Evaluation of Reduced Duration of Adjuvant Endocrine Therapy with Exemestane, Anastrozole, and Letrozole in Postmenopausal Women with Low-Risk HR+ HER2- Breast Cancer

The primary objective of this study is to prospectively demonstrate that an adjuvant **aromatase inhibitor** therapy duration limited to 2 years is associated with a high distant recurrence-free interval (DRFI) at 5 years in a selected population of post-menopausal women with localized luminal A breast cancer considered at low risk of metastatic recurrence. This is clinically relevant as it aims to reduce the duration of hormone therapy, potentially minimizing side effects and improving quality of life without compromising the efficacy of treatment in preventing distant metastasis.

Secondary objectives include:

• Evaluate Invasive Disease-Free Survival (iDFS)
• Evaluate Invasive Breast Cancer-Free Survival (iBCFS)
• Evaluate Breast Cancer Specific Survival (BCSS)
• Evaluate Overall Survival (OS)
• Assess quality of life (QoL) at baseline and annually for up to 5 years, focusing on general QoL, fatigue, psychological and geriatric characteristics (in patients aged ≥75 years), and cognitive functions
• Evaluate the safety of the treatment in the study population
• Describe DRFI, DDFS, iDFS, iBCFS, BCSS, and OS in patients not at "ultra-low" risk according to the Mammaprint® test
• Evaluate Distant Disease-Free Survival (DDFS)

The clinical trial involves a study population of **postmenopausal women** diagnosed with localized luminal A breast cancer, specifically those considered at low risk of metastatic relapse. The trial does not provide the total number of participants, as this information was not disclosed by the sponsor. Participants are exclusively female, with an age range that includes individuals aged 50 years and older. The trial population was selected based on specific criteria, including the absence of clinically or radiologically detectable metastases at the time of inclusion and a histologically proven diagnosis of invasive unilateral breast cancer. Participants must have undergone complete resection of the primary tumor and adequate axillary surgery. The study excludes male subjects and does not involve a vulnerable population. Participants are expected to comply with the study protocol, which includes scheduled visits, treatment plans, laboratory tests, and other procedures. The trial focuses on evaluating the efficacy of a limited duration of adjuvant aromatase inhibitor therapy in this specific population.

The clinical trial is designed to evaluate the efficacy of a **two-year adjuvant aromatase inhibitor therapy** in post-menopausal women with localized luminal A breast cancer at low risk of metastatic relapse. This is a Phase IV, single-arm study with a primary objective to demonstrate a high distant recurrence-free interval (DRFI) at five years. The trial involves the administration of **exemestane**, **anastrozole**, or **letrozole**, all in oral form, with a maximum daily dose of 25 mg, 1 mg, and 2.5 mg respectively, over a treatment period of 24 months. The study is expected to conclude by March 31, 2034, with recruitment having commenced on November 10, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as postmenopausal status, hormone receptor expression, and HER2 negativity. Follow-up visits will be scheduled to monitor treatment adherence, assess adverse events, and evaluate primary and secondary endpoints, including invasive disease-free survival and quality of life. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may result from non-compliance, adverse events, or withdrawal of consent.

The expected length of participant involvement is approximately 24 months, aligning with the treatment duration. Conditions that may lead to early termination include significant adverse events, non-compliance with the protocol, or voluntary withdrawal by the participant. The study aims to provide valuable insights into the potential for reducing the duration of hormone therapy in a specific patient population, thereby minimizing exposure to treatment while maintaining efficacy.

**Exemestane** is utilized in this clinical trial as an experimental medication. It is administered in the form of a **film-coated tablet**. The active substance, **exemestane**, is of chemical origin. The maximum daily dose is 25 mg, with a total maximum dose of 18,250 mg over the treatment period. The medication is administered **orally** once daily for a maximum treatment period of 24 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Anastrozole** is another experimental medication used in this study. It is provided as a **coated tablet** and contains the active substance **anastrozole**, also of chemical origin. The maximum daily dose is 1 mg, with a total maximum dose of 730 mg over the treatment period. This medication is administered **orally** once daily for up to 24 months. Compliance with the dosing regimen is monitored throughout the study duration.

**Letrozole** is included in the trial as an experimental treatment. It is available in the form of a **film-coated tablet**. The active substance, **letrozole**, is chemically derived. The maximum daily dose is 2.5 mg, with a total maximum dose of 1,825 mg over the treatment period. Letrozole is administered **orally** once daily for a maximum of 24 months. Participant adherence to the dosing schedule is regularly evaluated to ensure compliance.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this clinical trial. The study focuses on the administration of the aforementioned experimental medications to evaluate their efficacy in reducing the duration of adjuvant endocrine therapy in women with hormone receptor-positive, HER2-negative breast cancer at very low risk of metastasis.

Efficacy in this clinical trial will be assessed primarily through the **Distant Relapse-Free Interval (DRFI)**, which is defined as the time from the start of hormonotherapy to the first event of distant recurrence or breast cancer-related death. This primary endpoint will provide a measure of the effectiveness of the adjuvant aromatase inhibitor therapy in preventing distant metastasis in women with hormone receptor-positive, HER2-negative breast cancer at very low risk of metastasis.

Secondary endpoints will include several additional measures of efficacy: Invasive Disease-Free Survival (iDFS), Invasive Breast Cancer-Free Survival (iBCFS), Breast Cancer Specific Survival (BCSS), Overall Survival (OS), and Quality of Life. Safety will also be monitored, with adverse events graded according to the NCI-CTCAE v5.0. These endpoints will be evaluated to provide a comprehensive assessment of the treatment's impact on disease progression, patient survival, and overall well-being.