By Gary R. Shapiro, MD
Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin
Dr. Shapiro reports no financial relationships relevant to this field of study.
SYNOPSIS: After a median follow-up of 5 years, the aromatase inhibitor, anastrozole decreased the incidence of breast cancer in high-risk postmenopausal women by 53% compared to women receiving a placebo. This was accomplished with few side effects, mostly small increases in muscle aches and pains, and hot flashes.
Source: Cuzick J, et al. Anastrazole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomized placebo-controlled trial. Lancet 2014;383:1041-1048.
This international, double-blind, placebo-controlled trial randomized 3,864 post-menopausal women to receive either 1 mg of anastrozole or placebo for 5 years. Entry criteria required a relative risk of breast cancer at least 1.5 times higher than the general population in women aged 60-70 years old, 2 times higher in those aged 45-60 years old and 4 times higher in those participants aged 40-44 years old. The primary endpoint of the study was histologically confirmed breast cancer: invasive cancers or non-invasive ductal carcinoma in situ.
Women in the anastrozole and placebo groups were well balanced for age, parity, age at menarche and menopause, height and weight, body-mass index, previous use of hormone replacement therapy, hysterectomy, first-degree relatives with breast or ovarian cancer, lobular carcinoma in situ or atypical hyperplasia, estrogen receptor positive ductal carcinoma in situ within 6 months, 10-year Tyrer-Cuzick risk, and women using bisphosphonates during the trial.
After a median follow-up of 5 years, 40 women in the anastrozole group (2%) and 85 women in the placebo group (4%) had developed breast cancer (HR 0.47; 95% CI 0.32-0.68, p < 0.0001). The predicted cumulative incidence of all breast cancers (including ductal carcinoma in situ) after 7 years was 5.6% in the placebo group and 2.8% in the anastrozole group, suggesting that 36 women would need to be treated with anastrozole to prevent one cancer in 7 years of follow-up.
Anastrozole was associated with significantly reduced risk of all ductal carcinoma in situ (< 1% vs. 1% HR 0.30, p = 0.009) and invasive estrogen receptor positive cancers (1% vs. 2% HR 0.42, p = 0.001), but there was no difference for invasive estrogen receptor negative cancers (1% vs. 1%, HR 0.79, p = 0.538). Interestingly, the frequency of non-breast cancers was significantly lower in the anastrozole group (2% vs. 4%, RR 0.58, p = 0.005).
There were 18 deaths in the anastrozole group (two breast cancer, seven other cancers, two cerebrovascular, three cardiac arrest, four other) and 17 in the placebo group (0 breast cancer, 10 other cancers, two cerebrovascular, one cardiac, four other), and no specific causes were more common in one group than the other (p = 0.836). Adverse events were reported by 89% of women in both the anastrozole and placebo groups. Although the total number of fractures did not differ between groups, musculoskeletal adverse events (64% vs. 58%, RR 1.10, p = 0.0001), including arthralgia (51% vs. 46%, RR 1.10), joint stiffness (7% vs. 5%, RR 1.51), and carpal tunnel syndrome (3% vs. 2%, RR 1.58) were significantly more common in those taking anastrozole. Vasomotor symptoms were common in both groups, but significantly more frequent with anastrozole than placebo (57% vs. 49%, RR 1.15, p < 0.0001). Significantly more women taking anastrozole than those taking placebo reported dry eyes (4% vs. 2%, RR 1.45) and hypertension (5% vs. 3%, RR 1.64), but there was no difference in frequencies of thromboembolic events (1%), cerebrovascular events (< 1%) or myocardial infarctions (< 1%). Vaginal or uterine prolapse and vaginal pruritus were significantly reduced with anastrozole.
In 2013, the American Society of Clinical Oncology (ASCO) issued new guidelines recommending that chemoprevention (tamoxifen 20 mg per day for 5 years) "should be discussed as an option to reduce the risk of estrogen receptor positive breast cancer" in pre- and postmenopausal women at increased risk for the disease, and that raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) "should also be discussed as options for breast cancer risk reduction" in high-risk postmenopausal women.1 This was the first time that the ASCO recommended the use of an aromatase inhibitor in postmenopausal women, and was based on the results of a single large institution study (MAP.3) that had similar results to the Cuzick anastrozole trial.2 The National Comprehensive Cancer Network (NCCN) soon followed with its endorsement of exemestane,3 but the FDA has not yet approved the use of either agent in the chemoprevention setting.
Both the anastrozole and the exemestane studies showed that, compared with placebo, these aromatase inhibitors reduced the risk of breast cancer (both in situ and invasive disease) by at least 50 percent. Although this risk reduction is somewhat higher than that reported for tamoxifen, there are currently no data directly comparing the benefits and risks of either anastrozole or exemestane to tamoxifen, or to each other.
The side-effect profile of the aromatase inhibitors does appear more favorable than that of tamoxifen, especially the potentially debilitating and life-threatening risks related to thromboembolic events in older individuals taking tamoxifen. Although it is tempting to extrapolate data from what we know is the case in the treatment of breast cancer,4 neither the exemestane nor the anastrozole prevention studies adequately address the long-term effects of these agents on postmenopausal women who do not have breast cancer. The aromatase inhibitor prevention studies showed no difference in mortality, although there were too few deaths to allow for a meaningful estimate on survival. It is reassuring that the side effects of these agents were relatively few, but questions do remain as to long-term effects of these drugs on bone loss and cardiovascular risk. Furthermore, aromatase inhibitor-induced arthralgia and other musculoskeletal adverse events may limit patient acceptance of these medications.5
Chemoprevention of breast cancer is effective yet underutilized. Taken together, these studies do support the use of anastrozole or exemestane as an alternative to tamoxifen for postmenopausal women at high risk for breast cancer who wish to decrease their risk. Although these agents appear to have a relatively favorable toxicity profile, an individual’s comorbid conditions, bone density, musculoskeletal complaints, and overall vigor should be part of the risk-benefit analysis regarding their use for the prevention of breast cancer in high-risk postmenopausal women.