COMMENTARY
An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve
D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA
The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.
With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.
Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.
With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.
In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.
There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.
Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.
Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.
Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.
Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.
References
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. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor
Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.
So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.