Pooled analysis of POLE-mutant colorectal cancer characteristics.

e15515 Background: Colorectal cancers (CRC) with pathogenic mutations in POLE (mPOLE) represent a unique subgroup with distinct clinical and molecular features and may exhibit a robust response to immune checkpoint blockade. Due to low prevalence, clinical features of this subgroup remain incompletely characterized. Methods: We utilized data from the Oncology Research Information Exchange Network (ORIEN) , using the Total Cancer Care (TCC) protocol in 18 centers across the US, to identify mPOLE CRC cases through October 2020. Prevalence, genomic and clinical features of mPOLE CRC within ORIEN were compared with other public databases, including AACR GENIE (version 8.0) , TCGA pan-cancer atlas, and a cohort from DFCI via cbioportal . Given the small sample size of mPOLE patients in each cohort, we pooled available data to compare characteristics of mPOLE CRC with CRC cases without pathogenic mutations in POLE (wtPOLE). Results: Detailed results are illustrated in the table. Out of 1564 CRC patients in ORIEN, 140 patients (9%) had POLE mutations, but only 11 patients (<1%) had pathogenic POLE mutations, compared to <2% in TCGA, <1% in DFCI, and <0.5% in the AACR GENIE cohorts. mPOLE CRC was associated with significantly higher tumor mutational burden and lower copy number alterations in all cohorts with data. In ORIEN, median age at diagnosis was significantly lower in mPOLE patients and at least 5 years younger than mPOLE patients from other cohorts. No other variable was statistically significant within ORIEN. When available clinical data from all cohorts were pooled, mPOLE was significantly associated with male sex, younger age at diagnosis, and early stage (I/II) disease. Conclusions: The ORIEN data set showed <1% patients with pathogenic POLE mutations. When pooled with the available public data sets, we see emergence of a unique clinical phenotype. Additional outcome data from ORIEN TCC database will be reported. We acknowledge the participation and assistance of the ORIEN investigators, with thanks. wtPOLE vs mPOLE in pooled and individual large cohort studies.[Table: see text]