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British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Apr;79(11-12):1864–1869. doi: 10.1038/sj.bjc.6690297

A multifactorial approach including tumoural epidermal growth factor receptor, p53, thymidylate synthase and dihydropyrimidine dehydrogenase to predict treatment outcome in head and neck cancer patients receiving 5-fluorouracil

M C Etienne 1, X Pivot 1, J L Formento 1, R J Bensadoun 1, P Formento 1, O Dassonville 1, M Francoual 1, G Poissonnet 1, X Fontana 1, M Schneider 1, F Demard 1, G Milano 1
PMCID: PMC2362780  PMID: 10206306

Abstract

The prognostic value of tumoural epidermal growth factor receptor (EGFR), p53, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was analysed on 82 advanced head and neck cancer patients (71 men, 11 women; mean age 59). Induction treatment was cisplatin–5-FU ± folinic acid (61 patients, Chem group) or concomitant cisplatin–5-FU–radiotherapy (21 patients, RChem group). EGFR (binding assay), p53 protein (Sangtec immunoluminometric assay), TS and DPD activities (radioenzymatic assays) were measured on biopsies obtained at time of diagnosis. Significant positive correlation was demonstrated between p53 and EGFR. In the RChem group, p53 was higher in non-complete responders (median 1.03 ng mg−1) than in complete responders (median 0.08 ng mg−1) (P = 0.057). Univariate Cox analyses stratified on treatment group showed that specific survival (33 events) was significantly related to T staging, p53 taken as continuous or categorial (below vs over 0.80 ng mg−1) variable, and EGFR (below vs over 220 fmol mg−1); survival increased when EGFR and p53 were below thresholds. Multivariate stepwise analysis including T staging, EGFR and p53 revealed that T staging and EGFR were independent predictors of survival; relative risks were 3.68 for T staging and 2.65 for EGFR. Overall, EGFR remained an independent prognostic factor when response to treatment and T staging were considered in the multivariate analysis. © 1999 Cancer Research Campaign

Keywords: head and neck cancer, induction treatment, epidermal growth factor receptor, thymidylate synthase, p53, dihydropyrimidine dehydrogenase

