Successful Translation Research with Selective Oestrogen Receptor Modulators to Treat and Prevent Breast Cancer

Zusammenfassung

Vor 30 Jahren spielte die Antiöstrogentherapie mit Tamoxifen nur eine zweitrangige Rolle in der Mammakarzinomtherapie. Die Hoffnungen, die Heilung des metastasierten Mammakarzinoms erreichen zu können, fokusierten sich auf die Entwicklung neuer Zytostatika und der Hochdosischemotherapie mit Knochenmarktransplantation. Ähnliche Strategien wurden in der adjuvanten Behandlung des Mammakarzinoms verfolgt. Vereinfacht gesagt, das Ziel war es, die Krebszellen mit unspezifischen zytotoxischen Substanzen zu töten, während der Patient durch supportive Maßnahmen am Leben gehalten wurde. Aber die medizinische Forschung verläuft nicht nur gradlinig und alternative Ansätze, die die Kontrolle des Tumorwachstums mit minimalen Nebenwirkungen erlauben, wurden entwickelt - die sogenannte targeted therapy. Die Elemente dieser neuen Strategien waren seit 20 Jahren gestützt durch die Ergebnisse der Grundlagenforschung etabliert. Der Ansatz der Langzeitantihormontherapie zur Kontrolle des Zellwachstums über „targeting“ des Tumor-Östrogenrezeptors hat die Behandlung des Mammakarzinoms revolutioniert. Der Erfolg dieser Strategie wird an der Abnahme der Mortalität des Mammakarzinoms abgelesen. Die translationale Forschung über den Tumor-Östrogenrezeptor mit einer ganzen Bandbreite neuer antiöstrogener Substanzen (Aromatasehemmer, reine Antiöstrogene) lässt neue Therapiemodelle der „targeted therapy“ prophezeien. Wenn man sich die Pharmakologie der „Antiestrogene“ genauer anschaut, wird man erstaunt sein. Die nicht steroidalen „Antiöstrogene“ sind selektive Östrogenmodulatoren (SERMs). Mit anderen Worten, die Substanzen wirken an der Mamma als Antiöstrogene, als Östrogene im Knochen und vermindern den Cholesterinspiegel. Dieses Wissen ermöglicht einen praktischen Ansatz in der Chemoprävention des Mammakarzinoms bei Frauen mit hohem Risiko (Tamoxifen) und niedrigem Risiko (Raloxifene).

Abstract

Thirty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines and alternative approaches emerged to solve the problem of controlling tumour growth with minimal side effects. The approach was targeted therapy. All the elements of the new strategy were in place twenty years ago supported by scientific principles derived from laboratory research. The approach of using long-term antihormone therapy to control early stage breast cancer growth would revolutionise cancer care by targeting the tumour oestrogen receptor (OER). The success of the strategy would be evidenced by lives saved and contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumour OER with a range of new antioestrogenic drugs (aromatase inhibitors, pure antioestrogens) would presage the current fashion of blocking survival pathways for the tumour by developing novel targeted treatments. But a surprise was in store when the pharmacology of “antioestrogens” was studied in detail. The nonsteroidal “antioestrogens” are selective oestrogen modulators (SERMs). In other words, the compounds are antioestrogens in the breast, oestrogens in the bone and lower circulating cholesterol. This knowledge would establish a practical approach to breast cancer chemoprevention for both high risk (tamoxifen) and low risk (raloxifene) women.

