Abstract
427 Background: PC has not been well molecularly characterized and there is an unmet need in our understanding of the biological properties of PC. One previous study has found that the presence of CDKN2A mutations is an independent negative prognostic OS indicator. We evaluated molecular analysis on tumor specimens to determine whether increased mutational burden affects survival. Methods: PDAC samples from patients seen at the NYU Perlmutter Cancer Center at Winthrop Oncology Hematology Associates between 2015-2020 were profiled using next generation sequencing through Foundation Cdx. Genomic data was correlated with mined clinical data. Pt outcomes were correlated with the presence of mutations defined in 3 categories: 3 or less mutations, 4 mutations, 5 or more mutations. Results: Our cohort (N = 81) included 42% men and 58% women. 55% percent had primary (localized and locally advanced) disease and 44% had stage IV disease. Genetic mutations were most commonly found in KRAS, CDKN2A, TP53, NOTCH, SMAD4. Mutations seen less frequently were BRAF, HER2, RB1, ARID1A, MTAP, MLL, BRCA2. 43% of pts had 3 or less mutations, 15% 4 mutations, 42% had 5 or more mutations. There was no difference in number of mutations present between primary vs metastatic cancers. Median PFS was 13.5 months and overall survival (OS) for all pts was 20.0 months. The OS in primary group was 26.1 mos while it was 12.4 mos in the metastatic group. Patients with 5+ mutations had a 1.5 mos decreased OS and a 10% decreased 24-mos OS%. When stratified by primary (localized) disease, there was an 8.3 mos decrease in the 5+ mutation group vs 3 mutation group. When stratified by metastatic disease at diagnosis, there was no appreciable difference in OS between mutational groups. Conclusions: In the primary PC cohort, increasing burden of gene alteration patterns from 3 to 5+ mutations is correlated with decreased overall survival. The effect did not extend to the metastatic group likely due to disease burden driving survival whereas in primary PC group, survival reflected the tumor biology. This suggests that as additional carcinogenic pathways (DNA repair, growth, apoptosis) are mutated, tumor biology becomes more aggressive. This study provides an impetus for mutational profiling in early stage pancreatic cancer. These findings can contribute to the use of molecular profiles for prognostication and further development of targeted therapies. [Table: see text]
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