JAMA Oncol. Published online October 6, 2016. doi:10.1001/jamaoncol.2016.3340

Author
Gretchen L. Gierach, PhD, MPH¹; Rochelle E. Curtis, MA²; Ruth M. Pfeiffer, PhD³; Maeve Mullooly, PhD^1,4; Estelle A. Ntowe, MHS²; Robert N. Hoover, MD⁵; Sarah J. Nyante, PhD⁶; Heather Spencer Feigelson, PhD⁷; Andrew G. Glass, MD⁸; Amy Berrington de Gonzalez, DPhil²

Author information
¹Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
²Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Marylan
³Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Marylan
⁴Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Marylan
⁵Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
⁶Department of Radiology, School of Medicine, The University of North Carolina at Chapel Hill
⁷Kaiser Permanente Institute for Health Research, Denver, Colorado
⁸Kaiser Permanente Northwest Center for Health Research, Portland, Oregon

Abstract

Importance  
Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common.

Objective  
To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting.

Design, Setting, and Participants  
A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado).

Exposures  
Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records.

Main Outcomes and Measures  
Incident CBC based on long-term systematic follow-up.

Results  
Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive.

Conclusions and Relevance  
Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor–positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.