The aromatase inhibitor exemestane, taken for 5 years, significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk for the disease, in the large Canadian NCIC CTG MAP.3 randomized trial. Results of the trial were presented at the recent ASCO Annual Meeting by Paul Goss, MD, PhD, of Harvard Medical School in Boston,1 and were subsequently published in The New England Journal of Medicine.2
“Our study not only showed an impressive reduction in breast cancers, but also an excellent side-effect profile,” said Dr. Goss, who noted that the currently approved drugs for preventing breast cancers—tamoxifen and raloxifene—are associated with the potential for rare but serious side effects, including venous thromboembolism and endometrial cancer.
Exemestane is currently indicated for adjuvant endocrine treatment but is not FDA-approved for the prevention of breast cancer. “Exemestane causes less bone loss than other aromatase inhibitors and thus was our first choice for a breast cancer prevention trial,” Dr. Goss noted.
MAP.3 Study Details
The study is the first randomized trial to assess an aromatase inhibitor for breast cancer prevention in healthy women. The study enrolled 4,560 postmenopausal women from four countries who had at least one of the following risk factors: age ≥ 60 years; 5-year Gail risk score > 1.66%; prior atypical ductal hyperplasia, lobular hyperplasia, or lobular carcinoma in situ; or prior ductal carcinoma in situ (DCIS) with mastectomy. The study excluded BRCA1 and BRCA2 mutation carriers, women with DCIS who had undergone lumpectomy, and women with a history of cancer.
About half the population was considered at risk simply by virtue of being 60 years old or older, he noted.
Subjects were randomly assigned to exemestane at 25 mg/d or placebo, for 5 years. At a median follow-up time of 3 years, 11 invasive breast cancers occurred in the exemestane group vs 32 in the placebo group, for annual incidence rates of 0.19% vs 0.55%, respectively, and resulting in a 65% reduction in invasive cancers with exemestane (P = .002), Dr. Goss reported.
The protective effect was striking for estrogen receptor–positive tumors, 7 of which developed in the exemestane group compared with 27 in the placebo arm, for a 73% relative risk reduction (P = .0008). In all subgroups analyzed, the incidence of invasive breast cancer was reduced with exemestane.
The investigators also found a 53% reduction of invasive breast cancer and preinvasive DCIS, and fewer cases of cancer precursor lesions such as atypical ductal hyperplasia and atypical lobular hyperplasia with exemestane, he added.
Serious toxicities over 3 years were not seen, particularly fractures, self-reported osteoporosis, cardiovascular toxicities, or second cancers. The exemestane group did report more bodily pain—46% vs 41% (P < .001)—and had minimal worsening of quality of life. In addition, 88% of the exemestane group reported an adverse event, as did 85% of the placebo group, “which because of the large numbers was statistically significant (P = .003), but the differences were really quite small,” he said. “Patients with as little as one report of ‘worsening’ of quality of life (eg, pain) were conservatively reported as ‘worsening’ even though in many this resolved after a single report for the rest of the treatment period,” Dr. Goss added.
“The findings from MAP.3 indicate that exemestane is a promising new option for preventing breast cancer in menopausal women,” Dr. Goss commented.
While acknowledging that the median follow-up of 3 years in MAP.3 is short, Dr. Goss noted that “in early breast cancer trials, benefits including prevention of new primaries are durable and indeed increase up to 5 years on therapy and are durable beyond cessation of treatment up to at least another 5 years that we know of.” Further, the analysis was intent-to-treat, and he speculated the benefit may actually be greater in patients who were compliant with the medication for the full 5 years. The number needed to treat to prevent one breast cancer over 5 years is just 26, compared to 95 with tamoxifen.
Finally, the patent for exemestane (Aromasin) recently expired, and a generic form is now available, providing an even more cost-effective means of chemoprevention, he added. ■
Disclosure: Dr. Goss has received speaker’s honoraria from GlaxoSmithKline, Novartis, and Pfizer in the past.
1. Goss PE, Ingle JN, Ales-Martinez J, et al: Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial. 2011 ASCO Annual Meeting. Abstract LBA504. Presented June 5, 2011.
2. Goss PE, Ingle JN, Ales-Martinez J, et al: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364:2381-2391, 2011.