PROGNOSTIC AND PREDICTIVE VALUE OF ERBB2 AMPLIFICATION LEVEL

Int J Cancer. 2013 Dec 6. doi: 10.1002/ijc.28660. [Epub ahead of print]

High-Level ERBB2 Gene Amplification is Associated with a Particularly Short Time-to-Metastasis (TTM), but Results in a High Rate of Complete Response (CR) once Trastuzumab-based Therapy is Offered in the Metastatic Setting.

Fuchs EM, Köstler WJ, Horvat R, Hudelist G, Kubista E, Attems J, Zielinski CC, Singer CF.

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Abstract

Despite patient selection based on ERBB2-overexpression, not all patients benefit from trastuzumab therapy. We have investigated whether a ERBB2 gene dosage effect might provoke increased biological aggressiveness and altered trastuzumab sensitivity. Absolute ERBB2 copy numbers ("CN") and ERBB2/centromer 17 ratios ("R") were measured by FISH analysis in tumors of 127 patients receiving trastuzumab-based treatment for Her-2/neu over-expressing metastatic breast cancer. CN and R were both significantly associated with shorter time to first metastasis (TTM) (CN: OR: 1.099, 95% CI: 1.042-1.159; R: OR: 1.211, 95% CI: 1.080-1.357) and longer PFS (CN: OR: 0.917, 95% CI: 0.867-0.969; R: OR: 0.840, 95% CI: 0.743-0.949) in a continuous variable Cox Regression model. Tumors with ERBB2/centromer 17 ratios of <2 .2="" 2.2-6="" a="" amplification="" and="" had="" high-level="" longer="" low-level="" p="0.003)" pfs="" shorter="" significantly="" than="" ttm="" tumors="" with="">6). Interestingly, when ERBB2 copy numbers were analysed, a significantly shorter TTM (p=0.001) and longer PFS (p=0.026) were observed in the group with high-level amplified CN (CN:>13), while no difference was observed between non- and low-level amplified CN. R, but not CN, was an independent predictor of complete (CR; OR: 1.685; 95%CI: 1.122-2.532) and partial (PR; OR: 1.704; 95% CI: 1.136-2.556) response in Logistic Regression analysis. CR (p=0.016) rates were significantly higher in the high-level amplification group (R>6), but no difference existed in response rates between non- and low-level amplified tumors in Chi-Square tests.High-level ERBB2 amplification is associated with shorter TTM but improved response to trastuzumab in metastatic breast cancer. © 2013 Wiley Periodicals, Inc.