The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N = 5,252) or low bone mass (N = 4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95 % CI 0.25–0.68, P < 0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95 % CI 0.14–0.63, P = 0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95 % CI 0.13–0.71, P = 0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction = 0.31) and between low bone mass and osteoporosis groups (P interaction = 0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.
Arzoxifene Selective estrogen receptor modulator (SERM) Breast cancer prevention Clinical trial
This is a preview of subscription content, log in to check access.
This trial was sponsored by Eli Lilly and Company. The trial is registered at Clinicaltrial.gov number NCT00088010.
Powles, Wickerham, and Cummings have served in a consultant/advisory role for Eli Lilly and Company; Diem has received research funding from Eli Lilly and Company; Cox, Muram, Agnusdei, Dowsett and Amewou-Atisso are stockholders and full time employees at Eli Lilly and Company.
Conflict of interest
Conflict of interest have been declared in the attached manuscript. The study discussed in this paper was sponsored by Eli Lilly and Company
Fisher B, Costantino JP, Wickerham DL et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388PubMedCrossRefGoogle Scholar
Veronesi U, Maisonneuve P, Costa A et al (1998) Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 352:93–97PubMedGoogle Scholar
Powles T, Eeles R, Ashley S et al (1998) Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352:98–101PubMedGoogle Scholar
Cuzick J, Forbes J, Edwards R et al (2002) First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 360:817–824PubMedCrossRefGoogle Scholar
Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282:637–645PubMedCrossRefGoogle Scholar
Cummings SR, Eckert S, Krueger KA et al (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. [see comment] [erratum appears in JAMA 1999;282(22):2124]. JAMA 281:2189–2197PubMedCrossRefGoogle Scholar
Martino S, Costantino J, McNabb M et al (2004) The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trials. Oncologist 9:116–125PubMedCrossRefGoogle Scholar
Vogel VG, Costantino JP, Wickerham DL et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes. JAMA 295:2727–2741PubMedCrossRefGoogle Scholar
Cummings SR, Ensrud K, Delmas PD et al (2010) Lasofoxifene for postmenopausal women with osteoporosis. N Engl J Med 362:686–696PubMedCrossRefGoogle Scholar
La Croix A, Powles TJ, Osborn CK et al (2010) Breast cancer incidence in the PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J Natl Cancer Inst 102:1706–1715CrossRefGoogle Scholar
Silverman SL, Christiansen C, Genant HK et al (2008) Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 23:1923–1934PubMedCrossRefGoogle Scholar
Archer DF, Pinkerton JV, Utian WH et al (2009) Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 16:1109–1115PubMedCrossRefGoogle Scholar
Suh N, Glasebrook AL, Palkowitz AD et al (2001) Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res 61:8412–8415PubMedGoogle Scholar
Palkowitz AD, Glasebrook AL, Thrasher KJ, Hauser KL et al (1998) Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzothiophene: a novel, highly potent, selective estrogen receptor modulator. J Med Chem 40:1407–1416CrossRefGoogle Scholar
Sato M, Turner CH, Wang T, Adrian MD et al (1998) LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J Pharmacol Exp Ther 287:1–7PubMedGoogle Scholar
Buzdar A, O’Shaughnessy JA, Booser DJ et al (2003) Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer. J Clin Oncol 21:1007–1014PubMedCrossRefGoogle Scholar
Baselga J, Llombart-Cussac A, Bellet M et al (2003) Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients. Ann Oncol 14:1383–1390PubMedCrossRefGoogle Scholar
Deshmane V, Krishnamurthy S, Melemed AS, Peterson P, Buzdar AU (2007) Phase III double-blind trial of arzoxifene compared with tamoxifen for locally advanced or metastatic breast cancer. J Clin Oncol 25:4967–4973PubMedCrossRefGoogle Scholar
Fabian CJ, Kimler BF, Anderson J et al (2004) Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator. Clin Cancer Res 10:5403–5417PubMedCrossRefGoogle Scholar
Cummings SR, McClung M, Reginster JY et al (2011) Arzoxifene for prevention of fractures and invasive breast cancer in postmenopausal women. J Bone Miner Res 26:397–404PubMedCrossRefGoogle Scholar
Gail MH, Brinton LA, Byar DP et al (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81:1879–1886PubMedCrossRefGoogle Scholar
Cuzick J, Powles T, Veronesi U et al (2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296–300PubMedCrossRefGoogle Scholar
Vogel VG, Costantino JP, Wickerham DL et al (2010) Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res 3:696–706CrossRefGoogle Scholar
Cuzick J, Forbes JF, Sestak I et al (2007) Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99:272–282PubMedCrossRefGoogle Scholar
Powles TJ, Ashley S, Tidy A et al (2007) Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst 99:283–290PubMedCrossRefGoogle Scholar