USPSTF Releases Final Recommendation on Treatments for Reducing Breast Cancer Risk

Michael J. Barry, MD, MBBS, MRCP, director of the Informed Medical Decisions Program in the Health Decision Sciences Center at Massachusetts General Hospital, and professor of medicine at Harvard Medical School and a physician at Massachusetts General Hospital

Michael J. Barry, MD

Risk-reducing therapies, such as tamoxifen, raloxifene, or aromatase inhibitors, should be administered to women who are at an increased risk for breast cancer and at a low risk for adverse events (AEs) associated with these medications, according to an updated recommendation statement released by the United States Preventive Services Task Force (USPSTF).^1,2

In addition to this positive category B recommendation, the USPSTF also issued a category D recommendation against the regular use of these risk-reducing agents in those who are not at an increased risk for breast cancer. The D recommendation applies to asymptomatic women ≥35 years old. It also includes those with prior benign breast lesions, such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ, detected via biopsy. However, it is not applicable to women with a current or prior breast cancer or ductal carcinoma in situ (DCIS) diagnosis.

“There are medications available that can help some women prevent breast cancer, but they are not for everyone,” USPSTF member Michael J. Barry, MD, director of the Informed Medical Decisions Program in the Health Decision Sciences Center at Massachusetts General Hospital, and professor of medicine at Harvard Medical School and a physician at Massachusetts General Hospital, stated in a press release. “For women who are at increased risk for breast cancer, these medications can be beneficial and reduce their risk.”

While there is no standard approach to determine whether a woman is at increased risk for developing breast cancer, risk assessment tools, such as the National Cancer Institute Breast Cancer Risk Assessment Tool, or a combination of risk factors—such as older age, prior breast abnormality, and family history of disease—can be used to determine individual risk. Women determined to be of increased risk have a ≥3% risk of breast cancer in the next 5 years.

The statement was part of an objective by the USPSTF, which was to update the 2013 recommendation on medications for risk reduction of primary breast cancer. The organization reviewed evidence on the accuracy of risk assessment methods to identify females that may benefit from risk-reducing medications for breast cancer.

They also evaluated evidence on the efficacy, safety, and subgroup variants of these agents. Data were extracted from 10 trials, which comprised randomized studies, observational trials, and diagnostic accuracy studies of risk stratification models in those without preexisting DCIS or breast cancer. Most studies were multicenter and took place at various sites spanning several countries.

Four studies (n = 28,193 patients) evaluated tamoxifen in premenopausal and postmenopausal women at increased risk for breast cancer, 2 trials (n = 17, 806) looked at raloxifene in postmenopausal women not at an increased risk for breast cancer, 1 trial (n = 19, 747) was a head-to-head comparison of raloxifene with tamoxifen in postmenopausal women at increased risk for breast—known as Study of Tamoxifen and Raloxifene (STAR) trial—and 2 studies explored AIs (exemestane [n = 4560] and anastrozole [n = 3864]) in postmenopausal women at increased risk for breast cancer.

Each study used varying arrangements of risk criteria, such as age, family history, prior abnormal benign breast pathology, or predicted breast cancer risk as estimated by a risk tool for recruiting purposes. In the raloxifene trials, women were older with a median age of 67 to 67.5 years compared with those in the other studies, given that the raloxifene trials targeted postmenopausal women not at increased risk for breast cancer. Those in the tamoxifen trials had a median age range of 47 years to 53 years and included premenopausal women.

Results showed that the USPSTF had convincing evidence that the risk assessment tools are able to predict the number of breast cancer cases that are expected to occur in a population, but they work modestly in differentiating between individuals who will and will not develop breast cancer.

Moreover, their findings showed that tamoxifen, raloxifene, or AIs led to at least a moderate benefit in reducing the risk for invasive estrogen receptor (ER)—positive breast cancer in postmenopausal women who are at an increased risk for breast cancer. The inclusion of AIs among these risk-reducing drugs is a new addition compared with the 2013 recommendation statement.

