Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma

Background American Joint Committee on Cancer (AJCC) staging for pancreatic adenocarcinoma is a validated predictor of prognosis but insufficiently discriminates postresection survival. We hypothesized that genetic analysis of resected cancers would correlate with tumor biology and postoperative survival. Methods Resected pancreatic ductal and ampullary adenocarcinomas (n=50) were analyzed for loss of heterozygosity (LOH) at 15 markers including 5q(APC), 6q(TBSP2), 9p(p16), 10q(PTEN), 12q(MDM2), 17p(TP53), and 18q(DCC/SMAD4). KRAS exon 1 mutations were detected by sequencing. The primary endpoint of this interim data analysis was survival at 18 month median follow-up. Results Negative margins were achieved in 43 (86%) cases. AJCC stage was: Ia/b (3), IIa (16), IIb (31). KRAS mutations were detected in 31 cases (62%) and LOH in 26 (52%) with mean fractional allelic loss score 23 +/- 16%. Median survival was significantly shorter with LOH (15.2 months versus not reached; p=0.021) and KRAS mutations (19.6 months versus not reached; p=0.038). Combining KRAS mutation with LOH was a powerful negative predictor in Cox regression (HR=10.6, p=0.006). Stage, nodal and margin status were not predictive of survival. Conclusion LOH and KRAS mutations indicate aggressive tumor biology and correlate strongly with survival in resected pancreatic ductal and ampullary carcinomas. Genetic analysis may improve risk stratification in future clinical trials.