De-escalation of endocrine therapy in postmenopausal women with low-risk HR+ HER2- low Luminal A early breast cancer: a single-arm study of omission versus combination therapy

The primary objective is to evaluate if omitting endocrine therapy in women aged 60 years or older with node-negative early breast cancer characterized by tumors ≤ 1 cm and a Luminal A phenotype (estrogen receptor positive, progesterone receptor positive, HER2 negative, and Ki67 ≤ 15%) results in an acceptable risk of relapse or breast cancer-related death. Participants receiving adjuvant radiotherapy following breast-conserving surgery will be assessed for clinical outcomes following surgical excision with clear margins. 5

Secondary objectives include:

• Comparison of prognosis against an external synthetic control arm.
• Assessment of the incidence of ipsilateral ductal carcinoma in situ, contralateral ductal carcinoma in situ, and invasive breast cancer compared to a synthetic control arm.
• Description of health-related quality of life.
• Evaluation of cardiovascular health and the incidence of bone events, osteopenia, or osteoporosis.

This study involves 70 postmenopausal female participants aged 60 years or older. The population consists of individuals diagnosed with early breast cancer characterized by a Luminal A phenotype. Specifically, the subjects have hormone receptor-positive (ER ≥ 50% and PR > 20%) and HER2-negative tumors with a low Ki67 index of ≤15%. Eligible participants present with invasive carcinoma, such as ductal, tubular, or mucinous types, where the primary tumor size is ≤1 cm (pT1a-b) and there is no evidence of nodal involvement (pN0 or cN0). The study population includes those who have undergone mastectomy or breast-conserving surgery with microscopically clear margins and have no indication for adjuvant chemotherapy. For those treated with breast-conserving surgery, the administration of adjuvant radiotherapy is required.

This single-arm de-escalation trial is designed as a Phase 4 study to evaluate the safety and efficacy of omitting endocrine therapy in specific patients. The research focuses on postmenopausal individuals with early breast cancer characterized by a Luminal A phenotype, featuring hormone receptor positive, HER2 negative, and low Ki67 status. The study involves a screening process to confirm eligibility based on tumor size, nodal status, and histological grade. Participants undergo an initial assessment followed by a period of clinical observation to monitor the relapse-free interval, which is the primary endpoint. Secondary endpoints include the assessment of distant disease free survival, overall survival, and various adverse events such as osteoporosis or cardiovascular events. The estimated trial duration for recruitment and follow-up extends through March 2033. Study involvement requires adherence to scheduled clinical visits and laboratory tests to monitor safety and disease recurrence. Early termination of participation may occur if protocol compliance is not maintained.

The investigational treatment involving exemestane is administered via oral use.

The investigational treatment involving anastrozole is administered via oral use.

The investigational treatment involving letrozole is administered via oral use.

The investigational treatment involving tamoxifen is administered via oral use.

The primary efficacy endpoint is the relapse-free interval (RFI), which is defined as the duration between initial treatment and the first occurrence of ipsilateral breast tumor recurrence, distant or locoregional recurrence, or death from breast cancer. This assessment follows the STEEP system definition version 2.0. Secondary endpoints include the RFI of participants treated with adjuvant hormone therapy in the CANTO study, as well as the incidence of ipsilateral ductal carcinoma in situ (DCIS), contralateral DCIS, and invasive contralateral breast cancer at 5, 8, and 10 years. Additional secondary measures include distant disease free survival (DDFS), relapse free survival (RFS) rates at 5, 8, and 10 years, and overall survival (OS) at 5 and 10 years, all defined according to standardized STEEP v2.0 criteria.

Efficacy and safety assessments also involve the following:

• Patient-reported outcomes collected via the EORTC QLQC30, EORTC QLQ-BR42, and Hospital Anxiety and Depression Scale (HADS) questionnaires.
• Evaluation of bone-related events, osteopenia, osteoporosis, dyslipidemia, and cardiovascular events, such as myocardial infarction, stroke, and thromboembolic events, utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.