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Task force: Medications to reduce breast cancer risk ‘are not for everyone’
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Medications intended to reduce risk for breast cancer should be offered to women with an elevated risk for the disease but a low risk for adverse events associated with these agents, according to a U.S. Preventive Services Task Force draft recommendation statement.
The USPSTF advised against routine use of risk-reducing medications — such as tamoxifen or raloxifene — by women who are not at increased risk for breast cancer, and also added aromatase inhibitors as a possible option for women at higher risk.
“When deciding whether or not to offer medications, clinicians should carefully consider their patients’ risk factors for breast cancer and balance these against the potential harms from the medications,” Carol M. Mangione, MD, MSPH, a member of the task force and chief of the division of general internal medicine and health services research at David Geffen School of Medicine at University of California, Los Angeles, said in a press release. “These medications are not for everyone, and for women who are at increased risk for breast cancer, the harms of these medications are likely to outweigh the benefits.”
Data collection
The USPSTF sought to update its 2013 systematic review on the use of breast cancer risk-reducing medications using data from studies found in the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, EMBASE and MEDLINE, as well as through a manual review of reference lists.
Investigators selected discriminatory accuracy studies of breast cancer risk assessment methods; certain randomized controlled trials of tamoxifen, raloxifene and aromatase inhibitors for primary prevention of breast cancer among women with no pre-existing disease; and randomized controlled trials and observational studies of these medications’ harms.
One researcher extracted data on the following: study methods; setting; population characteristics; eligibility criteria; interventions; numbers of women enrolled and lost to follow-up; method of outcome determination; and results for each outcome. A second investigator reviewed the data for accuracy, and two researchers independently evaluated the quality of the studies.
The investigators found that 17 risk models analyzed in 24 studies had overall low discriminatory accuracy for predicting breast cancer risk for an individual (c-statistics, 0.55-0.65). Most of these models barely outperformed age alone as a risk predictor. The studies did not assess optimal ages for treatment or frequencies of risk assessment.
Assessing the findings
Placebo-controlled trial results showed reductions in invasive breast cancer risk with tamoxifen (risk ratio [RR] = 0.69; 95% CI, 0.59-0.84; seven fewer cases per 1,000 women over 5 years of use; 95% CI, 4-12; four trials); raloxifene (RR = 0.44; 95% CI, 0.24-0.8; nine fewer cases; 95% CI, 3-15; two trials) and the aromatase inhibitors exemestane and anastrozole (RR = 0.45; 95% CI, 0.26-0.7; 16 fewer cases; 95% CI, 8-24; two trials).
The STAR head-to-head trial showed a higher risk for invasive breast cancer with raloxifene than tamoxifen (RR = 1.24; 95% CI, 1.05-1.47) after long-term follow-up. Tamoxifen trials with long-term follow-up showed that the drug provided sustained risk reduction at least 8 years after treatment cessation. All medications decreased ER-positive breast cancer but not ER-negative, invasive breast cancer. In two trials, tamoxifen reduced noninvasive cancer. Investigators observed no reductions in breast cancer-specific and all-cause mortality.
Tamoxifen and raloxifene appeared most effective for reducing risk for invasive breast cancer among women with previous breast lesions, including lobular carcinoma in situ, atypical ductal hyperplasia or atypical lobular hyperplasia.
Weighing the costs
Adverse effects — including vasomotor or musculoskeletal symptoms — were reported for all medications analyzed but varied by drug.
Results of placebo-controlled trials showed increased thromboembolic events with tamoxifen (RR = 1.93; 95% CI, 1.33-2.68; four trials) and raloxifene (RR = 1.56; 95% CI, 1.11-2.6; two trials), whereas the STAR trial showed fewer of these events with raloxifene (RR = 0.75; 95% CI, 0.6-0.93) than tamoxifen.
The placebo-controlled trials also showed increases in endometrial cancer (RR = 2.25; 95% CI, 1.17-4.41; three trials), cataracts (RR = 1.22; 95% CI, 1.08-1.48; three trials) and cataract surgery with tamoxifen, but not with raloxifene and aromatase inhibitors.
Due to the seriousness of some of the effects, the USPSTF encouraged clinicians to assess patients’ breast cancer risk using one of several tools or combinations of risk factors before deciding whether to prescribe risk-reducing medications.
“Too many American women and families are faced with the challenge of dealing with a breast cancer diagnosis,” task force member Michael J. Barry, MD, director of the informed medical decisions program in Health Decision Sciences Center at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said in the press release. “Women who are at increased risk for breast cancer should be offered medications that can help reduce that risk.” – by Jennifer Byrne
For more information:
The U.S. Preventive Services Task Force’s draft recommendation statement is available at www.uspreventiveservicestaskforce.org. Public comment will be accepted through Feb. 11.
Disclosure: Barry reports receiving multiple grants and authoring publications related to prostate cancer. Mangione reports no relevant financial disclosures. Please see the U.S. Preventive Services Task Force website for a list of all task force members’ relevant financial disclosures.
Perspective
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Adam M. Brufsky, MD, PhD
Breast cancer is the most common form of nonskin cancer among American women, and it is the leading cause of cancer-related death. Prognosis from this disease has improved markedly over the past 30 years, likely from a combination of better screening as well as better systemic therapy. The majority of women diagnosed with breast cancer in this year likely will be cured of their disease.
Nonetheless, when one in eight women are at risk for developing breast cancer, and the diagnosis of cancer can be devastating emotionally and physically to many women, steps toward prevention are always welcome.
With this background, breast cancer prevention trials such as STAR and others — in which a variety of endocrine agents have been shown to reduce the relative risk of breast cancer by 50% or more — provide an evidence-based option for women at high risk for breast cancer.
However, as the USPSTF report makes clear, clinicians need to weigh the absolute benefit of intervention — often in the low single digits for incidence of new breast cancer, with no decrease in mortality — versus the possible side effects of the intervention. These effects — which may include bone loss, cataracts, thromboembolic events or endometrial cancer — all occur at incidence rates in the single digits, as well.
A reasonable compromise floated by the USPSTF is for there to be at least a 3% absolute risk for breast cancer in the next 5 years for the intervention to be worthwhile.
In my practice — when talking with families of women who have breast cancer, as well as women at possible high risk for breast cancer — this seems to be a reasonable option, and one that I will follow.
It is our role as physicians with expertise in breast cancer to weigh the possible consequences of a breast cancer diagnosis against risk for side effects of the preventive medications we prescribe, in a manner that takes the individual fears — as well as coexisting comorbidities of our patients — into account.
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