High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy

Paolo Nuciforo, Sheeno Thyparambil, Claudia Aura, Ana Garrido-Castro, Marta Vilaro, Vicente Peg, José Jimenez, Rocio Vicario, Fabiola Cecchi, William Hoos, Jon Burrows, Todd Hembrough, Juan Carles Ferreres, José Perez-Garcia, Joaquin Arribas, Javier Cortes, Maurizio Scaltriti

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62 Citations (Scopus)


© 2015 The Authors. 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.
Original languageEnglish
Pages (from-to)138-147
JournalMolecular Oncology
Issue number1
Publication statusPublished - 1 Jan 2016


  • Breast cancer
  • HER2
  • Immunohistochemistry
  • In situ hybridization
  • Mass spectrometry
  • Trastuzumab


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