Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting

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.

Figure 1

Inclusion and exclusion criteria for study participants. Women diagnosed with invasive breast cancer at Kaiser Permanente (KP) Northwest (1990–2008) or Colorado (1994–2008) were followed until the earliest of the following events: contralateral breast cancer diagnosis, other second cancer diagnosis, exited the KP plan, death, last tumor-registry follow-up, or end of study date (December 31, 2010 for KP Northwest or 2011 for KP Colorado).

Figure 2

Relative risks (RR) and 95% confidence intervals (CI) for contralateral breast cancer associated with adjuvant tamoxifen by time since last use and duration of therapy, Kaiser Permanente Northwest and Colorado. Poisson models were stratified by study site (NW/CO), age at diagnosis (<40, 40–49, 50–59, 60–69, 70+ years), stage at diagnosis (I, II, III, unknown stage), ER status of the initial tumor (positive, negative, unknown/indeterminate), time since initial breast cancer in yearly categories up to 15 years or more, and, to account for potential cohort effects, year of diagnosis (1990–94, 1995–99, 2000–04, 2005–2008). We also adjusted models simultaneously for aromatase inhibitor use (with or without tamoxifen), chemotherapy with an alkylating agent, and radiotherapy. Numbers of contralateral breast cancer cases, RRs and 95% CIs may be found in Supplementary Table 2.

Figure 3

Cumulative incidence of contralateral breast cancer adjusted for competing risks by tamoxifen use and duration among 3,732 women who survived 5+ years after being diagnosed with an ER-positive first breast cancer.