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

作者：Nuciforo Paolo^*; Thyparambil Sheeno; Aura Claudia; Garrido Castro Ana; Vilaro Marta; Peg Vicente; Jimenez Jose; Vicario Rocio; Cecchi Fabiola; Hoos William; Burrows Jon; Hembrough Todd; Ferreres Juan Carles; Perez Garcia Jose; Arribas Joaquin; Cortes Javier; Scaltriti Maurizio^*

来源：Molecular Oncology, 2016, 10(1): 138-147.

DOI：10.1016/j.molonc.2015.09.002

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

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/mu g levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/mu g 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/mu g 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.

• 出版日期2016-1