A Study of Anastrozole in Breast Cancer Chemoprevention

Results from the IBIS-II trial in postmenopausal women with high-risk of breast cancer

Five years of treatment with a potent, non-steroidal aromatase inhibitor, anastrozole, reduced the incidence of primary breast cancer in postmenopausal women at high risk for developing the disease, according to an analysis of the international, double-blind, randomised placebo controlled study. The results were presented at the 2013 San Antonio Breast Cancer Symposium (10-14 December) and published simultaneously in the journal Lancet by Prof. Jack Cuzick of the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK on behalf of the IBIS-II study investigators.

The study

IBIS-II randomly assigned 3,864 postmenopausal women at high risk of breast cancer (either due to family history, atypia, lobular carcinoma in situ, or breast density) to treatment with anastrozole or placebo for 5 years. As a background information for studying anastrozole in that setting, the investigators explained a fact that aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women.

Between February 2003 and 31 January 2012, they recruited postmenopausal women aged 40 to 70 years from 18 countries. Eligible women had an increased risk of breast cancer as judged on specific criteria. The women were then randomly assigned 1:1 to receive anastrozole or placebo every day for 5 years (1920 women were assigned to anastrozole arm and 1944 to placebo arm). The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat.

At a median follow-up of 5 years, breast cancer occurred in 40 women in the anastrozole arm (2%) and 85 women (4%) in the placebo arm (hazard ratio 0.47, 95% CI 0.32—0.68, p < 0.0001). The predicted cumulative incidence of primary breast cancers (including ductal carcinoma in situ) occurring after 7 years was 5.6% of women in the placebo arm vs. 2.8% of the anastrozole arm, representing a 53% decrease in risk (p < 0.0001).

Oestrogen receptor–positive invasive breast cancers developed in 3.3% of the placebo arm vs. 1.4% of the anastrozole group, representing a 58% decrease in risk (p = 0.001). No effect of anastrozole was seen in oestrogen receptor–negative tumours.

In total, 18 deaths were reported in the anastrozole arm and 17 in the placebo arm, and no specific causes were more common in one group than the other.

Adverse events profile

Five years of treatment were completed by 72% of placebo patients and 68% of those taking anastrozole. Drop-out in the anastrozole group were mostly due to drug-related side effects.

Bone fractures occurred in 7.7% of those on placebo compared to 8.5% of women receiving anastrozole. All participants had a dual X-ray absorptiometry scan upfront and osteoporotic women were given bisphosphonate treatment, which could account for a smaller-than-expected incidence of musculoskeletal/fracture side effects.

Musculoskeletal aches and pains were the most common adverse events in the anastrozole group and were 10% higher than in the placebo patients. At baseline many women in both groups reported joint pains. However, the researchers believe that most of these complaints were not treatment-related. Other joint symptoms were also increased in the anastrozole group, including joint stiffness and carpal tunnel syndrome.

A lower incidence of cancers other than breast cancer was noted in the anastrozole group compared to the placebo group (40 cases of other cancers in the anastrozole group vs. 70 cases in the placebo group). These were primarily skin cancers and colorectal cancers. The reasons for this effect are unclear, but according to study investigators such finding was also seen in the exemestane trials.

Are the study findings practice changing?

The study authors interpreted their findings with conclusion that anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. They wrote “this finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer”.

However, according to moderator of the session in which the study has been presented Dr Fabrice Andre of the Institut Gustave Roussy, Villejuif, France, there are other good options for breast cancer prevention that are FDA-approved for this indication, including tamoxifen and exemestane.

According to Dr David Cameron  of Scotland's Edinburgh Cancer Centre, UK, the key question is whether any primary prevention drugs actually prevent breast cancer deaths and improve overall survival for the price in toxicity, which no trial has yet shown, as argued in his commentary entitled “Breast cancer chemoprevention: little progress in practice?” that accompanied the IBIS-II article in Lancet.

He wrote that "the consistent finding of an increased effect of prevention therapy on hormone-receptor-positive tumors supports the prediction made by modelling data that pharmacological prevention of breast cancer is actually early treatment of extant subclinical tumors".

"With two-thirds of the anastrozole benefit in screen-detected cancers, in view of their better outcomes, the likelihood of an eventual breast cancer mortality benefit seems small." In addition, side effects and cost are more likely to be deciding factors in the absence of any evidence that it will save women's lives, according to Dr Cameron. About half or more of the women in both groups in the trial had musculoskeletal and vasomotor symptoms, while about a fifth had gynecologic adverse events.

"Although the increase in frequency with anastrozole [versus placebo] was modest for musculoskeletal (6%) and vasomotor (8%) events, more than 100 to 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," he argued.

But the study researchers took a different view of the same finding. "Although many side-effects recorded have been associated with estrogen deprivation, they were only slightly more frequent in the anastrozole group than in the placebo group, indicating that most of these symptoms are not drug related," they wrote.

This IBIS-II trial is registered under number ISRCTN31488319.


Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. The Lancet, Early Online Publication, 12 December 2013 doi:10.1016/S0140-6736(13)62292-8.

Cameron D. Breast cancer chemoprevention: little progress in practice? The Lancet, Early Online Publication, 12 December 2013 doi:10.1016/S0140-6736(13)62555-6.

The study was funded by Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.