Abstract 543: ctDNA MRD detection from plasma and urine and personalized oncogenomic analysis in oligometastatic colorectal cancer
Authors: Pellini Bruna , Pejovic Nadja , Feng Wenjia , Earland Noah , Harris Peter K. , Usmani Abul , Szymanski Jeffrey J. , Qaium Farid , Mudd Jacqueline , Kim Hyun , Tan Benjamin , Fields Ryan C. , Chaudhuri Aadel A. 
Published: July 2021

Abstract
BACKGROUND: Circulating tumor DNA (ctDNA) can detect molecular residual disease (MRD) in plasma after curative-intent treatment of non-metastatic solid tumor malignancy when prior mutational knowledge from either tumor or pre-treatment plasma is available. We hypothesized that ctDNA MRD analysis without prior mutational knowledge could be performed to assess oligometastatic colorectal cancer (CRC) treated with curative intent by applying an error-corrected ultra-deep targeted sequencing approach. We also investigated urine as an alternative analyte for ctDNA MRD detection in this non-genitourinary setting.
METHODS: We applied AVENIO, a ctDNA technology derived from CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) with integrated digital error suppression (iDES), to plasma, tumor, and urine samples acquired on the day of surgery from 24 prospectively enrolled oligometastatic CRC patients. We sequenced patients' white blood cell DNA to remove age-related clonal hematopoiesis variants. Plasma and urine ctDNA MRD detection were then correlated with residual disease present in tumor tissue, and adjuvant treatment strategies were proposed based on plasma ctDNA-inferred tumor mutational burden and targetable genomic alterations.
RESULTS: Tumor-naïve plasma ctDNA analysis detected MRD at a median level of 0.62% with 95% sensitivity and 100% specificity. Plasma ctDNA MRD levels correlated with tumor size at the time of surgery (ρ= 0.68, P = 0.0003) and were significantly lower in patients without evidence of disease in their surgical specimen compared to those with residual tumor cells (P = 0.02). In urine, ctDNA MRD detection specificity remained high at 100%, but sensitivity was lower at 64%, with median levels being 11-fold lower than in plasma (P &lt; 0.0001). Cell-free DNA fragments containing mutations were shorter in urine with an average size of 150.1 bp, compared to 180.2 bp in plasma (P &lt; 0.0001). Personalized ctDNA MRD oncogenomic analysis revealed that 81% of patients had a high inferred tumor mutational burden (&gt;10 mutations/megabase), and 10% also had a targetable PIK3CA mutation.
CONCLUSION: Tumor-naïve plasma ctDNA analysis can sensitively and specifically detect MRD in patients with oligometastatic CRC after neoadjuvant chemotherapy. Urine-based ctDNA MRD detection is also feasible in these patients; however, it is less sensitive than plasma. Analysis of oligometastatic CRC patients' ctDNA MRD also revealed potentially actionable results that might have implications for personalized adjuvant treatment regimens.
Citation Format: Bruna Pellini, Nadja Pejovic, Wenjia Feng, Noah Earland, Peter K. Harris, Abul Usmani, Jeffrey J. Szymanski, Farid Qaium, Jacqueline Mudd, Hyun Kim, Benjamin Tan, Ryan C. Fields, Aadel A. Chaudhuri. ctDNA MRD detection from plasma and urine and personalized oncogenomic analysis in oligometastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 543.