ASCO Adds New Drug to Breast Cancer Prevention Guidelines

The American Society of Clinical Oncology (ASCO) has published updated guidelines, “Use of Pharmacologic Interventions for Breast Cancer Risk Reduction,” for women at high risk of developing breast cancer. The guidelines are published in the Journal of Clinical Oncology.

Ball-and-stick model of exemestane

The new guidelines now include exemestane (Aromasin), an aromatase inhibitor, for the prevention of breast cancer in postmenopausal women at risk for estrogen receptor (ER)-positive disease. The previous guidelines, published in 2009, emphasized that exemestane should only be used to help prevent breast cancer in a clinical trial setting.

The guidelines also updated the recommendations for both tamoxifen and raloxifene as a prophylactic measure to prevent ER-positive breast cancer, based on studies published since 2009.

Scott M. Lippman, MD, director of the University of California San Diego Moores Cancer Center and colleagues reviewed 19 randomized, controlled studies from 2007 to 2012 for the updated guidelines, which are intended for clinicians who treat women with breast cancer (including medical and surgical oncologists, primary care physicians, gynecologists, and general practitioners). An increased risk is defined as a “projected 5-year absolute risk of breast cancer greater than or equal to 1.66% using the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure.”

The chemopreventive drugs considered include the estrogen-receptor modulators tamoxifen, raloxifene, arzoxifene, and lasofoxifene; and the aromatase inhibitors exemestane and anastrozole.

For women who are 35 years or older, 5 years of tamoxifen at 20 mg per day is listed as an option to reduce the risk of developing invasive, ER-positive breast cancer or for those who have lobular carcinoma in situ. Tamoxifen for 5 years is recommended for both premenopausal and postmenopausal women. However, the oral therapy is not indicated for women with a history of blood clots, stroke, or transient ischemic heart attacks. Four phase III trials-the National Surgical Adjuvant Breast and Bowel Project P-1 (NSABP-P1), the International Breast Cancer Intervention Study (IBIS-I), the Royal Marsden Tamoxifen Prevention Trial, and the Italian Randomized Tamoxifen Prevention Trial-have prospectively assessed tamoxifen for reducing the risk of breast cancer.

Raloxifene at 60 mg per day for 5 years is another option for women who are postmenopausal, but it is not indicated for women who have not yet reached menopause. Like tamoxifen, raloxifene is not indicated for women with a history of blood clots, stroke, or heart attacks. A total of three trials-Raloxifene Use for the Heart (RUTH), Multiple Outcomes of Raloxifene Evaluation (MORE), and Continuing Outcomes Relevant to Evista (CORE)-evaluated raloxifene, specifically in postmenopausal women.

At a dose of 25 mg per day, the aromatase inhibitor exemestane is now an option to reduce the risk of ER-positive breast cancer in postmenopausal women, based on results of the MAP.3 trial. Exemestane is not currently approved for prevention by the US Food and Drug Administration (FDA). Exemestane is FDA-approved for the treatment of early- or late-stage breast cancer in postmenopausal women.

The MAP.3 trial results, published in the New England Journal of Medicine, showed that women who take exemestane had a relative reduction in breast cancer incidence of 65% compared with those who took placebo (P = .002). The incidence of both invasive and noninvasive breast cancers in the exemestane arm was 0.35% compared with 0.77% in the placebo arm (P = .004).

The best risk-to-benefit profile for either tamoxifen or raloxifene, based on the published studies, is for those women with the greatest risk of breast cancer.

The guideline committee highlighted the strong evidence from phase III randomized trials with both tamoxifen and raloxifene that have demonstrated a significant reduction in breast cancer risk. However, none of the tamoxifen or raloxifene studies were powered to detect differences in breast cancer mortality, rather, incidence of breast cancer was the primary clinical endpoint.

Thus far, there have not been any results from phase III trials assessing risk reduction of breast cancer with raloxifene or aromatase inhibitors for women who are BRCA1 or BRCA2 mutation carriers. While clinical trials with tamoxifen have included BRCA mutation carriers, there have not been enough of these participants in trials to measure a statistically significant effect of the agents on this population of women.

Communication between patient and physician is key in determining the patient’s risk of breast cancer and deciding on a suitable course of prevention. As many as 2 million women may benefit from chemopreventive drugs, but the number of women, even those at the highest risk for developing breast cancer, do not commonly opt for these longer term chemopreventive measures mostly because of the side effects that come with the prophylaxis. The patient–clinician conversation also needs to include lifestyle and surgery options which were not included in these specific guidelines, as well as adverse effects and cost issues.