Portland, OR—While the good news is that medications to reduce the risk of breast cancer are effective for women at increased risk, according to a new survey, that is tempered by evidence that the drugs also cause adverse effects.

An updated evidence report and systematic review for the U.S. Preventive Services Task Force (USPSTF) notes that tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women. Oregon Health & Science University–led researchers point out that not only were preventative therapies associated with adverse effects, but those differed among medications.

The study team updated the 2013 USPSTF systematic review on medications to reduce risk of primary invasive breast cancer in women. To do that, researchers used the Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019), conducting a manual review of reference lists.

The focus was on studies of breast cancer risk-assessment methods, including randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention. Researchers also zeroed in on medication adverse effects.

Areas under review included:
Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]);
• Incidence of breast cancer, fractures;
• Thromboembolic events;
• Coronary heart disease events;
• Stroke;
• Endometrial cancer;
• Cataracts; and
• Mortality.

Included in the review were 46 studies, encompassing more than 82 articles and more than 5 million participants. Results from 18 risk-assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65).

Researchers report that, in placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; four trials [n = 28,421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; two trials [n = 17,806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; two trials [n = 8424]) were associated with a lower incidence of invasive breast cancer.

The study adds that risk for invasive breast cancer was higher for raloxifene than tamoxifen in one trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19,747). In terms of adverse effects, raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; two trials [n = 16,929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; one trial [n = 13,388]) compared with placebo, they write.

Tamoxifen and raloxifene both were associated with increased thromboembolic events compared with placebo, however, and tamoxifen was associated with more events than raloxifene, according to the study team. In addition, tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo, point out the researchers, who note that symptomatic effects, such as vasomotor and musculoskeletal, varied by medication.

“Clinical trials indicate that the selective estrogen receptor modulators raloxifene and tamoxifen and the aromatase inhibitors anastrozole and exemestene are associated with reduced incidence of primary invasive breast cancer,” the authors write. “However, these medications are also associated with adverse effects, and candidates for risk-reducing medications need to be accurately identified to optimize potential benefits and minimize harms.”

The study recounts how, in 2013, the USPSTF issued a B recommendation for clinicians to offer to prescribe risk-reducing medications for women at increased risk for breast cancer and low risk for adverse medication effects. It adds that use of medications for breast cancer risk reduction remains low in clinical practice because of patient concerns about adverse effects and fear that benefits are not worth the harms.

Other barriers to use include difficulty in identifying candidates for therapy, and primary care physicians’ unfamiliarity with tamoxifen and aromatase inhibitors, which are usually used for breast cancer treatment, according to the study. In light of that, the authors say they conducted the review to update evidence on the efficacy and harms of risk-reducing medications and the accuracy of clinical risk-assessment methods to select candidates for therapy to inform new USPSTF recommendations.

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