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The administration of daily aspirin did not improve invasive disease-free survival in patients with high-risk, HER2-negative breast cancer.
The administration of daily aspirin did not improve invasive disease-free survival (iDFS) in patients with high-risk, HER2-negative breast cancer, according to data from the phase 3 ABC trial (NCT02927249) presented during the February 2022 ASCO Plenary Series.1
At a median follow-up of 24.0 months (range, 0-56), and after 111 events in the aspirin arm and 90 events in the placebo arm, the median iDFS in both cohorts was not evaluable; the hazard ratio (HR) was 1.25 (95% CI, 0.94-1.65; P = .1258), which crossed the protocol-specified futility boundary HR of 1.03. Because the data indicated it was unlikely that aspirin would prevent disease recurrence, the study was closed early.2
“Although follow-up was short, the futility bound was clearly crossed,” lead study author Wendy Y. Chen, MD, MPH, senior physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, said during the presentation on the data. “We had reached 50% of the events to speak for power, and there was a numerically higher number of events in the aspirin arm. Therefore, it was unlikely that even with further follow-up that there would net any benefit associated with aspirin.”
Multiple epidemiologic studies had reported improved breast cancer survival among regular aspirin users compared with non-users, and in-vitro and in-vivo evidence has suggested that aspirin could elicit an antitumor effect.3 Additionally, pooled data from randomized trials investigating aspirin for cardiovascular disease showed a decreased risk of metastatic cancer among those who received it.
The double-blinded, placebo-controlled, ABC trial investigated the use of aspirin as adjuvant therapy compared with placebo. The trial enrolled patients between the ages of 18 years and 70 years, who were diagnosed with a primary invasive HER2-negative breast cancer.
For those who had hormone receptor–positive disease, tumors were required to be node positive within 10 years of diagnosis. For those with hormone receptor–negative disease, tumors had to be high-risk, node negative or node positive within 18 months of diagnosis. Those who were anticoagulated at the time of enrollment or who had a prior history of gastrointestinal (GI) bleeding, atrial fibrillation, or myocardial infarction, were excluded from the trial.4 Patients who regularly used aspirin were required to stop 30 days prior to enrollment.
Study participants were randomized 1:1 to received aspirin at a daily dose of 300 mg (n = 1511) or daily placebo (n = 1510) for 5 years. Stratification factors included hormone receptor status (positive vs negative), body mass index (BMI; higher than 30 kg/m2 vs lower than 30 kg/m2, disease stage (I/II vs III), and time since diagnosis (less than 18 months vs 18 months or longer).
The primary end point of the trial was iDFS in patients with high-risk, HER2-negative breast cancer. Secondary end points included effects on overall survival, cardiovascular disease, toxicity, and adherence.
Between January 2017 and December 2020, a total of 3021 patients were enrolled to the trial at 338 sites. To increase accrual, 2 key modifications were made to the trial. In 2018, the eligibility for those with hormone receptor positivity changed to less than 10 years following diagnosis, and in 2020, they allowed remote consents and visits because of COVID-19.
Most patients enrolled to the study were between 50 and 60 years of age (38.4%); 8.1% were under 40 years, 29.1% were between 40 and 50 years, and 24.4% were older than 60 years. The majority of patients were White (81.8%) and female (99.5%). Moreover, 18.8% of patients were premenopausal, 87.5% of patients had hormone receptor–positive disease for less than 5 years since diagnosis, 85.7% had node-positive disease, and 11.0% had hormone receptor–negative disease. The median BMI was 29 kg/m2 (range, 15-69), and the median time since diagnosis was 13.0 months (range, 0-226). Additionally, 83.3% of patients received chemotherapy.
At the time of study close, 55.9% and 56.0% of patients on the aspirin and placebo arms, respectively, remained on treatment. The most common reason for treatment discontinuation on the aspirin arm (n = 667) was patient withdrawal (59.7%), followed by other reasons not specified (15.1%), toxicity (12.0%), recurrence (10.2%), and loss to follow-up (3.0%). In the placebo arm, treatment discontinuation due to patient withdrawal was noted in 57.4% of 664 patients; 10.4% stopped treatment due to recurrence, 10.8% stopped because of adverse effects (AEs), 2.2% were lost to follow-up, and 19.1% stopped for other reasons.
A total of 12 deaths were reported; 8 patients on the aspirin arm died, as well as 4 patients on the placebo arm. Moreover, 84 patients in the aspirin arm experienced invasive disease progression; 23 of these patients had a local recurrence and 61 experienced a distant recurrence. Comparatively, 71 patients in the placebo arm experienced invasive disease progression, with 16 experiencing local recurrence and 55 having distant recurrence. Nineteen patients in the aspirin arm developed a new primary, as did 15 patients in the placebo arm.
Compliance, plus use of off-protocol aspirin and nonsteroidal anti-inflammatory drugs, were noted to be similar between the cohorts, according to Chen.
In terms of safety, 7.7% of 1392 evaluable patients in the aspirin arm and 8.3% of the 1416 evaluable patients in the placebo arm experienced AEs that were grade 3 or higher in severity. Common grade 3 or higher AEs reported in the aspirin and placebo arms, respectively, were hematologic (n = 11; n = 14), cardiac (n = 7 for both ), GI (n = 20; n = 11), musculoskeletal (n = 13; n = 9), and vascular (n = 20; n = 21).
Grade 4 or higher AEs occurred in 1.0% of those who received aspirin and 1.4% of those given placebo. In the aspirin arm, 1 patient experienced a grade 4 or higher vascular AE, and 2 patients in the placebo arm each had a grade 4 or higher cardiac AE.
Despite the study results, Chen noted inflammation may still play a key role in cancer, and aspirin may have different effects in other disease spaces and settings.
"It is important to underscore that negative trials are valuable, particularly when there has been meticulous biospecimen collection, such as in the ABC trial," Angela DeMichele, MD, MSCE, of Abramson Cancer Center, said in a discussion following the presentation. "These analyses will be really helpful to us in gaining knowledge about the role of inflammation in recurrence and other interventions, regardless of this trial's outcome."