DSMB review

This randomized phase III trial studies how well aspirin works in preventing the cancer from coming back (recurrence) in patients with human epidermal growth factor receptor 2 (HER2) negative breast cancer after chemotherapy, surgery, and/or radiation therapy. Aspirin is a drug that reduces pain, fever, inflammation, and blood clotting. It is also being studied in cancer prevention. Giving aspirin may reduce the rate of cancer recurrence in patients with breast cancer.

This is a randomized double-blind placebo-controlled phase III trial of aspirin (300 mg daily) in early stage node-positive HER2 negative breast cancer patients. Patients will be randomized 1:1 within stratum defined by: Hormone Receptor status (HR positive vs HR negative), body mass index (<30 vs ≥ 30 kg/m2) and stage (Stage II vs III).

The primary objective of this trial is to compare the effect of aspirin versus placebo upon invasive disease free survival (iDFS).

Primary objective To compare the effect of aspirin (300 mg daily) versus placebo upon invasive disease free survival (iDFS) in early stage node-positive HER2 negative breast cancer patients.

Secondary objectives

1. To compare the effect of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients upon:

   1. Distant disease-free survival
   2. Overall survival
   3. Cardiovascular disease (see Section11.3)

2. To compare the toxicity of aspirin versus placebo in early stage node-positive HER2 negative breast cancer patients.

3. To assess adherence to aspirin and placebo among early stage node-positive HER2 negative breast cancer patients.

4. To bank tumor and germline deoxyribonucleic acid (DNA), plasma and urine collected at baseline and sequential plasma and urine collected 2 years later for future measurement of inflammatory markers.

5. To determine if there are subgroups of participants characterized by lifestyle factors associates with greater inflammation for whom there is greater benefit of aspirin versus placebo upon iDFS.

Patients are followed up to 10 years after study enrollment.

• Histologic documentation of women or men with node positive, HER2 negative, anatomic stage II or III breast carcinoma and high risk node negative (defined as estrogen receptor [ER] and progesterone receptor [PR] negative and tumor size > 2 cm) within one year of diagnosis and free of recurrence; patients with pN1mic are eligible; if neoadjuvant therapy was received, either initial clinical stage (determined by physical and or radiologic examination) or post-operative pathologic stage can be used for eligibility purposes, with the higher stage determining eligibility; histologic documentation of node positivity is required; bilateral breast cancers are allowed, as long as both cancers are HER2 negative and at least one of the cancers meets eligibility
• Any ER/progesterone receptor (PgR) status allowed
• Prior adjuvant treatment with chemotherapy and/or endocrine therapy, as determined by the treating physician, is allowed; the last dose of chemotherapy or radiation therapy must be at least 30 days prior to study registration; concurrent hormonal therapy will be allowed
• Regular nonsteroidal anti-inflammatory drug (NSAID)/aspirin use at any dose (including baby aspirin) (defined as >= 5 days per week) is allowed if aspirin and/or NSAIDs are stopped for 30 days prior to study entry and throughout the study period; participants will be encouraged to use acetaminophen for minor pain and fever
• Patients must be enrolled within 1 year after diagnosis
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patients with a prior history of gastric/duodenal ulcers documented on endoscopy can be enrolled as long as the ulcers did not cause bleeding requiring a blood transfusion/major intervention; for patients who are Helicobacter pylori positive, a course of Helicobacter pylori eradication treatment must have been completed
• No history of gastrointestinal bleeding (GI) bleeding requiring a blood transfusion, endoscopic or operative intervention
• No history of any prior stroke (hemorrhagic or ischemic)
• No concurrent anticoagulation with warfarin or heparin/heparin analogues, clopidogrel, oral direct thrombin inhibitors, or direct factor XA inhibitors
• No history of atrial fibrillation or myocardial infarction
• No history of grade 4 hypertension, defined as hypertension resulting in life-threatening consequences (e.g., malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis)
• No chronic (duration > 30 days) daily use of oral steroids
• No known allergy to aspirin
• No prior malignancy of any type (including ductal breast carcinoma in situ [DCIS]) within the past 5 years except for current diagnosis of breast cancer, and any prior diagnosis of basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix; patients with a prior history of breast cancer greater than 5 years from study screening may participate in this study
• Concurrent enrollment on a non-chemotherapy treatment trial will be allowed, as long as that trial allows concurrent daily aspirin use