Mammakarzinom - Prävention - Tamoxifen - SERM - DICS

breast cancer - prevention - tamoxifen - SERM - DICS

References

• 1 Jensen E V, Jordan V C. The estrogen receptor: a model for molecular medicine. The Dorothy P. Landon AACR Prize for Translational Research.  Clin Cancer Res. 2003;  9 1980-1989
• 2 Jordan V C. Tamoxifen: a most unlikely pioneering medicine.  Nature Reviews Drug Discovery. 2003;  2 205-213
• 3 Jordan V C. Tamoxifen (ICI 46474) as a targeted therapy to treat and prevent breast cancer.  Brit J Pharmacol. 2006;  147 S269-S276
• 4 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) . Tamoxifen for early breast cancer: an overview of the randomised trials.  Lancet. 1998;  354 1451-1467
• 5 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) . Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.  Lancet. 2005;  365 1687-1717
• 6 Buzdar A, Marcus C, Holmes F, Hug V, Hortobagyi G. Phase II evaluation of Ly156758 in metastatic breast cancer.  Oncology. 1988;  45 344-345
• 7 Cummings S R, Eckert S, Krueger K A, Grady D, Powles T J, Cauley J A, Norton L, Nickelsen T, Bjarnason N H, Morrow M, Lippman M E, Black D, Glusman J E, Costa A, Jordan V C. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation.  JAMA. 1999;  281 2189-2197
• 8 Harper M J, Walpole A L. Mode of action of I.C.I. 46474 in preventing implantation in rats.  J Endocrinol. 1967;  37 83-92
• 9 Williamson J G, Ellis J P. The induction of ovulation by tamoxifen.  J Obstet Gynaec Br Commonw. 1973;  80 844-847
• 10 Cole M P, Jones C T, Todd I D. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474.  Br J Cancer. 1971;  25 270-275
• 11 Ward H W. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels.  Br Med J. 1973;  1 13-14
• 12 Jordan V C. The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole.  Breast Cancer Res Treat. 1988;  11 197-209
• 13 Anonymous. Review of mortality results in randomized trials in early breast cancer.  Lancet. 1984;  ii 1205
• 14 EBCTCG . Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women.  N Engl J Med. 1988;  319 1681-1692
• 15 EBCTCG . Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women.  Lancet. 1992;  339 1-15
• 16 Jordan V C. Biochemical pharmacology of antiestrogen action.  Pharmacol Rev. 1984;  36 245-276
• 17 Beall P T, Misra K L, Young R L, Spiut H J, Evan H J, LeBlanc A. Clomiphene protects against osteoporosis in the mature ovariectomized rat.  Calcif Tissue Int. 1985;  36 123-125
• 18 Jordan V C, Phelps E, Lindgren J U. Effects of anti-estrogens on bone in castrated and intact female rats.  Breast Cancer Res Treat. 1987;  10 31-35
• 19 Turner R T, Wakley G K, Hannon K S, Bell N H. Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats.  J Bone Miner Res. 1987;  2 449-456
• 20 Turner R T, Wakley G K, Hannon K S, Bell N H. Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats.  Endocrinology. 1988;  122 1146-1150
• 21 Turken S, Siris E, Seldin D, Flaster E, Hyman G, Lindsay R. Effects of tamoxifen on spinal bone density in women with breast cancer.  J Natl Cancer Inst. 1989;  81 1086-1088
• 22 Love R R, Mazess R B, Barden H S, Epstein S, Newcomb P A, Jordan V C, Carbone P P, DeMets D L. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer.  N Engl J Med. 1992;  326 852-856
• 23 Love R R, Newcomb P A, Wiebe D A, Surawicz T S, Jordan V C, Carbone P P, DeMets D L. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer.  J Natl Cancer Inst. 1990;  82 1327-1332
• 24 Love R R, Wiebe D A, Newcomb P A, Cameron L, Leventhal H, Jordan V C, Feyzi J, DeMets D L. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women.  Ann Intern Med. 1991;  115 860-864
• 25 Gottardis M M, Robinson S P, Satyaswaroop P G, Jordan V C. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse.  Cancer Res. 1988;  48 812-815
• 26 Hardell L. Tamoxifen as risk factor for carcinoma of corpus uterus [letter].  Lancet. 1988;  2(8610) 563
• 27 Jordan V C. Tamoxifen and endometrial cancer [letter].  Lancet. 1988;  2(8618) 1019
• 28 Fornander T, Rutqvist L E, Cedermark B, Glas U, Mattsson A, Silfversward C, Skoog L, Somell A, Theve T, Wilking N, Hjalmar M-L. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers.  Lancet. 1989;  1 117-120
