Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis

SIMPLE SUMMARY: Over the past few years, a great deal of considerable research has been conducted to develop more effective targeted agents for metastatic breast cancer (mBC) patients. This systematic review and meta-analysis of 47 randomized clinical trials identified CDK4/6i + Fulvestrant 500 as the best treatment option in improving efficacy outcomes in endocrine therapy-sensitive (ETS) patients. Chemotherapy had a higher likelihood of therapeutic success in endocrine therapy-resistant (ETR) patients. In ETR settings, with visceral and bone metastases, CDK4/6i +Fulvestrant 500 was the best regimen, while in ETS patients, CDK4/6i + Fulvestrant 500 was the best for bone metastases and CDK4/6i + aromatase inhibitors (AI) for visceral metastases. This study assessed the relative efficacies and provided a rank order of ET-based regimens in the key endpoints PFS and OS for HR+/HER2- mBC patients with different endocrine sensitivity statuses. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice. ABSTRACT: Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (mBC). Methods: We performed a systematic search with a predefined search strategy in PubMed, Embase and Cochrane CENTRAL databases to perform a network meta-analysis and evaluate the relative efficacies of ET-based treatment regimens in HR+/HER2- mBC patients with different endocrine sensitivity statuses. The study was registered in the PROSPERO database (CRD42021235570). Results: A total of 47 trials (20,267 patients) were included. Analysis of progression-free survival (PFS) in endocrine therapy-sensitive (ETS) patients revealed cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) + fulvestrant 500 mg (Ful 500) (random effect (RE): hazard ratio (HR), 0.46; 95% credibility interval (CrI), 0.27–0.78; surface under the cumulative ranking curve (SUCRA), 0.93; fixed effect (FE): HR, 0.48; 95% CrI, 0.40–0.58; SUCRA, 0.99) to be the best therapy followed by CDK4/6i + aromatase inhibitors (AIs) (RE: HR, 0.53; 95% CrI, 0.40–0.72; SUCRA, 0.86; FE: HR, 0.54; 95% CrI, 0.48–0.61; SUCRA, 0.91). Chemotherapy followed by CDK4/6i + Ful 500 appears to be the most effective option for the endocrine therapy-resistant (ETR) group. Analysis of overall survival revealed CDK4/6i + Ful 500 (SUCRA: 0.99) and AKTi + Ful 500 (SUCRA: 0.87) to be the first-rank regimen for the ETS group and ETR groups, respectively. Conclusion: Our comprehensive analysis suggests that CDK4/6i combined with ETs may be the best treatment option in terms of PFS for ETS patients and chemotherapy for ETR patients with HR+/HER2- mBC. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice.