Skip to main content
SpringerLink
Log in

Tamoxifen and Secondary Tumours

An Update

  • Review Article
  • Drug Experience
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

The nonsteroidal antiestrogen tamoxifen is the most widely used anticancer drug. In women with breast cancer, adjuvant therapy with tamoxifen reduces relapse and improves overall survival. In advanced breast cancer, the response rate is more than 50% in hormonal dependent disease. In women treated with adjuvant tamoxifen the incidence of new primary beast cancers is decreased. This latter observation has led to the initiation of prevention trials.

In 1989 the first report from a large prospective randomised trial showed a significant increase of endometrial carcinoma among women treated with adjuvant tamoxifen. This effect may be linked to the somewhat paradoxical estrogenic properties of tamoxifen. The endometrial effects should be considered in the long term use of tamoxifen, and should also be taken into account in the evaluation of the prevention trials.

Animal data indicate that tamoxifen can induce tumours in other organ systems, for example the liver, but no increase in primary liver cancer has been reported from the randomised trials. In some of theses trials an increase in other gastrointestinal cancers (e.g. colon and gastric carcinoma) has been observed. The mechanism behind this may be different from that of the endometrium. In animal systems, tamoxifen has shown to induce DNA damage, with formation of DNA adducts. The risk of secondary gastrointestinal cancer needs to be further evaluated.

The adverse effects of tamoxifen have led to the development of new antiestrogenic drugs and other estrogen reducing agents (e.g. aromatase inhibitors).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Part 2. Lancet 1992; 339: 71–85

    Google Scholar 

  2. Degenshein GA, Bloom N, Tobin E. The value of progesterone receptor assays in the management of advanced breast cancer. Cancer 1980; 46: 2789–93

    PubMed  CAS  Google Scholar 

  3. Dodds EC, Goldberg L, Lawson W, et al. Oestrogenic activity of certain synthetic compounds. Nature 1948; 141: 247–8

    Google Scholar 

  4. Legha SS, Carter SK. Antiestrogens in the treatment of breast cancer. Cancer Treat Rev 1976; 3: 205–16

    PubMed  CAS  Google Scholar 

  5. Rose C, Theilade K, Boesen E, et al. Treatment of advanced breast cancer with tamoxifen. Breast Cancer Res Treat 1982; 2: 395–400

    Google Scholar 

  6. Mouridsen H, Palshof T, Patterson J, et al. Tamoxifen in advanced breast cancer. Cancer Treat Rev 1978; 5: 131–41

    PubMed  CAS  Google Scholar 

  7. Ingle JN, Mailliard JA, Schaid DJ, et al. A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer. Cancer 1991; 68: 34–9

    PubMed  CAS  Google Scholar 

  8. McGuire WL. Steroid receptors in human breast cancer. Cancer Res 1978; 38: 4289–91

    PubMed  CAS  Google Scholar 

  9. Vollenweider-Zerargui L, Barrelet L, Wong Y, et al. The predictive value of estrogen and progesterone receptors concentrations on the clinical behaviour of breast cancer in women. Cancer 1986; 7: 1171–80

    Google Scholar 

  10. Fornander T, Cedermark B, Mattsson A, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; I: 117–20

    Google Scholar 

  11. Powles TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer with tamoxifen - an update on the Royal Marsden Hospital pilot programme. Eur J Cancer 1990; 26: 680–4

    PubMed  CAS  Google Scholar 

  12. Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the national surgical adjuvant breast and bowel project (NSABP) B-14. J Natl Cancer Inst; 86: 527-37

  13. Robinson DC, Bloss JD, Schiano MA. A retrospective study of tamoxifen and endometrial cancer in breast cancer patients. Gynecol Oncol 1995; 59: 186–90

    PubMed  CAS  Google Scholar 

  14. Love RR, Wiebe DA, Newcomb PA, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 1991; 115: 860–4

    PubMed  CAS  Google Scholar 

  15. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ 1991; 303: 435–7

    PubMed  CAS  Google Scholar 

  16. Rutqvist LE, Mattson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. J Natl Cancer Inst 1993; 85: 1398–406

    PubMed  CAS  Google Scholar 

  17. Borgna J-L, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem 1981; 256: 859–68

    PubMed  CAS  Google Scholar 

  18. Jordan VC, Dix CJ, Rowsby L, et al. Studies on the mechanism of action of the non-steroidal antiestrogen tamoxifen (ICI 46.474) in the rat. Mol Cell Endocrinol 1977; 7: 177–92

