1304P Characterizing the clinico-genomic landscape and outcomes of KRAS G12C mutated pancreas cancer

Abstract

KRAS is a critical oncogenic driver of malignancy and KRAS mutations are observed in >90% of pancreas cancer (PC). KRASG12C mutations (G12C) occur in 1-2% of PC and allele specific inhibitors of G12C have entered the clinic. Herein, we evaluate comprehensive clinico-genomic data in a sizeable cohort of PC with G12C. Patients at Memorial Sloan Kettering with PC and G12C were identified using MSK-IMPACT, or through circulating tumor DNA (ctDNA) by MSK-ACCESS. Clinical data (demographics, anthropometric data, lifestyle risk factors), tumor details, treatment patterns, survival outcomes, and genomic data, were analyzed. Genomic data of patients with PC and G12C from the AACR Project GENIE registry were also included. N=40 with PC and G12C from MSK were identified between 2012 and 2022. Female (22/40, 55%); age >60 years (33/40, 83%), BMI >25 (25/32, 82%), with active/previous smoking history (68%, 27/40), were observed. Histology: Adenocarcinoma (36/40, 90%), adenosquamous (2/39, 5.1%), neuroendocrine (1/40, 2.5%), intraductal papillary mucinous neoplasm (1/40, 2.5%). Most (27/40, 68%) had stage III/IV disease at diagnosis. For stage I, II, preinvasive disease 13/13 (100%) underwent resection. Median overall survival for the entire group (N= 40) 19.4 months, and 13.1 months for de novo metastatic disease (N=17, 43%). N=3 received an inhibitor of G12C. Several G12C were identified by ctDNA. Genomic data for N=74 (AACR Project GENIE, including overlap from above clinically annotated MSK patients) are presented in the table.Table: 1304PSomatic Variants - Canonical Oncogenic Variants (AACR Project GENIE and MSK)Total N=74%TP535372CDKN2A2534SMAD42230Somatic Variants - Select Other Oncogenic Variants (AACR Project GENIE and MSK)Total N=74%ARID1A1520Germline Variants (MSK only)Total N=35%Pathogenic/likely pathogenic variants720Microsatellite Instability Status by MSI Sensor (MSK only)Total N=34%Microsatellite Stable (MSS)3392Microsatellite Unstable (MSI)1* (*POLD1 mutation)3Tumor Mutational Burden (MSK only)Total N=37Median (Mutations/Mb)4.9Range (Mutations/Mb)0.9 – 44.8* (*POLD1 mutation) Open table in a new tab PC with G12C represents a small, but important subset of patients. Notable characteristics include smoking history, overweight/obese and 20% with germline alterations. The somatic co-mutational spectrum appears typical of PC, with notable findings of ARID1A gene variant enrichment (20%) and slightly higher median TMB, noted. Ongoing studies are establishing the role of direct KRASG12C inhibition with single/combination strategies.