Wiener Medizinische Wochenschrift

, Volume 157, Issue 21–22, pp 554–561 | Cite as

Biomarker – der Weg zur individualisierten Chemotherapie beim nicht-kleinzelligen Bronchialkarzinom

Themenschwerpunkt

Zusammenfassung

Erkenntnisse aus der Tumorbiologie beeinflussen vermehrt therapeutische Entscheidungen in der Behandlung des nichtkleinzelligen Bronchialkarzinoms (NSCLC). Eine Reihe von potentiellen Biomarkern wird derzeit mit der Hoffnung untersucht, dass diese zukünftig bei der Selektion von Patienten für die optimale Therapie hilfreich sein könnten. Patienten mit einer erhöhten DNA-Reparaturkapazität, angezeigt durch eine erhöhte Expression von ERCC1 (excision repair cross complementation group-1) oder RRM1 (ribonucleodid reductase subunit M1), haben ein schlechteres Ansprechen auf cisplatin- oder gemcitabinhältige Chemotherapie. Eine Überexpression des Zellzyklusregulators p27 führt zu einer Resistenz gegen verschiedene Zytostatika und eine erhöhte Expression von Klasse III β-Tubulin ist mit Taxanresistenz assoziiert. Aufgrund bisheriger, viel versprechender Ergebnisse sollte eine individuell angepasste Chemotherapie mit Hilfe von prädiktiven Biomarkern möglich sein und könnte zu einer weiteren Verbesserung der Behandlung des NSCLC beitragen.

Schlüsselwörter

Nichtkleinzelliges Bronchialkarzinom Chemotherapie Prädiktive Faktoren Biomarker 

Biomarkers – the way towards individualized chemotherapy in non-small cell lung cancer (NSCLC)

Summary

Tumor biology is increasingly important when choosing the optimal therapy for patients with non-small cell lung cancer (NSCLC). A number of potential biomarkers is under investigation in the hope that it will be possible to identify markers that assist in the selection of patients for specific therapies in the future. Patients with an elevated DNA repair capacity, indicated by an increased tumoral expression of excision repair cross complementation group-1 (ERCC1) or ribonucleotid reductase subunit M1 (RRM1) may benefit less from cisplatin-based and gemcitabine-based chemotherapy, respectively. Overexpression of the cell cycle regulator p27 affects response to various anticancer drugs and increased levels of class III β-Tubulin are associated with taxane resistance. Promising results so far suggest that customized therapy for individual patients with the help of predictive biomarkers is possible and it is likely that this strategy will improve treatment of NSCLC in the future.