    PubMed  CAS  Google Scholar 

  19. Lau CK, Subramaniam M, Rasmussen K, et al. Rapid induction of the c-protooncogene in the avian oviduct by the antiestrogen tamoxifen. Proc Natl Acad Sci USA 1981; 88: 829–33

    Google Scholar 

  20. Webster NJG, Green S, Jin JR, et al. The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell 1988: 54: 199–207

    PubMed  CAS  Google Scholar 

  21. Lønning PE, Lien EA. Mechanisms of action of endocrine treatment in breast cancer. Crit Rev Oncol Hematol 1995; 21: 158–93

    PubMed  Google Scholar 

  22. Berry M, Meztger D, Chambon P. Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. EMBO J 1990; 9(9): 2811–8

    PubMed  CAS  Google Scholar 

  23. Parker MG. Action of ‘pure’ antiestrogens in inhibiting estrogen receptor action. Br J Cancer Res Treat 1993; 26: 131–7

    CAS  Google Scholar 

  24. Jordan VC, Collins MM, Rowsby L, et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 1977; 75; 305–16

    PubMed  CAS  Google Scholar 

  25. Furr BJA, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127–205

    PubMed  CAS  Google Scholar 

  26. Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984; 36: 245–76

    PubMed  CAS  Google Scholar 

  27. Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev 1990; 11: 578–610

    PubMed  CAS  Google Scholar 

  28. Love RR, Mazess RB, Barden HS et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 236: 852–6

    Google Scholar 

  29. Wilking N, Carlström K, Gustafsson S, et al. Oestrogen receptors and metabolism of oestrone sulphate in human mammary carcinoma. Eur J Cancer 1980; 16: 1339–44

    PubMed  CAS  Google Scholar 

  30. Santner SJ, Feil PD, Santen RJ. In situ estrogen production via estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab 1984; 59: 29–33

    PubMed  CAS  Google Scholar 

  31. Gelly C, Pasqualini JR. Effect of tamoxifen and tamoxifen derivatives on the conversion of estrone sulfate to estradiol in the R-27 cells, a tamoxifen-resistant line derived from MCF-7 human breast cancer cells. J Steroid Biochem 1988; 30: 321–4

    PubMed  CAS  Google Scholar 

  32. Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumour agents. Endocrine Rev 1990; 11: 578–610

    CAS  Google Scholar 

  33. Noguchi S, Motomura K, Inaji H, et al. Down-regulation of transforming growth-factor-alpha by tamoxifen in human breast cancer. Cancer 1993; 72: 131–6

    PubMed  CAS  Google Scholar 

  34. Thomp AM, Kerr DJ, Steel CM. Transforming growth factor β1 is implicated in failure of tamoxifen therapy in human breast cancer. Br J Cancer 1991; 63: 609–14

    Google Scholar 

  35. Lipton A, Morris ID. Calcium antagonism by the antiestrogen tamoxifen. Cancer Chemother Pharmacol 1986; 18: 17–20

    PubMed  CAS  Google Scholar 

  36. Boccardo F, Guarneri D, Rubagotti A, et al. Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori 1984; 70: 61–8

    PubMed  CAS  Google Scholar 

  37. Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 1985; 69: 237–8

    PubMed  CAS  Google Scholar 

  38. Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium [letter]. Lancet 1989; I: 616

    Google Scholar 

  39. Ribeiro G, Swindell R. The Christie hospital adjuvant tamoxifen trial: status at 10 years. Br J Cancer 1988; 57: 601–3

    PubMed  CAS  Google Scholar 

  40. van Leeuwen FE, Benreadt J, Coebergh JWW, et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 1994; 343: 448–52

    PubMed  Google Scholar 

  41. Andersson M, Storm HH, Mouridsen HT. Incidence of new primary cancers after adjuvant therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 1991; 83: 1013–7

