Giving the aromatase inhibitor exemestane (Pfizer’s Aromasin) to healthy post-menopausal women at increased risk of breast cancer could be an effective way of warding off the disease with fewer side-effects than on currently available preventive therapies, new data have shown.

Results from MAP.3 (Mammary Prevention Trial-.3), the first randomised trial to assess an aromatase inhibitor as a tool for breast-cancer prevention in healthy women, showed that after a median follow-up of three years, women given exemestane were 65% less likely to develop invasive breast cancer than those on placebo, with no serious toxic side-effects and minimal impact on health-related quality of life.

The data were presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, US and were published simultaneously online by the New England Journal of Medicine.

Preventive indication

The MAP.3 trial was led by Canada’s NCIC (National Cancer Institute of Canada) Clinical Trials Group and was part-supported by Pfizer.

The chances of the company applying for a preventive indication for Aromasin look somewhat slim, though, as the drug has already lost its patent protection in the US and is facing generic competition in other key markets.

The randomised, double-blind Phase III study enrolled 4,560 post-menopausal women in total from the US, Canada, Spain and France with at least one of the following risk factors for breast cancer: age greater than or equal to 60 years; five-year Gail risk score greater than 1.66%; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with prior mastectomy.

The median age of the MAP.3 participants was 62.5 years and the median Gail risk score was 2.3%.

65% reduction

After an average of 35 months’ follow-up, 11 invasive breast cancers were detected in women randomised to exemestane and 32 in the placebo group, amounting to a 65% relative reduction in the annual incidence of breast cancer.

The annual incidence of invasive plus non-invasive (ductal carcinoma in situ) breast cancer was 0.35% in the exemestane group and 0.77% on placebo. There were also fewer cases of cancer precursor lesions such as atypical ductal and atypical lobular hyperplasia in the exemestane group.

Adverse events occurred in 88% of women on exemestane and 85% of those on placebo, with frequent incidences of symptoms such as hot flashes, fatigue, sweating, insomnia and arthralgia.

These side-effects were slightly more frequent on exemestane, although they did not appear to affect self-reports of overall health-related quality of life in the exemestane group.

There were no significant differences between the two groups in reports of more serious adverse events such as bone fractures, osteoporosis, hypercholesterolaemia, adverse cardiovascular events and other, non-breast cancers.

New option

The anti-oestrogens tamoxifen and Raloxifene (Eli Lilly’s Evista) have already been approved in the US to prevent breast cancer in women at high risk of the disease.

However, Evista appears to be less effective than tamoxifen in the preventive setting, while tamoxifen itself is associated with a higher risk of serious adverse effects such as uterine cancer and blood clots.

These are estimated to have limited acceptance of tamoxifen for breast cancer prevention to just 4% of high-risk women and 0.08 percent of all women in the US.

In line with expectations

The 65% risk reduction in the MAP.3 trial was “exactly in line with our

expectations”, commented Dr Paul Goss, lead study author and professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston, US.

“The numbers of tumours are small but there also appeared to be fewer of the more aggressive tumours on exemestane,” Dr Goss added. “Our study not only showed an impressive reduction in breast cancers, but also an excellent side-effect profile, although my cautionary note is that average follow-up to date has been only three years.”

Once the study is unblinded, women on active therapy will be offered exemestane to complete a five-year programme, while MAP.3 sites will have the option of offering five years of exemestane to patients initially randomised to placebo, Dr Goss noted.

 “Long-term results in women with early breast cancer show durable long-term reductions in new breast cancers with exemestane without accumulation of late toxicities,” he commented. “So we are hopeful and optimistic that this will be the case in this prevention setting.”