Exemestane Significantly Reduces Risk of Invasive, Preinvasive Breast Cancers in Postmenopausal Women at High Risk

CHICAGO--Exemestane, an aromatase inhibitor (AI), can be considered a new option for primary prevention of breast cancer in postmenopausal women, results of a randomized, placebo-controlled trial reported upon during the American Society of Clinical Oncology's 2011 Annual Meeting and published online in The New England Journal of Medicine1 have found.

According to Paul E. Goss, MD, PhD, Massachusetts General Hospital, Boston, and colleagues, exemestane significantly reduced invasive and preinvasive breast cancers with no serious toxicities in postmenopausal women at moderately increased risk for breast cancer.

The MAP.3 (Mammary Prevention Trial-.3) study, led and coordinated by the National Cancer Institute of Canada Clinical Trials Group, is the first randomized trial to assess an aromatase inhibitor to prevent breast cancer in healthy women. At a median follow-up of three years, the trial met its primary goal of detecting a 65% reduction in annual incidence of invasive breast cancer in women treated with exemestane compared with placebo.

Dr. Goss explained that the antiestrogens tamoxifen and raloxifene are approved in the US to reduce breast cancer risk; however, rare endometrial cancer and thromboembolism have, in part, limited use of tamoxifen in particular to approximately 4% of women at increased risk. Aromatase inhibitors are superior to tamoxifen in early breast cancer, including the reduction of contralateral breast cancer, and may offer an option to prophylactic bilateral mastectomy for women at increased risk.

“Women and practitioners now have three options for breast cancer chemoprevention: tamoxifen, raloxifene, and exemestane—agents of proven efficacy that are among the best-studied drugs in the world,” wrote Nancy E. Davidson, MD, and Thomas W. Kensler, PhD, in an accompanying editorial in The New England Journal of Medicine.2 “Breast cancer is the second most common cause of death from cancer and one of the most feared diagnoses for women in the United States. We have the knowledge and tools to reduce its incidence today. We have run out of excuses. What are we waiting for?”

Between 2004–2010, the study randomized 4,560 eligible postmenopausal women from the USA, Canada, Spain, and France with one or more of the following risk factors to exemestane or placebo: ≥60 years; Gail 5-year risk score >1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia (ADH/ALH) or lobular carcinoma in situ (LCIS); or ductal carcinoma in situ (DCIS) with mastectomy.

Mean age was 62.5 years (range, 37–90 years); Gail score 2.3% (range, 0.6–21%); and BMI 28.0 kg/m2 (range, 15.9–65.4 kg/m2). At a median follow-up of 35 months, 11 cases of invasive breast cancer had occurred in the women receiving exemestane and 32 in the placebo group (annual incidence 0.19% vs 0.55%; HR 35 [0.18-0.70]; P=0.002). There were 10 cases of ductal and one of lobular carcinoma in the exemestane group and 27 and five cases, respectively, in the placebo group. Most of the tumors were estrogen-receptor positive, Her2/neu negative, TNM stage T1, node negative, and nonmetastatic.

A 60% reduction of invasive breast cancer plus preinvasive DCIS was observed among the 66 cases in the study women. Exemestane also reduced the risk of known breast-cancer precursor lesions—ADH, ALH, and LCIS—suggesting possibility of reductions in future cancers.

Hot flashes, fatigue, sweating, insomnia, and arthralgia were frequent in all women on the study but occurred slightly more commonly among those receiving exemestane; 88% vs. 85% for those on placebo. After stopping aromatase inhibitors, estrogen levels return to normal and side effects dissipate, Dr. Goss pointed out. Exemestane did not cause any serious toxicities, such as osteoporosis, clinical fractures, cardiovascular events, or second malignancies.

To prevent one case of invasive breast cancer with exemestane therapy, the number needed to treat was 94 in three years and 26 in five years. This number might be reduced by identifying subgroups of women who would benefit most or who would be most vulnerable to toxic effects. Plans are ongoing to refine the target population.

After unblinding, women taking exemestane have the opportunity to continue until five years of therapy are completed. Study sites also have the option of offering five years of exemestane treatment to those in the placebo arm.

The editorial noted that in premenopausal women in whom tamoxifen remains the drug of choice, aromatase inhibitors should not be used for chemoprevention.2 Exemestane is currently FDA approved for use in patients with early breast cancer.

1.      Goss PE, Ingle, JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. Published online June 4, 2011 (10.1056/NEJMoa1103507).

2.      Davidson NE, Kensler TW. MAPping the course of chemoprevention in breast cancer. N Engl J Med. Published online June 4, 2011 (10.1056/NEJMe1106052).