Study Examines Impact of Exemestane on High-Risk Women

By Janine E. Guglielmino, LBBC Staff; reviewed by Paul E. Goss, MD, PhD, FRCPC, FRCP

ExCel clinical trial is first to explore whether an aromatase inhibitor can lower the incidence of invasive breast cancer in women at high risk of developing the disease

Trial Starts: 2/1/2004

Sponsored By: National Cancer Institute of Canada Clinical Trials Group

A large international clinical trial led Paul Goss, MD, MD, PhD, FRCPC, FRCP of Massachusetts General Hospital Cancer Center is testing whether taking an aromatase inhibitor can help prevent breast cancer in healthy women at high risk of developing the disease.

The ExCel research study, also known as NCT00083174 and NCIC CTG MAP3, seeks more than 4,500 healthy postmenopausal participants in the United States, Canada and abroad. Women will take either exemestane (brand name: Aromasin) or placebo (an inactive sugar pill) every day for five years.

The researchers hope the results will provide an alternative treatment to tamoxifen and raloxifene (brand name: Evista), the only hormonal therapies approved to prevent breast cancer in high-risk women who have not had the disease. Aromatase inhibitors do not have some of the potentially life-threatening side effects associated with tamoxifen and raloxifene.

Estrogen and Breast Cancer

About three-quarters of breast cancers depend on estrogen to grow. These breast cancers, called estrogen-receptor (ER) or progesterone-receptor (PR) positive, thrive because of high levels of circulating estrogen and total exposure to estrogen throughout life. Even after the ovaries stop working (menopause), the body continues to convert enzymes in body fat, skin and muscle into estrogen.

What We Know About Hormonal Therapies to Prevent Breast Cancer

In 1998 the U.S. Food and Drug Administration approved the hormonal therapy tamoxifen for prevention. The approval was based largely on results of the NSABP P-1 trial, which showed that healthy women who took tamoxifen daily for five years decreased their risk of developing breast cancer by almost 50 percent. This study and others also showed that tamoxifen has two rare but significant side effects, blood clots and uterine (endometrial) cancer.

In 2007 the FDA approved a second medicine for breast cancer prevention, raloxifene. The agency based its approval on results from the STAR trial, which compared the effectiveness of raloxifene to tamoxifen. The results showed raloxifene to be as effective as tamoxifen at reducing the incidence of invasive breast cancer but less effective at decreasing the incidence of pre-invasive breast cancers like lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS). Participants who took raloxifene had fewer endometrial cancers, blood clots and cataracts.

Aromatase Inhibitors and Prevention

In the past decade, research has shown that aromatase inhibitors, a newer type of hormonal therapy, are more effective than tamoxifen in all settings at preventing breast cancer in women already diagnosed with the disease. Aromatase inhibitors are particularly effective at preventing contralateral breast cancer, or cancer in the opposite breast.

Aromatase inhibitors work by limiting the body’s ability to produce estrogen after menopause. Researchers hope that exemestane, a powerful tool for inhibiting the conversion of enzymes into estrogen in postmenopausal women with breast cancer, also will prevent the disease.

Aromatase inhibitors do not increase the chances of blood clots or uterine cancer. However, in lowering estrogen levels, aromatase inhibitors mimic the symptoms of menopause, like hot flashes and vaginal dryness. Low estrogen also can lead to bone thinning (osteopenia), osteoporosis and bone fractures.

With the ExCel study, researchers hope to show that exemestane is more effective than tamoxifen and raloxifene in preventing breast cancer from developing in the first place.

Exemestane for Prevention

For this trial, Dr. Goss chose to study exemestane because its chemical structure may make it the best choice for prevention in healthy women.

Exemestane is a steroidal aromatase inhibitor and works differently than the other two nonsteroidal aromatase inhibitors available, letrozole (brand name: Femara) and anastrozole (brand name: Arimidex). Studies have suggested extemestane does not increase the chances of bone thinning, osteoporosis and bone fractures, side effects associated with letrozole and anastrozole. One study has shown exemestane may strengthen bone. Other data suggest that the impact of exemestane on bones "reverses" itself after women stop taking it, making it "an ideal medicine to study preventing cancer in healthy women," Dr. Goss says.

