Medications for the Primary Prevention of Breast Cancer

Breast cancer is the most common non-skin cancer and the second-leading cause of death from cancer among women, with an estimated 276,000 new cases diagnosed each year in the United States.¹ Breast cancer screening leads to early detection, but does not prevent the development of breast cancer. Several medications are effective at reducing breast cancer incidence. For instance, randomized trials have shown that taking tamoxifen for 5 years continues to reduce breast cancer risk for an additional 15 years after stopping.² However, use of medications for primary prevention of breast cancer has been low.³ Reasons for low uptake include women’s low perceived need for preventive therapy and their concerns about the harms of treatment. This article provides an overview of the risks and benefits of medications for breast cancer risk reduction in order to promote their appropriate use.

Identifying candidates for risk reduction

Careful risk assessment is required to ensure that the benefits of primary prevention outweigh the harms. Several breast cancer risk models have been developed and validated in the general U.S. population (Supplement). These include the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC) Risk Calculator, and the International Breast Cancer Intervention Study (IBIS) Risk Assessment Tool. A 2019 study at a large mammography center found that the BCRAT and BCSC model were better calibrated (predicted risk in a population matches the observed risk) than the IBIS model, and that the BCSC model had the highest discrimination (risk in women developing cancer is greater than the risk in women not developing cancer).⁴ The United States Preventive Services Task Force (USPSTF) notes that the benefits of risk reducing medications generally outweigh the risks in women with an estimated 5-year breast cancer risk ≥3%.⁵

Medications

Two classes of medications are used for breast cancer risk reduction, the selective estrogen receptor modulators (SERMs) which include tamoxifen and raloxifene, and the aromatase inhibitors (AIs) which include anastrozole and exemestane. The USPSTF recommended SERMs for breast cancer prevention in 2013 and reaffirmed their recommendation in 2019 with the addition of aromatase inhibitors.⁵ Only SERMs have U.S. Food and Drug administration approval for breast cancer risk reduction.

SERMs have the strongest evidence supporting their effectiveness (Supplement). Meta-analyses report that the absolute risk reduction with SERMs is 7 to 9 fewer invasive breast cancers for every 1000 women treated over 5 years compared to women who were not treated. In a clinical trial that compared raloxifene with tamoxifen, the drugs were not significantly different at 6 years (RR 1.02, 95% CI 0.82–1.28). After 9.7 years, raloxifene compared to tamoxifen was associated with a higher risk of invasive cancer (RR 1.19, 95% CI 1.04–1.37), but a lower risk of overall mortality (RR 0.87, 95% CI 0.75–1.00).⁶ SERMs increase bone density and their use is associated with a decreased risk of fractures in postmenopausal women.⁷

There are several differences in the adverse effects of tamoxifen and raloxifene (eTable). Both increase the risk of venous thromboembolism (VTE), but raloxifene has a lower relative risk for VTE compared to tamoxifen (RR 0.75, 95% CI 0.60–0.93, absolute risk difference 1.1 per 1000 women treated for 5 years). Additionally, tamoxifen is associated with an increased risk of uterine cancer, or 4 excess cases per 1000 women over 5 years.⁵ Raloxifene is not associated with an increased risk of uterine cancer. Both SERMs can cause hot flashes, but tamoxifen causes more menstrual abnormalities, sexual dysfunction, and vaginal discharge.

AIs may reduce breast cancer risk by 16 fewer cases per 1000 women over 5 years (eTable).⁷ However, these estimates are based on single trials of anastrozole (RR 0.53, 95% CI 0.40–0.71)⁸ and exemestane (RR 0.35, 95% CI 0.18–0.70).⁷ The primary adverse effects of AIs are arthralgias, myalgias, and decreased bone mineral density. AIs can also cause hot flashes, though these symptoms are generally less severe than with SERMs.

Practical considerations

Several professional society guidelines recommend shared decision-making about breast cancer screening at age 40.⁵ Clinicians can use this opportunity to assess a woman’s breast cancer risk and identify candidates for risk reduction. Clinicians should also consider risk assessment in younger women with a strong family history of breast cancer or a breast biopsy showing atypical hyperplasia or lobular carcinoma in situ. A suggested approach is shown in the Figure. Starting a risk reducing medication at a younger age optimizes the risk-benefit tradeoff for two reasons. First, the risk reduction effect of SERMs extends for at least 15–20 years, so younger women have a longer time horizon to benefit. Second, the baseline incidence of harms without treatment (VTE, uterine cancer) increases with age, so the absolute number of harms is lower in younger women.

Figure.

Suggested Approach to Choosing Medication for Breast Cancer Risk Reduction

The choice of medication should be guided by individual patient characteristics, including menopausal status, prior hysterectomy, and comorbidities (Figure), although this approach has not been evaluated and validated in rigorous clinical studies. Tamoxifen is the only medication that has been studied and approved for use in premenopausal women. In postmenopausal women, tamoxifen or raloxifene are first-line options. Raloxifene is associated with lower rates of significant harms, but tamoxifen has stronger evidence of long-term benefit and may be preferred in women who have had a hysterectomy because they are no longer at risk for endometrial cancer. Clinicians may consider AIs for postmenopausal women with elevated venous thromboembolism risk and who are not at high risk for osteoporosis.

The recommended duration of treatment is five years.⁵ Women taking risk-reducing medications should continue guideline-based breast cancer screening. Importantly, risk-reducing medications do not decrease the incidence of estrogen receptor-negative breast cancers. For women taking AIs, clinicians could consider obtaining a baseline bone density measurement followed by periodic surveillance.

Future Directions

Integrating breast cancer risk models into the electronic medical record could allow automated risk assessment and could facilitate the identification of candidates for breast cancer risk reduction through panel management. Genetic variants improve the performance of breast cancer risk models and may help to refine clinical decision-making. Changes in intermediate markers of risk, such as breast density, may identify women who are not responding to therapy and should stop. There is active work to identify other risk reducing medications with greater benefits and/or fewer harms.

Conclusions

Four medications have been shown in randomized trials to reduce the risk for invasive breast cancer. Primary care physicians should consider the risks and benefits of these medications when offering them to women at high risk for breast cancer (5-year risk ≥ 3%).