    PubMed  CAS  Google Scholar 

  42. Bocklage T, Lee KR, Belinson JL. Uterine mullerian adenosarcoma following adenomyoma in a woman on tamoxifen therapy. Gynecol Oncol 1992; 44: 104–9

    PubMed  CAS  Google Scholar 

  43. Altaras MM, Aviram R, Cohen I, et al. Role of prolonged stimulation of tamoxifen therapy in the etiology of endometrial sarcomas. Gynecol Oncol 1993; 49: 255–8

    PubMed  CAS  Google Scholar 

  44. Clarke MR. Uterine malignant mixed mullerian tumor in a patient on long-term tamoxifen therapy for breast cancer. Gynecol Oncol 1993; 51: 411–5

    PubMed  CAS  Google Scholar 

  45. Cuenca RE, Giachino J, Arredondo MA, et al. Endometrial carcinoma associated with breast carcinoma. Cancer 1996; 77: 2058–63

    PubMed  CAS  Google Scholar 

  46. Assikis VJ, Jordan VC. Gynecologic effects of tamoxifen and the association with endometrial carcinoma. Int J Gynecol Obstet 1995; 49: 241–57

    CAS  Google Scholar 

  47. Cohen I, Altaras MM, Shapira J, et al. Postmenopausal tamoxifen treatment and endometrial pathology. Obst Gynecol Surv 1994; 49: 823–9

    CAS  Google Scholar 

  48. Ross D, Whitehead M. Hormonal manipulation and gynaecological cancer: the tamoxifen dilemma. Curr Opin Obstet Gynecol 1995; 7: 63–8.

    PubMed  CAS  Google Scholar 

  49. Vessey MR Exogenous hormones in the aetiology of cancer in women. J R Soc Med 1984; 77: 542–9

    PubMed  CAS  Google Scholar 

  50. Schwartzbaum JA, Hulka BS, Fowler WCJ, et al. The influence of exogenous estrogen use on survival after diagnosis of endometrial cancer. Am J Epidemiol 1987; 126: 851–60

    PubMed  CAS  Google Scholar 

  51. Silva E, Tornos C, Folien-Mitchell M. Malignant neoplasm of the uterine corpus in patients with breast carcinoma: the effects of tamoxifen. Int J Gynecol Pathol 1994; 13: 248–58

    PubMed  CAS  Google Scholar 

  52. Deligdisch L, Cohen CJ, Dottino P. Tamoxifen therapy and endometrial neoplasia. Eur J Cancer 1991; 27 Suppl. 2: 127

    Google Scholar 

  53. Segna RA, Dottino DR, Deligdisch L, et al. Tamoxifen and endometrial cancer. Mt Sinai J Med 1992; 59: 416–8

    PubMed  CAS  Google Scholar 

  54. Barakat RR, Wong G, Curtin JP, et al. Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with higher incidence of adverse histologic features. Gyncol Oncol 1994; 55: 164–8

    CAS  Google Scholar 

  55. De Muylder X, Neven P, De Somer M, et al. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynaecol Obstet 1991; 36(2): 127–30

    PubMed  Google Scholar 

  56. Neven P, De Muylder X, Van Belle Y, et al. Hysteroscopic follow-up during tamoxifen treatment. Eur J Obstet Gynecol Reprod Biol 1990; 35: 235–8

    PubMed  CAS  Google Scholar 

  57. Cohen I, Rosen DJD, Shapiro J, et al. Endometrial changes in postmenopausal women treated with tamoxifen for breast cancer. Br J Obstet Gynaecol 1993; 100: 567–70

    PubMed  CAS  Google Scholar 

  58. Lahti E, Blanco G, Kauppila A, et al. Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 1993; 81: 660–4

    PubMed  CAS  Google Scholar 

  59. Nuovo MA, Nuovo GJ, McCaffrey RM, et al. Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Pathol 1989; 8: 125–31

    PubMed  CAS  Google Scholar 

  60. Cohen I, Shapira Y, Altaras M, et al. Endometrial decidual changes in a postmenopausal woman treated with tamoxifen and megestrol acetate. Br J Obstet Gynaecol 1992; 99: 773–4

