Therapeutics

Tamoxifen for 5 years reduced 16-year risk for breast cancer in women at increased risk

Cuzick J, Sestak I, Cawthorn S, et al; IBIS-I Investigators. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16:67-75.

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Question In women at increased risk for breast cancer, does 5 years of tamoxifen therapy reduce long-term risk for breast cancer?

Methods Design: Long-term follow-up of a randomized placebocontrolled trial (International Breast cancer Intervention Study I [IBIS-I]). Current Controlled Trials ISRCTN 91879928. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, and data collectors). Follow-up period: Median 16 years. Setting: 37 genetics clinics and breast care clinics in Australia, Belgium, Finland, Ireland, New Zealand, Spain, Switzerland, and the UK. Patients: 7169 women 35 to 70 years of age (median age 50 y, 54% postmenopausal) who were at increased risk for breast cancer (2-fold increased risk in women 45 to 70 y, > 2-fold increased risk in women < 45 y). Exclusion criteria included desire to become pregnant or history of invasive cancer, deep venous thrombosis, or pulmonary embolism. Intervention: Oral tamoxifen, 20 mg/d (n = 3585), or placebo (n = 3584), for 5 years. Outcomes: Breast cancer (including ductal carcinoma in situ). Secondary outcomes included invasive estrogen receptor– positive breast cancer, mortality, and adverse events. Patient follow-up: ≥ 92% of women had > 10 years of follow-up (intention-to-treat analysis).

Main results Tamoxifen reduced risk for breast cancer and invasive estrogen receptor–positive breast cancer, but not mortality, compared with placebo (Table). Tamoxifen increased risk for nonmelanoma skin cancer (odds ratio 1.39, 95% CI 1.04 to 1.87) but not cancer overall, gynecologic cancers, gastrointestinal cancers, or lung cancer (all P > 0.059).

For correspondence: Professor J. Cuzick, Queen Mary University, London, England, UK. E-mail [email protected]. 

Commentary Long-term follow up of IBIS-I has shown that women at high risk for breast cancer continue to benefit from tamoxifen chemoprevention, with reductions in invasive breast cancer > 10 years after treatment. These results are consistent with several studies testing different chemoprevention agents (1). None of the studies were designed to assess the effect of chemoprevention on overall survival. However, IBIS-I showed that only 37 high-risk women would need to be treated with tamoxifen for 5 years to prevent 1 additional case of invasive breast cancer—a diagnosis that is associated with anxiety and morbidity of treatment—after 16 years. Despite the impressive evidence for benefits with tamoxifen, uptake of breast cancer chemoprevention is low (2). Primary care physicians are comfortable prescribing raloxifene for bone health—why not tamoxifen for prevention of breast cancer? Physicians may be concerned about side effects, but common ones (i.e., hot flashes, vaginal discharge) reverse upon drug discontinuation, and serious ones (i.e., venous thromboembolism, endometrial cancer) are rare and almost never occur in women < 50 years of age (1). Thus, young women at high risk would probably benefit most. Because there is no overall survival benefit, it is reasonable to stop therapy if side effects become too onerous. More accessible prediction models are needed to guide primary care physicians and their patients in deciding whether to start tamoxifen. One excellent model applies to postmenopausal patients only (3). More precise decision analysis tools are critical because of both the morbidity and mortality associated with breast cancer therapy and the potential benefits of endocrine manipulations. Further studies are needed to identify new, safe agents for prevention of hormone-insensitive breast cancer and molecular biomarkers of individual risk. Heather Parsons, MD, MPH Vered Stearns, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland, USA

Conclusion In women at increased risk for breast cancer, 5 years of tamoxifen therapy reduced 16-year risk for breast cancer. References

*See Glossary. Sources of funding: Cancer Research UK and National Health and Medical Research Council (Australia).

Tamoxifen vs placebo for 5 years in women at increased risk for breast cancer† Outcomes

Event rates Tamoxifen

1. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:2942-62. 2. Waters EA, McNeel TS, Stevens WM, Freedman AN. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res Treat. 2012;134:875-80. 3. Freedman AN, Yu B, Gail MH, et al. Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol. 2011;29:2327-33.

At a median 16 y

Placebo RRR (95% CI)

NNT (CI)

Breast cancer

7.0%

9.8%

28% (16 to 39)

37 (27 to 63)

Invasive estrogen receptor–positive breast cancer

4.5%

6.7%

33% (18 to 45)

46 (34 to 82)

RRI (CI)

NNH

Mortality

5.1%

4.6%

9% (⫺12 to 35) Not significant

†Abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and hazard ratios or odds ratios in article.

19 May 2015

Annals of Internal Medicine

ACP Journal Club

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姝 2015 American College of Physicians