High HER2 Protein Levels Correlate With Increased Survival in Breast Cancer Patients Treated With anti-HER2 Therapy

Mol Oncol. 2016 Jan;10(1):138-147. doi: 10.1016/j.molonc.2015.09.002. Epub 2015 Sep 15.

Abstract

Introduction: Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments.

Methods: Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy.

Results: Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting.

Conclusion: Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy.

Keywords: Breast cancer; HER2; Immunohistochemistry; In situ hybridization; Mass spectrometry; Trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Female
  • Humans
  • Lapatinib
  • Mass Spectrometry
  • Quinazolines / therapeutic use
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism*
  • Survival Analysis
  • Trastuzumab / therapeutic use

Substances

  • Antibodies, Monoclonal, Humanized
  • Quinazolines
  • Lapatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • pertuzumab
  • Trastuzumab