Comparing Different Endocrine Therapies for Male Breast Cancer, ETHAN Trial
This phase II trial compares different endocrine therapies in treating male breast cancer. Tamoxifen is in a class of medications known as antiestrogens. It blocks the activity of estrogen (a female hormone) in the breast. This may stop the growth of some breast tumors that need estrogen to grow. Anastrozole is in a class of medications called nonsteroidal aromatase inhibitors. It works by decreasing the amount of estrogen the body makes. This can slow or stop the growth of many types of breast cancer cells that need estrogen to grow. Degarelix inhibits a hormone (luteinizing hormone-releasing hormone) which is made by the pituitary gland to control how much testosterone is made by the testicles. Testosterone can be converted into estrogen. Abemaciclib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Tamoxifen is the standard of care for the treatment of breast cancer in men. Anastrozole is a standard treatment in women with breast cancer and works more effectively than tamoxifen. This study hopes to learn if anastrozole may also be effective in men and how the addition of degarelix and abemaciclib works in comparison to standard of care tamoxifen.
Inclusion Criteria
- Men aged 18 years or older, with diagnosis of invasive breast cancer who have not undergone surgical resection of the primary tumor and axillary nodes
- Stage I, II, or III per American Joint Committee on Cancer (AJCC) staging 8th edition
- Breast cancer must be hormone receptor-positive and HER2-negative according to definition below assessed by local pathology * Hormone receptor-positive is defined as: positivity for at least one of the hormone receptors (estrogen receptor [ER] or progesterone receptor [PR]) by immunohistochemistry (IHC). ER and PR assays are considered positive if there are > 1% positive tumor nuclei in the samples * HER2-negative is defined per the current American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline
- Patients with multifocal or multicentric disease are eligible if the treating investigator has determined the patient should be treated as ER-positive and HER2-negative
- Bilateral breast cancers are allowed if the treating investigator has determined the patient should be treated as ER-positive and HER2-negative
- Patients with a history of ipsilateral or contralateral breast ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Hemoglobin >= 8 g/dl
- Platelets >= 50,000/mm^3
- Serum creatinine =< 3.0 x upper limit of normal (ULN) (institutional)
- Total bilirubin =< 2.0 x ULN (institutional)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5.0 x ULN (institutional)
- Men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 6 months after the last dose of study treatment
- Non-English-speaking patients are eligible but will be exempt from patient-completed questionnaires
- Willing and able to sign informed consent
- Willing to undergo breast biopsy after completion of window phase
- Archival tissue will be submitted for all participants. Tissue must be confirmed available prior to registration
- Patient is able to swallow oral medications
Exclusion Criteria
- Prior anti-cancer therapy (e.g., endocrine therapy, chemotherapy, radiation therapy, or investigational therapy) for the current breast cancer diagnosis
- Prior anti-cancer therapy (e.g., endocrine therapy, systemic therapy, radiation therapy, or investigational therapy) for any other malignancy within the past 12 months
- Diagnosis of inflammatory breast cancer (T4d)
- Other concurrent serious diseases that may interfere with planned treatment, including severe cardiac disease, congestive heart failure (CHF) of New York Heart Association (NYHA) Class III or higher, severe pulmonary conditions/illness, uncontrolled infections
- Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30 ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea)
- Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), uncontrolled fungal infection, or uncontrolled viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment
- History of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest
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PRIMARY OBJECTIVES:
I. To evaluate the comparative efficacy of tamoxifen, anastrozole, and anastrozole in combination with degarelix for the treatment of men with stage I to III hormone receptor (HR)+ HER2- breast cancer, as measured by reduction of Ki-67 from the diagnostic biopsy to the research biopsy at the end of the three-week window period.
II. To evaluate the comparative efficacy of tamoxifen with or without abemaciclib, and anastrozole plus degarelix with or without abemaciclib for the neoadjuvant treatment of men with stage I to III HR+ HER2- breast cancer, as measured by residual cancer burden (RCB) index at surgery.
SECONDARY OBJECTIVES:
I. To evaluate the physiologic endocrine changes that occur as a result of treatment with tamoxifen, anastrozole and anastrozole with degarelix as measured by estradiol and testosterone levels at baseline, at the end of the three-week window period and during the neoadjuvant phase.
II. To evaluate the comparative efficacy of the experimental treatments as measured by PEPI score at surgery.
III. To determine the safety and tolerability of the study treatments.
IV. To assess for feasibility and futility of the trial design and treatments used.
V. To evaluate the impact of the treatments on patient-reported outcomes (PROs) and quality of life (QoL) measures using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLC-C30) and Breast Cancer-Specific Questionnaire (BR23), adapted by replacing female-specific items with male-specific sexual activity/function items from PR25.
EXPLORATORY OBJECTIVES:
I. To compare tumor genomic profiles before and after treatment with abemaciclib, with a focus on genes related to CDK4/6 inhibition (RB1, CCNE1, CCNE2, CCND1, AKT1, RAS, AURKA).
II. To evaluate germline BRCA status as a predictor of response to the specific endocrine regimens.
III. To evaluate event-free survival (EFS).
IV. To evaluate endocrine therapy response at the molecular level and in in-vivo models.
V. To quantify the degree of apoptosis induced by endocrine therapy with or without abemaciclib.
OUTLINE:
WINDOW PHASE: Patients are randomized to 1 of 3 arms.
ARM A: Patients receive tamoxifen orally (PO) once daily (QD) on days 1-21 in the absence of disease progression or unacceptable toxicity. Patients then undergo a biopsy. Patients also undergo mammography with ultrasound or magnetic resonance imaging (MRI) during screening.
ARM B: Patients receive anastrozole PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity. Patients then undergo a biopsy. Patients also undergo mammography with ultrasound or MRI during screening.
ARM C: Patients receive anastrozole PO QD on days 1-21 and degarelix subcutaneously (SC) on day 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo a biopsy. Patients also undergo mammography with ultrasound or MRI during screening.
NEOADJUVANT PHASE: Patients in Arm A are randomized to Arm D or Arm E. Patients in Arm B and Arm C are randomized to Arm F or Arm G.
ARM D: Patients receive tamoxifen PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients also undergo collection of blood samples and undergo mammography with ultrasound or MRI on the trial.
ARM E: Patients receive tamoxifen PO QD and abemaciclib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients also undergo collection of blood samples and undergo mammography with ultrasound or MRI on the trial.
ARM F: Patients receive anastrozole PO QD on days 1-28 and degarelix SC on day 1 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients also undergo collection of blood samples and undergo mammography with ultrasound or MRI on the trial.
ARM G: Patients receive anastrozole PO QD and abemaciclib PO BID on days 1-28 and degarelix SC on day 1 of each cycle. Cycles repeat every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Patients also undergo collection of blood samples and undergo mammography with ultrasound or MRI on the trial.
After completion of study treatment, patients are followed up every year for up to 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorJose Pablo Leone
- Primary ID22-225
- Secondary IDsNCI-2023-08848
- ClinicalTrials.gov IDNCT05501704