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Introduction: Matrix metalloproteinases degrade the extracellular matrix components allowing cell migration through the basement membrane, promote tumor-induced angiogenesis and proliferation. Among over two dozen endogenous MMPs, MMP1 (collagenase), MMP3 (stromelysin-1), and MMP12 (macrophage metalloelastase) contain putative functional polymorphisms and are located adjacent to each other on chromosome 11q22-23. MMP polymorphisms have been associated with both risk and outcomes of several cancers. Methods: We evaluated the MMP1 -1607 1G/2G, MMP3 -1171 5A/6A, MMP12 -82A/G and MMP12 -1082A/G polymorphisms in 100 incident cases of histologically confirmed locally advanced or metastatic pancreatic adenocarcinoma. Genotyping was performed by Taqman using the ABI 7900HT Sequence Detection System and in silico haplotyping using an expectation substitution approach. Results: Ninety percent of individuals had ECOG performance status (PS) of 0 or 1. Forty nine percent were stage 2, and 51% were stage 3 or 4. Median age was 64 years. Median progression free survival (PFS) was 15 months for stage 2, and 5.6 months for stages 3-4 patients. Median follow-up was 25 months. No significant associations were found for the MMP1 and MMP3 polymorphisms. For MMP12 -82AG and -357AG polymorphisms, 25% and 13% of the patients carried at least one variant allele, respectively. Within the group of patients with stage 2 disease, individuals carrying the MMP12 -82AA genotype had a PFS of 20 months, while for individuals carrying at least one MMP12 -82G allele the PFS was 7.5 months: the hazard ratio (HR) was 2.5 (95%CI 1.1-5.9) after adjustment for PS. Within the stage 3-4 patient group, PFS was 8.9 months in patients carrying the MMP12 -1082A/A genotype and 4.0 months in patients carrying at least one MMP12 -1082G allele: the HR was 3.1 (1.3-7.1). Results were similar when analyzing MMP haplotypes in place of individual polymorphisms. Conclusions: MMP polymorphisms have stage-specific effects on progression-free survival of pancreatic cancer patients.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA