Circulating Tumor DNA and Circulating Tumor Cells As Predictor of Outcome in the PRODIGE14-ACCORD21-METHEP2 Phase II Trial

We prospectively detected circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) levels in patients (pts) included in the PRODIGE14-ACCORD21-METHEP2 randomized phase II trial. The trial enrolled colorectal cancer pts with potentially resectable liver metastases & no prior treatment; the primary endpoint was the rate of R0/R1 liver metastases resection achieved by 1st line regimen (targeted therapies & bi- vs tri-chemotherapy; Ychou, ASCO 2016). Blood samples were collected at inclusion, after 1 month of therapy and before any liver metastases surgery. CTCs (CellSearch) & ctDNA (ddPCR, BioRad) were detected in an experienced laboratory (Inst. Curie). 153 pts had at least one blood analysis. High CTC count (≥3 CTC/7.5ml) was detected in 25/132 pts (19%) at baseline and associated with synchronous liver metastases (p = 0.03) and % of liver involvement (p = 0.001). At baseline, a 91% sensitivity of KRAS ctDNA detection was observed (42/46 pts with KRAS mutated tumors, as determined per standard of care). In addition, 6 of 79 pts (7%) with tumors considered as KRASwt had >150 KRASmut copies/ml at baseline. After 1 month of therapy, only 3/108 pts (3%) had high CTC count and KRAS ctDNA "sensitivity" dropped to 63% (22/35 pts with KRAS mutated tumors). Among pts planned for liver metastases surgery, none had high CTC count before surgery (0/57) and ctDNA "sensitivity" was 19% (4/21 pts with KRAS mutated tumors). Interestingly, persistently high CTC count (p = 0.06) and detectable KRAS mutated copies (p = 0.002) after 1 month of therapy were significantly associated with a lower R0/R1 liver metastasis resection rate (main study endpoint). Regarding overall survival, CTC count impacted OS at baseline and after 1 month of therapy (p = 0.001), while ctDNA was a prognostic marker only before liver surgery (p = 0.0001). This is the first study to assess CTC and ctDNA clinical validity in pts with potentially resectable liver metastases. ctDNA detection demonstrated excellent sensitivity at baseline but detection rates dropped during therapy. The major finding is that persistently elevated ctDNA and CTCs after 1 month of therapy may help to select pts that won't undergo later R0/R1 liver metastasis resection.