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High‐level ERBB2 gene amplification is associated with a particularly short time‐to‐metastasis, but results in a high rate of complete response once trastuzumab‐based therapy is offered in the metastatic setting
Author(s) -
Fuchs EvaMaria,
Köstler Wolfgang J.,
Horvat Reinhard,
Hudelist Gernot,
Kubista Ernst,
Attems Johannes,
Zielinski Christoph C.,
Singer Christian F.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28660
Subject(s) - trastuzumab , medicine , logistic regression , metastasis , oncology , proportional hazards model , breast cancer , gastroenterology , cancer
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 overexpressing 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's regression model. Tumors with ERBB2/centromer 17 ratios of <2.2 had a significantly shorter TTM ( p = 0.002) and significantly longer PFS ( p = 0.003) than tumors with low‐level ( R : 2.2–6) and high‐level amplification ( R : >6). Interestingly, when ERBB2 copy numbers were analyzed, 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.