• 29 Fisher B, Costantino J P, Wickerham D L, Cecchini R S, Cronin W M, Robidoux A, Bevers T B, Kavanah M T, Atkins J N, Margolese R G, Runowicz C D, James J M, Ford L G, Wolmark N. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P‐1 study.  J Natl Cancer Inst. 2005;  97 1652-1662
• 30 Fisher B, Costantino J P, Wickerham D L, Redmond C K, Kavanah M, Cronin W M, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P‐1 Study.  J Natl Cancer Inst. 1998;  90 1371-1388
• 31 Gottardis M M, Jordan V C. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model.  Cancer Res. 1987;  47 4020-4024
• 32 Jordan V C. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations.  Cancer Invest. 1988;  6 589-595
• 33 Lerner L J, Jordan V C. The development of antiestrogens for the treatment of breast cancer: Eighth Cain Memorial Award Lecture.  Cancer Res. 1990;  50 4177-4189
• 34 Black L J, Jones C D, Falcone J F. Antagonism of estrogen action with a new benzothiophene derived antiestrogen.  Life Sci. 1983;  32 1031-1036
• 35 Jordan V C, Gosden B. Inhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018.  Endocrinology. 1983;  113 463-468
• 36 Gottardis M M, Jiang S Y, Jeng M H, Jordan V C. Inhibition of tamoxifen-stimulated growth of an MCF‐7 tumor variant in athymic mice by novel steroidal antiestrogens.  Cancer Res. 1989;  49 4090-4093
• 37 Ettinger B, Black D M, Mitlak B H, Knickerbocker R K, Nickelsen T, Genant H K, Christiansen C, Delmas P D, Zanchetta J R, Stakkestad J, Gluer C C, Krueger K, Cohen F J, Eckert S, Ensrud K E, Avioli L V, Lips P, Cummings S R. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators [see comments] [published erratum appears in JAMA 1999; 282: 2124].  JAMA. 1999;  282 637-645
• 38 Cauley J A, Norton L, Lippman M E, Eckert S, Krueger K A, Purdie D W, Farrerons J, Karasik A, Mellstrom D, Ng K W, Stepan J J, Powles T J, Morrow M, Costa A, Silfen S L, Walls E L, Schmitt H, Muchmore D B, Jordan V C, Ste-Marie L G. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.  Breast Cancer Res Treat. 2001;  65 125-134
• 39 Vogel V G, Costantino J P, Wickerham D L, Cronin W M, Cecchini R S, Atkins J N, Bevers T B, Fehrenbacher L, Pajon (jr) E R, Wade J L, Robidoux A, Margolese R G, James J, Lippman S M, Runowicz C D, Ganz P A, Reis S E, McCaskill-Stevens W, Ford L G, Jordan V C, Wolmark N. The Study of Tamoxifen and Raloxifene (STAR): Report of the National Surgical Adjuvant Breast and Bowel Project P‐2 Trial.  JAMA. 2006;  295 2727-2741
• 40 Barrett-Connor E, Mosca L, Collins P, Geiger M J, Grady D, Kornitzer M, McNabb M A, Wenger N K. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.  N Engl J Med. 2006;  355 125-137
• 41 Martino S, Cauley J A, Barrett-Connor E, Powles T J, Mershon J, Disch D, Secrest R J, Cummings S R. For the CORE Investigators Continuing Outcomes Relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.  J Natl Cancer Inst. 2004;  96 1751-1761
• 42 Jordan V C. Optimising endocrine approaches for the chemoprevention of breast cancer. Beyond the Study of Tamoxifen and Raloxifene (STAR) Trial.  European Journal of Cancer. 2006;  42 2909-2913
• 43 Jordan V C. What if tamoxifen (ICI 46474) had been found to produce rat liver tumors in 1973? A personal perspective.  Ann Oncol. 1995;  6 29-34
• 44 Jordan V C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents.  J Med Chem. 2003;  46 1081-1111
• 45 Jordan V C. Selective estrogen receptor modulation: concept and consequences in cancer.  Cancer Cell. 2004;  5 207-213
• 46 Yao K, Lee E S, Bentrem D J, England G, Schafer J I, O'Regan R M, Jordan V C. Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice.  Clin Cancer Res. 2000;  6 2028-2036
• 47 Lewis J S, Meeke K, Osipo C, Bell E, Kidawi N, Chandel N S, Jordan V C. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.  JNCI. 2005;  97 1746-1759
• 48 Jordan V C, Collins M M, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity.  J Endocrinol. 1977;  75 305-316
• 49 Rossouw J E, Anderson G L, Prentice R L, LaCroix A Z, Kooperberg C, Stefanick M L, Jackson R D, Beresford S A, Howard B V, Johnson K C, Kotchen J M, Ockene J. Writing Group for the Women's Health Initiative Investigators: . Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women.  JAMA. 2002;  288 321-332
• 50 Million Women Study Collaborators . Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;  362 419-427