Methylated circulating tumor DNA in plasma as a biomarker for treatment efficacy in metastatic colorectal cancer

In first-line, progression-free survival (PFS) is a clinically relevant and validated endpoint for treatment efficacy in metastatic colorectal cancer (mCRC), and independent of subsequent treatments. Using imaging and Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1), the first response evaluation is performed after two months, but a reliable evaluation at an earlier stage may be preferable. Methylated circulating tumor DNA (ctDNA) can be measured in plasma in most patients with mCRC. Our prospective study investigated the association between PFS and hypermethylated neuropeptide Y ctDNA (meth-NPY) response after the first cycle of chemotherapy in patients with mCRC compared to first objective response according to RECIST 1.1. The study included 70 patients with mCRC for first-line treatment with 5-FU, oxaliplatin, and irinotecan plus delta-tocotrienol or placebo in a randomized, double-blind, placebo-controlled study. Meth-NPY in plasma was analyzed by droplet digital PCR before treatment start and after the first cycle. Meth-NPY response rate was defined as the fraction of patients converting from a baseline measurable level of NPY to unmeasurable after the first treatment cycle. The unmeasurable level comprised zero-values and those with the lower 95% CI overlapping zero. Response evaluation according to RECIST 1.1 was performed after eight weeks. 59 patients were evaluable for analysis of meth-NPY after the first cycle and 65 patients were evaluable according to RECIST 1.1 response after eight weeks. The meth-NPY response rate was 31% compared to 38% according to RECIST 1.1. PFS was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p=0.02). Patients with a response according to RECIST 1.1, had a PFS of 10.0 months compared to 8.3 months for non-responders, which was not statistically different (p=0.33). In this first-line setting of mCRC, early meth-NPY response proved to be superior compared to response according to RECIST 1.1 with respect to predict improved PFS. Early meth-NPY response is a promising marker not only for the individual patient, but also for faster drug evaluation in trials.