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Tamoxifen Resistant and Refractory Breast Cancer

The Value of Aromatase Inhibitors

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Abstract

Tamoxifen has dominated endocrine treatment of breast cancer for over two decades. It is useful in metastatic breast cancer, adjuvant therapy, preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However, breast cancer may be refractory to tamoxifen or develop resistance to it with ongoing treatment. This resistance involves several mechanisms including receptor mutation causing ‘estrogen hypersensitivity’ and an increasing agonist effect of tamoxifen. Megestrol (megestrol acetate), in North America, and aminoglutethimide, in Europe, have been the traditional second line therapies after tamoxifen in advanced breast cancer.

Aromatase (estrogen synthetase) inhibitors are a logical alternative to tamoxifen to antagonise the effects of estrogen on breast cancer. The third-generation non-steroidal aromatase inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor exemestane, have been studied after tamoxifen versus either megestrol or aminoglutethimide. They showed enhanced efficacy and significantly superior toxicity profiles. Compliance with the inhibitors was also significantly better than with the traditional treatments.

Aromatase inhibitors have most recently been shown to be superior to tamoxifen as initial therapy and are being extensively tested in the adjuvant setting after, or instead of, tamoxifen. Pilot studies of chemoprevention are also being undertaken. The aromatase inhibitors are an important new addition to the armamentarium of breast cancer therapy.

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References

  1. Cooper AP. The Principles and Practice of Surgery. London: Cox, 1836: 333–5

    Google Scholar 

  2. Siiteri PK, MacDonald PC. Role of extraglandular estrogen in human endocrinology. In: Greep RO, Astwood EB, editors. Handbook of physiology Section 7: Endocrinology. Vol II. Female Reproductive System, Pt 1. Washington, DC: American Physiological Society; 1973: 619–29

    Google Scholar 

  3. Simpson ER, Zhao Y, Agarwal VR, et al. Aromatase expression in health and disease. Recent Prog Horm Res 1997;52: 185–213

    PubMed  CAS  Google Scholar 

  4. Geisler J, King N, Anker G, et al. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res 1998; 4: 2089–93

    PubMed  CAS  Google Scholar 

  5. Lonning PE. Pharmacology of new aromatase inhibitors. Breast 1996; 5: 202–8

    Article  Google Scholar 

  6. Santen RJ, Samojlik E, Wells SA. Resistance of the ovary to blockade of aromatization with aminoglutethimide. J Clin Endocrinol Metab 1980; 51: 473–7

    Article  PubMed  CAS  Google Scholar 

  7. Santen RJ, Yue W, Naftolin F. The potential of aromatase inhibitors in breast cancer prevention. Endocr Relat Cancer 1999; 6(2): 235–43

    Article  PubMed  CAS  Google Scholar 

  8. Szyczak J, Milewicz A, Thijssen JHH, et al. Concentration of sex steroids in adipose tissue after menopause. Steroids 1998; 63: 319–21

    Article  Google Scholar 

  9. Brodie A, Lu Q, Liu Y, et al. Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. Oncology 1998; 12 (3 Suppl. 5): 36–40

    PubMed  CAS  Google Scholar 

  10. Miller WR, Forrest APM. Oestradiol synthesis from C19 steroids by human breast cancers. Br J Cancer 1976; 33: 116–8

    Article  PubMed  CAS  Google Scholar 

  11. Bradlow HL. A reassessment of the role of breast tumor aromatization. Cancer Res 1982; 42 (8 Suppl.): 3382s–6s

    PubMed  CAS  Google Scholar 

  12. Tilson-Mallett N, Santner SJ, Feil RD, et al. Biological significance of aromatase activity in human breast tumors. J Clin Endocrinol Metab 1983; 57(6): 1125–8

    Article  PubMed  CAS  Google Scholar 

  13. Bulun SE, Price TM, Mahendroo MS, et al. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 1993; 77: 1622–8

    Article  PubMed  CAS  Google Scholar 

  14. Harada N. Aberrant expression of aromatase in breast cancer tissues. J Steroid Biochem Mol Biol 1997; 61: 175–84

    Article  PubMed  CAS  Google Scholar 

  15. James VHT, McNeill JM, Lai LC, et al. Aromatase activity in normal breast and breast tumor tissues: in vivo and in vitro studies. Steroids 1987; 50: 269–79

