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Evolving First-Line Endocrine Therapy in HR+/HER2- Metastatic Breast Cancer: CDK4/6 Inhibition, Biomarker-Guided

Hikmat Abdel-Razeq1,2, Baha Sharaf1

  • 1Section of Hematology and Medical Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan.

Current Oncology (Toronto, Ont.)
|July 27, 2026
PubMed

Insights

Hormone receptor-positive metastatic breast cancer treatment is shifting towards dynamic, biomarker-driven strategies. Integrating CDK4/6 inhibitors and liquid biopsies may improve outcomes and personalize care for patients.

Area of Science:

  • Oncology
  • Medical Genetics
  • Pharmacology

Background:

  • Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) is the most common subtype, primarily driven by estrogen receptor (ER) signaling.
  • Endocrine therapy (ET) is the standard first-line treatment, but resistance often limits efficacy.
  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have significantly improved outcomes in advanced HR+/HER2- MBC.

Purpose of the Study:

  • To review recent advances in the treatment of first-line HR+/HER2- MBC.
  • To highlight the impact of molecular profiling and emerging biomarkers on therapeutic strategies.
  • To discuss the integration of novel agents and technologies for improved patient care.

Main Methods:

  • Review of current literature and clinical trial data on HR+/HER2- MBC treatment.
  • Analysis of the role of CDK4/6 inhibitors, next-generation endocrine agents, and PI3K inhibitors.
  • Evaluation of circulating tumor DNA (ctDNA)-based liquid biopsy for resistance mutation detection.

Main Results:

  • CDK4/6 inhibitors have reshaped the treatment landscape, even in aggressive disease subsets.
  • Liquid biopsy enables real-time detection of resistance mutations, such as in ESR1.
  • Combination therapy with PI3K inhibitors (inavolisib) showed improved outcomes in PIK3CA-mutated patients.

Conclusions:

  • Treatment for first-line HR+/HER2- MBC is moving towards a dynamic, biomarker-driven approach.
  • Integrating CDK4/6 inhibitors with novel endocrine agents and liquid biopsy-guided therapy holds promise for delaying resistance and improving survival.
  • Personalized treatment strategies are essential for optimizing outcomes in advanced breast cancer.
Keywords:
CDK4/6 inhibitorsESR1HR-positivectDNAendocrine therapymetastatic breast cancer

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