Keywords

NSCLC Chemotherapy Predictive factors Biomarkers 

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Literatur

  1. Reed E (1998) Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev 24: 331–344PubMedCrossRefGoogle Scholar
  2. Dip R, Camenisch U, Naegeli H (2004) Mechanisms of DNA damage recognition and strand discrimination in human nucleotide excision repair. DNA Repair (Amst) 3: 1409–1423CrossRefGoogle Scholar
  3. Simon GR, Ismail-Khan R, Bepler G (2007) Nuclear excision repair-based personalized therapy for non-small cell lung cancer: From hypothesis to reality. Int J Biochem Cell Biol 39: 1318–1328PubMedCrossRefGoogle Scholar
  4. Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E (1992) ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst 84: 1512–1517PubMedCrossRefGoogle Scholar
  5. Metzger R, Leichman CG, Danenberg KD, Danenberg PV, Lenz HJ, Hayashi K, Groshen S, Salonga D, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Konda B, Leichman L (1998) 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 16: 309–316PubMedGoogle Scholar
  6. Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, Cardenal F, Sánchez JM, Gumerlock PH, Tarón M, Sánchez JJ, Danenberg KD, Danenberg PV, Rosell R (2002) Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 8: 2286–2291PubMedGoogle Scholar
  7. Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Su L, Christiani DC (2004) 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 10: 4939–4943PubMedCrossRefGoogle Scholar
  8. Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, Cambieri A, Selvaggi G, Saviozzi S, Calogero R, Papotti M, Scagliotti GV (2006) ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 17: 1818–1825PubMedCrossRefGoogle Scholar
  9. Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC; IALT Bio Investigators (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355: 983–991PubMedCrossRefGoogle Scholar
  10. Azuma K, Komohara Y, Sasada T, Terazaki Y, Ikeda J, Hoshino T, Itoh K, Yamada A, Aizawa H (2007) Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci 98: 1336–1343PubMedCrossRefGoogle Scholar
  11. Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F, Reed E (2000) Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 16: 555–560PubMedGoogle Scholar
  12. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J (2004) Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350: 351–360PubMedCrossRefGoogle Scholar
  13. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators (2005) Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352: 2589–2597PubMedCrossRefGoogle Scholar
  14. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P (2006) 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 7: 719–727PubMedCrossRefGoogle Scholar
  15. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, Viñolas N, Paz-Ares L, Lopez-Vivanco G, Muñoz MA, Felip E, Alberola V, Camps C, Domine M, Sanchez JJ, Sanchez-Ronco M, Danenberg K, Taron M, Gandara D, Rosell R (2007) 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 25: 2747–2754PubMedCrossRefGoogle Scholar
  16. Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA (2004) An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res 64: 3761–3766PubMedCrossRefGoogle Scholar
  17. Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, Simon G (2006) RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 24: 4731–4737PubMedCrossRefGoogle Scholar
  18. Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, Provencio M, Isla D, Taron M, Diz P, Artal A; Spanish Lung Cancer Group (2004) Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 10: 1318–1325PubMedCrossRefGoogle Scholar
  19. Bepler G, Sharma S, Cantor A, Gautam A, Haura E, Simon G, Sharma A, Sommers E, Robinson L (2004) RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol 22: 1878–1885PubMedCrossRefGoogle Scholar
  20. Simon G, Sharma A, Li X, Hazelton T, Walsh F, Williams C, Chiappori A, Haura E, Tanvetyanon T, Antonia S, Cantor A, Bepler G (2007) Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 25: 2741–2746PubMedCrossRefGoogle Scholar
  21. Sherr CJ (1996) Cancer cell cycles. Science 274: 1672–1677PubMedCrossRefGoogle Scholar
  22. Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154: 313–323PubMedGoogle Scholar
  23. St Croix B, Flørenes VA, Rak JW, Flanagan M, Bhattacharya N, Slingerland JM, Kerbel RS (1996) Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents. Nat Med 2: 1204–1210PubMedCrossRefGoogle Scholar
  24. Dimanche-Boitrel MT, Micheau O, Hammann A, Haugg M, Eymin B, Chauffert B, Solary E (1998) Contribution of the cyclin-dependent kinase inhibitor p27KIP1 to the confluence-dependent resistance of HT29 human colon carcinoma cells. Int J Cancer 77: 796–802PubMedCrossRefGoogle Scholar
  25. Eymin B, Haugg M, Droin N, Sordet O, Dimanche-Boitrel MT, Solary E (1999) p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells. Oncogene 18: 1411–1418PubMedCrossRefGoogle Scholar
  26. Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, Caputi M, Baldi F, Pagano M, Giordano A (1997) Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res 57: 3381–3385PubMedGoogle Scholar
  27. Yatabe Y, Masuda A, Koshikawa T, Nakamura S, Kuroishi T, Osada H, Takahashi T, Mitsudomi T, Takahashi T (1998) p27KIP1 in human lung cancers: differential changes in small cell and non-small cell carcinomas. Cancer Res 58: 1042–1047PubMedGoogle Scholar
