Genomic profiling of biliary tract carcinomas by their location.

person Zoran Gatalica Exact Sciences, Phoenix, AZ info_outline Zoran Gatalica, David K. Edwards, Cynthia A. Flannery, David W. Hall, Jess R Hoag, Nishitha Therala, Janine R. LoBello, Snehal Govind Thakkar, Gargi D. Basu, Maen Abdelrahim

Authors person Zoran Gatalica Exact Sciences, Phoenix, AZ info_outline Zoran Gatalica, David K. Edwards, Cynthia A. Flannery, David W. Hall, Jess R Hoag, Nishitha Therala, Janine R. LoBello, Snehal Govind Thakkar, Gargi D. Basu, Maen Abdelrahim Organizations Exact Sciences, Phoenix, AZ, Exact Sciences, Redwood City, CA, Houston Methodist Cancer Center, Houston, TX Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Exact Sciences Background: Historically, biliary tract cancers have had a poor prognosis. Genomic profiling allows identification of alterations in genes with FDA-approved matched therapies either in these cancers ( FGFR2/3 fusions, certain IDH1 missense mutations), in all solid tumors (e.g. BRAF V600E mutations), or in other cancers (e.g. BRCA1/2 loss-of-function mutations) that could inform treatment. Here we examine the frequency of matched therapies in biliary tract carcinomas and the association with tumor location. Methods: All biliary tract carcinoma patient samples receiving the OncoExTra assay between April 2018 and November 2022 were included. The assay uses tumor-normal, whole-exome, whole-transcriptome sequencing to identify genomic alterations. Alterations in genes with FDA-approved matched therapies in any cancer, with matched clinical trials, or with evidence in cancer guidelines or the literature for possible matched therapies were recorded. Results: A total of 155 patient samples were processed: 92 intrahepatic CCA, 34 gall bladder carcinomas, 9 extrahepatic CCA, and 20 ampulla of Vater carcinomas. Targetable alterations were found in 153 (98.7%) samples; 31 (20.3%) had FDA-approved matched therapies, including 5 (3.3%) with microsatellite unstable and/or tumor mutational burden-high (eligible for immunotherapy) and 7 (4.6%) homologous recombinational repair deficient. Alterations of several genes showed a significant association with tumor type (Table). Cancers in the ampulla of Vater were enriched for KRAS , APC and ARID2 alterations; TP53 alterations were less frequent in biliary tract/intrahepatic cancers. Among the 15 FGFR1/2/3 alterations, there were 3 amplifications (1 FGFR1 , 1 FGFR2 , 1 FGFR3 ), 3 missense FGFR2 mutations, and 9 FGFR2 fusions. Conclusions: Comprehensive genomic profiling of biliary tract cancers identifies numerous targetable alterations. The distribution of altered genes varies, suggesting that appropriate therapies may differ by location, reflecting different lineage types. Distribution of gene alterations across biliary tract carcinomas for genes altered in ≥7% of samples. Co-mutated biomarker Samples with alteration (of 155 samples) Intrahepatic CCA (N=92) Gallbladder (N=34) Extrahepatic CCA (N=9) Ampulla of Vater (N=20) p-value q-value TP53 62 (40%) 23 (25.0%) 21(61.8%) 6 (66.7%) 12 (60.0%) <0.001 0.003 KRAS 57 (36.8%) 32 (34.8%) 7 (20.6%) 3 (33.3%) 15 (75.0%) <0.001 0.020 ARID1A 26 (16.8%) 14 (15.2%) 8 (23.5%) 3 (33.3%) 1 (5.0%) 0.15 0.40 FGFR1/2/3 15 (9.7%) 14 (15.2%) 1 (2.9%) 0 (0.0%) 0 (0.0%) 0.063 0.33 APC 14 (9%) 4 (4.3%) 3 (8.8%) 1 (11.1%) 6 (30.0%) 0.006 0.083 IDH1 13 (8.4%) 12 (13.0%) 1 (2.9%) 0 (0.0%) 0 (0.0%) 0.14 0.40 BAP1 12 (7.7%) 11 (12.0%) 0 (0.0%) 0 (0.0%) 1 (5.0%) 0.12 0.38 CDKN2A 12 (7.7%) 6 (6.5%) 2 (5.9%) 2 (22.2%) 2 (10.0%) 0.3 0.54 PIK3CA 12 (7.7%) 8 (8.7%) 3 (8.8%) 0 (0.0%) 1 (5.0%) >0.99 >0.99 ARID2 11 (7.1%) 3 (3.3%) 2 (5.9%) 1 (11.1%) 5 (25.0%) 0.011 0.099