Background

The purpose of this review is to evaluate the comparative effectiveness of tamoxifen citrate, raloxifene, and tibolone to reduce risk for primary breast cancer, assess the nature and magnitude of harms, and examine how benefits and harms vary by age, breast cancer risk status, and other factors. In addition, it examines issues related to clinical effectiveness, such as patient choice, concordance, adherence, and persistence of use, and evaluates methods to appropriately select patients for medication therapy to reduce risk of breast cancer.

Breast cancer is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer death after lung cancer among women in the United States.¹ In 2008, an estimated 182,460 cases of invasive breast cancer and 67,770 cases of in situ breast cancer were diagnosed, and 40,480 women died of breast cancer.² The National Cancer Institute estimates that 14.7% of women born today will develop breast cancer in their lifetimes, 12.3% with invasive disease.² The probability of a woman developing breast cancer in her forties is 1 in 69, in her fifties 1 in 38, and in her sixties 1 in 27.³

Breast cancer is a proliferation of malignant cells that arises in the breast tissue, specifically in the terminal ductal-lobular unit. Breast cancer represents a continuum of disease, ranging from noninvasive to invasive carcinoma.⁴ Noninvasive carcinoma is confined to either the mammary duct, as with ductal carcinoma in situ (DCIS), or to the lobule, as with lobular carcinoma in situ (LCIS). LCIS is not considered a precursor lesion for invasive lobular carcinoma, but believed to be a marker for increased risk of invasive ductal or lobular breast cancer development in either breast.⁵ DCIS is thought to be a precursor lesion to invasive ductal carcinoma. Unlike in situ lesions, invasive breast cancers have metastatic potential.

Although several risk factors have been associated with breast cancer, most cases occur in women with no specific risk factors other than sex and age. Family history of breast and ovarian cancer are strong risk determinants. Family history is further characterized by the number of affected relatives, closeness of the degree of relationships, and ages of diagnosis. Although uncommon, hereditary mutations in tumor suppressor genes BRCA1 and BRCA2 increase individual risks for breast cancer 60–85% and may be identified in 5–10% of all breast cancer cases.⁶

Personal history of in situ breast cancer, previous abnormal breast biopsy containing LCIS, or atypical ductal or lobular hyperplasia increase risk for invasive breast cancer. High mammographic breast density is also associated with increased risk of breast cancer.^7,8 Endogenous estrogen exposure is associated with increased risk; thus early menarche, late menopause, older age at birth of first child, nulliparity, and obesity are implicated as risk factors. Use of combination postmenopausal hormone therapy (estrogen and progestin) was associated with an increased risk for breast cancer compared to placebo in the Women’s Health Initiative (WHI) randomized controlled trial.⁹ Use of alcohol at levels more than 1 to 2 drinks per day is also associated with increased breast cancer.⁹

Recent clinical trials have demonstrated the efficacy of tamoxifen citrate and raloxifene, selective estrogen receptor modulators (SERM), and the selective tissue estrogenic activity regulator (STEAR) tibolone, to reduce the risk of invasive breast cancer in women without pre-existing cancer (Table 1). Tamoxifen is approved by the U.S. Food and Drug Administration (FDA) to reduce the incidence of breast cancer in women at high risk of developing the disease defined as those with a breast biopsy with lobular carcinoma in situ or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer of ≥ 1.66% calculated by the modified Gail model. Tamoxifen is primarily used for the treatment of early and advanced estrogen receptor positive breast cancer in pre and postmenopausal women and for reduction of contralateral breast cancer. Raloxifene was initially approved by the FDA for osteoporosis prevention (1997) and treatment (1999) and has been primarily used for these indications. In September 2007, the FDA approved raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.

Table 1

Medications included in Comparative Effectiveness Review.

