CHEMOPREVENTION FOR BREAST CANCER

The American Society of Clinical Oncology (ASCO) has changed the tenor of its recommendations in its clinical practice guideline on the use of chemoprevention for breast cancer.

The new guideline now more strongly recommends the use of pharmacological prevention interventions for women who are at increased risk for invasive breast cancer.

The new 2013 guidance, which was published today in theJournal of Clinical Oncology, says that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene (Evista, Lily) "should be discussed as an option" to reduce the risk of estrogen receptor (ER)-positive breast cancer.

This is more forceful than the 2009 guidance, which stated that tamoxifen "may be offered" to reduce the risk of invasive breast cancer and that raloxifene "may also be considered."

The change in tone was enabled by longer follow-up and "more convincing data" from clinical trials of these agents, Kala Visvanathan, MBBS, MD, who is cochair of the guideline panel, told Medscape Medical News in an interview. She is from the Johns Hopkins Bloomberg School of Public Health and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in Baltimore.

The new guidance also, for the first time, recommends the use of an aromatase inhibitor (AI), exemestane (Aromasin, Pfizer), as an alternative to reduce the risk for invasive, ER-positive breast cancer in postmenopausal women.

Will any of these changes improve on the very low rate of breast cancer chemoprevention?

The guideline authors do not hazard a guess about that, but do acknowledge that these agents have a "low uptake" among eligible women. "There are many possible explanations for the low uptake of breast cancer chemoprevention agents, including concerns about adverse effects, lack of potential benefit, and lack of awareness among both women at increased risk and health care providers," write the guideline authors.

And the situation has not been improving. From 2000 to 2010, there was no overall increase in the use of tamoxifen and raloxifene as chemoprevention, the guideline authors say, citing the National Health Interview Survey (Breast Cancer Res Treat. 2012;134:875-880).

Nonetheless, the benefits of chemoprevention, which was first recommended by ASCO in 1999, can be significant. "For some women, these therapies can reduce the risk of breast cancer by up to 50%," said Dr. Visvanathan.

Women with an elevated risk for invasive breast cancer who are potential candidates for treatment include those with atypical hyperplasia or lobular carcinoma in situ and postmenopausal women with a positive family history, she added.

The target audiences for the guidance are medical oncologists, surgical oncologists, gynecologists, primary care physicians, and general practitioners. However, one breast cancer expert has expressed, in recent years, a desire to see breast cancer prevention largely take place in the context of internal medicine.

"We have kept preventive oncology in the realm of oncology," said Kathy Miller, MD, in 2011, in herMiller on Oncology Medscape blog. She is from Indiana University, in Indianapolis. "That means that primary care physicians simply don't think this is their job. They don't feel equipped and well trained. They are not comfortable with our medicines. In their minds, the benefits of a SERM or an AI for prevention are too small to justify prescribing it."

However, Dr. Miller pointed out that, at that time, the number of patients needed to treat with a statin to prevent 1 heart attack or 1 stroke was identical to the number of patients needed to treat with a SERM or an AI to prevent 1 case of breast cancer (n = 275 - 325).

The new ASCO guidance comes at a time when chemoprevention for breast cancer is gaining steam among medical authorities. In June, the chemoprevention of breast cancer with tamoxifen and raloxifene was recommended for women at high risk in the United Kingdom in an updated guideline from the National Institute of Clinical Excellence, as reported by Medscape Medical News.

In addition, chemoprevention with the 2 SERMs was recommended for women at the highest risk for breast cancer by the US Preventive Services Task Force (USPSTF). After a systemic review found evidence of broad benefit for chemoprevention (Ann Intern Med. 2013;158:604-614), it appeared in the USPSTF draft recommendations published in April.

Dr. Visvanathan believes that demographic changes are amplifying the importance of chemoprevention in the United States. "As our population ages and the incidence of breast cancer increases, prevention becomes more important," she said.

Who Is at Risk, and Contraindications

The key recommendations of the new guideline for reducing the risk for invasive, ER-positive breast cancer are:

• Tamoxifen (20 mg per day orally for 5 years) should be discussed as an option to reduce risk in premenopausal or postmenopausal women.
• Raloxifene (60 mg per day orally for 5 years) should also be discussed as an option to reduce risk in postmenopausal women.
• Exemestane (25 mg per day orally for 5 years) should be discussed as an alternative to reduce the risk in postmenopausal women.
• All 3 agents should be discussed (including risks and benefits) with women aged 35 years or older without a personal history of breast cancer who are at increased risk of developing invasive breast cancer.

The recommendations for tamoxifen and raloxifene are "strong evidence" based on multiple randomized controlled trials, the guideline authors point out. The recommendation of exemestane is based on "moderate evidence." Exemestane is approved for the treatment of breast cancer, but not breast cancer prevention, the authors point out. This new ASCO recommendation is based on data from a clinical trial that showed up to a 70% reduction in overall and ER-positive invasive breast cancer incidence with exemestane compared with placebo over 3 years (N Engl J Med. 2011;364:2381-2391).

Breast cancer risk is commonly determined using the National Cancer Institute's Breast Cancer Risk Assessment Tool, a modified version of the well-established Gail model.

The tool uses a woman’s age, race, and medical and reproductive history to determine the risk for breast cancer. Women are at increased risk if their projected absolute risk of developing breast cancer in the next 5 years is > 1.66%, according to ASCO.

The risk for breast cancer may also be determined by using other validated models.

The guideline specifies that tamoxifen and raloxifene are not recommended for use in women with a history of deep-vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. In addition, tamoxifen is not recommended for use in women who are pregnant or may become pregnant or are nursing mothers, and should not be used in combination with hormone therapy.

ASCO has also developed clinical tools and resources to help clinicians implement the new guideline. The resources are available on ASCO’s cancer information Web site.

Multiple guideline authors have financial ties with pharmaceutical companies.

J Clin Oncol 31. DOI: 10.1200/JCO.2013.49.3122. Abstract