P5-13-07: MET and Hepatocyte Growth Factor (HGF) Increased Gene Copy Number Is Associated to Trastuzumab Failure in HER2 Positive Metastatic Breast Cancer (MBC).
Authors: Minuti G , Duchnowska R , Jassem J , Roncalli M , O'Brien T , Fabi A , Landi L , Di Marsico R , Biernat W , Czartoryska-Arlukowicz B , Jankowski T , Zuziak D , Zok J , Szostakiewicz B , Foszczynska-Kloda M , Tempinska-Szalach A , Rossi E , Varella-Garcia M , Cappuzzo F 
Published: June 2012

Abstract
Background: The ErbB2-targeting monoclonal antibody trastuzumab has remarkable efficacy in metastatic breast cancer (MBC) patients (pts) with HER2 overexpression or amplification (HER2+), either alone or in combination with chemotherapy. However, the response rate to trastuzumab is modest and not all pts derive benefit from this treatment. Predictive mechanisms of sensitivity and/or resistance are largely unknown. Recently, preclinical and limited clinical data showed that aberrant MET expression in MBC is a predictor of poor prognosis and is involved in trastuzumab resistance. Aim of the present study was to investigate whether increased gene copy number of MET or its ligand, the hepatocyte growth factor (HGF), affect trastuzumab sensitivity.
Patients and Methods: This retrospective study included 130 HER2+ MBC pts treated with trastuzumab as monotherapy (N=21) or in combination with chemotherapy (N=109). Main inclusion criteria were presence of at least one measurable lesion and availability of paraffin-embedded tumor tissue from primary cancer. MET and HGF gene copy number (GCN) were assessed by fluorescence in situ hybridization (FISH). Receiver operating characteristic (ROC) analysis was used for identifying the best MET and HGF mean GCN cut-off.
Results: In the whole population response rate (RR), including complete (CR) and partial response (PR) was 49.2%, disease control rate, including CR+PR+ stable disease (SD) was 76.2%, median time to progression (TTP) 9.4 months, and median survival (OS) 28.3 months. MET FISH analysis was successfully performed in all 130 cases. Median MET mean GCN was 2.96 (range 1.66−8.40), with no gene amplification. ROC curve identified a mean of 3.72 MET GCN as the optimal cut-off value for discriminating between sensitive (CR+PR+SD) and refractory pts (pts with progressive disease [PD] at the first disease assessment). MET FISH+ (N=36, mean ≥3.72) had a significantly higher PD rate (44.4% versus 16.0%; p=0.001) and a significantly shorter TTP (5.7 versus 9.9 months; HR 1.74 95% C.I. 1.16−2.62; p=0.006) than MET FISH- pts (N=94, mean &lt;3.72). HGF GCN was successfully evaluated in 84 pts (64.6%). Median HGF mean GCN was 2.80 (range 1.14−6.90). ROC analysis identified a cut-off of 3.01 mean HGF GCN as the best discriminating between sensitive (CR+PR+SD) and refractory pts. HGF FISH+ (N=33, mean ≥ 3.01) had a significantly higher PD rate (30.3% versus 7.8%; p=0.007) and a non-significant shorter TTP (9.9 versus 10.5 months, HR 1.10 95% C.I. 0.70−1.74, p=0.66).
Conclusions: High GCNs of MET or HGF associate with an increased risk of trastuzumab failure in HER2+ MBC. These data support a further development of combining anti-HER2 with anti-MET strategies in MBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-07.