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The Effects of HER2 on CDK4/6 Activity in Breast Cancer

William D Sinclair1, Xiaoyan Cui2

  • 1Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, 43210, OH.

Clinical Breast Cancer
|October 5, 2021
PubMed
Abstract

Insights

HER2-positive breast cancer shows higher CDK4/6 activity, indicated by pRb levels. This suggests HER2-positive cases may benefit from CDK4/6 inhibitors, with pRb as a potential predictive biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are established treatments for hormone receptor-positive, HER2-negative advanced breast cancer.
  • The efficacy of CDK4/6 inhibitors in HER2-positive breast cancer remains largely undetermined.
  • Investigating the relationship between HER2 status and CDK4/6 activity is crucial for expanding treatment options.

Purpose of the Study:

  • To investigate the impact of HER2 (human epidermal growth factor receptor 2) on CDK4/6 activity in breast cancer.
  • To assess if HER2-positive breast cancer cases may be responsive to CDK4/6 inhibitors.
  • To evaluate phosphorylated retinoblastoma protein (pRb) as a potential biomarker for predicting response to CDK4/6 inhibitors.

Main Methods:

  • Analysis of 130 invasive breast carcinoma biopsies, categorizing them into HER2-positive (77 cases) and HER2-negative (53 cases).
  • Immunohistochemical assessment of pRb levels using the H-score (intensity multiplied by the percentage of positive cells).
  • Statistical comparison of pRb levels between HER2-positive and HER2-negative groups, and correlation analysis with HER2 gene copy number in HER2-positive cases.

Main Results:

  • HER2-positive breast cancer cases exhibited significantly higher pRb levels compared to HER2-negative cases (P = .001).
  • Average pRb H-scores were 115.8 ± 75.8 for ER-PR-HER2+, 93.1 ± 68.6 for ER+PR±HER2+, and 63.1 ± 65.6 for ER-PR-HER2-.
  • A non-significant trend towards positive correlation was observed between HER2 gene copy number and pRb levels in HER2-positive cases (r = 0.192, P = .09).

Conclusions:

  • HER2 positivity in breast cancer is associated with elevated CDK4/6 activity, as indicated by increased pRb levels.
  • HER2-positive breast cancers may potentially respond to CDK4/6 inhibitors.
  • pRb could serve as a predictive biomarker for patient response to CDK4/6 inhibitor therapy.
Keywords:
CDK4/6 inhibitorCDK=cyclin-dependent kinaseER=estrogen receptorHER2Phosphorylated retinoblastoma protein. Abbreviations: HER2=Human epidermal growth factor receptor 2Rb=retinoblastoma proteinbreast cancerpRb=phosphorylated retinoblastoma protein

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