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Breast Cancer Chemoprevention: Targeting the Estrogen Receptor

Rowan T. Chlebowski, MD, PhD; Radhika Prabhaker, MD; Tomoko Tagawa, MD
Published: Sunday, Jan 31, 2016

Rowan T. Chlebowski, MD, PhD

Rowan T. Chlebowski, MD, PhD


Updated findings from breast cancer chemoprevention trials inform our understanding regarding benefits and risks of available interventions. In full-scale, randomized chemoprevention trials, the selective estrogen receptor modulators tamoxifen and raloxifene and the aromatase inhibitors exemestane and anastrozole all reduce breast cancer incidence in postmenopausal women. However, long-term follow-up of the International Breast Cancer Intervention Study I and the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene chemoprevention trials question the primacy of tamoxifen use in the prevention setting. Long-term follow-up of the Women’s Health Initiative hormone therapy clinical trials identifies complex and changing influences on breast cancer risk during intervention and postintervention periods, but confirms findings that estrogen plus progestin increases breast cancer incidence, whereas estrogen alone decreases risk. New strategies to increase the uptake of these proven breast cancer risk-reduction interventions in general clinical practice are needed.


Both tamoxifen and raloxifene have FDA approval for breast cancer risk reduction. These recommendations are endorsed by an American Society of Clinical Oncology (ASCO) guideline,1 by the National Comprehensive Cancer Center Network (NCCN) guideline,2 and, importantly, by the US Preventive Services Task Force (USPSTF).3 Despite these recommendations, uptake of selective estrogen receptor modulators (SERMs) for breast cancer chemoprevention in clinical practice has been extremely limited.4 In addition, updated, long-term follow-up of two of these chemoprevention trials raises questions regarding the role of tamoxifen in this setting. Updated analyses from the Women’s Health Initiative (WHI) randomized hormone therapy trial (Table 2) have informed understanding of the relationships between exogenous estrogen and exogenous progestin and breast cancer risk, with relevance for breast cancer prevention.

SERMs and Breast Cancer

The SERM tamoxifen has been compared with placebo in 4 breast cancer prevention trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] P-1,5 International Breast Cancer Intervention Study I [IBIS-I],6 the Royal Marsden Hospital Tamoxifen Prevention Trial,7 and the Italian Randomized Tamoxifen Prevention Trial),8 where, when combined in an updated meta-analysis, a statistically significant 38% reduction in invasive breast cancer incidence was seen.9 The SERM raloxifene has been compared with placebo in 3 trials (Raloxifene Use for The Heart [RUTH],10 Multiple Outcomes of Raloxifene Evaluation [MORE],11 and Continuing Outcomes Relevant to Evista [CORE]).12 In these three trials, a statistically significant reduction in breast cancer incidence was seen. Finally, the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial13 directly compared these agents in a breast cancer prevention setting (Table 1).47 Newer SERMs have been evaluated in full-scale trials,14,15 but, for various reasons, are unlikely to receive approval in the United States.16

In IBIS-I,6 7154 women were randomized to either tamoxifen or placebo for 5 years in a primary breast cancer prevention trial. Study findings were recently updated with 16 years’ follow-up.17 A reduced breast cancer incidence persisted throughout follow-up (214 vs 289 cases; hazard ratio [HR], 0.73; 95% CI, 0.61-0.84; P <.0001). However, there were more deaths in the tamoxifen group (187 [5.1%]) vs 166 deaths [4.6%], respectively; odds ratio [OR], 1.10; 95% CI, 0.88-1.37)17 (Table 1). In an accompanying commentary, Chlebowski questioned the greater mortality in the tamoxifen group and suggested that although the findings could reflect the play of chance in a small sample, less favorable alternative explanations include tamoxifen only decreasing breast cancers with favorable prognosis or tamoxifen increasing breast cancers with unfavorable prognosis.18

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