First-Line Ribociclib Plus Endocrine Therapy Versus Chemotherapy With or Without Subsequent Endocrine Therapy in Patients With Rapidly Progressive HR-Positive/HER2-Negative Advanced Breast Cancer

Prior treatment

• Prior systemic anticancer therapy for recurrent or metastatic disease.
• Prior CDK4/6 inhibitor therapy in the neoadjuvant or adjuvant setting.

Other illness

• Known contraindication or serious hypersensitivity to ribociclib or the selected endocrine agent.
• Severe or active cardiovascular, hepatic, respiratory, renal, hematologic, infectious, or psychiatric disease that may increase risk or interfere with efficacy assessment.
• Inability to swallow oral medication or clinically significant gastrointestinal disease that may impair drug absorption.
• Clinical condition judged by the investigator to preclude safe systemic treatment.
• Any other condition that, in the investigator's opinion, makes participation inappropriate.
  • Eligibility for the historical external control cohort
  • The external control cohort must satisfy the same core disease, treatment-line, biomarker, rapid-progression, and measurable-disease criteria as the prospective cohort. The following retrospective adaptations are permitted:

Lab values

• Clinically significant uncontrolled cardiac disease, arrhythmia, congenital long-QT syndrome, uncorrected electrolyte abnormality, or baseline QTcF at or above 450 ms.
• Rapid disease progression will be determined from contemporaneous symptoms, laboratory findings, imaging descriptions, physician notes, and the treatment-decision context.
• Baseline laboratory values will be the closest available results within the prespecified window before the index chemotherapy date.

Other

• Symptomatic central nervous system metastasis requiring urgent local intervention. Treated, clinically stable, asymptomatic CNS metastasis may be permitted at investigator discretion.
• Pregnancy or breastfeeding.
• ECOG PS may be taken from an explicit medical-record entry. If functional descriptions are mapped to ECOG PS according to a prespecified rule, the inferred status will be flagged and excluded in sensitivity analyses.
• At least one measurable lesion must be retrospectively assessable according to RECIST 1.1. Patients with unavailable or inadequate imaging will be excluded.
• Patients with critically missing baseline covariates, treatment details, tumor-response information, or follow-up outcomes will be excluded according to prespecified data-quality rules.

• Female patient aged 18 years or older.
• ECOG PS of 0-2.
• Histologically or cytologically confirmed recurrent, metastatic, or unresectable locally advanced breast cancer not amenable to curative surgery or radiotherapy.
• HR-positive/HER2-negative disease: ER expression in at least 10% of tumor-cell nuclei; HER2 IHC 0 or 1+, or IHC 2+ with negative FISH/ISH. When metastatic-tissue pathology is available, the metastatic result is preferred.
• At least one feature of rapid disease progression, as determined by the investigator: symptomatic visceral metastasis; rapidly progressive disease or impending visceral compromise; or markedly symptomatic nonvisceral disease.
• No prior systemic anticancer therapy for recurrent or metastatic disease. Prior neoadjuvant or adjuvant therapy is permitted.
• At least one measurable lesion according to RECIST 1.1.
• Postmenopausal, premenopausal, or perimenopausal status. Premenopausal or perimenopausal patients must agree to receive OFS.
• Adequate baseline organ function: hemoglobin at least 90 g/L; white blood cell count at least 3.5 × 10\^9/L; absolute neutrophil count at least 1.5 × 10\^9/L; platelet count at least 100 × 10\^9/L; serum creatinine not above the institutional ULN; and clinically acceptable hepatic function.
• Negative pregnancy test for patients of childbearing potential and agreement to use effective contraception according to applicable product information and institutional requirements.
• Written informed consent and ability to comply with treatment and follow-up procedures.