Aromatase inhibitors in breast cancer.

Until recently, tamoxifen, a nonsteroidal antiestrogen, was the mainstay of endocrine treatment of breast cancer. However, new aromatase inhibitors that are many times more potent and specific than the first such agent, aminoglutethimide, are changing the management of breast cancer in postmenopausal women. This review discusses the role of aromatase inhibitors such as letrozole, anastrozole, and exemestane in the treatment of breast cancer.

[1]  H. Lamb,et al.  Exemestane: a review of its use in postmenopausal women with advanced breast cancer. , 1998, Drugs.

[2]  M. Blankenstein,et al.  Endogenous oestrogens and androgens in normal and malignant endometrial and mammary tissues. , 1989, European journal of cancer & clinical oncology.

[3]  R. Santen,et al.  Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. , 1978, The Journal of clinical endocrinology and metabolism.

[4]  J. Cuzick,et al.  Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the 'Arimidex and tamoxifen alone or in combination' (ATAC) trial. , 2001, British journal of cancer.

[5]  G. Cocconi,et al.  Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  F. Cavalli,et al.  First-line fadrozole HCI (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer. Prospective randomised trial of the Swiss Group for Clinical Cancer Research SAKK 20/88. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  J. Wolter,et al.  Hormonal treatment for metastatic breast cancer. An eastern cooperative oncology group phase III trial comparing aminoglutethimide to tamoxifen , 1994, Cancer.

[8]  A. LaCroix,et al.  Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. , 1998, JAMA.

[9]  R. Casper,et al.  Aromatase inhibition for ovarian stimulation: future avenues for infertility management , 2002, Current opinion in obstetrics & gynecology.

[10]  D. Tripathy,et al.  Tamoxifen for early breast cancer: An overview of the randomised trials , 1999 .

[11]  T. Key,et al.  Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. , 2002, Journal of the National Cancer Institute.

[12]  S. Bulun,et al.  Estrogen production and action. , 2001, Journal of the American Academy of Dermatology.

[13]  James N Ingle,et al.  American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  C. Osborne,et al.  Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu , 1992, Breast Cancer Research and Treatment.

[15]  A. Howell,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. , 1996, European journal of cancer.

[16]  P. Kellokumpu-Lehtinen,et al.  Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen Versus nandrolone decanoate , 1987, Cancer.

[17]  L. Kuller,et al.  Coronary heart disease mortality and adjuvant tamoxifen therapy. , 1997, Journal of the National Cancer Institute.

[18]  P. Dombernowsky,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. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  F. Cavalli,et al.  Formestane 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 (SAKK 20/90). Swiss Group for Clinical Cancer Research (SAKK) , 1997, European journal of cancer.

[20]  P. Dombernowsky,et al.  Toremifene and tamoxifen in advanced breast cancer - a double-blind cross-over trial , 2004, Breast Cancer Research and Treatment.

[21]  M. Morgan,et al.  Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  R. Santen,et al.  A randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer , 1982, Cancer research.

[23]  J. Dixon,et al.  Antiaromatase agents: preclinical data and neoadjuvant therapy. , 2000, Clinical breast cancer.

[24]  Yaakov Stern,et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease , 1996, The Lancet.

[25]  M. Piccart,et al.  The third-generation non-steroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  A. Howell,et al.  Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  L. Lipton,et al.  Preoperative/neoadjuvant medical therapy for early breast cancer. , 2001, The Lancet. Oncology.

[28]  L. Melton,et al.  Role of Low Levels of Endogenous Estrogen in Regulation of Bone Resorption in Late Postmenopausal Women , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  Gynecologists.  ACOG (American College of Obstetricians and Gynecologists) committee opinion. Genetic screening for hemoglobinopathies, number 238, July 2000 (replaces number 168, February 1996). Committee on Genetics. , 2001, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[30]  L. Rutqvist,et al.  Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. , 1993, Journal of the National Cancer Institute.

[31]  R. Santen,et al.  A randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer. , 1982, Cancer.

[32]  J. Cuzick,et al.  Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial , 2002, The Lancet.

[33]  L. Case,et al.  Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  T. Powles,et al.  Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  J. Ingle,et al.  Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. , 1981, The New England journal of medicine.

[36]  N. Boyd,et al.  Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  M. Dowsett,et al.  Comparison of the systemic and intratumoral effects of tamoxifen and the aromatase inhibitor vorozole in postmenopausal patients with primary breast cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  C. Boni,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. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  J. Dixon,et al.  Endocrine and clinical endpoints of exemestane as neoadjuvant therapy. , 2002, Cancer control : journal of the Moffitt Cancer Center.

[40]  M. Elisaf,et al.  Effect of letrozole on the lipid profile in postmenopausal women with breast cancer. , 2001, European journal of cancer.

[41]  D. Campos,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 (AR/BC3). , 1998, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  A. Harris,et al.  Tamoxifen versus aminoglutethimide in advanced breast carcinoma: a randomized cross-over trial. , 1981, British medical journal.

[43]  H. Gundacker,et al.  Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[44]  P. Lønning,et al.  Decreased serum concentrations of tamoxifen and its metabolites induced by aminoglutethimide. , 1990, Cancer research.

[45]  A. Howell,et al.  Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro. , 1994, British Journal of Cancer.

[46]  F. Cognetti,et al.  Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable? , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  A. Buzdar,et al.  Fadrozole HCL (CGS‐16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: Results of two randomized double blind controlled multiinstitutional trials , 1996, Cancer.

