Evaluation of Adjuvant Chemotherapy with Cyclophosphamide, Doxorubicin, and Docetaxel in ER-Positive HER2-Negative Breast Carcinoma in Women Over 70

The primary objective of this study is to evaluate the benefit of **adjuvant chemotherapy** on overall survival (OS) in a subgroup of elderly patients with a high risk of relapse according to **Genomic Grade (GG)**. This is clinically relevant as it aims to determine the efficacy of chemotherapy in improving survival outcomes in older patients with **oestrogen-receptor (ER)-positive HER2-negative breast carcinoma**, a population that may have different treatment responses and tolerances compared to younger cohorts.

Secondary objectives include:

• Overall survival (OS) considering competing mortality causes such as comorbidities, functional status, and nutritional status.
• Breast cancer-specific survival (BCSS) and non-specific survival.
• Health-related quality of life using QLQ C30 and the specific elderly scale QLQ-ELD15.
• Invasive disease-free survival (iDFS) and distant DFS (dDFS).
• Event-free survival (EFS).
• Relapse-free survival (RFS) and distant RFS (dRFS).
• Toxicity assessment using NCI-CTC V4.0.
• Geriatric assessment and G8 validation in an elderly breast cancer population.
• Prospective validation of a 4-year mortality score and its French version in an elderly cancer population.
• Q-TWiST analysis.
• Evaluation of treatment acceptability through a willingness test questionnaire.
• Prognostic value of GG by RT-PCR and test performance in the elderly breast cancer population compared to standardized histopathological criteria.
• Cost-effectiveness analysis to assess the medico-economic impact of introducing adjuvant chemotherapy for women over 70 with a high risk of relapse according to GG.
• Follow-up of a cohort of elderly breast cancer patients not treated with adjuvant chemotherapy, including those not eligible due to GG.
• Prospective banking of frozen, formalin-fixed tumor, and frozen serum and blood for future translational studies in genomics and proteomics.
• An ancillary study objective applicable only for France: evaluating the prognostic value of GG testing on iDFS and D-DFS/D-RFS for the first 500 patients included in the screened population with a follow-up of 36 months.

The clinical trial focuses on evaluating the benefit of adjuvant chemotherapy on overall survival in elderly patients with a high risk of relapse due to **oestrogen-receptor (ER)-positive HER2-negative breast carcinoma**. The study population comprises women aged 70 years and older, with a creatinine clearance of at least 40 mL/min and a performance status (ECOG) of 2 or less. Participants must have undergone complete surgery, either radical modified mastectomy or breast-conserving surgery, with sentinel lymph node procedure or axillary lymph node dissection. The trial excludes individuals with clinically or radiologically detectable metastases. Participants are required to have normal haematological and hepatic function prior to genomic grade evaluation. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring participants are able to comply with the protocol and have signed informed consent. The study does not include male or vulnerable populations, and lifestyle factors such as diet and physical activity are not specified.

The clinical trial is designed to evaluate the benefit of adjuvant chemotherapy on overall survival in elderly patients with **oestrogen-receptor (ER)-positive HER2-negative breast carcinoma**. This is a multicenter, phase III trial employing a randomized, double-blind, controlled design. The trial is expected to run from April 2012 to April 2026, with a median follow-up period of four years. Participants will be randomly assigned to receive either chemotherapy combined with endocrine treatment or endocrine treatment alone. The primary endpoint is overall survival, while secondary endpoints include breast cancer-specific survival, invasive disease-free survival, and quality of life assessments, among others.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age, creatinine clearance, and performance status. Participants must have histologically proven invasive breast cancer and have undergone complete surgery prior to enrollment. Follow-up visits will occur regularly to assess treatment efficacy, monitor adverse events, and evaluate quality of life using standardized questionnaires. The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any long-term effects.

Participant involvement is expected to last up to 12 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events that compromise safety, or withdrawal of consent. The trial will utilize **cyclophosphamide**, **doxorubicin hydrochloride**, **doxorubicin**, and **docetaxel**, all administered via intravenous use, with specific dosing regimens tailored to each participant's needs. The trial aims to provide valuable insights into the effectiveness of chemotherapy in improving survival outcomes for this specific patient population.

The clinical trial involves the administration of several **experimental medications**. **Cyclophosphamide** is provided in the form of a **powder for solution for injection**. It is administered via **intravenous use** with a maximum daily dose of 600 mg/m² and a maximum total dose of 2400 mg/m² over a treatment period of 12 weeks. The active substance is of chemical origin, and the formulation is not pediatric.

**Myocet liposomal**, containing **doxorubicin hydrochloride**, is supplied as a **powder, dispersion, and solvent for concentrate for dispersion for infusion**. This medication is also administered intravenously. The maximum daily dose is 60 mg/m², with a total dose not exceeding 240 mg/m² over 12 weeks. The product is chemically derived and is not formulated for pediatric use.

**Doxorubicin** is available as a **solution for injection** and is administered intravenously. The dosing schedule allows for a maximum daily dose of 60 mg/m² and a total dose of 240 mg/m² over a 12-week period. The active substance is of chemical origin, and the formulation is not intended for pediatric patients.

**Docetaxel** is provided as a **solution for infusion** and is administered via intravenous use. The maximum daily dose is 75 mg/m², with a total dose limit of 300 mg/m² over a 12-week treatment period. The active substance is chemically derived, and the formulation is not pediatric.

All medications are administered under strict compliance monitoring to ensure adherence to the dosing schedules. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy of these chemotherapeutic agents in the specified patient population.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, which will be evaluated with a follow-up period of four years. Secondary endpoints include **Breast Cancer-Specific Survival (BCSS)**, **Invasive Disease-Free Survival (iDFS)**, **Event-Free Survival (EFS)**, **Relapse-Free Survival (RFS)**, and the evaluation of toxicity. Quality of life will be assessed using the national version of EORTC QLQ-C30 (version 3) and QLQ-ELD15, which is a supplement module for evaluating quality of life in elderly cancer patients. Additional analyses will include Q-TWiST, geriatric assessment, treatment acceptability, and the predictive value of a four-year mortality score.

The trial will also explore the usefulness of Genomic Grade (GG) by RT-PCR as a prognostic signature, comparing its performance in an elderly population to standardized routine histopathological criteria and results obtained in the general non-elderly population. A cost-effectiveness analysis will be conducted, and a cohort of elderly breast cancer patients not treated with adjuvant chemotherapy will be followed. An ancillary study will assess the prognostic value of HalioDx GG testing on iDFS and D-DFS/D-RFS in the first 500 patients with a follow-up of 36 months. These efficacy parameters will be measured and collected at specified intervals throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on the patient population.