Women who are thought to be of increased risk of developing breast cancer are now often offered chemo-prevention, usually with an oestrogen receptor modulator such as tamoxifen or raloxifane.

These drugs have been shown to reduce the incidence of invasive breast cancer in at-risk groups but have limited acceptance, principally because they are associated with rare but serious adverse effects including venous thrombo-embolism and an increase in endometrial cancer risk.

There is therefore much interest in whether alternative drugs, such as aromatase inhibitors, might combine similar chemo-preventive effects with a better safety profile. The aromatase inhibitor exemestane is considered to be particularly suitable for this because of its anti-oestrogenic effects.

The NCIC Clinical Trials Group's Mammary Prevention.3 trial (NCIC CTG MAP.3) was set up to investigate the effect of exemestane on the incidence of invasive breast cancer in post-menopausal women at risk of the disease.

Lead investigator Paul Goss, of Massachusetts General Hospital, Boston, MA, USA and his co-workers have now published the results of this trial. This was a two-arm, placebo controlled double-blind trial: a total of 4560 women were recruited between 2004 and 2010 and randomly assigned to receive either exemestane or placebo.

All subjects were post-menopausal, at least 35 years old, and had at least one other recognised risk factor for breast cancer. Women previously diagnosed with invasive cancer and known carriers of mutations in the BRCA1 and BRCA2 genes were ineligible.

Incidence of invasive breast cancer was taken as the primary outcome, with the incidence of other cancers (including carcinoma in situ) and other adverse health outcomes, and health- and menopause-related quality of life scores as secondary outcomes. All subjects underwent mammography in the 12 months before randomization and then every 12 months for the duration of the trial.

Approximately 85% of participants in each group were compliant with the main study requirements, and approximately 93% attended all required mammography appointments. After a median of 35 months of follow-up, eleven cases of invasive breast cancer were diagnosed in the exemestane group compared to 32 in the placebo group.

This represents an annual incidence of 0.19% in the exemestane group and 0.55% in the placebo group (hazard ratio 0.35; 95% confidence interval 0.18-0.70). Hazard ratios were less than 0.5 in all participant sub-groups apart from those with a prior diagnosis of hyperplasia or carcinoma in situ, where the effect was slightly less marked. There was little difference in the types of breast cancer diagnosed in each group, with most cancers being node-negative, HER2/neu- negative, and oestrogen receptor positive.

Some adverse effects were reported in 88% of the exemestane group compared to 85% of the placebo group. There were no significant differences between the groups in the incidence of serious skeletal problems, cardiovascular events, or other cancers, although, interestingly, participants in the exemestane group reported more unpleasant menopause-related symptoms such as insomnia and hot flushes.

Goss and his co-workers concluded that the study shows clearly that exemestane can offer significant protection against breast cancer to post-menopausal women at raised risk of developing the disease, and that its side effect profile is generally very good. They recognise, however, that a median follow-up time of three years is relatively limited, and they are conducting further trials including some in younger women and in patients with early breast cancer to profile the efficacy and toxicity of exemestane as a chemo-preventive in all these groups.

Article: Goss, P.E., Ingle, J.N., Alés-Martínez, J.E. and 17 others, for the NCIC CTG MAP.3 study investigators. Exemestane for Breast-Cancer Prevention in Postmenopausal Women. N. Engl. J. Med. 364: 2381-91. DOI: 0.1056/NEJMoa1103507