Metastatic bulk to predict subclonal heterogeneity by ctDNA in RAS/RAF-wildtype colorectal cancer.

186 Background: Distinct molecular subgroups of colorectal cancer (CRC) have been afforded with use of next-generation sequencing (NGS) as standard in clinical practice for advanced disease. We have previously demonstrated that disease bulk predicts clinical resistance to EGFR inhibition in RAS/RAF-wildtype (WT) CRC. We hypothesized bulky disease would predict advanced subclonal heterogeneity by circulating tumor DNA (ctDNA) in RAS/RAF CRC. Methods: Following IRB-approval, a retrospective review of molecular profiles in advanced CRC (n = 965) were compiled from the Veteran Administration’s (VA) National Precision Oncology Program (NPOP) and University of Wisconsin Precision Medicine Molecular Tumor Board (MTB). Disease bulk was defined as the longest diameter of metastatic disease or short axis for advanced lymphadenopathy. Molecular profiling was performed using commercially available platforms including Strata Oncology (MTB) and FoundationOne (NPOP). Bulky was compared as categorical (> 35 cm) and continuous variable against the count of pathologic variants. Results: The population was largely representative of advanced CRC with alterations in TP53 (80.5%), KRAS (44.8%), PIK3CA (22.0%) and BRAF (12.8%). Veterans had increased frequency of alterations in PIK3CA (22.7% v. 13.0%, p < 0.02) and BRAF (13.3% v. 6.9%, p < 0.05). There was no difference in metastatic bulk at the time of NGS for tissue biopsy between MTB and NPOP populations (t = 0.80). Disease bulk did not predict the number of pathologic variants from tissue sampling in RAS/RAF CRC (n = 96, t = 0.24). RAS/RAF cancers had increased frequency of subclonal alterations by ctDNA (9.1±4.0) v. RAS/RAF (4.5±3.4, p < 0.0001). Using ctDNA, bulky disease in RAS/RAF CRC was not predictive of increased pathologic variants (8.8±3.5 v. 9.5±4.8, t = 0.62). Bulky disease (> 35mm) in RAS/RAF CRC predicted increased subclonal variants (6.2±3.6 v. 3.5±2.9, p < 0.02). As a continuous variable, disease bulk predicted the number of pathologic variants in RAS/RAF CRC (R = 0.51). Conclusions: These data indicate that metastatic bulk is a predictor of subclonal heterogeneity by ctDNA in RAS/RAF CRC. Molecular profiling of tissue alone did not predict differences in subclonal heterogeneity when stratified by disease bulk in RAS/RAF CRC. Limited subclonal heterogeneity in non-bulky cancers support ongoing prospective investigations to select non-bulky cancers for early incorporation of anti-EGFR inhibition (NCT04587128).

Duke Scholars

Author Michael John Kelley Medicine, Medical Oncology