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In 356 patients whose pancreatic cancer was removed, the more of the four main driver genes were broken the worse the outcome, KRAS G12D was the worst allele, CDKN2A loss shortened survival, and SMAD4 status made no difference.
KRAS, CDKN2A, SMAD4 and TP53 were assessed by immunohistochemistry and next-generation sequencing in 356 resected pancreatic adenocarcinomas from Dana-Farber/Brigham, Rochester and Stanford. KRAS-mutant tumours had worse disease-free (12.3 versus 16.2 months) and overall survival (20.3 versus 38.6 months; 5-year 13.0% versus 30.2%) than wild-type; KRAS G12D carried median overall survival 15.3 months. Loss of CDKN2A expression gave disease-free survival 11.5 versus 14.8 and overall survival 19.7 versus 24.6 months. SMAD4 status was not associated with outcome; TP53 only with shorter disease-free survival (hazard ratio 1.33). Four altered genes against 0 to 2 gave a disease-free survival hazard ratio of 1.79; 5-year overall survival 18.4%, 14.1% and 8.2% for 0 to 2, 3 and 4 alterations.
The driver count is a prognostic score in itself, and the allele matters: G12D is the pancreatic allele with the worst outlook and the one the new selective inhibitors chase.
Shares KRAS G12D (and other non-G12C KRAS mutations), KRAS mutation subtypes (G12C, G12D, G12V), KRAS, Pancreatic ductal adenocarcinoma.
Shares SMAD4, CDKN2A, TP53, Resectable pancreatic ductal adenocarcinoma.
Shares SMAD4, CDKN2A, Dana-Farber Brigham Cancer Center, RAS / RAF / MEK / ERK (MAPK).
Shares SMAD4, TP53, KRAS, Pancreatic ductal adenocarcinoma.
Shares KRAS G12D (and other non-G12C KRAS mutations), KRAS mutation subtypes (G12C, G12D, G12V), RAS / RAF / MEK / ERK (MAPK), KRAS.