Effect of Aromatase Inhibitors on Bones and Genes

NCT00603967 | Completed

• 2 other identifiers: 05-0918Grant
• Study Type: interventional
• Target: 151
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this 2-year pilot project is to test the hypothesis that skeletal response to aromatase inhibitors is determined by polymorphisms of the CYP19 gene.

Conditions

Breast Cancer; Postmenopausal

Keywords

Breast Cancer; Postmenopausal; Aromatase

Outcome Measures

Primary Outcomes (2)

• Skeletal effects of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer.

  2 years

• Influence of polymorphisms of the CYP19 gene on the skeletal response to aromatase inhibitors.

  2 years

Secondary Outcomes (1)

• Influence of the CYP19 gene polymorphisms on the menopausal symptoms in women on aromatase inhibitor therapy.

  2 years

Study Arms (1)

Aromatase inhibitor

OTHER

Procedure: Dual x-ray absorptiometry (DXA); Procedure: Blood draw; Behavioral: Questionnaire

Interventions

Dual x-ray absorptiometry (DXA) PROCEDURE

Baseline, 6 months, and 12 months

Aromatase inhibitor

Blood draw PROCEDURE

Baseline - genotyping Baseline, 6 months, and 12 months - markers of bone turnover and hormonal assays

Aromatase inhibitor

Questionnaire BEHAVIORAL

Menopausal symptom questionnaire - baseline, 3 months, 6 months, 12 months Cognitive tests - baseline, 6 months, 12 months Depression assessment - baseline, 6 months, 12 months Dietary calcium intake questionnaire - baseline

Aromatase inhibitor

Eligibility Criteria

• Age: 40 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Postmenopausal women aged greater than or equal to 40 years, at least 12 months from last menstrual period. For subjects who are amenorrheic for \< 12 months (including patients who had hysterectomy, received ERT/HRT, or rendered amenorrheic by chemotherapy), they must have serum FSH =50 UI/L.
• Must have diagnosis of breast cancer stages I-IIIA.
• Planned therapy for the treatment group must include aromatase inhibitors using third generation non-steroidal aromatase inhibitors, anastrozole or letrozole. Those who are already treated with aromatase inhibitors and have bone density measurements prior to initiation of aromatase inhibitors or will be switched from tamoxifen to third generation aromatase inhibitors will also be included in the study.
• Bone mineral density measurement must range from normal to osteopenia (T-scores between +2.0/-2.0). Those with T-scores of \<-2.0 in either the lumbar spine or the femoral neck as well as those with a history of osteoporosis-related fractures or vertebral deformities on lateral spine radiographs will be excluded from the study.
• Must be ambulatory willing and able to provide informed consent.

You may not qualify if:

• No current use of medications affecting bone metabolism, namely: estrogen, raloxifene, tamoxifen, bisphosphonates, GnRH analogues, glucocorticoids of at least 5 mg daily for 1 month or more, anabolic steroids and dilantin.
• No evidence of diseases known to interfere with bone metabolism, such as hyperparathyroidism, hyperthyroidism, osteomalacia, chronic liver disease, renal failure, hypercortisolism, malabsorption, and immobilization.
• No current alcohol or tobacco abuse.
• No evidence of bone metastasis or evidence of abnormal clinical laboratory parameters that are assessed as clinically significant by the investigator.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (40)

• Campos SM. Aromatase inhibitors for breast cancer in postmenopausal women. Oncologist. 2004;9(2):126-36. doi: 10.1634/theoncologist.9-2-126.

  PMID: 15047917 BACKGROUND

• Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, 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 Sep 16;90(18):1371-88. doi: 10.1093/jnci/90.18.1371.

  PMID: 9747868 BACKGROUND

• Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists' Group. 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. Lancet. 2002 Jun 22;359(9324):2131-9. doi: 10.1016/s0140-6736(02)09088-8.

  PMID: 12090977 BACKGROUND

• Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. doi: 10.1016/S0140-6736(04)17666-6.

  PMID: 15639680 BACKGROUND

• Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. doi: 10.1056/NEJMoa032312. Epub 2003 Oct 9.

  PMID: 14551341 BACKGROUND

• Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. doi: 10.1056/NEJMoa040331.

  PMID: 15014181 BACKGROUND

• Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. 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. J Clin Oncol. 2000 Nov 15;18(22):3748-57. doi: 10.1200/JCO.2000.18.22.3748.

  PMID: 11078487 BACKGROUND

• Vergote I, Bonneterre J, Thurlimann B, Robertson J, Krzakowski M, Mauriac L, Koralewski L, Webster A, Steinberg M, von Euler M. Randomised study of anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women. Eur J Cancer. 2000 Sep;36 Suppl 4:S84-5. doi: 10.1016/s0959-8049(00)00239-2.

  PMID: 11056332 BACKGROUND

• Mouridsen H, Sun Y, Gershanovich M, Perez-Carrion R, Becquart D, Chaudri-Ross HA, Lang R. Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability. Oncologist. 2004;9(5):489-96. doi: 10.1634/theoncologist.9-5-489.