  28. Catzavelos C, Tsao MS, DeBoer G, Bhattacharya N, Shepherd FA, Slingerland JM (1999) Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. Cancer Res 59: 684–688PubMedGoogle Scholar
  29. Hommura F, Dosaka-Akita H, Mishina T, Nishi M, Kojima T, Hiroumi H, Ogura S, Shimizu M, Katoh H, Kawakami Y (2000) Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers. Clin Cancer Res 6: 4073–4081PubMedGoogle Scholar
  30. Oshita F, Kameda Y, Nishio K, Tanaka G, Yamada K, Nomura I, Nakayama H, Noda K (2000) Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer. Oncol Rep 7: 491–495PubMedGoogle Scholar
  31. Tsoli E, Gorgoulis VG, Zacharatos P, Kotsinas A, Mariatos G, Kastrinakis NG, Kokotas S, Kanavaros P, Asimacopoulos P, Bramis J, Kletsas D, Papavassiliou AG, Kittas C (2001) Low levels of p27 in association with deregulated p53-pRb protein status enhance tumor proliferation and chromosomal instability in non-small cell lung carcinomas. Mol Med 7: 418–429PubMedGoogle Scholar
  32. Tsukamoto S, Sugio K, Sakada T, Ushijima C, Yamazaki K, Sugimachi K (2001) Reduced expression of cell-cycle regulator p27(Kip1) correlates with a shortened survival in non-small cell lung cancer. Lung Cancer 34: 83–90PubMedCrossRefGoogle Scholar
  33. Hayashi H, Ogawa N, Ishiwa N, Yazawa T, Inayama Y, Ito T, Kitamura H (2001) High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients. Lung Cancer 34: 59–65PubMedCrossRefGoogle Scholar
  34. Hirabayashi H, Ohta M, Tanaka H, Sakaguchi M, Fujii Y, Miyoshi S, Matsuda H (2002) Prognostic significance of p27KIP1 expression in resected non-small cell lung cancers: analysis in combination with expressions of p16INK4A, pRB, and p53. J Surg Oncol 81: 177–184; discussion 184PubMedCrossRefGoogle Scholar
  35. Takahashi S, Kamata Y, Tamo W, Koyanagi M, Hatanaka R, Yamada Y, Tsushima T, Takaya S, Fukuda I (2002) Relationship between postoperative recurrence and expression of cyclin E, p27, and Ki-67 in non-small cell lung cancer without lymph node metastases. Int J Clin Oncol 7: 349–355PubMedCrossRefGoogle Scholar
  36. Yoo J, Jung JH, Lee MA, Seo KJ, Shim BY, Kim SH, Cho DG, Ahn MI, Kim CH, Cho KD, Kang SJ, Kim HK (2007) Immunohistochemical analysis of non-small cell lung cancer: correlation with clinical parameters and prognosis. J Korean Med Sci 22: 318–325PubMedGoogle Scholar
  37. Filipits M, Pirker R, Dunant A, Lantuejoul S, Schmid K, Huynh A, Haddad V, André F, Stahel R, Pignon JP, Soria JC, Popper HH, Le Chevalier T, Brambilla E (2007) Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program. J Clin Oncol 25: 2735–2740PubMedCrossRefGoogle Scholar
  38. Burkhart CA, Kavallaris M, Band Horwitz S (2001) The role of beta-tubulin isotypes in resistance to antimitotic drugs. Biochim Biophys Acta 1471: O1–O9PubMedGoogle Scholar
  39. Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 77: 1561–1565PubMedCrossRefGoogle Scholar
  40. Wilson L, Jordan MA (1995) Microtubule dynamics: taking aim at a moving target. Chem Biol 2: 569–573PubMedCrossRefGoogle Scholar
  41. Sève P, Mackey J, Isaac S, Trédan O, Souquet PJ, Pérol M, Lai R, Voloch A, Dumontet C (2005) 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 4: 2001–2007PubMedCrossRefGoogle Scholar
  42. Kavallaris M, Burkhart CA, Horwitz SB (1999) Antisense oligonucleotides to class III beta-tubulin sensitize drug-resistant cells to Taxol. Br J Cancer 80: 1020–1025PubMedCrossRefGoogle Scholar
  43. Kavallaris M, Kuo DY, Burkhart CA, Regl DL, Norris MD, Haber M, Horwitz SB (1997) Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest 100: 1282–1293PubMedCrossRefGoogle Scholar
  44. Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW, Hudes GR (1998) Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 77: 562–566PubMedGoogle Scholar
  45. Liu B, Staren E, Iwamura T, Appert H, Howard J (2001) Taxotere resistance in SUIT Taxotere resistance in pancreatic carcinoma cell line SUIT 2 and its sublines. World J Gastroenterol 7: 855–859PubMedGoogle Scholar
  46. Liu B, Staren ED, Iwamura T, Appert HE, Howard JM (2001) Mechanisms of taxotere-related drug resistance in pancreatic carcinoma. J Surg Res 99: 179–186PubMedCrossRefGoogle Scholar
  47. Mozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, Gallo D, Martinelli E, Ranelletti FO, Ferrandina G, Scambia G (2005) Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res 11: 298–305PubMedGoogle Scholar
  48. Paradiso A, Mangia A, Chiriatti A, Tommasi S, Zito A, Latorre A, Schittulli F, Lorusso V (2005) Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol 16 (Suppl 4): iv14–iv19CrossRefPubMedGoogle Scholar
  49. Monzó M, Rosell R, Sánchez JJ, Lee JS, O'Brate A, González-Larriba JL, Alberola V, Lorenzo JC, Núñez L, Ro JY, Martín C (1999) Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 17: 1786–1793PubMedGoogle Scholar
  50. Sève P, Isaac S, Trédan O, Souquet PJ, Pachéco Y, Pérol M, Lafanéchère L, Penet A, Peiller EL, Dumontet C (2005) 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 11: 5481–5486PubMedCrossRefGoogle Scholar
  51. Sève P, Lai R, Ding K, Winton T, Butts C, Mackey J, Dumontet C, Dabbagh L, Aviel-Ronen S, Seymour L, Whitehead M, Tsao MS, Shepherd FA, Reiman T (2007) Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: analysis of NCIC JBR. 10. Clin Cancer Res 13: 994–999PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Institut für Krebsforschung, Universitätsklinik für Innere Medizin IMedizinische Universität WienWienAustria

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