Previous observational studies and several randomized trials have demonstrated a reduction in cancer risk and risk of metastasis, including for breast cancer (BC), with the use of aspirin. However, these results were often secondary findings. To help further explore this issue, the Alliance for Clinical Trials in Oncology (Alliance clinical trial) was conducted.
AO11502 is the first randomized, double-blind, placebo-controlled phase III trial intended to determine whether adjuvant aspirin decreases the risk of invasive cancer events among survivors of BC. Individuals aged 18 to <70 years who had a history of ERBB2-BC treated with standard therapy based on routine clinical care, who had completed all local therapy and chemotherapy (endocrine therapy could be continued), and who resided in the United States or Canada were eligible for enrollment in the study. Patients with hormone receptor–positive (HR+) tumors (estrogen or progesterone positive) had to have a positive lymph node indicative of micrometastases and had to be enrolled within 10 years of BC diagnosis. For HR– tumors (both estrogen and progesterone receptors were negative), the study participant had to have a positive lymph node or tumor >2 cm and had to be enrolled within 18 months of diagnosis.
Nonsteroidal anti-inflammatory agents (NSAIAs) had to be discontinued 30 days prior to enrollment in the study. Exclusion criteria included age 70 years or older; long-term daily use of oral steroids; anticoagulation (warfarin, heparin, heparin analogues, clopidogrel, direct thrombin inhibitors, or direct factor Xa inhibitors); or history of gastrointestinal bleeding, stroke, atrial fibrillation, myocardial infarction, or grade 4 hypertension. Patients were randomized 1:1 to aspirin or placebo and stratified based on hormone-receptor status, BMI, BC stage, and time since diagnosis.
The intervention group received aspirin 300 mg daily. Medication was allowed to be held if the patient was having a procedure that was deemed to carry a bleeding risk. If patients continued to use NSAIAs, the use of these drugs was documented, and the patient was continued in the study. As initially planned, patients would be monitored at baseline and every 6 months up to 2 years. Study drug adherence was assessed by medication diaries and pill counts and was defined as taking >80% of study doses in the previous 6 months.
The primary endpoint was invasive disease–free survival (IDFS; i.e., the time from randomization to the first occurrence of any of the following events: distant or locoregional recurrence, ipsilateral or contralateral BC, second primary [nonbreast] invasive cancer, or death from any cause). Overall survival (OS) was a secondary endpoint and was measured from randomization to death from any cause.
A total of 3,020 evaluable participants (mean age: 53 years; included 16 men) were enrolled from 534 academic and community sites between January 6, 2017, and December 4, 2020. At randomization, 18.9% of women were premenopausal. The vast majority (88.9%) had node-positive disease, 88.6% were hormone receptor–positive, and 83.2% had received chemotherapy. Median time from diagnosis to enrollment was 13 months.
At the first prespecified interim analysis in November 2021, the stratified hazard ratio (HR) comparing aspirin with placebo crossed the prespecified futility boundary, and it was recommended that the trial be unblinded and that the study be terminated. Median time enrolled was 19.5 months in the aspirin group and 19.6 months in the placebo group. Median follow-up at 33.8 months revealed no statistically significant difference in HR for adverse events between the two groups (HR 1.27; 95% CI, 0.99-1.63, P = .06). All IDFS outcomes, except contralateral breast cancer, occurred more commonly in the aspirin group, but this finding was not statistically significant. A nonsignificant increase in deaths was observed in the aspirin group as well but OS did not differ. Treatment adherence was 91.4% for the aspirin group and 89.2% for the placebo group at 12 months and increased slightly to 91.5% and 92.1%, respectively, at 24 months. Grade 2 and 4 adverse events were similar between the two groups.
This study had limitations, including that there was inadequate power to evaluate effect by BC phenotype. However, data from this trial will be pooled with the Add-Aspirin trial that is ongoing in the United Kingdom to explore further differences in BC subtype.
The authors concluded that aspirin at 300 mg/day does not offer any benefit against disease recurrence or for improved survival to survivors of early BC. Pharmacists should be cognizant of these findings and should discourage the routine use of aspirin for the intent of improving BC outcomes.
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