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. 1998 Jun;77(12):2267–2273. doi: 10.1038/bjc.1998.377

Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer.

T A Järvinen 1, K Holli 1, T Kuukasjärvi 1, J J Isola 1
PMCID: PMC2150425  PMID: 9649144

Abstract

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.

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Selected References

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  1. Asano T., An T., Mayes J., Zwelling L. A., Kleinerman E. S. Transfection of human topoisomerase II alpha into etoposide-resistant cells: transient increase in sensitivity followed by down-regulation of the endogenous gene. Biochem J. 1996 Oct 1;319(Pt 1):307–313. doi: 10.1042/bj3190307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asano T., Zwelling L. A., An T., McWatters A., Herzog C. E., Mayes J., Loughlin S. M., Kleinerman E. S. Effect of transfection of a Drosophila topoisomerase II gene into a human brain tumour cell line intrinsically resistant to etoposide. Br J Cancer. 1996 Jun;73(11):1373–1380. doi: 10.1038/bjc.1996.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. BLOOM H. J., RICHARDSON W. W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957 Sep;11(3):359–377. doi: 10.1038/bjc.1957.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bitran J. D., Samuels B., Trujillo Y., Klein L., Schroeder L., Martinec J. Her2/neu overexpression is associated with treatment failure in women with high-risk stage II and stage IIIA breast cancer (>10 involved lymph nodes) treated with high-dose chemotherapy and autologous hematopoietic progenitor cell support following standard-dose adjuvant chemotherapy. Clin Cancer Res. 1996 Sep;2(9):1509–1513. [PubMed] [Google Scholar]
  5. Boege F., Andersen A., Jensen S., Zeidler R., Kreipe H. Proliferation-associated nuclear antigen Ki-S1 is identical with topoisomerase II alpha. Delineation of a carboxy-terminal epitope with peptide antibodies. Am J Pathol. 1995 Jun;146(6):1302–1308. [PMC free article] [PubMed] [Google Scholar]
  6. Bose R., Verheij M., Haimovitz-Friedman A., Scotto K., Fuks Z., Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell. 1995 Aug 11;82(3):405–414. doi: 10.1016/0092-8674(95)90429-8. [DOI] [PubMed] [Google Scholar]
  7. Carson D. A., Lois A. Cancer progression and p53. Lancet. 1995 Oct 14;346(8981):1009–1011. doi: 10.1016/s0140-6736(95)91693-8. [DOI] [PubMed] [Google Scholar]
  8. Chen A. Y., Liu L. F. DNA topoisomerases: essential enzymes and lethal targets. Annu Rev Pharmacol Toxicol. 1994;34:191–218. doi: 10.1146/annurev.pa.34.040194.001203. [DOI] [PubMed] [Google Scholar]
  9. Davies S. L., Popert R., Coptcoat M., Hickson I. D., Masters J. R. Response to epirubicin in patients with superficial bladder cancer and expression of the topoisomerase II alpha and beta genes. Int J Cancer. 1996 Jan 3;65(1):63–66. doi: 10.1002/(SICI)1097-0215(19960103)65:1<63::AID-IJC11>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  10. Davies S. M., Robson C. N., Davies S. L., Hickson I. D. Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem. 1988 Nov 25;263(33):17724–17729. [PubMed] [Google Scholar]
  11. Epstein R. J. Drug-induced DNA damage and tumor chemosensitivity. J Clin Oncol. 1990 Dec;8(12):2062–2084. doi: 10.1200/JCO.1990.8.12.2062. [DOI] [PubMed] [Google Scholar]
  12. Falkson G., Gelman R., Falkson C. I., Glick J., Harris J. Factors predicting for response, time to treatment failure, and survival in women with metastatic breast cancer treated with DAVTH: a prospective Eastern Cooperative Oncology Group study. J Clin Oncol. 1991 Dec;9(12):2153–2161. doi: 10.1200/JCO.1991.9.12.2153. [DOI] [PubMed] [Google Scholar]
  13. Froelich-Ammon S. J., Osheroff N. Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J Biol Chem. 1995 Sep 15;270(37):21429–21432. doi: 10.1074/jbc.270.37.21429. [DOI] [PubMed] [Google Scholar]
  14. Gartenhaus R. B., Wang P., Hoffmann P. Induction of the WAF1/CIP1 protein and apoptosis in human T-cell leukemia virus type I-transformed lymphocytes after treatment with adriamycin by using a p53-independent pathway. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):265–268. doi: 10.1073/pnas.93.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gudkov A. V., Zelnick C. R., Kazarov A. R., Thimmapaya R., Suttle D. P., Beck W. T., Roninson I. B. Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3231–3235. doi: 10.1073/pnas.90.8.3231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Guillot C., Falette N., Courtois S., Voeltzel T., Garcia E., Ozturk M., Puisieux A. Alteration of p53 damage response by tamoxifen treatment. Clin Cancer Res. 1996 Sep;2(9):1439–1444. [PubMed] [Google Scholar]
