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Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization-positive patients with metastatic breast cancer treated with trastuzumab†
Article first published online: 3 NOV 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 22, pages 5168–5178, 15 November 2010
How to Cite
Lipton, A., Köstler, W. J., Leitzel, K., Ali, S. M., Sperinde, J., Weidler, J., Paquet, A., Sherwood, T., Huang, W., Bates, M. and the Trastuzumab Response Biomarker Group (2010), Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization-positive patients with metastatic breast cancer treated with trastuzumab. Cancer, 116: 5168–5178. doi: 10.1002/cncr.25430
Data presented at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 10-14, 2008.
- Issue published online: 3 NOV 2010
- Article first published online: 3 NOV 2010
- Manuscript Accepted: 13 APR 2010
- Manuscript Revised: 7 APR 2010
- Manuscript Received: 8 DEC 2009
- metastatic breast cancer;
- predictive biomarker;
- fluorescence in situ hybridization;
Only a portion of breast cancer patients currently selected for trastuzumab therapy respond.
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.
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).
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. Cancer 2010. © 2010 American Cancer Society.