Abstract
Abstract only 285 Background: Extrahepatic cholangiocarcinoma (EHCC), intrahepatic cholangiocarcinoma (IHCC), and gallbladder carcinoma (GBCA) are rare tumors with poor prognosis that tend to be chemo-resistant. The underlying molecular alterations and their correlation with altered responses to therapies are not well understood. We hypothesized that delineation of different molecular alterations in the cancer types might potentially yield different therapeutic options. Methods: 815 cases (126 EHCC, 434 IHCC, 244 GBCA, 11 NOS) were tested by a commercial multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Tests included sequencing (Sanger, NGS), gene amplification (CISH/FISH), and protein expression (IHC). Results: 24 of 47 genes tested had mutations, with the highest rates in TP53 (28%), KRAS (18%), IDH1 (9%), and SMAD4 (6%). BRCA1/2 mutations were seen in 3/41 (7.3%) and 5/40 (12.5%) cases. Overall,IHC showed high TOPO1, TOP2A, PD-1, SPARC and PD-L1 in 56%, 49%, 40%, 39% and 15% of cases and low RRM1, ERCC1 and TS in 82%, 72% and 79%, respectively, suggesting potential utility of chemotherapeutic and immunomodulatory agents targeting these alterations in selected cases. Mutually exclusive protein loss of chromatin modifiers BAP1 and PBRM1 were seen in 17% and 27%. ROS1 break-apart FISH showed negative results in 16 cases tested. Comparing the three carcinomas (EHCC, IHCC and GBCA, Table), EHCC had the highest KRAS mutation rate; IHCC had the highest IDH1 mutation; GBCA and EHCC had significantly higher TP53 mutation and HER2 amplification than IHCC.IDH1 and TP53 mutations were mutually exclusive, and IDH1-mutated IHCC had higher P-glycoprotein expression than TP53-mutated IHCC (82% vs. 37%). GBCA had high TOP2A by FISH and IHC, and a high loss of PBRM1(all p<0.05). Conclusions: Multiplatform cancer profiling reveals distinctbiomarker characteristics of biliary tract carcinomas, offering insights into disease biology and suggests potential sensitivity to novel and conventional therapies. Further analyses with clinical correlation are warranted. [Table: see text]