  PMID: 15477633 BACKGROUND

• Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart M; European Organization for the Research and Treatment of Cancer (EORTC)- Investigational Drug Branch for Breast Cancer (IDBBC). Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol. 2003 Sep;14(9):1391-8. doi: 10.1093/annonc/mdg362.

  PMID: 12954578 BACKGROUND

• Forney JP, Milewich L, Chen GT, Garlock JL, Schwarz BE, Edman CD, MacDonald PC. Aromatization of androstenedione to estrone by human adipose tissue in vitro. Correlation with adipose tissue mass, age, and endometrial neoplasia. J Clin Endocrinol Metab. 1981 Jul;53(1):192-9. doi: 10.1210/jcem-53-1-192. No abstract available.

  PMID: 7240376 BACKGROUND

• Heshmati HM, Khosla S, Robins SP, O'Fallon WM, Melton LJ 3rd, Riggs BL. Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res. 2002 Jan;17(1):172-8. doi: 10.1359/jbmr.2002.17.1.172.

  PMID: 11771665 BACKGROUND

• Leelawattana R, Ziambaras K, Roodman-Weiss J, Lyss C, Wagner D, Klug T, Armamento-Villareal R, Civitelli R. The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss. J Bone Miner Res. 2000 Dec;15(12):2513-20. doi: 10.1359/jbmr.2000.15.12.2513.

  PMID: 11127217 BACKGROUND

• Masi L, Becherini L, Gennari L, Amedei A, Colli E, Falchetti A, Farci M, Silvestri S, Gonnelli S, Brandi ML. Polymorphism of the aromatase gene in postmenopausal Italian women: distribution and correlation with bone mass and fracture risk. J Clin Endocrinol Metab. 2001 May;86(5):2263-9. doi: 10.1210/jcem.86.5.7450.

  PMID: 11344237 BACKGROUND

• Somner J, McLellan S, Cheung J, Mak YT, Frost ML, Knapp KM, Wierzbicki AS, Wheeler M, Fogelman I, Ralston SH, Hampson GN. Polymorphisms in the P450 c17 (17-hydroxylase/17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2004 Jan;89(1):344-51. doi: 10.1210/jc.2003-030164.

  PMID: 14715870 BACKGROUND

• Gennari L, Masi L, Merlotti D, Picariello L, Falchetti A, Tanini A, Mavilia C, Del Monte F, Gonnelli S, Lucani B, Gennari C, Brandi ML. A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism. J Clin Endocrinol Metab. 2004 Jun;89(6):2803-10. doi: 10.1210/jc.2003-031342.

  PMID: 15181061 BACKGROUND

• Tofteng CL, Kindmark A, Brandstrom H, Abrahamsen B, Petersen S, Stiger F, Stilgren LS, Jensen JE, Vestergaard P, Langdahl BL, Mosekilde L; Danish Osteoporosis Prevention Study. Polymorphisms in the CYP19 and AR genes--relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: The Danish Osteoporosis Prevention Study. Calcif Tissue Int. 2004 Jan;74(1):25-34. doi: 10.1007/s00223-002-2158-3. Epub 2003 Oct 2.

  PMID: 14517714 BACKGROUND

• Ravdin PM, Green S, Dorr TM, McGuire WL, Fabian C, Pugh RP, Carter RD, Rivkin SE, Borst JR, Belt RJ, et al. Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study. J Clin Oncol. 1992 Aug;10(8):1284-91. doi: 10.1200/JCO.1992.10.8.1284.

  PMID: 1634918 BACKGROUND

• Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998 May 16;351(9114):1451-67.

  PMID: 9605801 BACKGROUND

• Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998 Nov 26;339(22):1609-18. doi: 10.1056/NEJM199811263392207. No abstract available.

  PMID: 9828250 BACKGROUND

• Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. 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. J Clin Oncol. 2000 Nov 15;18(22):3758-67. doi: 10.1200/JCO.2000.18.22.3758.

  PMID: 11078488 BACKGROUND

• Webb PM, Cummings MC, Bain CJ, Furnival CM. Changes in survival after breast cancer: improvements in diagnosis or treatment? Breast. 2004 Feb;13(1):7-14. doi: 10.1016/S0960-9776(03)00129-2.

  PMID: 14759710 BACKGROUND

• Goss PE, Qi S, Josse RG, Pritzker KP, Mendes M, Hu H, Waldman SD, Grynpas MD. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone. 2004 Mar;34(3):384-92. doi: 10.1016/j.bone.2003.11.006.

  PMID: 15003786 BACKGROUND

• Zarrabeitia MT, Hernandez JL, Valero C, Zarrabeitia AL, Garcia-Unzueta M, Amado JA, Gonzalez-Macias J, Riancho JA. A common polymorphism in the 5'-untranslated region of the aromatase gene influences bone mass and fracture risk. Eur J Endocrinol. 2004 May;150(5):699-704. doi: 10.1530/eje.0.1500699.

