Early-onset colorectal cancer: Real-world genomic data from the community-based Sarah Cannon Cancer Centers Network.

198 Background: Rising incidence in early-onset colorectal cancer (EO-CRC) is a recent phenomenon observed especially in the US. We exploited Sarah Cannon’s web-based analytics platform, to compare the genomic profiles of EO-CRC to late-onset colorectal cancer (LO-CRC). Methods: Commercial NGS testing performed in oncology practices are routinely extracted and harmonized into the Genospace database. Data from CRC adenocarcinomas were selected; patients (pts) with unknown microsatellite instability (MSI) status were excluded. To reduce the confounding effect of MSI-high hypermutated tumors, only MSI-stable (MSS) tumors were analyzed. Reports generated from archival tissue samples were analyzed separately from those generated from plasma, since liquid biopsies were more likely to be post-treatment. Results: NGS reports from 1,477 MSS CRC pts were analysed. Compared to LO, EO pts had same sex distribution and significantly lower prevalence of Caucasian ethnicity (53% LO vs. 43% EO, p < 0.01). 1029 were tissue (18.7% EO) and 448 plasma (17.8% EO) tests. Of 68 CRC-related genes assessed in tissue, 2 were significantly enriched in EO: BRCA1 mutation (3% LO vs. 7.3% EO p 0.01); PTEN mutation (3% LO vs. 6.2% EO p 0.05). Looking at panel-wide gene association, 19 genes (tissue) were enriched in EO, though none were significant after multiple testing correction. In plasma, ATM alterations were significantly higher in LO (17.3% LO vs. 3.8% EO p <0.001, FDR 0.16), (likely clonal haematopoiesis). No difference in tissue nor plasma TMB were observed [tissue: median (IQ): LO 5.04 (3.5 - 7); EO 4.39 (2.5 – 6.1); TMB >10: 7% LO vs. 6% EO; plasma: median (IQ): LO 8.73 (5.7 – 13.4); EO 7.19 (2.9 – 12.6); TMB >10: 12% LO vs. 14% EO]. Overall, tissue and plasma genomic profiles were concordant, except for EGFR alterations (4.5% tissue, 21.6% plasma, possibly acquired amplification post-EGFR therapy). Conclusions: Here we provide real-world insight from pts across the US. In MSS CRC, tissue and plasma genomic profiles of EO pts do not significantly differ from LO pts. Epigenetic and transcriptional events should be investigated. Enrichment for BRCA1 and PTEN mutations in EO pts may have important screening and therapeutic implications; germline status will be further investigated.