Who Can Participate in ExCel

This study is open to women at high risk of developing breast cancer who have never had invasive disease. For the purposes of this study, you are considered high risk if you are age 60 or over, or age 35 or over, postmenopausal (no menstrual cycle for the past 12 months) and have one of the following:

• You started your menstrual period early, have not had children or had your first child after age 30
• You have a mother, sister or daughter with breast cancer
• You have had a breast biopsy
• You have been diagnosed with atypical ductal hyperplasia (a pre-cancer in the ducts of the breast) or lobular carcinoma in situ (LCIS, or cancer contained to the lobules of the breast)
• You have been diagnosed with ductal carcinoma in situ (DCIS, cancer confined to the ducts of the breast) and had a mastectomy

During the study you may not take hormone replacement therapy (HRT) or any other hormonal therapies other than the study medication. You must go off hormone-based medicines at least three months before joining the trial.

If you wish, you may continue to take a low dose of daily aspirin or a bisphosphonate (like alendronate/Fosamax or Etidronate/Didronel), medicines that help build bone.

Goals of the ExCel Study

The primary goal is to compare the incidence of invasive breast cancer in participants who take exemestane to those who do not.

The researchers also will compare the two groups for: the higher reduction in the incidence of invasive breast cancer and DCIS; incidence of hormone receptor-negative breast cancer, LCIS, DCIS and atypical ductal hyperplasia; number of breast biopsies, bone fractures and heart disease; menopausal symptoms and quality of life; and incidence of non-breast cancers.

Structure of the Study

The researchers seek 4,560 women who have not had invasive breast cancer. Participants will be randomly assigned to one of two treatment arms:

Arm 1 participants will receive exemestane by mouth daily for five years

Arm 2 participants will receive a placebo by mouth daily for five years

This study is double-blinded, meaning neither you nor your doctors will know which medicine you are taking. This design helps to protect the integrity of the study by ensuring beliefs do not impact the outcome.

At the start of the study, you will be given a bone mineral density x-ray to measure the thickness of your bones and a mammogram, if you have not had one in the last 12 months. You will visit the doctor every six months for the first year, and annually for the next four years, receiving a mammogram each time. The doctor will take blood, do routine tests and ask you to fill out a survey about your quality of life.

What You Should Know about Prevention Studies

Breast cancer clinical trials traditionally focus on treatment rather than prevention. Some people believe preventive methods should receive more attention because they could save women the physical, emotional and financial toll of treatment.

Prevention trials, including the ExCel study, can be controversial. Advocates and researchers sometimes disagree about whether healthy women with no evidence of breast cancer should take medicine to prevent a disease they may never develop. Some advocates contend that with so little data, women cannot make informed decisions about taking part in prevention trials. Others say that without prevention trials, researchers will never get the data they need to help women make educated choices.

All medicines have side effects, or unwanted effects on healthy tissues or organs. Some question whether the benefit of the knowledge gained from clinical trials equals the impact of side effects, especially when limited information exists on the long-term impact of medicines under study.

Another major concern is defining which women are at high risk of developing breast cancer. Clinical studies have strict rules for participation, but most are designed separately from one another, meaning there is no consensus in the medical community about what constitutes high risk. Elements of the ExCel study are designed to close this gap by identifying which participants gain most, or at all, from exemestane therapy.

As a potential participant in a clinical study, only you can decide whether you want to take on the risks for the potential benefits. Talk with your doctor and your loved ones, and weigh your options based on your health, lifestyle and comfort level. Let your healthcare team and advocacy groups like LBBC know how you feel so we can support you in your decision.

Read more about the breast cancer prevention trial with exemestane.

For more information, contact: 800.4.CANCER, in United States; 888.939.3333, in Canada; http://www.excelstudy.com

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