Comparative molecular analyses of pancreatic cancer (PC): Younger vs. older patients (pts)

Abstract

Background: There is limited data on molecular tumor characteristics and outcome in younger pts with PC. The effect of an individual's age on their tumor molecular profile is unknown. Methods: Molecular profiles-using protein expression (IHC), gene amplification (ISH) and sequencing-of PC tumors were reviewed and correlated with pt outcomes. A Chi-squared test determined differences between age groups; Kaplan-Meier methodology estimated survival. Results: In total, 2426 PC tumors were examined. The most frequently mutated genes were KRAS (85%), TP53 (63%), SMAD4 (13%), BRCA2 (12%), ATM/APC/NTRK1 (5% each), BRCA1 (4%), and cMET/PIK3CA (3% each) Subgroup analysis of tumors from 568 younger (median age 50; range 21-55 yr) and 1113 older (71; 65-90) pts was performed. When compared with older pts, younger pts' tumors had a greater frequency of mutations in MLH1 (4% vs. 0.3%, p = 0.003), PTEN (3% vs. 0.5%, p = 0.008), EGFR (2.2% vs. 0%, p = 0.003), CTNNB1 (2.3% vs. 0.5%; p = 0.04), c-KIT (2% vs. 0.3%; p = 0.02), and NTRK1 (20% vs. 0%; p = 0.002; assessed in only 10 and 45 pts, respectively), whereas KRAS mutations were significantly higher in older pts (80% vs. 70%, p = 0.0003). The mutation rates (older vs. younger) of BRCA1 (both 5%), BRCA2 (14% vs. 12%), BRAF (both 1%), GNAS (2.4% vs. 1.6%), PIK3CA (both 3%), NOTCH1 (0.9% vs. 1.6%), cMET (2.8% vs. 3.9%), and RET (0.4% vs. 0.8% were similar in both age groups. Older pts' tumors had higher rates of low RRM1 expression (85% vs. 79%, p = 0.03) and high PDGFR expression (22% vs. 7%, p = 0.03), whereas younger pts had higher TOP2A expression (59% vs. 50%, p = 0.02). There was no difference in either PD-L1 expression in tumor cells (8% vs. 7%) or the frequency of PD-1 expression on tumor-infiltrating lymphocytes (41% vs. 37%). Outcomes were evaluable for 73 pts. There were no survival differences between the two age groups. Low ERCC1, MGMT, PRM1, and TLE3 expressions appeared to be associated with prolonged survival in older but not younger pts; however, larger studies are needed to define the significance of this finding. Conclusions: Young pts with PC may carry genetic alterations that are different from older pts. A wider gene panel is needed to aid in the discovery of targeted mutations and provide therapeutic opportunities.