The United States Preventive Services Task Force (USPSTF) has issued an updated recommendation statement on the use of medication to reduce the risk of breast cancer. Breast cancer is the most frequently occurring nonskin cancer and the second most common cause of cancer-related death among women, but for whom is the reduction in cancer risk worth the potential adverse effects of the medications?
The guidelines, published in JAMA, recommend the use of risk-reducing medications for asymptomatic women age 35 and older who are at increased risk of breast cancer, including women with previous breast lesions found to be benign on biopsy. In addition, candidates for risk-reducing medication should be at low risk of medication-related adverse events. The recommendations do not apply to women with a current or previous diagnosis of breast cancer or ductal carcinoma in situ (DCIS). Tamoxifen, raloxifene, and aromatase inhibitors are all recommended for risk reduction in postmenopausal women; only tamoxifen is indicated in premenopausal women.
There is convincing evidence for the moderate benefit of tamoxifen, raloxifene, or the aromatase inhibitors exemestane and anastrozole in reducing the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women at increased risk, but the benefits are minimal in women not at increased risk for the disease, reports the USPSTF review of the evidence, published in JAMA alongside the guidelines. Led by first author Heidi D. Nelson, MD, MPH, MACP, FRCP, Research Professor of Medical Informatics and Clinical Epidemiology in the School of Medicine of Oregon Health & Science University, the reviewers report that there is convincing evidence of small to moderate harms with tamoxifen and raloxifene and adequate evidence of small to moderate harms with the aromatase inhibitors. Raloxifene had a higher risk of invasive breast cancer than tamoxifen and a lower risk of vertebral fractures; tamoxifen had a lower risk of nonvertebral fractures. Both tamoxifen and raloxifene increased the risk of thromboembolic events compared with placebo, with tamoxifen increasing the risk more than raloxifene. Tamoxifen also increased the risks of endometrial cancer and cataracts compared with placebo.
The USPSTF recommendations suggest that physicians use the various risk assessment tools that estimate a woman's 5-year risk of developing breast cancer. "There is no single cutoff for defining increased risk for all women," state the guidelines. "Women at greater risk, such as those with at least a 3% risk for breast cancer in the next 5 years, are likely to derive more benefit than harm from risk-reducing medications and should be offered these medications if their risk of harms is low."
However, the recommendations warn that risk assessment tools have their failings: "The USPSTF found convincing evidence that risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer."
As an alternative, the recommendations suggest that clinicians can use combinations of risk factors, including some that are not outlined in risk assessment tools but that would have permitted enrollment in some of the risk reduction trials. Some of these would include women age 65 or older with one immediate (first-degree) relative with breast cancer, women age 45 or older with more than one immediate relative with breast cancer or one immediate relative with breast cancer prior to age 50, women age 40 or older with an immediate relative with bilateral breast cancer, or the presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a previous biopsy.
Women who received chest radiation are at an increased breast cancer risk. Those with BRCA1 mutations have a cumulative risk for breast cancer of 72% by age 80, and those with BRCA2 mutations have a cumulative risk of 69%, compared with a 12% lifetime risk in the general population. However, the authors state, "the USPSTF was not able to find sufficient evidence on the benefits and harms of risk-reducing medications in women with BRCA1/2 gene mutations or women with a history of chest radiation, and the comprehensive management of these risk factors is beyond the scope of this Recommendation Statement."
Noting the lack of evidence on the best interval at which to reassess the need for risk-reducing medications, the recommendations suggest repeating risk assessment whenever there is a significant change in risk factors, such as when a family member is diagnosed with breast cancer or a patient has a new diagnosis of atypical hyperplasia or lobular carcinoma in situ.
"These recommendations are similar to those in the 2013 USPSTF Recommendation Statement, except that the 2019 Recommendation Statement now includes aromatase inhibitors," note Lydia E. Pace, MD, MPH, Assistant Professor of Medicine at Harvard Medical School, and Nancy L. Keating, MD, MPH, Professor of Health Care Policy at Harvard Medical School, in an editorial published alongside the guidelines in JAMA.
Mary B. Daly, MD, PhD, Chair in Cancer Research at Fox Chase Cancer Center, and Eric Ross, PhD, Assistant Vice President of Biometrics and Information Sciences at Fox Chase Cancer Center, note in a separate editorial published in JAMA Oncology that the current recommendations include an expanded discussion of how to assess breast cancer risk.
"The current USPSTF statement continues to bring attention to the challenges of implementation of breast cancer chemoprevention," comment Dr. Daly and Dr. Ross. "It is estimated that more than 10 million women in the United States would be eligible for tamoxifen therapy for breast cancer prevention. However, data from the National Health Interview Study in 2010 found that fewer than 1% of eligible women were taking or had taken tamoxifen or raloxifene for prevention. A 2016 meta-analysis of breast cancer chemoprevention uptake among 21,423 women estimated a higher uptake at 16.3%... Current and emerging risk-assessment models are complex and often cumbersome and time consuming for busy clinicians. Successful implementation… requires that clinicians must understand the scope of factors that would predict a favorable benefit/risk profile, and be able and willing to educate their patients about their risk for breast cancer and the risks and benefits of taking risk-reducing drugs to ensure a fully informed decision, which is a challenge in current clinical practice where clinic encounter times are constantly shrinking."
Dr. Daly and Dr. Ross emphasize the importance of tailoring pharmacologic risk reduction for the individual patient: "In the new era of precision medicine, there is a realization that one size fits all is no longer acceptable for most treatments. The new USPSTF statement mirrors this trend by making a strong case for the need to consider the unique risk profiles... More efficient and sophisticated tools to more precisely quantify each individual's benefit/risk for a variety of chemoprevention drugs may ultimately translate into precision medicine for breast cancer prevention."
For More Information
Nelson HD, Fu R, Zakher B, et al (2019). Medication use for the risk reduction of primary breast cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA, 322(9):868-886. DOI:10.1001/jama.2019.5780
Image credit: Bill Branson. Courtesy of the National Cancer Institute