    PubMed  CAS  Google Scholar 

  61. Cohen I, Figer A, Altaras MM, et al. Common endometrial decidual reaction in postmenopausal breast cancer patients treated with tamoxifen and progestins. Int J Gynecol Pathol 1996; 15: 17–22

    PubMed  CAS  Google Scholar 

  62. Ugwumado AHN, Bower D, Ho PK. Tamoxifen-induced adenomyosis and adenomyomatous endometrial polyp. Br J Obstet Gynaecol 1993; 100: 386–88

    Google Scholar 

  63. Corley D, Rowe J, Curtis MT, et al. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Obstet Gynecol 1992; 79: 111–6

    PubMed  CAS  Google Scholar 

  64. Ford MRW, Turner MJ, Wood C, et al. Endometriosis developing during tamoxifen therapy. Am J Obstet Gynecol 1988; 158: 119

    Google Scholar 

  65. Cano A, Matallin P, Legua V, et al. Tamoxifen and the uterus and endometrium. Lancet 1989; I: 376

    Google Scholar 

  66. Le Bouedec G, Kauffman P, Pingeon JM. Postmenopausal endometriosis developed during tamoxifen treatment. Rev Fr Gynecol Obstet 1991; 86: 407–10

    PubMed  Google Scholar 

  67. Cohen I, Altaras M, Lew S, et al. Ovarian endometroid carcinoma and endometriosis developing in a postmenopausal breast cancer patient during tamoxifen therapy: a case report and review of the literature. Gynecol Oncol 1994; 55: 443–7

    PubMed  CAS  Google Scholar 

  68. Leo L, Lanza A, Re A, et al. Leiomyomas in patients receiving tamoxifen. Clin Exp Obstet Gynecol 1994; 2: 94–8

    Google Scholar 

  69. Cohen I, Beyth Y, Tepper R, et al. Adenomyosis in postmenopausal breast cancer patients treated with tamoxifen: a new entity? Gynecol Oncol 1995; 58: 86–91

    PubMed  CAS  Google Scholar 

  70. Cohen I, Rosen DJD, Shapira J, et al. Endometrial changes with tamoxifen: comparison between tamoxifen-treated and nontreated asymtomatic, postmenopausal breast cancer patients. Gynecol Oncol 1994; 52: 185–90

    PubMed  CAS  Google Scholar 

  71. Kedar RP, Borne TH, Powles TJ, et al. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 1994; 343: 1318–21

    PubMed  CAS  Google Scholar 

  72. Gorodeski GI, Beery R, Lunenfeld B, et al. Tamoxifen increases plasma estrogen-binding equivalents and has an estradiol agonistic effect on histologically normal premenopausal and postmenopausal endometrium. Fertil Steril 1992; 57: 320–7

    PubMed  CAS  Google Scholar 

  73. Touraine P, Driques P, Cartier I, et al. Lack of induction of endometrial hyperplasia with tamoxifen. Lancet 1995; 345: 254–5

    PubMed  CAS  Google Scholar 

  74. Cohen CJ, Rahaman J. Endometrial cancer. Cancer 1995; Suppl. 10; 76: 2044–52

    PubMed  CAS  Google Scholar 

  75. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994; 47: 827–33

    PubMed  CAS  Google Scholar 

  76. Sismondi P, Biglia N, Volpi E, et al. Tamoxifen and endometrial cancer. Am NY Acad Sci 1994; 734: 310–21

    CAS  Google Scholar 

  77. Goldstein SR, Nachtigall M, Snyder JR, et al. Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding. Am J Obstet Gynecol 1990; 163: 119–21

    PubMed  CAS  Google Scholar 

  78. Granberg S, Wikland M, Karlsson B, et al. Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality. Am J Obstet Gynecol 1991; 164: 47–53

    PubMed  CAS  Google Scholar 

  79. Cohen I, Rosen DJD, Tepper R, et al. Ultrasonographic evaluation of the endometrium with correlation to endometrial sampling in postmenopausal patients treated with tamoxifen. J Ultrasound Med 1993; 5: 275–80