  17. Guillot C., Falette N., Paperin M. P., Courtois S., Gentil-Perret A., Treilleux I., Ozturk M., Puisieux A. p21(WAF1/CIP1) response to genotoxic agents in wild-type TP53 expressing breast primary tumours. Oncogene. 1997 Jan 9;14(1):45–52. doi: 10.1038/sj.onc.1200803. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Hayward J. L., Carbone P. P., Heuson J. C., Kumaoka S., Segaloff A., Rubens R. D. Assessment of response to therapy in advanced breast cancer: a project of the Programme on Clinical Oncology of the International Union Against Cancer, Geneva, Switzerland. Cancer. 1977 Mar;39(3):1289–1294. doi: 10.1002/1097-0142(197703)39:3<1289::aid-cncr2820390340>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  20. Hellemans P., van Dam P. A., Geyskens M., van Oosterom A. T., Buytaert P., Van Marck E. Immunohistochemical study of topoisomerase II-alpha expression in primary ductal carcinoma of the breast. J Clin Pathol. 1995 Feb;48(2):147–150. doi: 10.1136/jcp.48.2.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hietanen P., Blomqvist C., Wasenius V. M., Niskanen E., Franssila K., Nordling S. Do DNA ploidy and S-phase fraction in primary tumour predict the response to chemotherapy in metastatic breast cancer? Br J Cancer. 1995 May;71(5):1029–1032. doi: 10.1038/bjc.1995.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Houlbrook S., Addison C. M., Davies S. L., Carmichael J., Stratford I. J., Harris A. L., Hickson I. D. Relationship between expression of topoisomerase II isoforms and intrinsic sensitivity to topoisomerase II inhibitors in breast cancer cell lines. Br J Cancer. 1995 Dec;72(6):1454–1461. doi: 10.1038/bjc.1995.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Isola J., Visakorpi T., Holli K., Kallioniemi O. P. Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst. 1992 Jul 15;84(14):1109–1114. doi: 10.1093/jnci/84.14.1109. [DOI] [PubMed] [Google Scholar]
  24. Jacks T., Weinberg R. A. Cell-cycle control and its watchman. Nature. 1996 Jun 20;381(6584):643–644. doi: 10.1038/381643a0. [DOI] [PubMed] [Google Scholar]
  25. Järvinen T. A., Kononen J., Pelto-Huikko M., Isola J. Expression of topoisomerase IIalpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer. Am J Pathol. 1996 Jun;148(6):2073–2082. [PMC free article] [PubMed] [Google Scholar]
  26. Kallioniemi O. P. Comparison of fresh and paraffin-embedded tissue as starting material for DNA flow cytometry and evaluation of intratumor heterogeneity. Cytometry. 1988 Mar;9(2):164–169. doi: 10.1002/cyto.990090211. [DOI] [PubMed] [Google Scholar]
  27. Kallioniemi O. P., Holli K., Visakorpi T., Koivula T., Helin H. H., Isola J. J. Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer. 1991 Nov 11;49(5):650–655. doi: 10.1002/ijc.2910490504. [DOI] [PubMed] [Google Scholar]
  28. Kallioniemi O. P., Visakorpi T., Holli K., Heikkinen A., Isola J., Koivula T. Improved prognostic impact of S-phase values from paraffin-embedded breast and prostate carcinomas after correcting for nuclear slicing. Cytometry. 1991;12(5):413–421. doi: 10.1002/cyto.990120506. [DOI] [PubMed] [Google Scholar]
  29. Kaufmann S. H., Karp J. E., Jones R. J., Miller C. B., Schneider E., Zwelling L. A., Cowan K., Wendel K., Burke P. J. Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. Blood. 1994 Jan 15;83(2):517–530. [PubMed] [Google Scholar]
  30. Keith W. N., Douglas F., Wishart G. C., McCallum H. M., George W. D., Kaye S. B., Brown R. Co-amplification of erbB2, topoisomerase II alpha and retinoic acid receptor alpha genes in breast cancer and allelic loss at topoisomerase I on chromosome 20. Eur J Cancer. 1993;29A(10):1469–1475. doi: 10.1016/0959-8049(93)90022-8. [DOI] [PubMed] [Google Scholar]
  31. Kingma P. S., Osheroff N. Apurinic sites are position-specific topoisomerase II poisons. J Biol Chem. 1997 Jan 10;272(2):1148–1155. doi: 10.1074/jbc.272.2.1148. [DOI] [PubMed] [Google Scholar]
  32. Kingma P. S., Osheroff N. Spontaneous DNA damage stimulates topoisomerase II-mediated DNA cleavage. J Biol Chem. 1997 Mar 14;272(11):7488–7493. doi: 10.1074/jbc.272.11.7488. [DOI] [PubMed] [Google Scholar]
  33. Kuukasjärvi T., Kononen J., Helin H., Holli K., Isola J. Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol. 1996 Sep;14(9):2584–2589. doi: 10.1200/JCO.1996.14.9.2584. [DOI] [PubMed] [Google Scholar]
