Abstract 5655: Association between tumor genomic variants and the long term post surgical recurrence as detected by a tumor informed ctDNA assay
Authors: Friedman Noah , Richters Megan , Ortiz J. Bryce , Burns Robert , Bristow Sara L. , Liu Minetta C. , Aleshin Alexey , Jurdi Adham , Costa Helio A. 
Published: March 2024

Abstract
Background: While surgical resection of early stage cancers is often curative, a number of patients will experience disease recurrence. Given the genomic heterogeneity of cancer, we hypothesized that different driver mutations present in a patient’s tumor may influence whether and when recurrence occurs. To investigate this, the association between the presence of driver mutations and rates of molecular residual disease (MRD) detection by circulating tumor DNA (ctDNA) was evaluated in patients with stage I-III colorectal cancer (CRC).
Methods: This was a retrospective evaluation of patients who underwent commercial ctDNA testing (SignateraTM) following curative surgical resection for stage I-III CRC from 2019 to February 2023. For this analysis, patients who were ctDNA-negative post-surgery (2-12 weeks) and had ctDNA testing performed between 6-24 months after surgery were included. Patients were stratified based on the presence or absence of mutations in driver genes and the associated percentage of patients with ctDNA-positivity over time was calculated.
Results: Of 11,436 patients with stage I-III CRC, 45.7% (5,230) had ctDNA testing performed between 2-12 weeks post-surgery. During this window, 81% (4,239/5,230) had a negative post-surgical ctDNA test result available. For this analysis, 78.4% (3,323/4,239), 46.7% (1,979/4,239), 24% (1,017/4,239) and 8.2% (348/4,239) had follow-up ctDNA testing performed for at least 6, 12, 18, and 24 months post-surgery, respectively. Certain driver mutations were associated with increased risk of post-surgical ctDNA-positivity rate. In patients with stage I CRC, APC mutations were associated with elevated rates of ctDNA positivity at 12 months [(APC-mutated: 13% (11/85) vs. APC-wildtype 3% (1/31); p=0.06)] and 18 months [(APC-mutated: 38% (12/32) vs. APC-wildtype: 6% (1/18); p=0.02)]. Interestingly, similar findings were not observed in stage II or stage III CRC. Similarly in patients with stage III CRC, SMAD4 mutations exhibited a substantially increased probability of ctDNA-positivity at 6 months [(SMAD4-mutated: 8% (15/194) vs. wildtype: 4% (54/1267) p=0.09)], 12 months [(SMAD4-mutated: 25% (32/129) vs. wildtype: 12.4% (102/817); p=0.0005)], and 24 months [(SMAD4-mutated: 69% (41/59) vs. wildtype: 53% (149/279); p=0.02)].
Conclusions: These findings point to several genomic alterations that may underlie cancer recurrence after a long period of undetectable disease with a differential impact across different stages. This may allow, in the future, for a personalized surveillance strategy based on driver mutations and stage of the disease. Correlation of ctDNA positivity with clinical outcomes based on driver mutational status may inform to what extent tumor-specific characteristics drive patient outcomes following a successful surgery.
Citation Format: Noah Friedman, Megan Richters, J. Bryce Ortiz, Robert Burns, Sara L. Bristow, Minetta C. Liu, Alexey Aleshin, Adham Jurdi, Helio A. Costa. Association between tumor genomic variants and the long term post surgical recurrence as detected by a tumor informed ctDNA assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5655.