    Google Scholar 

  80. Anteby E, Yagel S, Zacut D, et al. False Sonographic appearance of endometrial neoplasia in postmenopausal women treated with tamoxifen. Lancet 1992; 340: 433–4

    PubMed  CAS  Google Scholar 

  81. Neven P, De Muylder X, Van Belle Y. Tamoxifen and the uterus and endometrium. Lancet 1989; I: 375–6

    Google Scholar 

  82. Amy JJ, Van Liedekerke D. Gynaecological monitoring during tamoxifen therapy. Lancet 1995; 345: 253–4

    PubMed  CAS  Google Scholar 

  83. Neven P, De Muylder X, Van Belle Y, et al. Tamoxifen and the uterus. BMJ 1994; 309: 1313–4

    PubMed  CAS  Google Scholar 

  84. Achiron R, Lipitz S, Sivan E, et al. Sonohysterography for ultrasonographic evaluation of tamoxifen-associated cystic thickened endometrium. J Ultrasound Med 1995; 14: 685–8

    PubMed  CAS  Google Scholar 

  85. Decensi A, Fontana V, Bruno S, et al. Effect of tamoxifen on endometrial proliferation. J Clin Oncol 1996; 14: 434–0

    PubMed  CAS  Google Scholar 

  86. Jordan VC, Morrow M. Should clinicians be concerned about the carcinogenic potential of tamoxifen? Eur J Cancer 1994; 30: 1714–21

    Google Scholar 

  87. Bisset D, Davis JA, George WD. Gynaecological monitoring during tamoxifen therapy. Lancet 1994; 344: 1244

    Google Scholar 

  88. Borne TH, Lawton F, Leather A, et al. Use of intracavity saline instillation and transvaginal ultrasonography to detect tamoxifen-associated endometrial polyps. Ultrasound Obstet Gynecol 1994; 4: 73–5

    Google Scholar 

  89. Jordan VC. Tamoxifen for breast cancer prevention. Proc Soc Exp Biol Med 1995 Feb: 208(2): 144–9

    PubMed  CAS  Google Scholar 

  90. Hirsimäki P, Hirsimäki Y, Payne BJ. Tamoxifen induces hepatocellular carcinoma in rat liver a study with two antiestrogens. Arch Toxicol 1993; 67: 49–54

    PubMed  Google Scholar 

  91. Greaves P, Goonetilleke R, Nunn G, et al. Two year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res 1993 Sep 1; 53: 3919–24

    PubMed  CAS  Google Scholar 

  92. Williams GM, Iatropoulos MJ, Djordjevic MV, et al. The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis 1993; 14: 315–7

    PubMed  CAS  Google Scholar 

  93. White IN, deMatteis F, Davis A, et al. Genotoxic potential of tamoxifen and analogues in female Fischer 344/n rats. DBA/2 and C57BL/6 mice and human MCL-5 cells. Carcinogenesis 1992; 13: 2197–203

    PubMed  CAS  Google Scholar 

  94. Carthew P, Martin EA, White IN, et al. Tamoxifen induces short-term cumulative DNA damage and liver tumours in rats: promotion by phenobarbital. Cancer Res 1995 Feb 1; 55(3): 544–7

    PubMed  CAS  Google Scholar 

  95. Fugh-Berman A, Epstein S. Tamoxifen: disease prevention or disease substitution? Lancet 1992 340: 1143–7

    PubMed  CAS  Google Scholar 

  96. Wanless IR, Mediine A. Role of estrogens as promoters of hepatic neoplasia. Lab Invest 1982 46(3): 313–20

    PubMed  CAS  Google Scholar 

  97. Edmonson HA, Reynolds TB, Henderson B. Regression of liver cell adenomas associated with oral contraceptives. Ann Intern Med 1977; 86: 180–2

    Google Scholar 

  98. Prentice RL. Epidemiologic data on exogenous hormones and hepatocellular carcinoma and selected other cancers. Prev Med 1991; 20: 38–46

