Background Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. Methods In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. Results A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P = 0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P = 0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = 0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatmentrelated deaths. Minimal quality-of-life differences were observed. Conclusions Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.)

/pdf/exemestane-for-breast-cancer-prevention-in-postmenopausal-2bgpaamrq2.pdf

Exemestane for Breast-Cancer Prevention in Postmenopausal Women

Purpose Aromatase inhibition depletes estrogen levels and may be associated with accelerated bone resorption. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study MA.17B evaluated bone turnover markers and bone mineral density (BMD) in postmenopausal women randomly assigned to MA.17, a placebo-controlled trial of letrozole after standard adjuvant tamoxifen. Patients and Methods Eligible women had a baseline BMD T score of at least 2.0 in either the hip or L2-4 spine; all received calcium 500 mg and vitamin D 400 U daily. Percentage change in BMD (L2-L4 spine and hip) at 12 and 24 months, rate of osteoporosis, and change in markers of bone formation (serum bone alkaline phosphatase) and resorption (serum C-telopeptide and urine N-telopeptide) at 6, 12, and 24 months were compared. Results Two hundred twenty-six patients (122 letrozole, 104 placebo) were enrolled. Baseline characteristics were similar in the two groups, including BMD, median age of 60.7 years (81% < 70 years), and ...

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2005.05.4882

Effect of Letrozole Versus Placebo on Bone Mineral Density in Women With Primary Breast Cancer Completing 5 or More Years of Adjuvant Tamoxifen: A Companion Study to NCIC CTG MA.17

Purpose To evaluate potential detrimental effects of exemestane on bone and lipid metabolism. Patients and Methods Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients. Results One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P .568) and 2.72% v 1.48% in the femoral neck (P .024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was 0.21 for exemestane and 0.11 on placebo in the hip, and 0.30 and 0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P .001) and apolipoprotein A1 (P .004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters. Conclusion

https://ascopubs.org/doi/pdf/10.1200/JCO.2005.07.097

Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer

Purpose In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non‐cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.

/pdf/exemestane-versus-anastrozole-in-postmenopausal-women-with-z1cgomheu3.pdf

Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial

Purpose Bone loss resulting from the treatment of breast and prostate cancer is an emerging problem. Bisphosphonates have a potential role in the prevention of this cancer treatment–induced bone loss (CTIBL). Methods Studies evaluating the incidence and prevalence of CTIBL in early breast and prostate cancer patients and trials evaluating the preventative role of bisphosphonates were identified by a search of the PubMed and Cochrane Library databases through the end of March 2008. Reference lists from retrieved articles were cross referenced, and further information was obtained from relevant scientific meetings. Results Several therapies commonly used in the treatment of women and men with breast and prostate cancers, in particular the aromatase inhibitors (AIs) for breast cancer and androgen deprivation therapy (ADT) for prostate cancer, are associated with significant bone loss and with an increase in fracture risk. The use of bisphosphonates seems to attenuate the bone loss, although the long-term imp...

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Papers

The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats.