Anastrozole may be effective for primary prevention of breast cancer in high-risk, postmenopausal women

A new study partially funded by industry indicated that the aromatase inhibitor anastrozole may be effective for primary prevention of breast cancer in high-risk, postmenopausal women, although an accompanying commentary did not agree.

IBIS-II (International Breast cancer Intervention Study II) was a randomized, double-blind, placebo-controlled trial comparing anastrozole, 1 mg orally per day, with matching placebo. Women from 18 countries were recruited for the trial from Feb. 2, 2003, to Jan. 31, 2012, if they were 40 to 70 years of age and were at increased risk for breast cancer. The primary end point of the study was histologically confirmed breast cancer, defined as invasive cancer or noninvasive ductal carcinoma in situ. The study, which was funded in part by Sanofi-Aventis and AstraZeneca, was published online Dec. 12 by The Lancet. Sanofi-Aventis and AstraZeneca also provided the study drug and matching placebo.

A total of 1,920 women were assigned to receive anastrozole and 1,944 were assigned to receive placebo. At study entry, the women's median age was 59.5 years; 695 women (18%) were older than 65 years. Over a median follow-up of 5 years, 40 women taking anastrozole developed breast cancer versus 85 taking placebo (2% vs. 4%; hazard ratio, 0.47; 95% CI, 0.32 to 0.68; P<0.001). Invasive estrogen-receptor-positive tumors were significantly less common in the anastrozole group than in the placebo group, but no difference for invasive estrogen-receptor-negative tumors was seen. The authors predicted a cumulative breast cancer incidence of 5.6% in those taking placebo and 2.8% in those taking anastrozole after 7 years.

Eighteen women died in the anastrozole group and 17 died in the placebo group, with no cause of death being more common in either group. Many side effects were reported, with musculoskeletal adverse events, vasomotor symptoms, hypertension and dry eyes being more common in the anastrozole group and vaginal or uterine prolapse and vaginal pruritus being more common in the placebo group. Thromboembolic events, cerebrovascular events and myocardial infarction did not differ between groups.

The authors acknowledged that trials with longer follow-up could more thoroughly confirm anastrozole's protective effects, especially over the long term, and that more data are needed in women with dense breasts. However, they concluded that anastrozole reduces the risk of invasive estrogen-receptor-positive breast cancer and ductal carcinoma in situ by more than 50%, more than has been reported for tamoxifen or raloxifene. They noted that although many of the reported side effects are often seen with estrogen deprivation, rates were only slightly higher with anastrozole compared with placebo.

“Our results strongly support the use of anastrozole for preventive treatment of high-risk postmenopausal women,” the authors wrote.

However, the author of an accompanying commentary pointed out that the study did not detect a difference in breast cancer or all-cause mortality with anastrozole and that the literature does not yet support a gain in overall breast cancer mortality with any primary chemoprevention, since the most protection has been seen in hormone-sensitive tumors and tumors detected by screening.

“Therefore, for any woman considering 5 years' anti-oestrogen therapy to reduce her risk of breast cancer without evidence to suggest that she will have a longer life, the perceived and actual toxicity of this intervention becomes important,” the commentary author wrote. “The financial costs of breast cancer chemoprevention might have decreased, but the toxicity cost to women has not.”

The commentary also addressed the side effects experienced by women in the current study, noting that although the increased frequency of musculoskeletal and vasomotor events was relatively modest with the study drug compared with placebo, “more than 100-200 additional women had these symptoms in the anastrozole group compared with the placebo group—quite often to a moderate or severe level—to prevent 15 symptomatically diagnosed breast cancers.”

The commentary author quoted the editorial that had accompanied IBIS-I in 2002, which had laid out 3 criteria to be met before chemoprevention could assume a prominent role in breast cancer treatment: long-term proof that reduced incidence translates to reduced breast cancer mortality, development of new drugs with better safety profiles, and development of targeted drugs for those likely to derive the most benefit.

“Unfortunately, although [the current authors] report important data, IBIS-II has not addressed any of these challenges,” the editorialist concluded.