    PubMed  CAS  Google Scholar 

  99. Sackett DL, Hayes RB, Tugwell P. Deciding whether your treatment has done harm. In: Sackett DL, Hayes RB, Tugwell P, editors. Clinical epidemiology: a basic science for clinical medicine. Boston: Little Brown & Co 1985: 223–4

    Google Scholar 

  100. Rutqvist LE, Johansson H, Signomklao T, et al. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 1995 May 3; 87(9): 645–51

    PubMed  CAS  Google Scholar 

  101. Rutqvist LE, Cedermark B, Glas U, et al. The Stockholm Trial on adjuvant tamoxifen in early breast cancer. Breast Cancer Res Treat 1987; 10: 255–66

    PubMed  CAS  Google Scholar 

  102. Rydén S, Möller T, Hafström LO, et al. Adjuvant therapy of breast cancer: compliance and data validity in a multi-center trial. Controlled Clin Trials 1986; 7: 290–305

    PubMed  Google Scholar 

  103. Mouridsen HT, Rose C, Overgaard M, et al. Adjuvant treatment of postmenopausal patients with high risk breast cancer: results from the Danish adjuvant trial DBCG77C Aud DBCG82C. Acta Oncol 1988; 27: 699–705

    PubMed  CAS  Google Scholar 

  104. Muhlemann K, Cook LS, Weiss NS. The incidence of hepatocellular carcinoma in US white women with breast cancer after the introduction of tamoxifen in 1977. Breast Cancer Res Treat 1994; 30: 201–4

    PubMed  CAS  Google Scholar 

  105. Popper H, Selikoff IJ, Maltoni C, et al. Comparison of neoplastic hepatic lesions in man and experimental animals. In: Hiatt HH, Watson JD, Winsten JA, editors. Origins of human cancer book C: human risk assessment. New York: Cold Spring Harbor Laboratory, 1977: 1359–82

    Google Scholar 

  106. Hard GC, Iatrapoulos MJ, Jordan K, et al. Major difference in the hepatocarcinogenicity and DNA forming ability between toremifene and tamoxifen in female Crl: CD(BR) rats. Cancer Res 1993; 53: 4534–41

    PubMed  CAS  Google Scholar 

  107. Iatropoulos M. Comparative histokinetic and xenodynamic considerations in toxicity. In: Welling PG, de la Iglesia FA, editors. Drug toxicokinetics. New York: Marcel Dekker, 1993: 245–66

    Google Scholar 

  108. Jordan VC. Tamoxifen and tumorigenicity a predictable concern. J Natl Cancer Inst 1995; 87: 623–6

    PubMed  CAS  Google Scholar 

  109. Watanabe M, Tanaka H, Koizumi, et al. General toxicity stuies of tamoxifen in mice and rats. Jichuken Enriskokenjuoko 1980; 6: 1–36

    CAS  Google Scholar 

  110. Maltoni C, Pino C, Paladini G. Project of experimental bioassays on chemoprevention agents performed at the Bologna institute of Oncology: report on tamoxifen control of spontaneous mammary tumours in Sprague-Dawley rats. Cancer Invest 1988; 6: 643–58

    PubMed  CAS  Google Scholar 

  111. Hirsimäki P, Hirsimäki Y, Nieminen L. The effects of tamoxifen citrate and toremifene citrate on the ultrastructure of the rat liver. Inst Phys Conf Ser 1988; 6: 643–58

    Google Scholar 

  112. Gau TC. Open letter concerning Nolvadex, 1987, Stuart Pharmaceuticals.

  113. Metzler M, Schiffman D. Structural requirements for the in vitro transformation of Syrian hamster embryo cells by stilbene estrogens and triphenylethylene type antiestrogens. Am J Clin Oncol 1991; 14: S30–5

    PubMed  Google Scholar 

  114. Han X, Liehr JG. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 1992; 52: 1360–3

    PubMed  CAS  Google Scholar 

  115. Mishkin SY, Farber E, Ho RK, et al. Evidence for the hormone dependency of malignant transformation after endogenous 17-beta estradiol and tamoxifen. Hepatology 1983; 3: 308–16

    PubMed  CAS  Google Scholar 

  116. Kohigashi K, Fukada Y, Imura H. Inhibitory effect of tamoxifen on DES-promoted hepatic tumorigenesis in male rats and its possible mechanism of action. Gann 1988; 79: 1335–9

