Feldman, Rebecca A.

505 Background: MSI is a tumor biomarker for immunotherapy efficacy that is closely associated w/deficient MMR, and is also variably associated w/somatic muts of the MMR genes, loss of MMR protein expression by immunohistochemistry (IHC), and high TMB. Germ-line muts (Lynch syndrome/LS) in the 4 MMR genes are recognized to have distinct cancer spectrums/penetrance in LS, yet across all tumors, gene-specific variability in MMR IHC, MMR muts, and TMB is understudied. Methods: Results of TGPs performed by Caris Lifesciences (2015-17) were analyzed in colorectal (CRC), endometrial (EC) and all other cancers/tumors (OT) as: 1) all MSI-H tumors (n = 1057) and 2) all tumors w/ ≥1 mut in an MMR gene (n = 470). A subset of cases had IHC for MMR protein and PD-L1 expression. MSI and TMB were determined by NGS. Results: Characteristics of MSI-H tumors and tumors w/ ≥1 MMR mut are seen in the Table. A single MSH6 mut [F1088fs] in a coding microsatellite represented 31% of all MMR muts detected. F1088fs was found in 58% tumors w/MLH1/PMS2 loss (IHC) but only 25% w/MSH2/MSH6 loss (p < 0.001), was more commonly seen in EC vs CRC/OT (p < 0.001), and was negatively associated w/somatic POLE mut (p = 0.002). Distinct mut signatures in the MMR genes (e.g. GLUàSTOP) were seen in tumors w/POLE muts and DNA repair genes. Conclusions: MSI-H and MMR mutated tumors demonstrate marked gene-specific heterogeneity in IHC patterns, TMBs, and somatic muts that may be relevant to treatment selection, resistance, and response. [Table: see text]

289 Background: Cholangiocarcinoma (CC), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC) are all devastating malignancies. Limited data exists about PD-1 and PDL1 expression in these cancers. We assessed expression of PD1/PDL1 in a large cohort of patients with hepato-pancreatico-biliary (HPB) cancers and explored the existence of accompanying genomic mutations associated with expression of PD-1/PD-L1. Methods: 524 patients with HPB cancers (354 PDAC, 58 HCC, 54 intrahepatic (ICC), 18 extrahepatic (ECC), and 40 gallbladder (GBC)) were included in the study and tumors tested centrally at a CLIA lab (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (next generation sequencing, Illumina TruSeq), protein expression (immunohistochemistry [IHC]) and gene amplification). PD-1 (SP142 antibody) and PD-L1 (MRQ-22 antibody) status was tested in all samples. Two-tailed Fisher's exact test was performed to test where proportions of positive results were different by subgroup (p²0.05). Results: Among those with PDAC, HCC, ICC, ECC, and GBC, rates of PD1 expression on tumor infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells is detailed in the Table. In PD-1+, compared with PD-1- HPB cancers, mutations in the following were more prevalent, though not statistically significant: BRCA2, ATM, CTNNB1, and PIK3CA. Among all theranostic biomarkers tested, TOP2A expression (IHC) was significantly increased in PD-L1+ versus PD-L1- tumors (82% vs 60%; p=0.0083). Conclusions: HPB tumors express PD-L1 at a frequency of 4-18%, and PD-1 at a frequency of 29-45%. A statistically significant association of mutations with PD-1+ or PD-L1+ tumors was not identified in this group of tumors. PD-L1 expression associates with TOP2a expression, a marker of proliferation and also anthracycline sensitivity. Further evaluation of this correlation and PDL1/PD-1 + anthracycline combination therapy may be warranted. [Table: see text]