NPY Gene Methylation in Circulating Tumor DNA as an Early Biomarker for Treatment Effect in Metastatic Colorectal Cancer

SIMPLE SUMMARY: Despite several limitations, imaging is still the gold standard in evaluating the treatment effect in metastatic colorectal cancer, and the best response is often achieved several months after treatment start. The present study investigated methylated circulating tumor DNA (ctDNA) in the blood and found that a reduction in ctDNA after one treatment cycle was a better marker of progression-free survival than imaging. Furthermore, ctDNA increases in the blood before progression are visible on imaging, allowing for a change in treatment at an earlier time point. Methylated ctDNA is an early indicator of treatment benefit and a promising endpoint in clinical trials. ABSTRACT: Despite several limitations, the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) are still the gold standard in response evaluation of metastatic colorectal cancer (mCRC). The aim of the present study was to investigate hypermethylated neuropeptide Y circulating tumor DNA (meth-NPY) as an early biomarker for treatment effect and monitoring in 70 mCRC patients receiving first-line treatment in the FOLFOXIRI-Toco trial. Meth-NPY was analyzed using droplet digital PCR, and the response rate was defined as the fraction of patients converting from a baseline detectable level to an undetectable level after the first treatment cycle (responders). A significant increase in meth-NPY was defined as a value with no overlap between the 95% CI of the current and preceding measurement. Progression-free survival (PFS) was significantly longer in meth-NPY responders compared to non-responders, 10.1 and 7.6 months, respectively (p = 0.02, HR = 0.43). Patients with response according to RECIST 1.1 had a PFS of 10.1 compared to 7.3 months for non-responders (p = 0.17, HR = 0.65). A significant increase in meth-NPY was found with a median of 49 days before radiological progression. In conclusion, early meth-NPY response proved superior to response according to RECIST 1.1 with respect to predicting improved PFS. Meth-NPY is an early indicator of progression, allowing treatment reorientation at an earlier timepoint.