Evaluation of Extended Adjuvant Endocrine Therapy with Tamoxifen, Exemestane, Anastrozole, and Letrozole in High-Risk Luminal Breast Cancer Patients

The primary objective of this study is to evaluate the efficacy of extended adjuvant **endocrine therapy** in patients with high-risk luminal **breast cancer**. Specifically, the study aims to determine if a switching strategy involving 5 years of **aromatase inhibitors** (AI) is more effective than continued **tamoxifen** therapy for 5 years in women who have transitioned from premenopausal to postmenopausal status after an initial 5-year adjuvant tamoxifen therapy. Additionally, the study seeks to assess whether a switching strategy to 5 years of tamoxifen is more effective than 2 years of AI in postmenopausal women following an initial 5-year AI therapy. These objectives are clinically relevant as they aim to optimize long-term treatment strategies for reducing recurrence and improving survival outcomes in breast cancer patients.

The clinical trial focuses on **breast cancer** and involves a study population exclusively composed of female participants. The age range of the participants falls within categories 3 and 4, indicating a middle-aged to older adult population. The trial does not include male subjects or vulnerable populations. Participants were selected based on their menopausal status and previous treatment history. Specifically, the trial includes two cohorts: premenopausal women at diagnosis who have converted to postmenopausal status after completing a 5-year tamoxifen regimen, and postmenopausal women at diagnosis who have completed a 5-year aromatase inhibitor regimen. Both cohorts consist of women with high-risk luminal breast cancer, characterized by estrogen-receptor positivity and HER2-negative status, who have shown no clinical signs of metastasis after their initial treatment. The trial aims to evaluate the efficacy of extended adjuvant endocrine therapy using a switching strategy. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of extended adjuvant endocrine therapy in patients with **breast cancer**. This study employs a **randomized**, **controlled**, and **double-blind** methodology to ensure the reliability and validity of the results. The trial will span an estimated duration from January 1, 2024, to December 31, 2036, with the primary objective of assessing overall survival. Secondary endpoints include invasive disease-free survival, distant disease-free survival, breast cancer-specific survival, toxicity, quality of life, adherence, healthcare resource utilization, sick leave, and early retirement.

Participants will be divided into two cohorts based on their menopausal status at diagnosis. Cohort 1 includes women who were pre- or perimenopausal at diagnosis and have converted to postmenopausal status after an initial 5-year treatment with **tamoxifen**. Cohort 2 consists of postmenopausal women at diagnosis who have completed a 5-year treatment with **aromatase inhibitors** (AIs). The trial will investigate whether a switching strategy of 5-year AI therapy is more effective than continued tamoxifen therapy for Cohort 1, and whether a 5-year tamoxifen regimen is more effective than a 2-year AI regimen for Cohort 2.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as estrogen-receptor positivity and HER2-negative disease, followed by regular follow-up visits to monitor treatment adherence and assess clinical outcomes. The end-of-study visit will evaluate the primary and secondary endpoints. The expected length of participant involvement is up to 120 months, depending on the treatment arm. Conditions that may lead to early termination from the study include the development of clinical signs of metastasis or significant adverse events related to the study medication.

Participants will receive oral administration of the study drugs, which include **exemestane**, **anastrozole**, **tamoxifen**, and **letrozole**, with specific dosing regimens tailored to each cohort. The trial is categorized as low intervention, as it involves treatment strategies already in use in normal clinical practice for this indication. The study aims to optimize extended adjuvant endocrine therapy, potentially improving outcomes for patients with high-risk luminal breast cancer.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in optimizing extended adjuvant endocrine therapy in patients with breast cancer. **Exemestane** is one of the experimental medications used in this study. It is provided in the form of a film-coated tablet and is administered orally. The maximum daily dose of exemestane is 25 mg, and the treatment period can extend up to 120 days. Exemestane is a chemical substance and is classified as a generic medicinal product.

Another experimental medication used in the trial is **Anastrozole**, which is also administered as a film-coated tablet. The route of administration is oral, with a maximum daily dose of 1 mg. The treatment duration for anastrozole is similarly set at a maximum of 120 days. Anastrozole is a chemical compound and is categorized as a generic product.

**Tamoxifen** is included in the study as well, provided in tablet form and taken orally. The maximum daily dose for tamoxifen is 20 mg, with a treatment period extending up to 120 days. Like the other medications, tamoxifen is a chemical substance and is considered a generic medicinal product.

Lastly, **Letrozole** is utilized in the trial, available in tablet form and administered orally. The maximum daily dose for letrozole is 2.5 mg, and the treatment duration is capped at 120 days. Letrozole is a chemical substance and is classified as a generic product.

All medications in this trial are administered orally, and the study does not involve any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **overall survival**, which will be measured to determine the effectiveness of the treatment strategies. Secondary endpoints include invasive disease-free survival, distant disease-free survival, breast cancer-specific survival, toxicity (grade 3 or 4), quality of life, adherence, healthcare resource utilization, sick leave, and early retirement. These endpoints will provide a comprehensive evaluation of the treatment's impact on patients with high-risk luminal breast cancer.

The trial involves a registry-based randomized design to compare the efficacy of extended adjuvant endocrine therapy using a switching strategy. In premenopausal women who have converted to postmenopausal status after 5 years of tamoxifen, the trial will assess if 5 years of aromatase inhibitors (AI) is more effective than continued tamoxifen therapy. For postmenopausal women, the trial will evaluate whether 5 years of tamoxifen is more effective than 2 years of AI following an initial 5-year AI therapy. The trial is designed to reflect normal clinical practice, as the investigational medicinal products (IMPs) are already in use for this indication.