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Selected References

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  1. Beck A., Etienne M. C., Chéradame S., Fischel J. L., Formento P., Renée N., Milano G. A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. Eur J Cancer. 1994;30A(10):1517–1522. doi: 10.1016/0959-8049(94)00216-r. [DOI] [PubMed] [Google Scholar]
  2. Chu E., Allegra C. J. The role of thymidylate synthase in cellular regulation. Adv Enzyme Regul. 1996;36:143–163. doi: 10.1016/0065-2571(95)00004-6. [DOI] [PubMed] [Google Scholar]
  3. Dassonville O., Formento J. L., Francoual M., Ramaioli A., Santini J., Schneider M., Demard F., Milano G. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol. 1993 Oct;11(10):1873–1878. doi: 10.1200/JCO.1993.11.10.1873. [DOI] [PubMed] [Google Scholar]
  4. Dimery I. W., Hong W. K. Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst. 1993 Jan 20;85(2):95–111. doi: 10.1093/jnci/85.2.95. [DOI] [PubMed] [Google Scholar]
  5. Etienne M. C., Bernard S., Fischel J. L., Formento P., Gioanni J., Santini J., Demard F., Schneider M., Milano G. Dose reduction without loss of efficacy for 5-fluorouracil and cisplatin combined with folinic acid. In vitro study on human head and neck carcinoma cell lines. Br J Cancer. 1991 Mar;63(3):372–377. doi: 10.1038/bjc.1991.88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Etienne M. C., Chéradame S., Fischel J. L., Formento P., Dassonville O., Renée N., Schneider M., Thyss A., Demard F., Milano G. Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity. J Clin Oncol. 1995 Jul;13(7):1663–1670. doi: 10.1200/JCO.1995.13.7.1663. [DOI] [PubMed] [Google Scholar]
  7. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  8. Harari P. M. Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol. 1997 May;15(5):2050–2055. doi: 10.1200/JCO.1997.15.5.2050. [DOI] [PubMed] [Google Scholar]
  9. Harris B. E., Song R., Soong S. J., Diasio R. B. Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res. 1990 Jan 1;50(1):197–201. [PubMed] [Google Scholar]
  10. Harris C. C. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst. 1996 Oct 16;88(20):1442–1455. doi: 10.1093/jnci/88.20.1442. [DOI] [PubMed] [Google Scholar]
  11. Hasegawa M., Mitsuhashi N., Yamakawa M., Furuta M., Maebayashi K., Imai R., Hayakawa K., Niibe H. p53 protein expression and radiation-induced apoptosis in human tumors transplanted to nude mice. Radiat Med. 1997 May-Jun;15(3):171–176. [PubMed] [Google Scholar]
  12. Johnston P. G., Fisher E. R., Rockette H. E., Fisher B., Wolmark N., Drake J. C., Chabner B. A., Allegra C. J. The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 1994 Dec;12(12):2640–2647. doi: 10.1200/JCO.1994.12.12.2640. [DOI] [PubMed] [Google Scholar]
  13. Johnston P. G., Mick R., Recant W., Behan K. A., Dolan M. E., Ratain M. J., Beckmann E., Weichselbaum R. R., Allegra C. J., Vokes E. E. Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer. J Natl Cancer Inst. 1997 Feb 19;89(4):308–313. doi: 10.1093/jnci/89.4.308. [DOI] [PubMed] [Google Scholar]
  14. Koch W. M., Brennan J. A., Zahurak M., Goodman S. N., Westra W. H., Schwab D., Yoo G. H., Lee D. J., Forastiere A. A., Sidransky D. p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma. J Natl Cancer Inst. 1996 Nov 6;88(21):1580–1586. doi: 10.1093/jnci/88.21.1580. [DOI] [PubMed] [Google Scholar]
  15. Lefebvre J. L., Chevalier D., Luboinski B., Kirkpatrick A., Collette L., Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996 Jul 3;88(13):890–899. doi: 10.1093/jnci/88.13.890. [DOI] [PubMed] [Google Scholar]
  16. Ludes-Meyers J. H., Subler M. A., Shivakumar C. V., Munoz R. M., Jiang P., Bigger J. E., Brown D. R., Deb S. P., Deb S. Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol. 1996 Nov;16(11):6009–6019. doi: 10.1128/mcb.16.11.6009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Maurizi M., Almadori G., Ferrandina G., Distefano M., Romanini M. E., Cadoni G., Benedetti-Panici P., Paludetti G., Scambia G., Mancuso S. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer. 1996 Oct;74(8):1253–1257. doi: 10.1038/bjc.1996.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res. 1997 Dec;3(12 Pt 2):2703–2707. [PubMed] [Google Scholar]
  19. Pestalozzi B. C., Peterson H. F., Gelber R. D., Goldhirsch A., Gusterson B. A., Trihia H., Lindtner J., Cortés-Funes H., Simmoncini E., Byrne M. J. Prognostic importance of thymidylate synthase expression in early breast cancer. J Clin Oncol. 1997 May;15(5):1923–1931. doi: 10.1200/JCO.1997.15.5.1923. [DOI] [PubMed] [Google Scholar]
  20. Raybaud-Diogène H., Tétu B., Morency R., Fortin A., Monteil R. A. p53 overexpression in head and neck squamous cell carcinoma: review of the literature. Eur J Cancer B Oral Oncol. 1996 May;32B(3):143–149. doi: 10.1016/0964-1955(95)00095-x. [DOI] [PubMed] [Google Scholar]
  21. Santini J., Formento J. L., Francoual M., Milano G., Schneider M., Dassonville O., Demard F. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck. 1991 Mar-Apr;13(2):132–139. doi: 10.1002/hed.2880130209. [DOI] [PubMed] [Google Scholar]
  22. Santini J., Milano G., Thyss A., Renee N., Viens P., Ayela P., Schneider M., Demard F. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer. 1989 Feb;59(2):287–290. doi: 10.1038/bjc.1989.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Spaulding M. B., Fischer S. G., Wolf G. T. Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol. 1994 Aug;12(8):1592–1599. doi: 10.1200/JCO.1994.12.8.1592. [DOI] [PubMed] [Google Scholar]
  24. Störkel S., Reichert T., Reiffen K. A., Wagner W. EGFR and PCNA expression in oral squamous cell carcinomas--a valuable tool in estimating the patient's prognosis. Eur J Cancer B Oral Oncol. 1993 Oct;29B(4):273–277. doi: 10.1016/0964-1955(93)90047-i. [DOI] [PubMed] [Google Scholar]
  25. Vokes E. E., Weichselbaum R. R., Lippman S. M., Hong W. K. Head and neck cancer. N Engl J Med. 1993 Jan 21;328(3):184–194. doi: 10.1056/NEJM199301213280306. [DOI] [PubMed] [Google Scholar]
  26. Voldborg B. R., Damstrup L., Spang-Thomsen M., Poulsen H. S. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997 Dec;8(12):1197–1206. doi: 10.1023/a:1008209720526. [DOI] [PubMed] [Google Scholar]

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