Tibolone is not currently approved by the FDA for use in the United States, but is approved to treat menopausal symptoms in 90 countries, and to prevent osteoporosis in 45 countries.¹⁰ Tibolone became available in the U.K. in the early 1990’s, and since then nearly 9 million women per year have taken it worldwide.¹¹ A recent evaluation of tibolone’s safety profile concluded that it is comparable to combined menopausal hormone therapy, and prescribing considerations for older women need to be taken into account for increased risk of stroke.¹¹

Current clinical recommendations, including those from the U.S. Preventive Services Task Force (USPSTF) issued in 2002, support tamoxifen use to reduce risk for primary breast cancer in women considered at high risk for breast cancer by the Gail model or other criteria and low risk for adverse events. However, use of risk reducing medications for breast cancer is believed to be low in the United States.¹² Primary care clinicians cite potential adverse effects, ranging from thromboembolism to hot flashes, as deterrents to prescribing tamoxifen to women without breast cancer. Now that raloxifene has also demonstrated breast cancer risk reduction benefits, recommendations need to be updated to include the most recent trials.

Scope and Key Questions

This report summarizes the available evidence comparing the effectiveness and safety of tamoxifen, raloxifene, and tibolone to reduce risk for primary breast cancer in women. The target population includes women without pre-existing breast cancer, noninvasive breast cancer, or precursor conditions who are not known carriers of breast cancer susceptibility mutations (BRCA1, BRCA2, or others). The report addresses the following questions.

Key Question 1. In adult women without pre-existing breast cancer, what is the comparative effectiveness of selective estrogen receptor modulators (SERMs) tamoxifen citrate and raloxifene, and the selective tissue estrogenic activity regulator (STEAR) tibolone, when used for the primary prevention of breast cancer on improving short-term and long-term outcomes including:

• – Invasive breast cancer
• – Noninvasive breast cancer including ductal carcinoma in situ (DCIS)
• – Breast cancer mortality
• – All-cause mortality
• – Osteoporotic fractures

Key Question 2. What is the evidence for harms of tamoxifen citrate, raloxifene, and tibolone when used for primary prevention of breast cancer? Harms may include but are not limited to:

• – Thromboembolic events (deep vein thrombosis, pulmonary embolism)
• – Cardiovascular events (coronary heart disease, stroke and transient ischemic attack, arrhythmias)
• – Metabolic disorders
• – Musculoskeletal symptoms (myalgia, leg cramps)
• – Mental health (mood changes, other)
• – Genitourinary outcomes (vaginal dryness, vaginal discharge, dyspareunia, sexual dysfunction, endometrial hyperplasia, abnormal uterine bleeding, other benign uterine conditions, hysterectomy, endometrial cancer, urinary symptoms, other)
• – Breast outcomes (biopsies, breast density, other)
• – Other malignancies (incidence, death)
• – Ophthalmologic disorders (cataracts, other)
• – Gastrointestinal/hepatobiliary disorders
• – Other adverse events that would impact quality of life (vasomotor symptoms, sleep disturbances, headaches, cognitive/memory changes, peripheral edema)

Key Question 3. How do outcomes for tamoxifen citrate, raloxifene, and tibolone when used for primary prevention of breast cancer vary by heterogeneity in subpopulations? Subpopulations include but are not limited to:

• – Age
• – Menopausal status (pre-, peri-, postmenopausal)
• – Hysterectomy status
• – Use of exogenous estrogen
• – Level of risk of breast cancer (family history, body mass index, parity [number of pregnancies], age at first live birth, age at menarche, personal history of breast abnormalities, prior breast biopsy, estradiol levels, breast density)
• – Ethnicity and race
• – Metabolism status (CYP 2D6 mutation)
• – Risk for thromboembolic events (obesity, others)

Key Question 4. What is the evidence that harms or noncancer benefits listed above affect treatment choice, concordance, adherence, and persistence to treatment with tamoxifen citrate, raloxifene, and tibolone when used for primary prevention of breast cancer?

Key Question 5. What methods, such as clinical risk assessment models, have been used to identify women who could benefit from breast cancer medications to reduce risk of breast cancer?