Abstract
4547 Background: In preclinical tumor models, VEGF and MMP-9 induced each other, resulting in the enhancement of tumor angiogenesis and the formation of metastases. This study evaluated MMP-9 and VEGF in patients (pts) with metastatic gastric cancer. Methods: Patient tumor samples from a phase III trial of the AIO were prospectively collected. VEGF and MMP-9 mRNA were isolated from paraffin embedded tissues using a new patented method based on nanotechnology. The expression was then assessed by qRT-PCR and by immunohistochemistry (IHC). Results: A total of 137 (training cohort 96; validation cohort 41) out of 220 pts enrolled were analyzed. In the training cohort, increased MMP-9 levels were strongly associated with increased VEGF expression, resistance to chemotherapy and shorter progression-free and overall survival. At the cut-off with the highest predictive value, the rate of disease progression as best response associated with elevated MMP9 expression was 50% (vs. 22.4%; Fisher's test p=.027) and median overall survival (OS) was 3.1 months (vs. 8.7 months, log rank p=.0000165). This prognostic value for survival was maintained when data were analyzed in the multivariate setting (relative hazard ratio for death 3.67, p=.00045) or were categorized according to the quartile (p=.004) or median (p=.024) distributions for MMP-9. VEGF showed a prognostic effect in pts with low MMP-9 expression, only. In the validation cohort, the prognostic value of increased MMP-9 expression could be confirmed at the best cut off derived from the training cohort, with the hazard ratio for death being 3.45 (p=.02). Interestingly, in the IHC, stromal but not tumoral MMP-9 protein expression predicted survival (log rank p=.033). Conclusions: Tumoral MMP-9 mRNA expression levels are the first validated molecular prognostic factor in metastatic gastric cancer. These results have implications for novel anti-protease/ anti-VEGF treatment strategies. [Table: see text]
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