Zosia Chustecka

June 04, 2011

June 4, 2011 (Chicago, Illinois) — The aromatase inhibitor exemestane offers a new option for breast cancer prevention in postmenopausal women at high risk for the disease.

Data from the Mammary Prevention (MAP).3 trial, released today here at the American Society of Clinical Oncology 2011 Annual Meeting, show that the drug more than halved the risk for invasive breast cancer (65% reduction). The data are simultaneously published online in the New England Journal of Medicine.

"This is a landmark study and it will change the paradigm of breast cancer prevention," declared Andrea De Censi, MD, from the Ente Ospedalerio Ospedali Galliera in Genoa, Italy, He acted as discussant for the study and said it had a number of "clear strengths."

Exemestane not only presents a new option for chemoprevention, it appears to be safer and more effective than the first class of drugs found to be effective in this setting — the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene. Both of these drugs have been proven effective at reducing the risk for breast cancer in women at high risk (tamoxifen by 50%, raloxifene by 38%), but healthy women have been reluctant to take these drugs prophylactically. Chemoprevention for breast cancer has, so far, been a resounding failure. One recent study suggested that only 0.08% of eligible women took up this option.

Dr. Paul Goss

The major impediment has been fear about the risk of potentially life-threatening adverse effects, such as stroke and pulmonary embolism, and for tamoxifen the risk for endometrial cancer, explained Paul Goss, MD, professor of medicine at Massachusetts General Hospital in Boston, and lead investigator on the MAP.3 study.

"A pill that carries of a risk of cancer taken in order to prevent a cancer has been a hard sell," he said.

"We have removed the obstacle of life-threatening toxicity," he said.

With exemestane, "we now have a very safe therapy that is highly effective," he told journalists at a briefing prior to the presentation of the results.

Will This Improve the Success of Chemoprevention?

The hope is that exemestane will succeed where the SERMs have failed. Chemoprevention is an effective option for reducing the risk for invasive breast cancer in women at high risk, and it is the source of great frustration among breast cancer experts that it is not more widely used, as reported previously by Medscape Medical News, and echoed now in an editorial that accompanies the published study.

"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," write editorialists Nancy Davidson. MD, and Thomas Kensler, PhD, from the University of Pittsburgh Cancer Institute in Pennsylvania.

We have run out of excuses. What are we waiting for?

"We have the knowledge and tools to reduce its incidence today," they write. "We have run out of excuses. What are we waiting for?"

Dr. Andrew Seidman

"I don't see these patients, but if I did, there would be a lot more use of these drugs . . . because I see the dark side, I see women dying of breast cancer," Andrew Seidman, MD, attending physician, breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News. Dr. Seidman was moderating the press conference at which the study was highlighted.

There needs to be better education among of the doctors who see these women at high risk for the disease, such as primary care physicians and breast surgeons, he said. "I'm always a bit chagrined by women who are willing to undergo body-altering surgery such as prophylactic mastectomy to the same end," he said.

"The medical oncology community needs to spread the notion that most breast cancer is preventable," Dr. De Censi noted. The data from this MAP.3 study "compare very well" with the data from cardiovascular prevention trials, such as the JUPITER study with rosuvastatin. "We need to learn lessons from cardiology," he said. "There has been an impressive decline in heart disease in the last 25 years," he pointed out, and some of this is related to the use of drugs, such as statins and antihypertensive agents, to prevent cardiovascular complications.

Impressive Reduction in Risk

The results for exemestane show "an impressive reduction in breast cancers," and "an excellent side-effect profile," said Dr. Goss, although he added a cautionary note that the average follow-up to date has been just 3 years.

The MAP.3 trial involved 4560 postmenopausal women in the United States, Canada, Spain, and France who were considered to be at high risk for breast cancer because they had at least 1 of the following risk factors: 60 years of age or older, Gail risk score above 1.66%, atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or ductal carcinoma in situ (DCIS) with previous mastectomy.

Women with BRCA mutations were excluded because the trial was placebo controlled, and it was judged not ethical to offer such women a placebo because of their heightened risk for breast cancer, Dr. Goss explained.

After a median follow-up of 3 years, women in the exemestane group showed a 65% reduction in invasive breast cancer, compared with those in the placebo group (11 vs 32 cases). There was also a 60% reduction in invasive breast cancer plus preinvasive DCIS in the 66 cases found. In addition, there were fewer cases of cancer precursor lesions, such as atypical ductal and atypical lobular hyperplasia, in the exemestane group.

Symptoms such as hot flashes, fatigue, sweating, insomnia, and arthralgia were reported by 88% of the women in the exemestane group and 85% of those in the placebo group.

More serious adverse events, such as bone fractures, osteoporosis, hypercholesterolemia, adverse cardiovascular events, and other nonbreast cancers, were reported by similar numbers in each group.

However, Dr. De Censi noted in his discussion that the osteoporosis was self-reported; hence, it might be underreported. This is one of the weaknesses of the study — there was no systemic follow-up with dual-emission x-ray absorptiometry to check for osteoporosis, he said.

"The were very few adverse events," noted Rowan Chlebowski, MD, PhD, from the Los Angeles Biomedical Research at Harbor-UCLA Medical Center in Torrance, California, who was a coauthor on the MAP.3 study. He explained that the experience with aromatase inhibitors in healthy women is different than that in the adjuvant setting in women who have already had breast cancer, and there was no osteoporosis and very little arthralgia reported in that population.

"This is a very different mind set," Dr. Chlebowski elaborated in an interview. The women taking part in the trial at his clinic were, for the most part, already taking other drugs for prevention, such as statins, aspirin, and vitamin B.

"There are some people who want to take pills for prevention." These tend to be healthy individuals who want to remain healthy, which is a very different situation from patients who have already been diagnosed and treated for breast cancer, and are now subjected to focused attention in an adjuvant setting, he noted. That may partly account for the lower incidence of adverse effects that were reported, he mused.

The lack of adverse effects with exemestane in this study is a big deal, said Dr. Chlebowski, because it might help to overcome the reluctance that healthy women have about using SERMs for prevention.

Tamoxifen and raloxifene are both approved for breast cancer prevention in the United States, but it is unclear whether exemestane will get such an approval. It is now off patent and it is unlikely that the manufacturer (Pfizer) will invest in the registration process; repeated questioning about its intentions in this regard were not answered, Dr. Goss explained. The good news is that there are now cheaper generic versions of exemestane available, and the price has come down so that it is comparable to that of tamoxifen, he added.

The MAP.3 study showed clear activity for exemestane in breast cancer prevention. "It's a large proof-of-principle study," Dr. De Censi explained. There are no mortality data, but for a prevention study, that is not necessary. It is incidence that is the main end point; the main purpose is to avoid a cancer diagnosis, and this is clinically meaningful, he added.

"We now need a confirmation study," he continued. Such a study is already underway — the IBIS-II study comparing anastrozole with placebo in women at high risk for breast cancer — higher than the women in MAP.3.

Dr. Goss reports serving on the advisory board of Pfizer/Wyeth. Dr. Chelbowski reports receiving honoraria from Amgen and Novartis, and serving as a consultant for AstraZeneca and Genomic Health. Several of the coauthors report links with pharmaceutical companies, as detailed in the published paper. Editorialists Dr. Davidson and Dr. Kensler have disclosed no relevant financial relationships.

N Engl J Med. Published online June 4, 2011. Abstract, Editorial

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting. Abstract LBA504. Presented June 4, 2011.

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