Abstract 450: Novel genomic differences in cell-free circulating tumor DNA (cfDNA) profiles of early versus older onset colorectal cancer (CRC)
Authors: Afsaneh Barzi, Carin R. Espenschied, Victoria M. Raymond, Richard B. Lanman, Heinz-Josef Lenz
Journal: Cancer Research (2019)

Abstract Background The incidence of early onset CRC, defined as a diagnosis under age 50 (&amp;lt;50), is steadily rising without an established cause. Small cohort studies have reported on tumor tissue sequencing results from patients (pts) &amp;lt;50 versus &amp;gt;50 and have included all cancer stages and grouped all mutation types. These studies found significant yet inconsistent genomic differences between cohorts concluding &amp;lt;50 CRC may have higher mutation rates and better survival. This study aimed to compare the cfDNA results in a large cohort of &amp;lt;50 versus &amp;gt;50 advanced CRC pts, which to our knowledge has not been reported. Methods Consecutive advanced CRC pts who received clinical cfDNA testing (Guardant360™) between 10/15-10/18 were analyzed. cfDNA analysis included next generation sequencing of 70-73 genes, assessing single nucleotide variants (SNVs), insertion/deletion alterations (indels), fusions, and amplifications (amps). High microsatellite instability (MSI-H) status was available for a subset of cases. Characteristics and mutation frequencies were compared between &amp;lt;50 and &amp;gt;50 groups, excluding variants of uncertain significance and synonymous alterations. Gene specific mutation frequencies were compared with Fisher’s exact test. Results Of 5341 stage IIIB-IV CRC pts tested, 4706 (88.1%) had alterations detected in cfDNA of which 984 (20.9%) were &amp;lt;50 and 3722 (79.1%) were &amp;gt;50. The &amp;lt;50 cohort was 51.7% male and the &amp;gt;50 cohort was 57.6% male. Both cohorts had a median of five alterations per pt (&amp;lt;50 range 1-207, &amp;gt;50 range 1-112). The median maximum variant allele fraction, including co-occurring amps, was 6.9% for the &amp;lt;50 cohort (range 0.02-94.9%) and 4.4% for the &amp;gt;50 cohort (range 0.03-97.1%). Of 2327 tested pts, MSI-H was detected in 3.3% (17/512) of &amp;lt;50 cases and 3.5% (64/1815) of &amp;gt;50 cases (not significant). In both cohorts SNVs and indels were most frequent in TP53, APC, KRAS, and PIK3CA. However, mutations in APC, KRAS, SMAD4, and ARID1A were more frequent in &amp;lt;50 CRC while &amp;gt;50 CRC had more TP53, ERBB2, and ATM mutations (all p&amp;lt;0.05). The most common amps in both cohorts were EGFR, BRAF, and CDK6 which may reflect aneuploidy, and MYC. BRAF, MYC, CCNE1, and CCND1 amps were more frequently observed in the &amp;lt;50 cohort (all p&amp;lt;0.03). RET, FGFR3, ALK, NTRK1, and FGFR2 fusions were seen in about 1% of both cohorts. Conclusions In the first comparison of cfDNA findings between &amp;lt;50 and &amp;gt;50 advanced CRC, significant differences in mutation and amp frequencies of several genes were observed, including genes important for prognosis and therapy selection such as KRAS and ERBB2. Rare but targetable biomarkers such as MSI-H and fusions were present in both age groups. Our previously unreported findings may be due to the strengths of this cfDNA analysis including a larger sample size, more uniform cancer stage, and stratification by mutation type. These results may help improve understanding and treatment of &amp;lt;50 CRC. Citation Format: Afsaneh Barzi, Carin R. Espenschied, Victoria M. Raymond, Richard B. Lanman, Heinz-Josef Lenz. Novel genomic differences in cell-free circulating tumor DNA (cfDNA) profiles of early versus older onset colorectal cancer (CRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 450.