    Article  PubMed  CAS  Google Scholar 

  16. Miller WR, O’Neill J. The importance of local synthesis of estrogen within the breast. Steroids 1987; 50: 537–48

    Article  PubMed  CAS  Google Scholar 

  17. Miller WR, Mullen P, Sourdaine P, et al. Regulation of aromatase activity within the breast. J Steroid Biochem Mol Biol 1997; 61: 193–202

    PubMed  Google Scholar 

  18. Brodie A, Lu Q, Liu Y, et al. Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 1999; 6(2): 205–10

    Article  PubMed  CAS  Google Scholar 

  19. Tekmal RR, Ramachandra N, Gubba S, et al. Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res 1996; 56: 3180–5

    PubMed  CAS  Google Scholar 

  20. Tekmal RR, Kirma N, Gill K, et al. Aromatase overexpression and breast hyperplasia, an in vivo model -continued over-expression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Endocr Relat Cancer 1999; 6(2): 307–14

    Article  PubMed  CAS  Google Scholar 

  21. Santner SJ, Pauley RJ, Tait L, et al. Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocr Metab 1997; 82: 200–8

    Article  PubMed  CAS  Google Scholar 

  22. Miller WR, Anderson TJ, Jack WJL. Relationship between tumour aromatase activity, tumour characteristics and response to therapy. J Steroid Biochem Mol Biol 1990; 37: 1055–9

    Article  PubMed  CAS  Google Scholar 

  23. Bolufer P, Ricart E, Luch A, et al. Aromatase activity and estradiol in human breast cancer: its relationship to estradiol and epidermal growth factor receptors and to tumor-node-metastasis staging. J Clin Oncol 1992; 10: 438–46

    PubMed  CAS  Google Scholar 

  24. Brueggemeier RW. Aromatase inhibitors -mechanisms of steroidal inhibitors. Breast Cancer Res Treat 1994; 30: 31–42

    Article  PubMed  CAS  Google Scholar 

  25. Bossche HV, Moereels H, Koymans LMH. Aromatase inhibitors — mechanisms for non-steroidal inhibitors. Breast Cancer Res Treat 1994; 30: 43–55

    Article  Google Scholar 

  26. Bhatnagar AS, Miller WR. Pharmacology of inhibitors of estrogen biosynthesis. In: Oettel M, Schillinger E, editors. Estrogens, antiestrogens II: pharmacology and clinical application of estrogens and antiestrogens. Vol 135/2. Heidelberg: Springer, 1999: 223–230

    Google Scholar 

  27. Yue W, Santen R. Aromatase inhibitors: rationale for use following anti-oestrogen therapy. Semin Oncol 1996; 23 (4 Suppl. 9): 21–7

    PubMed  CAS  Google Scholar 

  28. Gottardis MM, Jordan VC. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 1988; 48: 5183–7

    PubMed  CAS  Google Scholar 

  29. Norris JD, Paige LA, Christensen DJ, et al. Peptide antagonists of the human estrogen receptor. Science 1999; 285(5428): 744–6

    Article  PubMed  CAS  Google Scholar 

  30. McGuire WL, Chamness GC, Fuqua SA. Estrogen receptor variants in clinical breast cancer. Mol Endocrinol 1991; 5(11): 1571–7

    Article  PubMed  CAS  Google Scholar 

  31. Bilimoria MM, Assikis VJ, Muenzner HD, et al. An analysis of tamoxifen-stimulated carcinomas for mutations in the AF-2 region of the estrogen receptor. J Steroid Biochem Mol Biol 1996; 58: 479–88

    Article  PubMed  CAS  Google Scholar 

  32. Dowsett M, Daffada A, Chan CM, et al. Oestrogen receptor mutante and variants in breast cancer. Eur J Cancer 1997; 33: 1177–83

    Article  PubMed  CAS  Google Scholar 

  33. Osborne CK, Coronado E, Allred DC, et al. Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 1991; 83: 1477–82

    Article  PubMed  CAS  Google Scholar 

  34. Ragaz J. Status of aromatase inhibitors in relation to other breast cancer treatment modalities. EndocrRel Cancer 1999; 6: 277–91

    Article  CAS  Google Scholar 

  35. Canney PA, Griffiths T, Latief TN, et al. Clinical significance of tamoxifen withdrawal response. Lancet 1987; I(8523): 36

    Article  Google Scholar 

  36. Lipton A, Santen RJ: Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer 1974; 33: 503–12

    Article  PubMed  CAS  Google Scholar 

  37. Newsome HH, Brown PW, Terz JJ, et al. Medical and surgical adrenalectomy in patients with advanced breast carcinoma. Cancer 1977; 39: 542–6