Specifically, using pooled data from the placebo-controlled trials and projecting benefits over 5 years, the use of tamoxifen would result in 7 fewer cases of invasive breast cancer (risk ratio [RR], 0.69; 95% CI, 0.59-0.84]) and 8 fewer cases of ER-positive breast cancer (RR, 0.58; 95% CI, 0.42-0.81).

Raloxifene would lead to 9 fewer cases of invasive breast cancer (RR, 0.44; 95% CI, 0.24-0.80) and 8 fewer cases of ER-positive breast cancer (RR, 0.33; 95% CI, 0.15-0.73).

AIs would be linked with 16 fewer cases of invasive breast cancer (RR, 0.45; 95% CI, 0.26-0.70) and 15 fewer cases of ER-positive breast cancer (RR, 0.37; 95% CI, 0.19-0.63).

Both tamoxifen and raloxifene showed a reduction in the risk for fractures, leading to 3 fewer cases of nonvertebral fractures with tamoxifen (RR, 0.66; 95% CI, 0.45-0.98) and 7 fewer cases of vertebral fractures with raloxifene (RR, 0.61; 95% CI, 0.53-0.70).

Moreover, the risk reduction of both invasive and ER-positive breast cancers persisted ≤8 years after stopping tamoxifen use in 2 trials.

Overall, the trials showed that the efficacy of these agents did not vary by age or menopausal status. However, data from one study each of tamoxifen and of anastrozole showed that the risk reduction was higher in those with a history of breast abnormalities on biopsy.

Furthermore, long-term follow-up results of the STAR study showed that tamoxifen provided a greater risk reduction for invasive breast cancer at 5 fewer cases (95% CI, 1-9).

Overall, these data led to the USPSTF giving these agents a B recommendation as risk-reducing strategies for women at an increased risk for disease.

However, for those who are not at an increased risk of disease, the benefits of these therapies were found to be small, according to data from the same 10 studies.

Tamoxifen compared with placebo was associated with 5 more cases of venous thromboembolic events (VTEs; RR, 1.93; 95% CI, 1.33-2.68), 4 more cases of endometrial cancer (RR, 2.25; 95% CI, 1.17-4.41), and 26 more cases of cataracts (RR, 1.22; 95% CI, 1.08-1.48). While vasomotor symptoms were increased with tamoxifen, there were no significant differences on rates of deep vein thrombosis, pulmonary embolism, coronary heart disease (CHD) events, or stroke with this agent.

Raloxifene was associated with 7 more cases of VTE versus placebo (RR, 1.56; 95% CI, 1.11-2.60), and there was also an increase with vasomotor symptoms. However, there were no significant differences on the rates of CHD events, stroke, endometrial cancer, or cataracts.

Based on the STAR trial, more harms were reported with tamoxifen, including 4 more cases of VTE (95% CI, 1-7), 3 more cases of deep vein thrombosis (95% CI, 1-5), 5 more cases of endometrial cancer (95% CI, 2-9), and 15 more cases of cataracts (95% CI, 8-22) than with raloxifene.

Both AI trials reported more vasomotor and musculoskeletal symptoms with the AIs versus placebo. Moreover, there were major differences in rates of VTEs, deep vein thrombosis, pulmonary embolism, CHD events, stroke, endometrial cancer, or cataracts, but the investigators noted that primary prevention studies were likely underpowered to detect any differences in these outcomes.

Overall, the USPSTF noted tamoxifen and raloxifene had convincing evidence—AIs had adequate evidence—that the medications are linked with small to moderate AEs that outweigh the potential benefits for women at low-risk for breast cancer.

In the press release, the USPSTF concluded when deciding whether or not to offer any of these 3 medications, “clinicians should carefully consider their patients’ risk factors for breast cancer and balance these against the potential harms from the medications, some of which may be serious or even life threatening, such as blood clots or other cancers. The severity of these harms can vary by the specific medication and a woman’s risk factors for these specific harms.”

References

1. US Preventive Services Task Force. Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322(9):857—867. doi:10.1001/jama.2019.11885
2. U.S. Preventive Services Task Force Issues Final Recommendation Statement on Medications to Reduce Breast Cancer Risk. US Preventive Services Task Force. Published September 3, 2019. https://bit.ly/2k48xGm. Accessed September 4, 2019.