Impact of a metastatic site on circulating tumor DNA (ctDNA) analysis in patients (pts) with metastatic colorectal cancer (mCRC).

Abstract

3554 Background: ctDNA genotyping has been used as an alternative to tissue genotyping for precision oncology. In mCRC, although low plasma RAS variant allelic frequencies (VAFs) and low concordance with tissue RAS tests have been reported in pts with lung-only metastasis (mets) (Kagawa Y. et al., Clin Cancer Res 2021), the association of ctDNA identified using the next-generation sequencing method with metastatic sites is still unknown. Methods: We investigated the association between metastatic site and ctDNA detection by using the Guardant360 (G360), a ctDNA assay which detects 74 gene alterations including mutations with the 95% of limit of detection of 0.2%, in mCRC pts with single organ mets in pts who had not received anti-EGFR therapy in the SCRUM-Japan GOZILA study. We also evaluated the correlations between the size/number of mets by CT and detected VAFs. Results: Of 1187 mCRC pts enrolled in GOZILA, 138 pts (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only mets) were eligible for this study. The concordance of RAS/ BRAF status between G360 and tissue in-vitro diagnostic tests were 93.9% in liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only mets. The median maximum VAF (maxVAF) corresponding to the highest ctDNA fraction and the median numbers of detected variants were 23.1% and 5 in liver-only, 6.0% and 5 in lymph node-only, 0.4% and 3 in peritoneum-only, and 0.4% and 3 in lung-only (all P<0.001, Kruskal-Wallis test). A few pts with liver-only (2.0%) and lymph node-only mets (13.3%) had a maxVAF of <0.2%, but maxVAF was more frequently <0.2% in pts with lung-only (27.7%) or peritoneum-only mets (29.6%), especially in those with lung-only mets <20 mm as the longest diameter and <20 lesions (69.2%) or with peritoneum-only mets <20 mm as the longest diameter (87.5%). Conclusions: Lung-only and peritoneum-only mets had significantly lower maxVAF and lower numbers of detected variants, suggesting lower detections of subclonal variants. To ensure the sufficient clinical performance in G360 assay, inclusion of pts with lung-only mets ≥20 mm of longest diameter and/or ≥20 lesions, and ≥20 mm of the longest diameter in pts with peritoneum-only mets may be required.[Table: see text]