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September 3, 2019

Breast Cancer Chemoprevention—Can We Make a Case for Precision Medicine?

Author Affiliations
  • 1Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 2Population Studies Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania
JAMA Oncol. Published online September 3, 2019. doi:10.1001/jamaoncol.2019.3785

Among women in the United States, breast cancer remains the most common cancer and is the second leading cause of cancer-related deaths. The median age at diagnosis for white women is 63 years and is younger for black women at 59 years. In addition to earlier age at diagnosis, breast cancer tends to be more aggressive in black women, and they are more likely to die of complications of the disease at every age. While incidence rates have remained relatively stable, mortality rates have significantly declined over the past 30 years. This decline is thought to be related to earlier detection by widespread screening and improved therapies.1

The identification of risk factors has led to efforts to prevent or reduce the risk of breast cancer by avoiding exposures (eg, hormone replacement therapy, heavy alcohol use), adoption of healthy lifestyles (eg, healthy eating habits, exercise), and screening for precursor lesions. The use of chemopreventive agents to reduce breast cancer is an attractive option because it does not require changes in health behaviors and can be relatively easily disseminated.2

Over the past 20 years, several randomized clinical trials have established the efficacy of tamoxifen and raloxifene, both selective estrogen-receptor modulators, to reduce breast cancer risk in women at increased risk.3 The National Surgical Adjuvant Breast and Bowel Project P-1 trial randomized 13 388 women aged 35 years and older to 20 mg of tamoxifen daily vs placebo for a duration of 5 years. Women were eligible if their 5-year risk of breast cancer was 1.66 or greater, as determined by the Gail model, or if they had previous lobular carcinoma in situ. At 7 years of follow up, there was a 62% reduction in estrogen receptor–positive invasive breast cancers in the tamoxifen arm.4 The National Surgical Adjuvant Breast and Bowel Project P-2 trial, Study of Tamoxifen and Raloxifene (STAR), randomized 19 747 postmenopausal women to receive a 5-year course of tamoxifen or raloxifene. Eligibility was the same as P-1 except that all women were postmenopausal. Treatment with tamoxifen reduced the risk of invasive disease by 50% compared with 38% in the raloxifene arm. Endometrial cancer and thromboembolic events were more common in the tamoxifen arm, particularly among women 50 years and older. There was no significant mortality difference seen between the 2 groups.5 More recently, in 2 aromatase inhibitor (AI) trials, the use of anastrozole or exemestane vs placebo reduced breast cancer risk by 50% and 65%, respectively, thus expanding the repertoire of risk-reducing agents. Aromatase inhibitors have a different profile of toxic events, including hot flashes, diarrhea, and arthralgias.6 In all of the clinical trials, drug therapy was effective in reducing only estrogen receptor–positive breast cancers.

In the September 3, 2019, issue of JAMA,7 the US Preventive Services Task Force (USPSTF) has updated its 2013 recommendation,8 supported by an updated evidence report and systematic review,6 for the use of medications to reduce breast cancer risk. For women who are at increased risk for breast cancer but at low risk for adverse events, the USPSTF recommends that clinicians offer to prescribe tamoxifen, raloxifene, or AIs for prevention (B recommendation). The use of these risk-reducing medications is not recommended for women who are not at increased risk for breast cancer (D recommendation).

