Report prepared by Matt Stenger
The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1
In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.
The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).
At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).
Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.
Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.
Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.