STAR

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Vogel VG, et al. "Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes". Journal of the American Medical Association. 2006. 295(23):2727-2741.
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Clinical Question

In postmenopausal women, how does tamoxifen compare to raloxifene in primary breast cancer prevention and side effect profile?

Bottom Line

Tamoxifen is as effective as raloxifene in reducing the risk of invasive breast cancer, but carries a higher incidence of thromboembolic events and cataracts.

Major Points

Numerous placebo-controlled studies of women, including NSABP P-1 (1998), MORE[1] (1999), and CORE (2004), have demonstrated a reduction in the risk of breast cancer with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. Large prospective head-to-head comparisons of tamoxifen, a first generation agent, and raloxifene, a second generation agent, had not yet been performed.

Published in 2006, the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-2 study, also called the Study of Tamoxifen and Raloxifene (STAR), randomized nearly 20,000 postmenopausal females to either tamoxifen or raloxifene for primary prevention of breast cancer. All women had a Gail model[2] estimated 5-year risk of breast cancer of ≥1.66% or a history of LCIS treated solely with local excision. At a mean follow-up of 3.5 years, there were similar rates of invasive breast cancer in each study arm but more thromboembolic events and cataracts were seen with tamoxifen. In addition, there was a trend towards more invasive uterine carcinomas with tamoxifen (36 vs. 23), but this did not reach statistical significance.

Of note, the rates of endometrial cancer did not differ between those on raloxifene and placebo in MORE. As 52% of the participants in STAR had hysterectomies, the ability to detect differences in endometrial cancer rates may have been hampered due to underpowering. However, there was a significant reduction in rates of endometrial hyperplasia, regarded as a precancerous change, in the raloxifene group.

Guidelines

ASCO use of medications for breast cancer reduction (2009)[3]

  • Discuss risks and benefits of treatment
  • Offer treatment with tamoxifen or raloxifene daily for 5 years to postmenopausal women with a 5 year breast cancer risk ≥1.66% or with LCIS
  • Offer treatment with tamoxifen daily for 5 years to premenopausal women with 5 year breast cancer risk ≥1.66% or with LCIS
  • These medications should not be offered to women with previous DVT, PE, stroke, or TIA
  • Baseline and annual gynecologic exams

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=19,471 postmenopausal females
    • Tamoxifen (n=9,726)
    • Raloxifene (n=9,745)
  • Setting: ~200 centers throughout North America
  • Enrollment: 1999-2005
  • Follow-up: mean 3.9 years
  • Analysis: Intention-to-treat
  • Primary outcome: Invasive breast cancer

Population

Inclusion Criteria

  • Age ≥35 years
  • Gail model 5-year predicted breast cancer risk ≥1.66% or LCIS treated with local excision alone
  • Postmenopausal, defined as:
    • No spontaneous menstrual bleeding in prior 12 months
    • Documented hysterectomy and bilateral salpingo-oophorectomy
    • Age ≥55 years with hysterectomy ± oophorectomy
    • Age <55 years with hysterectomy and oophorectomy or unknown ovary status, and with FSH in postmenopausal range

Exclusion Criteria

  • Use of tamoxifen, raloxifene, hormone therapy, oral contraceptives, or androgens for prior 3 months
  • Use of warfarin or cholestyramine
  • History of stroke, PE, DVT
  • History of malignancy in prior 5 years (except SCC skin or cervical carcinoma in situ)
  • Uncontrolled atrial fibrillation, DM, or HTN
  • Psychiatric condition that would interfere with adherence
  • Performance status preventing "normal activity for a significant portion of the day"
  • LCIS treated by more than just local excision

Baseline Characteristics

Data are from tamoxifen group and are similar to raloxifene group.

  • Age: 58.5 years
    • <50 years: 9.1%
    • 50-59 years: 49.9%
    • 60-69 years: 32.2%
    • ≥70 years: 8.8%
  • Race and ethnicity:
    • White: 93.5%
    • African American: 2.4%
    • Hispanic: 2.0%
    • Other: 2.1%
  • No first-degree relatives with breast cancer: 28.9%
  • One first-degree relative with breast cancer: 52.2%
  • Two first-degree relatives with breast cancer: 15.9%
  • ≥3 first-degree relatives with breast cancer: 3.0%
  • History of hysterectomy: 51.3%
  • History of LCIS: 9.2%
  • History of breast atypical hyperplasia: 22.5%
  • Gail model predicted 5-year breast cancer risk:
    • ≤2%: 10.8%
    • 2.01-3.00%: 30.7%
    • 3.01-5.00%: 31.2%
    • ≥5.01%: 27.2%

Interventions

  • Randomized to oral tamoxifen 20mg vs. raloxifene 60mg by mouth daily over 5 years
  • Stratified by age, race, history of LCIS, and 5-year predicted breast cancer risk
  • Follow-up every 6 months through year 5, then annually
  • Clinical breast examination every 6 months, annual bilateral screening mammography
  • Annual gynecologic exam, CBC, and BMP

Outcomes

Comparisons are tamoxifen vs. raloxifene. However, relative risk (RR) is given for raloxifene vs. tamoxifen, as it was presented so in the original article.

Primary Outcome

Invasive breast cancer
163 vs. 168 (RR 1.02; 95% CI 0.82-1.28; P=0.96)

Secondary Outcomes

Noninvasive breast cancer
57 vs. 80 (RR 1.40; 95% CI 0.98-2.00)
Invasive uterine cancer
36 vs. 23 (RR 0.62; 95% CI 0.35-1.08)
Endometrial hyperplasia
84 vs. 14 (RR 0.16; 95% CI 0.09-0.29)
Hysterectomy during follow-up
244 vs. 111 (RR 0.44; 95% CI 0.35-0.56)
Thromboembolic events
141 vs. 100 (RR 0.70; 95% CI 0.54-0.91)
Osteoporotic fractures
104 vs. 96 (RR 0.92; 95% CI 0.69-1.22)
Developed cataracts
394 vs. 313 (RR 0.79; 95% CI 0.68-0.92)
Developed cataracts and had cataract surgery
260 vs. 215 (RR 0.82; 95% CI 0.68-0.99)
Death
101 vs. 96 (RR 0.94; 95% CI 0.71-1.26)

Funding

Funded primarily by the NCI; also from NIH and DHHS. Additional support from AstraZeneca (manufacturer of tamoxifen) and Eli Lilly (manufacturer of Evista, the brand name of raloxifene).

Criticisms

  • Differences in endometrial cancer rates may not have been detectable given that 52% of participants had hysterectomy

Further Reading

  1. Cummings SR, et al. "The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. Multiple Outcome of Raloxifene Evaluation." 1999;281(23):2189-2197.
  2. Gail model risk assessment tool
  3. Vivsanationa K, et al. "American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, ralosifene, and aromatase inhibition for breast cancer risk reduction." Journal of Clinical Oncology. 2009;27(19):3235-3258.