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Impact of PIK3CA Mutations on the Clinical Benefits of CDK 4/6 Inhibitors in HR+/HER2- Advanced Breast Cancer: An

Sheng-Fan Wang1,2,3,4, Chian-Ying Chou1,5, Yi-Wen Chao5

  • 1Department of Pharmacy, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou, Taipei 112, Taiwan.

Journal of Cancer
|July 31, 2025
PubMed

Insights

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and overall survival in advanced HR+/HER2- breast cancer. PIK3CA mutation status may impact CDK4/6i efficacy, especially in endocrine therapy-naïve patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer.
  • Challenges persist in identifying reliable biomarkers and determining overall survival (OS) outcomes for CDK4/6i therapy.

Purpose of the Study:

  • To systematically evaluate the clinical benefits and biomarker interactions of CDK4/6i in HR+/HER2- advanced breast cancer through an updated meta-analysis.
  • To assess the comparative efficacy of different CDK4/6i agents in specific patient populations.

Main Methods:

  • Systematic review and updated pairwise meta-analysis of randomized controlled trials.
  • Calculation of hazard ratios (HR) and 95% confidence intervals (CI) for progression-free survival (PFS) and OS.
  • Network meta-analysis to compare efficacy of different CDK4/6i agents and assess biomarker interactions, including PIK3CA mutation status.

Main Results:

  • CDK4/6i demonstrated significant improvements in PFS (HR 0.55) and OS (HR 0.80) for patients with HR+/HER2- advanced breast cancer.
  • PIK3CA mutation status emerged as a potential modifier of CDK4/6i efficacy, particularly in endocrine therapy-naïve patients (p=0.03 for interaction).
  • Network meta-analysis indicated comparable overall efficacy among CDK4/6i, with potential slight OS advantages for ribociclib over palbociclib in first-line settings.

Conclusions:

  • The updated meta-analysis confirms the overall survival benefit of CDK4/6i in HR+/HER2- advanced breast cancer.
  • PIK3CA mutation status appears to influence CDK4/6i efficacy more in endocrine therapy-naïve patients than in those receiving later-line therapy.
  • While approved CDK4/6 inhibitors show similar overall efficacy, individual clinical contexts may influence comparative effectiveness, warranting further investigation.
Keywords:
PIK3CAadvanced breast cancercyclin-dependent kinase 4/6hormone receptor-positivehuman epidermal growth factor receptor-2 negative

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