  34. Masters J. R., Camplejohn R. S., Millis R. R., Rubens R. D. Histological grade, elastosis, DNA ploidy and the response to chemotherapy of breast cancer. Br J Cancer. 1987 Apr;55(4):455–457. doi: 10.1038/bjc.1987.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Morgan J. M., Navabi H., Schmid K. W., Jasani B. Possible role of tissue-bound calcium ions in citrate-mediated high-temperature antigen retrieval. J Pathol. 1994 Dec;174(4):301–307. doi: 10.1002/path.1711740410. [DOI] [PubMed] [Google Scholar]
  36. Murphy D. S., McHardy P., Coutts J., Mallon E. A., George W. D., Kaye S. B., Brown R., Keith W. N. Interphase cytogenetic analysis of erbB2 and topoII alpha co-amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma in situ. Int J Cancer. 1995 Feb 20;64(1):18–26. doi: 10.1002/ijc.2910640106. [DOI] [PubMed] [Google Scholar]
  37. Muss H. B., Thor A. D., Berry D. A., Kute T., Liu E. T., Koerner F., Cirrincione C. T., Budman D. R., Wood W. C., Barcos M. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994 May 5;330(18):1260–1266. doi: 10.1056/NEJM199405053301802. [DOI] [PubMed] [Google Scholar]
  38. Nitiss J. L., Beck W. T. Antitopoisomerase drug action and resistance. Eur J Cancer. 1996 Jun;32A(6):958–966. doi: 10.1016/0959-8049(96)00056-1. [DOI] [PubMed] [Google Scholar]
  39. Peacock C. S., Thompson I. W., Van Noorden S. Silver enhancement of polymerised diaminobenzidine: increased sensitivity for immunoperoxidase staining. J Clin Pathol. 1991 Sep;44(9):756–758. doi: 10.1136/jcp.44.9.756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pietras R. J., Fendly B. M., Chazin V. R., Pegram M. D., Howell S. B., Slamon D. J. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene. 1994 Jul;9(7):1829–1838. [PubMed] [Google Scholar]
  41. Ravdin P. M., Chamness G. C. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers--a review. Gene. 1995 Jun 14;159(1):19–27. doi: 10.1016/0378-1119(94)00866-q. [DOI] [PubMed] [Google Scholar]
  42. Sandri M. I., Hochhauser D., Ayton P., Camplejohn R. C., Whitehouse R., Turley H., Gatter K., Hickson I. D., Harris A. L. Differential expression of the topoisomerase II alpha and beta genes in human breast cancers. Br J Cancer. 1996 Jun;73(12):1518–1524. doi: 10.1038/bjc.1996.286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Smith K., Houlbrook S., Greenall M., Carmichael J., Harris A. L. Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity. Oncogene. 1993 Apr;8(4):933–938. [PubMed] [Google Scholar]
  44. Soong R., Robbins P. D., Dix B. R., Grieu F., Lim B., Knowles S., Williams K. E., Turbett G. R., House A. K., Iacopetta B. J. Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas. Hum Pathol. 1996 Oct;27(10):1050–1055. doi: 10.1016/s0046-8177(96)90282-8. [DOI] [PubMed] [Google Scholar]
  45. Tsai C. M., Chang K. T., Wu L. H., Chen J. Y., Gazdar A. F., Mitsudomi T., Chen M. H., Perng R. P. Correlations between intrinsic chemoresistance and HER-2/neu gene expression, p53 gene mutations, and cell proliferation characteristics in non-small cell lung cancer cell lines. Cancer Res. 1996 Jan 1;56(1):206–209. [PubMed] [Google Scholar]
  46. Tuccari G., Rizzo A., Giuffrè G., Barresi G. Immunocytochemical detection of DNA topoisomerase type II in primary breast carcinomas: correlation with clinico-pathological features. Virchows Arch A Pathol Anat Histopathol. 1993;423(1):51–55. doi: 10.1007/BF01606432. [DOI] [PubMed] [Google Scholar]
  47. Vassetzky Y. S., Alghisi G. C., Roberts E., Gasser S. M. Ectopic expression of inactive forms of yeast DNA topoisomerase II confers resistance to the anti-tumour drug, etoposide. Br J Cancer. 1996 May;73(10):1201–1209. doi: 10.1038/bjc.1996.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Watt P. M., Hickson I. D. Structure and function of type II DNA topoisomerases. Biochem J. 1994 Nov 1;303(Pt 3):681–695. doi: 10.1042/bj3030681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Withoff S., de Vries E. G., Keith W. N., Nienhuis E. F., van der Graaf W. T., Uges D. R., Mulder N. H. Differential expression of DNA topoisomerase II alpha and -beta in P-gp and MRP-negative VM26, mAMSA and mitoxantrone-resistant sublines of the human SCLC cell line GLC4. Br J Cancer. 1996 Dec;74(12):1869–1876. doi: 10.1038/bjc.1996.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wright C., Cairns J., Cantwell B. J., Cattan A. R., Hall A. G., Harris A. L., Horne C. H. Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases. Br J Cancer. 1992 Feb;65(2):271–274. doi: 10.1038/bjc.1992.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zhang L., Hung M. C. Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase inhibitor emodin. Oncogene. 1996 Feb 1;12(3):571–576. [PubMed] [Google Scholar]

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