Exemestane Reduces Breast Cancer Risk in High-Risk Postmenopausal WomenAdapted from the NCI Cancer Bulletin.
The list of drugs that have been shown to reduce a woman's chance of developing breast cancer can now be expanded from two to three. Clinical trial results presented at the 2011 American Society of Clinical Oncology (ASCO) annual meeting showed that the aromatase inhibitor exemestane (Aromasin®)—commonly used to treat early and advanced-stage breast cancer—substantially reduced the risk of invasive breast cancer in postmenopausal women at high risk of developing the disease.
The findings were also published online June 4, 2011, in the New England Journal of Medicine (NEJM).
At 3 years of follow-up, women who took exemestane were 65 percent less likely than women who took a placebo to develop breast cancer. This is the largest reduction in risk seen in any of the four large breast cancer prevention trials that have been conducted to date. In previous trials, daily use of tamoxifen or raloxifene reduced breast cancer risk by approximately 50 percent and 38 percent, respectively, after 5 years of follow-up; both drugs were eventually approved by the Food and Drug Administration (FDA) to reduce breast cancer risk.
Some researchers cautioned that 3 years of follow-up may not be long enough to determine the extent of any serious side effects, including osteoporosis, from long-term use of aromatase inhibitors in this patient population.
Despite the limited follow-up, the trial's principal investigator, Paul Goss, M.B. BCh, Ph.D., of Harvard Medical School, said the findings were enough to establish exemestane "as a new option for breast cancer prevention in postmenopausal women." All women older than 60, who by virtue of their age alone have an increased breast cancer risk, "should be made aware of these results," he continued.
Sponsored by the National Cancer Institute of Canada, the trial, dubbed MAP.3, enrolled 4,560 women at increased risk of developing breast cancer. Women were determined to be at increased risk if they had at least one of several risk factors: age 60 years or older; a history of abnormal breast cell growth or having had a noninvasive lesion known as ductal carcinoma in situ (DCIS); or an elevated 5-year score on the Gail model, a commonly used breast cancer risk model.
Participants were randomly assigned to take exemestane or a placebo daily for 5 years. Overall, 11 women assigned to exemestane developed an invasive breast cancer, compared with 32 women who took the placebo. Exemestane use also led to statistically significant reductions in the development of DCIS, Dr. Goss said, and the invasive tumors that did develop in women taking exemestane were less aggressive than those in the placebo group.
Understanding the Side Effects
Importantly, Dr. Goss stressed, women taking exemestane had no increased risk of serious side effects. "We looked for serious toxicities, but we did not find them," he said. The incidence of osteoporosis, cardiac events, and bone fractures were identical for women taking exemestane and for those taking the placebo. However, women who took exemestane had a small, though not statistically significant, increase in menopausal symptoms, such as hot flashes and joint pain.
Overall, approximately 30 percent of participants stopped taking exemestane because of side effects, about 10 percent each year. This is similar to what is seen in clinical practice in women taking an aromatase inhibitor as an adjuvant treatment for early-stage breast cancer.
The data from the MAP.3 trial indicate that exemestane provides another option for risk reduction in the appropriate women, said Worta McCaskill-Stevens, M.D., of NCI's Division of Cancer Prevention (DCP). "But when thinking about prevention, women ask [about] the duration of use of the drug and [want] a clear understanding of its potential side effects," she cautioned.
Of particular concern is severe joint pain, or arthralgia, whose incidence has been relatively high in women being treated for cancer with aromatase inhibitors.
Several studies, however, have shown that women continue to experience the benefits of treatment after stopping aromatase inhibitors—a phenomenon known as a carry-over effect—and that they have fewer adverse events. The women who participated in MAP.3 will have to be followed to better assess the extent and significance of long-term side effects, especially osteoporosis, she stressed.
Overall, because of the short follow-up in the trial, it's too early to definitively understand the drug's risks, Dr. McCaskill-Stevens added. "We can't say that the adverse events in this group of women will be the same as those seen in women receiving an aromatase inhibitor for treatment," she continued. "That's a different patient population as it relates to assessing benefit and risk."
Victor Vogel, M.D., director of the cancer institute at Geisinger Health System in Danville, PA, who was involved in the tamoxifen and raloxifene prevention trials, called the risk reduction findings with exemestane "very impressive." Many of exemestane's side effects can be prevented and treated with monitoring, he explained.
Even if a woman stops taking exemestane for risk reduction because of side effects, Dr. Goss believes, the effort will have been worthwhile. "We feel comfortable that if a woman takes [exemestane] for 6 months or a year, she's gained benefit," he said.
Several clinical trials currently under way should provide more information about the safety and possible side effects of aromatase inhibitors when used for breast cancer risk reduction, explained Leslie Ford, M.D., of DCP.
The British IBIS-2 trial is comparing the aromatase inhibitor anastrazole with a placebo in women at high risk of breast cancer. And a U.S. trial being led by the National Surgical Adjuvant Breast and Bowel Project is comparing the aromatase inhibitor letrozole with tamoxifen in postmenopausal women with DCIS.
More Choices in the Clinic
The failure of tamoxifen and raloxifene to break through into the clinic has been well documented, with women and their doctors citing toxicity as one of their chief concerns. "The good news is that exemestane has a completely different toxicity profile," said Susan Domchek, M.D., director of the Cancer Risk Evaluation Program at the University of Pennsylvania Abramson Cancer Center, who was a site investigator on the trial. "For some women, exemestane will be viewed as a nice choice because of that difference."
As Dr. Vogel stressed, it's not medical oncologists but primary care physicians who would talk with women about their breast cancer risk and whether they should consider taking a drug for prevention. This group of clinicians, along with women themselves, needs to be educated about breast cancer prevention, he explained.
"We need to train primary care physicians about how to do risk assessment; how to counsel these patients," said Dr. Vogel. "And we need to ensure that reimbursement is available so that doctors get paid for taking the time to counsel their patients about preventive interventions."
Several research groups are developing tools to help clinicians with some of the risk assessment and counseling issues, Dr. Domchek noted. In an accompanying editorial in NEJM, Nancy Davidson, M.D., and Thomas Kensler, Ph.D., of the University of Pittsburgh Cancer Institute noted the need to better identify "high-risk cohorts and biomarkers that can predict response to a particular intervention."
Indeed, as Andrew Seidman, M.D., of Memorial Sloan-Kettering Cancer Center noted, unlike with blood pressure or cholesterol medicines, one cannot measure whether tamoxifen, raloxifene, or exemestane is having its intended preventive effect. "There's no feedback loop," he said, to let doctors and women know whether the drug is having the intended effect.
The patent for exemestane expired in 2010, and Pfizer, which manufactures the drug, has not said whether it will apply to the FDA to market exemestane for breast cancer risk reduction.
Editor's Note: A study examining bone health in a subgroup of 351 MAP.3 trial participants revealed that, even with calcium and vitamin D supplementation, women who received daily exemestane had a greater decrease in bone mineral density (BMD) after 2 years of treatment than women who received placebo. The results were published online February 6, 2012, in Lancet Oncology. Longer follow-up will be necessary to determine whether the differences in BMD changes observed in the MAP.3 substudy will be reflected in differences in fracture risk. An increased risk of fracture due to exemestane would be of particular concern in the breast cancer prevention setting.