    PubMed  CAS  Google Scholar 

  117. Taper HS. The effect of estradiol-17-phenylpropionate and estadiol benzoate on N-nitrosmorpholine-induced liver carcinogenesis in ovariectomized female rats. Cancer 1978; 42: 462–7

    PubMed  CAS  Google Scholar 

  118. Vickers AE, Nelson K, McCoy Z, et al. Changes in estrogen receptor, DNA ploidy, and estrogen metabolism in rat hepatocytes during a two-stage model for hepatocarcinogenesis using 17-alfa- ethinylestradiol as the promoting agent. Cancer Res 1989; 49: 6512–20

    PubMed  CAS  Google Scholar 

  119. Dragan YP, Fahey S, Street K, et al. Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats. Breast Cancer Res Treat 1994; 31(1): 11–25

    PubMed  CAS  Google Scholar 

  120. Jordan VC, Morrow M. Should clinicians be concerned about the carcinogenic potential of tamoxifen. Eur J Cancer 1994; 30A(11): 1714–21

    PubMed  CAS  Google Scholar 

  121. Powles TJ, Hickish T. Tamoxifen therapy and carcinogenic risk. J Natl Cancer Inst 1995 Sep 20; 87(18): 1343–45

    PubMed  CAS  Google Scholar 

  122. Mani C, Kupfer D. Cytochrome P-450 mediated activation and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver; possible involvement of flavin-containing mono-oxygenases in tamoxifen activation. Cancer Res 1991; 51: 6052–8

    PubMed  CAS  Google Scholar 

  123. Randerath K, Moorthy B, Mabon N, et al. Tamoxifen: evidence by 32P postlabelling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite. Carcinogenesis 1994; 15: 2087–94

    PubMed  CAS  Google Scholar 

  124. Pathak DN, Pongracz K, Bodell WJ. Microsomal and peroxidase activation of 4-hydroxytamoxifen to form DNA adducts: comparison with DNA adducts formed in Sprague-Dawley rats treated with tamoxifen. Carcinogenesis 1994; 16: 11–5

    Google Scholar 

  125. Pongracz K, Pathak DN, Nakamura T, et al. Activation of the tamoxifen derivative metabolite E to form DNA adducts: comparison with the adducts formed by microsomal activation of tamoxifen. Cancer Res 1995; 55: 3012–5.

    PubMed  CAS  Google Scholar 

  126. Taningher M, Saccomanno G, Santi L, et al. Quantitative predictability of carcinogenicity of the covalent binding index of chemical to DNA: comparison of the in vivo and in vitro assays. Environ Health Perspect 1990; 84: 183–92

    PubMed  CAS  Google Scholar 

  127. Pathak GA, Bodell WJ. DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems. Carcinogenesis 1994; 15: 529–32

    PubMed  CAS  Google Scholar 

  128. Martin EA, Rick KJ, White IN. DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis 1995; 16: 1651–4

    PubMed  CAS  Google Scholar 

  129. Martin EA, Rich KJ, Heydon R, et al. A comparison of 32P postlabelled tamoxifen liver DNA adducts in rats, mice and breast cancer patients. The Toxicologist 1994; 14: 405

    Google Scholar 

  130. Potter GA, McCague R, Jarman M. A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis 1994; 15: 439–42

    PubMed  CAS  Google Scholar 

  131. Ioannides C, Parke DV. The cytochromes P448 — a unique family of enzymes involved in chemical toxicity and carcinogenesis. Biochem Pharmacol 1987; 36: 4197–207

    PubMed  CAS  Google Scholar 

  132. Ahotupa M, Hirsimäki P. The effect of tamoxifen citrate and toremifen citrate on lipid peroxidation, antioxidant enzymes and xenobiotic metabolizing enzymes in rat liver. Vth International Congress of toxicology: 1989; Brighton, England

    Google Scholar 

  133. Ahotupa M, Hirsimäki P, Pärssinen R, et al. Alterations of drug metabolizing and antioxidant enzyme activities during tamoxifen-induced hepatocarcinogenesis in the rat. Carcinogenesis 1994; 15(5): 863–8