In its current recommendation, the USPSTF has expanded its discussion of how to best assess breast cancer risk. Both the P-1 and STAR trials used the Gail model to determine eligibility. That model uses age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and breast biopsy history to calculate 5-year and lifetime risks for breast cancer.9 The 2013 statement8 considered risk based on a series of benefit/risk indices that quantify the benefits and risks of chemoprevention with tamoxifen or raloxifene using incidence estimates based on data from the Gail model; P-1; STAR; the Women’s Health Initiative; and Surveillance, Epidemiology, and End Results Program race-specific incidence rates.10 In this model, weights were assigned to health outcomes based on severity of events. Life-threatening events included invasive breast cancer, endometrial cancer, hip fracture, stroke, and pulmonary embolism. Severe events included in situ breast cancer and deep vein thrombosis. Other events included Colles and spine fractures and cataracts. A weight of 1.0 was assigned to life-threatening events, 0.5 to severe events, and 0 to other events. The projected number of adverse events in a population of 10 000 women over 5 years was defined as the number of life-threatening events plus half of the number of severe events. Benefit/risk estimates for tamoxifen and raloxifene use were illustrated in tables as the projected difference between the expected number of life-threatening events in 5 years in women with or without chemoprevention by age, race, and hysterectomy status. Based on these tables, in 2013 the USPSTF8 chose a 5-year risk of breast cancer of 3.0% or greater as the point at which women would derive more benefit than risk from using tamoxifen or raloxifene. The benefit/risk indices had the advantage of providing specific estimates for risk of life-threatening events by age, race, and hysterectomy status, which allowed clinicians to tailor recommendations for individual women to these factors. The benefit/risk indices, however, also had shortcomings, including the assumptions that gave the same weight to invasive breast cancer as endometrial cancer, hip fracture, pulmonary embolism, and stroke. The indices did not take into account other relevant risk factors for endometrial cancer, such as nulliparity and obesity, or other risk factors for stroke, including underlying cardiac or vascular disease.3,11

In the past 20 years, several new models have emerged that incorporate additional risk factors, such as BRCA1/2 status, breast density, menopausal status, use of hormone replacement therapy, body mass index, diet, alcohol use, and exercise. Most recently, some models are beginning to incorporate polygenic risk scores derived from large genome-wide association studies involving tens of thousands of cases, primarily among white Western European populations.12 The current USPSTF statement broadens the combinations of risk factors for clinicians to consider when recommending risk-reducing medications for breast cancer to include histologic type of benign breast biopsy and age-specific family history profiles. The USPSTF has always cautioned that breast cancer risk-reducing medications only be considered for women at a significantly high risk to outweigh the adverse events associated with use of the drugs. The recognition that multiple risk factors may influence a woman’s risk for breast cancer places a heavy burden on clinicians to interpret the benefits and risks for each woman in view of her personal risk profile and her tolerance for risk, as well as strengthens the emphasis placed by the authors of the revised recommendations on a dialogue between clinician and patient about their individual risk profile and personal preferences.

The current USPSTF statement continues to bring attention to the challenges of implementation of breast cancer chemoprevention. 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.13 A 2016 meta-analysis of breast cancer chemoprevention uptake among 21 423 women estimated a higher uptake at 16.3%. Some factors associated with higher uptake included having abnormal biopsy results, a physician recommendation, and older age.14 One factor related to the prescribing behaviors of clinicians is the ease of determining eligibility.15 Current and emerging risk-assessment models are complex and often cumbersome and time consuming for busy clinicians. Successful implementation of risk-reducing medications for breast cancer prevention 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.

Finally, the authors of the USPSTF statement point to the continuing need to address knowledge gaps and research needs. There are several areas where additional research is needed. New models that incorporate lifestyle factors, breast density, germline mutation status, and polygenic risk scores are emerging. These new models may offer an opportunity to truly personalize benefit and risk estimates for women considering breast cancer chemoprevention. More data are needed on the long-term effects of AIs, which have very different risk profiles. Data on the benefits and risks of all of the available drugs are sparse for African American and Hispanic women. Reluctance to take risk-reducing medications by many women may in part be related to the widespread dissatisfaction with and distrust of the medical community, especially when it comes to the use of pharmacologic agents. Research is needed to explore ways to overcome this barrier.

The updated USPSTF recommendation7 continues to support the option for pharmacologic intervention for breast cancer prevention. 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 of potential chemoprevention candidates and incorporate this complex information into risk models for individualized decision-making. 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.

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Article Information

Corresponding Author: Mary B. Daly, MD, PhD, Department of Clinical Genetics, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 (mary.daly@fccc.org).

Published Online: September 3, 2019. doi:10.1001/jamaoncol.2019.3785

Conflict of Interest Disclosures: Dr Ross reports receiving grants from the National Cancer Institute and has a patent pending regarding methods for screening patients with muscle invasive bladder cancer for neoadjuvant chemotherapy responsiveness. No other disclosures were reported.

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