Evaluation of Gene Expression-Driven Adjuvant Chemotherapy Versus Standard Care in Premenopausal HR-Positive/HER2-Negative Breast Cancer Using Paclitaxel and Drug Combination

The primary objective is to demonstrate the non-inferiority of a personalized treatment strategy, guided by Prosigna® gene expression profiling, compared to the standard of care involving adjuvant chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative early breast cancer. This evaluation focuses on invasive breast cancer free survival (IBCFS) as the key clinical outcome to determine if de-escalation of treatment can safely be applied to this population. 5

Secondary objectives include:

• Demonstrating the non-inferiority of endocrine therapy (ET) including ovarian function suppression (OFS) alone versus chemotherapy plus ET regarding IBCFS in patients with a Prosigna® score ≤60.
• Comparing the efficacy of Prosigna®-driven treatment against standard clinical practice using distant recurrence-free interval (DRFI), distant recurrence-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS).
• Assessing the impact of the personalized strategy on quality of life (QoL), including physical and psychosocial symptoms, and common breast cancer side effects.
• Evaluating health and safety outcomes, specifically osteoporosis, cardiovascular disease, and fertility, alongside health behaviors such as adherence to ET.
• Analyzing communication, uncertainties, and concerns related to treatment de-escalation trials.
• Establishing the cost-effectiveness of the Prosigna®-driven approach by assessing direct and indirect healthcare costs and quality-adjusted life years.
• Evaluating the perceived ease of use of the digital research platform.

This study involves 450 premenopausal female participants with breast cancer. The population consists of individuals aged 35 years or older diagnosed with invasive hormone receptor-positive (HR-positive) and HER2-negative primary tumors. Participants are selected based on specific tumor size and axillary lymph node status, requiring either involvement of 1-3 lymph nodes with any invasive tumor size, or node-negative status with an invasive tumor size of at least 50mm. The study population must have completed breast and axillary surgery within 12 weeks prior to randomization and possess an available formalin-fixed paraffin-embedded (FFPE) tumor sample for gene expression analysis. Inclusion requires the ability to undergo endocrine therapy and fitness to receive adjuvant chemotherapy. Bilateral or multiple ipsilateral breast cancers are permitted under specific clinical conditions regarding the contralateral or additional tumors.

This Phase III clinical trial evaluates a personalized treatment strategy for premenopausal women with high-risk HR-positive/HER2-negative breast cancer. The study utilizes a gene expression analysis via the Prosigna® assay to guide the decision between administering adjuvant chemotherapy or endocrine therapy alone. The primary objective is to demonstrate that a Prosigna®-driven approach is non-inferior to the standard of care in terms of invasive breast cancer free survival (IBCFS). Participants undergo a screening process to confirm eligibility based on tumor size, axillary lymph node status, and the availability of Formalin-Fixed Paraffin-Embedded (FFPE) tumor samples. Following randomization, participants receive assigned treatments, which may include agents such as letrozole, docetaxel, anastrozole, leuprorelin acetate, tamoxifen, epirubicin, doxorubicin, goserelin, triptorelin, exemestane, paclitaxel, or cyclophosphamide. The trial is expected to continue through March 2038. Secondary endpoints include assessments of distant recurrence free survival (DRFS), overall survival (OS), and various quality of life metrics.

Letrozole is administered via the oral route at a dosage of 2.5 mg.

Docetaxel is administered via intravenous infusion at a dosage of 100 mg/m2.

Anastrozole is administered via the oral route at a dosage of 1 mg.

Leuprorelin acetate is administered via subcutaneous injection at dosages of either 11.25 mg or 3.75 mg.

Tamoxifen is administered via the oral route at a dosage of 20 mg.

Epirubicin is administered via intravenous infusion at a dosage of 100 mg/m2.

Doxorubicin is administered via intravenous infusion at a dosage of 60 mg/m2.

Goserelin is administered via subcutaneous injection at dosages of either 10.8 mg or 3.6 mg.

Triptorelin is administered via subcutaneous injection at dosages of either 11.25 mg or 3 mg.

Exemestane is administered via the oral route at a dosage of 25 mg.

Paclitaxel is administered via intravenous infusion at a dosage of 175 mg/m2.

Cyclophosphamide is administered via intravenous infusion at a dosage of 600 mg/m2.

The primary efficacy endpoint is invasive breast cancer free survival (IBCFS), defined using the STEEP version 2.0 system as the interval from randomization to the first occurrence of ipsilateral loco-regional invasive breast cancer recurrence, distant breast cancer recurrence, contralateral new invasive primary breast cancer, or death from any cause.

Secondary endpoints include:

• IBCFS restricted to patients with a Prosigna score $\le$60.
• Distant recurrence free interval (DRFI), distant recurrence free survival (DRFS), and breast cancer specific survival (BCSS) in the global population.
• DRFI, DRFS, BCSS, and overall survival (OS) in the population with Prosigna scores $\le$60.
• Quality of life (QoL), physical and psychosocial symptoms, and frequent side effects assessed via EORTC QLQ-C30, BR42, GAD-7, PHQ8, FACT Cog, NCCN Distress thermometer, and return to work metrics.
• Health and safety outcomes, including osteoporosis (non-traumatic fractures), cardiovascular disease (major cardiovascular events, stroke, MI, heart failure, or cardiovascular deaths), fertility (number of pregnancies), physical activity levels (IPAQ), BMI, tobacco and alcohol consumption, and self-reported endocrine therapy (ET) adherence via VOILS.
• Psychological aspects including fear of cancer recurrence (FCRI-SF), motivation to enter the trial (SPECIFIC), treatment-related toxicity recall, decision conflict (SURE), and decision regret scale (DRS).
• Cost-effectiveness analysis summarized as the incremental cost-effectiveness ratio.
• Perceived ease of use (SUS) of the WeShare digital platform.