    Article  PubMed  CAS  Google Scholar 

  38. Goss PE, Gwyn KMEJ. Current perspectives on aromatase inhibitors in breast cancer. J Clin Oncol 1994; 12: 2460–70

    PubMed  CAS  Google Scholar 

  39. Wang J, Cehn S. Identification of a promoter and silencer at the 3’-end of the first intron of the human aromatase gene. Mol Endocrinol 1992; 6: 1479–88

    Article  PubMed  CAS  Google Scholar 

  40. Santen RJ, Worgul TJ, Samojlik E, et al. A randomised trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med 1981; 305: 545–51

    Article  PubMed  CAS  Google Scholar 

  41. Buzdar A, Jones SE, Vogel C, et al. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast cancer. Arimidex Study Group. Cancer 1997; 79: 730–9

    Article  PubMed  CAS  Google Scholar 

  42. Jonat W, Howell A, Blomqvist C, et al. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Arimidex Study Group. Eur J Cancer 1996; 32A(3): 404–12

    Article  PubMed  CAS  Google Scholar 

  43. Buzdar A, Jonat W, Howell A, et al. Anastrozole, a potent and selective aromatase inhibitor, versus megestrole acetate in postmenopausal women with advanced breast cancer: results of overview and analysis of two phase III clinical trials. Arimidex Study Group. J Clin Oncol 1996; 14(7): 2000–11

    PubMed  CAS  Google Scholar 

  44. Buzdar A, Jonat W, Howell A, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer 1998; 83: 1142–52

    Article  PubMed  CAS  Google Scholar 

  45. Gershanovich M, Chaudri HA, Campos D, et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group. Ann Oncol 1998; 9: 639–45

    Article  PubMed  CAS  Google Scholar 

  46. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998; 16: 453–61

    PubMed  CAS  Google Scholar 

  47. Bengtsson NO, Focan C, Gudgeon A, et al. A phase III trial comparing vorozole (RIVIZORTM) versus aminoglutethimide in the treatment of advanced postmenopausal breast cancer [abstract no. 656]. Vorozole Study Group. Eur J Cancer 1997; 33(8): 148

    Article  Google Scholar 

  48. Bergh J, Bonneterre J, Illiger HJ, et al. Vorozole (RivizorTM) versus aminoglutethimide in the treatment of postmenopausal breast cancer relapsing after tamoxifen [abstract no. 543]. Proc Am Soc Clin Oncol 1997; 16: 155a

    Google Scholar 

  49. Goss PE, Winer EP, Tannock IF, et al. Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. North American Vorozole Study Group. J Clin Oncol 1999; 17: 52–63

    PubMed  CAS  Google Scholar 

  50. Kaufmann M, Bajetta E, Dirix LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. Exemestane Study Group. J Clin Oncol 2000; 18: 1399–411

    PubMed  CAS  Google Scholar 

  51. Buzdar A, Smith R, Vogel C, et al. Fadrozole HC1 (CGS-1649A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomised double-blind controlled multiinstitutional trials. Cancer 1996; 77: 2503–13

    Article  PubMed  CAS  Google Scholar 

  52. Thürlimann B, Castiglione M, Hsu-Schmitz SF, et al. Formestan versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross-over trial of second-line hormonal treatment — The Swiss Group for Clinical Cancer Research. Eur J Cancer 1997; 33: 1017–24

    Article  PubMed  Google Scholar 

  53. Boccardo F, Rubagotti A, Amoroso D, et al. Tamoxifen (TAM) vs aminoglutethimide in breast cancer patients previously treated with adjuvant TAM. Preliminary results of a multicentric comparative study [abstract no. 273]. Proc Am Soc Clin Oncol 2000; 19: 71a

    Google Scholar 

  54. Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19(10): 2596–606

    PubMed  CAS  Google Scholar 

  55. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1-and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001 Sep 15; 19(18): 3808–16

    PubMed  CAS  Google Scholar 

  56. Eierman W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized multicenter study. Ann Oncol 2001 Nov; 12(11): 1527–32

    Article  Google Scholar 

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Acknowledgements

Dr Goss has received honoraria and research funding from Novartis and Pharmacia Upjohn.

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Correspondence to Paul E. Goss.

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Goss, P.E., Strasser, K. Tamoxifen Resistant and Refractory Breast Cancer. Drugs 62, 957–966 (2002). https://doi.org/10.2165/00003495-200262060-00007

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