[48]  L. Demers,et al.  Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat , 1998, Breast Cancer Research and Treatment.

[49]  J. Robertson,et al.  Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  M. Taskinen,et al.  Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  D. Easton,et al.  Adjuvant aminoglutethimide therapy for postmenopausal patients with primary breast cancer. , 1987, Cancer research.

[52]  M. Dowsett,et al.  ARIMIDEX™: A new oral, once-a-day aromatase inhibitor , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[53]  T. Powles,et al.  AMINOGLUTETHIMIDE IN TREATMENT OF METASTATIC BREAST CARCINOMA , 1978, The Lancet.

[54]  A. Hart,et al.  Tamoxifen, serum lipoproteins and cardiovascular risk. , 1988, British Journal of Cancer.

[55]  V. Gebski,et al.  Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. , 1993, Annals of oncology : official journal of the European Society for Medical Oncology.

[56]  W. Miller,et al.  The importance of local synthesis of estrogen within the breast , 1987, Steroids.

[57]  C. Falkson,et al.  A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[58]  A. Howell,et al.  Endocrine-Related Cancer ( 2000 ) 7 131 – 141 Preoperative endocrine therapy for breast cancer , 2000 .

[59]  H. Lamb,et al.  Letrozole. A review of its use in postmenopausal women with advanced breast cancer. , 1998, Drugs.

[60]  D. Hayes,et al.  Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  A. Howell,et al.  Preoperative endocrine therapy for breast cancer. , 2000, Endocrine-related cancer.

[62]  M. Dowsett,et al.  LOW-DOSE AMINOGLUTETHIMIDE IN TREATMENT OF ADVANCED BREAST CANCER , 1984, The Lancet.

[63]  T. Powles,et al.  Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  I. Tannock,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. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  P. Lønning,et al.  The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer. , 1992, British Journal of Cancer.

[66]  M. Dowsett,et al.  Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[67]  P. Lønning.  Pharmacological profiles of exemestane and formestane, steroidal aromatase inhibitors used for treatment of postmenopausal breast cancer , 2004, Breast Cancer Research and Treatment.

[68]  Anthony Howell,et al.  Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma , 1998, Cancer.

[69]  A. Howell,et al.  Recent advances in endocrine therapy of breast cancer , 1997, BMJ.

[70]  K. Boo-Chai.  Tamoxifen versus aminoglutethimide in advanced breast carcinoma: A randomised cross‐over trial , 1982 .

[71]  L. Wiseman,et al.  Anastrozole. A review of its use in the management of postmenopausal women with advanced breast cancer. , 1998, Drugs & aging.

[72]  W. Boon,et al.  Aromatase--a brief overview. , 2002, Annual review of physiology.

[73]  P. Goss,et al.  Aromatase inhibitors in the treatment and prevention of breast cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  M. Ellis,et al.  Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[75]  I. Smith.  Neoadjuvant Endocrine Therapy , 2004 .

[76]  N. Zilembo,et al.  Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[77]  C. Mendelson,et al.  Isolation and characterization of a complementary DNA specific for human aromatase-system cytochrome P-450 mRNA. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[78]  P. Lønning,et al.  The influence of CGS 16949A on peripheral aromatisation in breast cancer patients. , 1991, British Journal of Cancer.

[79]  Leslie J. Browne,et al.  In vitro and in vivo studies demonstrating potent and selective estrogen inhibition with the nonsteroidal aromatase inhibitor CGS 16949A , 1987, Steroids.

[80]  P. Lønning,et al.  Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  L. Katz,et al.  Effect of Estrogen on Brain Activation Patterns in Postmenopausal Women During Working Memory Tasks , 1999 .

[82]  D B Evans,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. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years. , 1994, Archives of internal medicine.

[84]  J. Dixon,et al.  Local endocrine effects of aromatase inhibitors within the breast , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[85]  A. Buzdar,et al.  Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  F. Alexander,et al.  Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial , 1995, BMJ.

[87]  M. Dowsett,et al.  Aromatase and its inhibitors: significance for breast cancer therapy. , 2002, Recent progress in hormone research.

[88]  P. Lønning,et al.  Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[89]  C. Longcope,et al.  Androgen and estrogen metabolism: relationship to obesity. , 1986, Metabolism: clinical and experimental.

[90]  U. Chetty,et al.  A HUMAN TUMOUR MODEL , 1986, The Lancet.

[91]  G. Beatson.  On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases , 1896, Transactions. Medico-Chirurgical Society of Edinburgh.

[92]  H. Muss,et al.  Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  A. Forrest,et al.  Significance of aromatase activity in human breast cancer. , 1982, Cancer research.

[94]  E. Regnier.  Hormonal treatment of advanced breast cancer. , 1956, Minnesota medicine.

[95]  R. Santen,et al.  Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer , 1977, Cancer.

[96]  L. Katz,et al.  Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. , 2000, JAMA.

[97]  A Howell,et al.  Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[98]  L. Dirix,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. The Exemestane Study Group. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  M Baum,et al.  First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial , 2002, The Lancet.

[100]  C K Redmond,et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. , 1999, Journal of the National Cancer Institute.

[101]  M. Mesiti,et al.  Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  P. Lønning,et al.  In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[103]  E. Winer,et al.  American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[104]  J. Elmore,et al.  Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. , 2001, Journal of the National Cancer Institute.

[105]  V. Gebski,et al.  Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. , 1993, Annals of oncology : official journal of the European Society for Medical Oncology.

[106]  G. Hortobagyi,et al.  Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.