Cyclin-Dependent Kinase 4/6 (CDK4/6) Inhibitors in Early Breast Cancer Practice Guideline

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors:
    • Are indicated in early breast cancer primarily for patients with:
      • Hormone receptor-positive
      • HER2-negative
      • Node-positive breast cancer:
        • At high risk of recurrence
  • The American Society of Clinical Oncology (ASCO) recommends:
    • The use of abemaciclib in combination with endocrine therapy (ET) for these patients:
      • Particularly those who meet the criteria of the intention-to-treat (ITT) population from the monarchE trial:
        • This includes patients with resected breast cancer with:
          • ≥ 4 positive axillary lymph nodes (ALNs) or 1 to 3 positive ALNs plus additional high-risk features such as grade 3 disease, tumor size ≥ 5 cm, or a Ki-67 index ≥ 20% [1]
        • The rationale for this recommendation is based on the sustained improvement in invasive disease-free survival (IDFS) observed in the monarchE trial:
          • With a hazard ratio (HR) of 0.680 and a 5-year absolute improvement in IDFS of 7.6% compared to ET alone [1]
        • The FDA has expanded the approval of abemaciclib to include patients without the Ki-67 testing requirement:
          • Acknowledging benefits across the broader ITT population [1]
  • Ribociclib:
    • Is another CDK4/6 inhibitor evaluated in the NATALEE trial:
      • Which included patients with:
        • Stage II to III hormone receptor-positive
        • HER2-negative early breast cancer
    • However, ASCO’s panel suggests that ribociclib may not provide meaningful clinical benefit to all eligible patients:
      • Especially those with lower-risk disease, and recommends considering individual patient factors such as risks, benefits, costs, and preferences when deciding on its use [1]
  • The indications for cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in early breast cancer are:
    • Primarily for patients with hormone receptor-positive (HR+), HER2-negative breast cancer who are at high risk of recurrence
    • This includes patients with:
      • Node-positive disease and additional high-risk features
    • The monarchE trial:
      • Demonstrated a significant invasive disease-free survival (iDFS) benefit with the use of abemaciclib in combination with endocrine therapy (ET) in patients with:
        • Node-positive early breast cancer, leading to its approval for this indication [2]
    • The NATALEE trial:
      • Evaluated ribociclib in combination with ET in a broad population of patients with:
        • Stage II or III HR+, HER2-negative early breast cancer
      • The trial showed a significant iDFS benefit:
        • With a 25.2% lower risk of invasive disease, recurrence, or death compared to ET alone [2]
      • Ribociclib was administered at a dose of 400 mg per day:
        • Which was associated with a lower incidence of dose-dependent toxic effects compared to the higher dose used in advanced breast cancer [2]
  • The efficacy of CDK4/6 inhibitors in early breast cancer has been variable across different trials:
    • While the PALLAS and PENELOPE-B trials did not show a significant benefit with palbociclib, the monarchE and NATALEE trials demonstrated significant iDFS benefits with abemaciclib and ribociclib, respectively [2][3]
  • These findings highlight the importance of patient selection and the specific characteristics of the trials in determining the benefit of CDK4/6 inhibitors in early breast cancer
  • References:
Mechanisms of Action and Resistance in Estrogen Receptor (ER)–Targeted Therapy.
Burstein HJ. Systemic Therapy for Estrogen Receptor-Positive, HER2-Negative Breast Cancer. The New England Journal of Medicine. 2020;383(26):2557-2570. doi:10.1056/NEJMra1307118.
The mechanisms of action and resistance in estrogen receptor (ER)-targeted therapy, including the role of CDK4/6 inhibitors in inhibiting cell cycle progression in ER-positive breast cancer. This figure underscores the biological rationale for using CDK4/6 inhibitors in combination with endocrine therapy to improve outcomes in early breast cancer.
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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