  PMID: 15132727 BACKGROUND

• Kristensen VN, Harada N, Yoshimura N, Haraldsen E, Lonning PE, Erikstein B, Karesen R, Kristensen T, Borresen-Dale AL. Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene. 2000 Mar 2;19(10):1329-33. doi: 10.1038/sj.onc.1203425.

  PMID: 10713674 BACKGROUND

• Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab. 2003 Jul;88(7):3075-81. doi: 10.1210/jc.2002-021691.

  PMID: 12843146 BACKGROUND

• Kristensen VN, Andersen TI, Lindblom A, Erikstein B, Magnus P, Borresen-Dale AL. A rare CYP19 (aromatase) variant may increase the risk of breast cancer. Pharmacogenetics. 1998 Feb;8(1):43-8. doi: 10.1097/00008571-199802000-00006.

  PMID: 9511180 BACKGROUND

• Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab. 1973 Feb;36(2):207-14. doi: 10.1210/jcem-36-2-207. No abstract available.

  PMID: 4688315 BACKGROUND

• Armamento-Villareal RC, Napoli N, Klug T, Civitelli R. The oxidative metabolism of estrogen modulates response to ERT/HRT in postmenopausal women. Bone. 2004 Sep;35(3):682-8. doi: 10.1016/j.bone.2004.05.010.

  PMID: 15336604 BACKGROUND

• Martucci CP, Fishman J. P450 enzymes of estrogen metabolism. Pharmacol Ther. 1993 Feb-Mar;57(2-3):237-57. doi: 10.1016/0163-7258(93)90057-k.

  PMID: 8361994 BACKGROUND

• Badawi AF, Cavalieri EL, Rogan EG. Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism. 2001 Sep;50(9):1001-3. doi: 10.1053/meta.2001.25592.

  PMID: 11555828 BACKGROUND

• Napoli N, Villareal DT, Mumm S, Halstead L, Sheikh S, Cagaanan M, Rini GB, Armamento-Villareal R. Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. J Bone Miner Res. 2005 Feb;20(2):232-9. doi: 10.1359/JBMR.041110. Epub 2004 Nov 16.

  PMID: 15647817 BACKGROUND

• Goss PE, Qi S, Cheung AM, Hu H, Mendes M, Pritzker KP. Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res. 2004 Sep 1;10(17):5717-23. doi: 10.1158/1078-0432.CCR-04-0438.

  PMID: 15355898 BACKGROUND

• Vanderschueren D, Boonen S, Ederveen AG, de Coster R, Van Herck E, Moermans K, Vandenput L, Verstuyf A, Bouillon R. Skeletal effects of estrogen deficiency as induced by an aromatase inhibitor in an aged male rat model. Bone. 2000 Nov;27(5):611-7. doi: 10.1016/s8756-3282(00)00363-x.

  PMID: 11062346 BACKGROUND

• Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002 Jun 1;359(9321):1929-36. doi: 10.1016/S0140-6736(02)08761-5.

  PMID: 12057569 BACKGROUND

• Villareal DT, Binder EF, Williams DB, Schechtman KB, Yarasheski KE, Kohrt WM. Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. JAMA. 2001 Aug 15;286(7):815-20. doi: 10.1001/jama.286.7.815.

  PMID: 11497535 BACKGROUND

• Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf). 2000 Nov;53(5):561-8. doi: 10.1046/j.1365-2265.2000.01131.x.

  PMID: 11106916 BACKGROUND

• Guthrie JR, Ebeling PR, Hopper JL, Barrett-Connor E, Dennerstein L, Dudley EC, Burger HG, Wark JD. A prospective study of bone loss in menopausal Australian-born women. Osteoporos Int. 1998;8(3):282-90. doi: 10.1007/s001980050066.

  PMID: 9797914 BACKGROUND

• Armamento-Villareal R, Civitelli R. Estrogen action on the bone mass of postmenopausal women is dependent on body mass and initial bone density. J Clin Endocrinol Metab. 1995 Mar;80(3):776-82. doi: 10.1210/jcem.80.3.7883830.

  PMID: 7883830 BACKGROUND

• Kado DM, Browner WS, Blackwell T, Gore R, Cummings SR. Rate of bone loss is associated with mortality in older women: a prospective study. J Bone Miner Res. 2000 Oct;15(10):1974-80. doi: 10.1359/jbmr.2000.15.10.1974.

  PMID: 11028450 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Absorptiometry, Photon; Blood Specimen Collection; Surveys and Questionnaires

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Radiography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Densitometry; Photometry; Chemistry Techniques, Analytical; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Punctures; Surgical Procedures, Operative; Data Collection; Epidemiologic Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Antonella Rastelli, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2008
• First Posted: January 29, 2008
• Study Start: March 1, 2006
• Primary Completion: October 1, 2009
• Study Completion: October 1, 2009
• Last Updated: May 24, 2013

Record last verified: 2013-05

Locations

US (1)