    PubMed  CAS  Google Scholar 

  134. Farber E. Cellular biochemistry of the stepwise development of cancer with chemicals: GHA Clowes Memorial lecture. Cancer Res 1984; 44: 5463–74

    PubMed  CAS  Google Scholar 

  135. Vancutsem PM, Lazarus P, Williams GM. Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. Cancer Res 1994 Jul 15; 54: 3864–7

    PubMed  CAS  Google Scholar 

  136. Lullmann H, Lullmann-Rauch R. Tamoxifen-induced generalised lipidosis in rats subchronically treated with high doses. Toxicol Appl Pharmacol 1981; 61: 138–46

    PubMed  CAS  Google Scholar 

  137. Simon R. Discovering the truth about tamoxifen: problems of multiplicity in statistical evaluation of biomedicai data. J Natl Cancer Inst 1995 May 3; 87(9): 6–8

    Google Scholar 

  138. CRC Adjuvant breast trial working party. Cyclofosfamide and tamoxifen as adjuvant therapies in the management of breast cancer. Br J Cancer 1988; 57: 604–7

    Google Scholar 

  139. Ribeiro G, Swindell R. The Christie hospital adjuvant tamoxifen trial. Br J Cancer 1988; 57: 601–3

    PubMed  CAS  Google Scholar 

  140. Teppo L, Pukkala E, Saxén E. Multiple cancer an epidemiologic exercise in Finland. J Natl Cancer Inst 1985; 75: 207–17

    PubMed  CAS  Google Scholar 

  141. Harvey EB, Brinton LA. Second cancer following cancer of breast in Connecticut, 1935–1982. Natl Cancer Inst Monogr 1985; 68: 99–112

    PubMed  CAS  Google Scholar 

  142. Ewertz M, Mouridsen HT. Second cancer following cancer of female breast in Denmark, 1943-1980. Natl Cancer Inst Monogr 1985; 68: 325–9

    PubMed  CAS  Google Scholar 

  143. Furner SE, Davis FG, Nelson RL, et al. A case control study of large bowel cancer and hormone exposure in women. Cancer Res 1989; 49: 4936–40

    PubMed  CAS  Google Scholar 

  144. Chute CG, Willett WC, Colditz GA, et al. A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Cancer Res 1989; 49: 4936–40

    Google Scholar 

  145. Gerhardsson de Verdier M, London S. Reproductive factors, exogenous female hormones and colorectal cancer by subsite. Cancer Causes Control 1992; 3: 355–60

    PubMed  CAS  Google Scholar 

  146. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1–15

    Google Scholar 

  147. Cook LS, Weiss NS, Schwartz SM, et al. Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. J Natl Cancer Inst 1995 Sep 20; 87(18): 1359–64

    PubMed  CAS  Google Scholar 

  148. Storm HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 1991 July 17; 83(14): 1013–7

    PubMed  Google Scholar 

  149. Kaufman M, Jonat W, Albel U, et al. Adjuvant randomized trials of doxorubicin/ cyclofosfamide versus doxorubicin/ cyclofosfamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node positive breast cancer. J Clin Oncol 1993; 11: 454–60

    Google Scholar 

  150. Baum M, Houghton J, Riley D. Results of the Cancer Research Campaign adjuvant trial for perioperative cyclophosphamide and long-term tamoxifen in early breast cancer reported at the tenth year of follow-up. Acta Oncol 1992; 3: 251–7

    Google Scholar 

  151. Fischer B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989 Feb 23; 320: 479–84

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Radiumhemmet, Karolinska Hospital, S-171 76, Stockholm, Sweden

    Nils Wilking, Erika Isaksson & Eva von Schoultz

Authors
  1. Nils Wilking
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erika Isaksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva von Schoultz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nils Wilking.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilking, N., Isaksson, E. & von Schoultz, E. Tamoxifen and Secondary Tumours. Drug-Safety 16, 104–117 (1997). https://doi.org/10.2165/00002018-199716020-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199716020-00003

Keywords

Search

Navigation