Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization tastatic breast cancer treated with trastuzumab

Allan Lipton, Wolfgang J. Köstler, Kim Leitzel, Suhail M. Ali, Jeff Sperinde, Jodi Weidler, Agnes Paquet, Thomas Sherwood, Weidong Huang, Michael Bates

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39 Scopus citations


BACKGROUND: Only a portion of breast cancer patients currently selected for trastuzumab therapy respond. METHODS: Using a novel assay (HERmark) to quantify total human epidermal growth factor receptor 2 (HER2) expression, the authors examined outcomes in 102 trastuzumab-treated metastatic breast cancer patients previously assessed as immunohistochemistry (IHC) 3+ by local but not central IHC, or fluorescence in situ hybridization (FISH) positive, and then retested by central FISH. RESULTS: Of 102 MBC patients previously scored as IHC 3+ or 2+/FISH-positive and treated with trastuzumab-containing regimens, 98 had both central FISH and HER2 total expression values. Sixty-six of 76 central FISH-positive patients (87%) had high HER2 total expression levels (concordant positive), and 19 of 22 central FISH-negative patients (86%) were HER2 total expression low (concordant negative). Fourteen percent (3 of 22) of central FISH-negative patients were HER2 total expression high (discordant HER2 total expression high), and 13% (10 of 76) of central FISH-positive patients were HER2 total expression low (discordant HER2 total expression low). The concordant positive group had a significantly longer time to progression (TTP, median = 11.3 months) compared with the concordant negative group (median TTP, 4.5 months; hazard ratio [HR] = 0.42, P <.001), and also compared with the discordant HER2 total expression low group (median TTP, 3.7 months; HR = 0.43, P =.01). The discordant HER2 total expression low group behaved similarly compared with concordant negatives (HR = 1, P =.99). In analyses restricted to central FISH-positive patients only (n = 77), Cox proportional hazards multivariate regression identified HER2 total expression as an independent predictor of TTP (HR = 0.29, P =.0015) and overall survival (HR = 0.19, P <.001). CONCLUSIONS: A subset of patients with HER2 gene amplification by FISH express low levels of HER2 protein and have reduced response to trastuzumab-containing therapy, similar to FISH-negative patients. This cohort represents a training dataset, and the observed relationships and derived cutoffs require validation in an independent cohort of trastuzumab-treated metastatic breast cancer patients.

Original languageEnglish (US)
Pages (from-to)5168-5178
Number of pages11
Issue number22
Publication statusPublished - Nov 15 2010


All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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