583 TUMOR RESPONSE IN A PHASE 2 STUDY OF FIRST-LINE BRIVANIB IN HEPATOCELLULAR CARCINOMA (HCC): COMPARISON OF MODIFIED WHO AND MODIFIED RECIST CRITERIA

Abstract

were analyzed for the presence of mutation on 8 genes (TP53, CTNNB1, AXIN1, H-/K-/N-RAS, BRAF, PTEN). In addition, tumors were genotyped with diallelic markers for 14 chromosome arms frequently deleted in PLC. Results: One third of HCCs were presenting Wnt pathway alterations either on CTNNB1 (25%) or AXIN1 (7%). One hepatocellular and one cholangiocellular tumors were mutated for the RAS pathway. Among the rare TP53 mutations (7%), one was a R249S transversion, hallmark of aflatoxin B1 (AFB1) exposure. This mutation occured in the tumor from a HBs(+) patient who lifelong resided in Romania. Chromosome instability (CIN), was not restricted as elsewhere in Europe to chromosomes 17p and 8p but was rather involving several additional targets. The mean Fractional Allelic Loss (FAL) was 30% in HCC and 37% in cholangiocellular carcinomas i.e. values similar to that observed in regions with high mutagen exposure like Eastern-Asia. HCC patients living in cities were significantly younger than those from the countryside (mean 59±9 vs 66±6y.o., P = 0.03) and presented less differentiated tumors (Edmonson-Steiner III-IV 83 vs 30%, P = 0.01) with a trend for a higher CIN (FAL 33±8 vs 23±10 %, P = 0.08, NS). Conclusions: Molecular epidemiology of PLC in Romania is distinct from that observed in western Europe with a conspicuous high CIN. Furthermore, our data indicate that in selected cases AFB1 may play a role in liver tumorigenesis. The major differences observed between rural and urban patients emphasize the potentially important role played by environmental exposures in Romania. An increase of patients recruitment in the current series is, however, mandatory to confirm this preliminary analysis.