Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor-Treated Patients: CCTG MA.27

Abstract

Background: Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence.

Methods: In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided.

Results: Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01).

Conclusion: Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.

Trial registration: ClinicalTrials.gov NCT00066573.

Figure 1.

CONSORT diagram for Canadian Cancer Trials Group MA.27.

Figure 2.

Survival by celecoxib use. A) Event-free survival. B) Distant disease–free survival. C) Overall survival. Each graphic is a Kaplan-Meier survival plot for 811 women who were allocated celecoxib and 811 women not allocated celecoxib. At a median follow-up of 4.1 years, both the 811 patients allocated and those not allocated celecoxib had 93 (11.5%) event-free survival events (stratified log-rank P = .92); those allocated celecoxib experienced 38 (4.7%) distant disease–free survival events, while those not had 42 (5.2%) events (P = .55), and those allocated or not allocated celecoxib had, respectively, 60 (7.4%) and 65 (8.0%) deaths from any cause (P = .56).

Figure 3.

Survival by aspirin use. A) Event-free survival. B) Distant disease–free survival. C) Overall survival. Each graphic is a Kaplan-Meier survival plot for 476 women who used low-dose aspirin and 1733 women who did not. At a median follow-up of 4.1 years, the 476 aspirin users had 72 (15.1%) event-free survival events, while the nonusers had 177 (10.2%) events (stratified log-rank P = .006); those who used aspirin experienced 21 (4.4%) distant disease–free survival events, while those who did not had 87 (5.0%) events (P = .72), and those who used or did not use aspirin had, respectively, 56 (11.8%) and 110 (6.4%) deaths from any cause (P < .001).