; 118 521-522
74 Asahina H, Yamazaki K, Kinoshita I. et al . A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006; 95 998-1004
75 Rosell R, Taron M, Sanchez J J. et al . Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol. 2007; 3 277-283
76 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 3340-3346
77 Paz-Ares L, Sanchez M I, Garcia-Velasco A. et al . A prospective phase II trial of erlotinib in advanced non-small cell lung cancer patients with mutations in the tyrosine kinase domain of the EGF-R. Proc. ASCO. 2006; 24 7020
78 Sequist L V, Bell D W, Lynch T J. et al . Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. 2007; 25 587-595
79 Kobayashi S, Boggon T J, Dayaram T. et al . EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005; 352 786-792
80 Pao W, Miller V A, Politi K A. 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
81 Kwak E L, Sordella R, Bell D W. et al . Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005; 102 7665-7670
82 Han S W, Kim T Y, Jeon Y K. 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 2538-2544
83 Pao W, Wang T Y, Riely G J. et al . KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005; 2 e17
84 Eberhard D A, Johnson B E, Amler L C. 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
85 Hirsch F R, Bunn Jr P A. Epidermal growth factor receptor inhibitors in lung cancer: smaller or larger molecules, selected or unselected populations?. J Clin Oncol. 2005; 23 9044-9047
86 Bell D W, Lynch T J, Haserlat S M. et al . Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23 8081-8092
87 Mukohara T, Engelman J A, Hanna N H. et al . Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 2005; 97 1185-1194
88 Hanna N, Lilenbaum R, Ansari R. et al . Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol. 2006; 24 5253-5258
89 Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003; 3 421-429
90 Falck J, Petrini J H, Williams B R. et al . The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet. 2002; 30 290-394
91 Das A K, Sato M, Story M D. et al . Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation. Cancer Res. 2006; 66 9601-9608
92 Raben D, Helfrich B, Chan D C. et al . The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res. 2005; 11 795-805
93 Bonner J A, Harari P M, Giralt J. et al . Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354 567-578
94 Rosell R, Cobo M, Isla D. et al . Pharmacogenomics and gemcitabine. Ann Oncol. 2006; 17 Suppl 5 v13-v16
95 Rosell R, Crino L, Danenberg K. et al . Targeted therapy in combination with gemcitabine in non-small cell lung cancer. Semin Oncol. 2003; 30 19-25
96 Shepherd F A, Rosell R. Weighing Tumor Biology in Treatment Decisions for Patients with Non-small Cell Lung Cancer. J Thorac Oncol. 2007; 2 68-76
97 Rosell R, Danenberg K D, 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
98 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
99 Cobo M, Gutierrez V, Alcaide J. et al . A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status. Lung Cancer. 2007; 56 255-262
100 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
101 Seve P, Dumontet C. Chemoresistance in non-small cell lung cancer. Curr Med Chem Anticancer Agents. 2005; 5 73-88
102 Seve P, Isaac S, Tredan O. et al . Expression of class III {beta}-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy. Clin Cancer Res. 2005; 11 5481-5486
103 Seve P, Mackey J, Isaac S. et al . Class III beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther. 2005; 4 2001-2007

PD Dr. med. Wolfgang Brückl

Leiter der pneumologischen Onkologie, Medizinische Klinik 1Universitätsklinikum Erlangen

Ulmenweg 18

91054 Erlangen

Email: wolfgang.brueckl@uk-erlangen.de