Dynamic Monitoring of HER2 Amplification in Circulating DNA of Patients with Metastatic Colorectal Cancer Treated with Cetuximab

714 Background: Addition of cetuximab has shown clinical benefit in RAS and BRAF wild-type (wt) patients with metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 2 ( HER2) amplification was reported to be one of the resistance mechanisms to cetuximab. We investigated whether monitoring of HER2 amplification in circulating DNA allows early detection of progression and informs about resistance to cetuximab. Methods: We analyzed HER2 amplification in circulating DNA by 8 week-interval using droplet digital polymerase chain reaction (ddPCR) from 30 RAS and BRAF wt patients, who progressed after failure of cetuximab-containing regimens between Jul 2015 and Jun 2017. Results: 16.7% (5/30) of patients exhibited dynamic fluctuations of HER2 amplification in plasma, one of whom was found to be positive for HER2 amplification in matched tumor tissue sample using FISH. Two patients had HER2 and c-MET co-amplification. All 5 primary sites were left side, 4 rectums and 1 descending colon. 3 patients received cetuximab as first line therapy, whereas 2 patients in the 2 nd line setting. Among these 5 patients, changes in circulating DNA levels showed good agreement with changes in tumor volume. Furthermore, quantifications of HER2 amplification showed obvious increase with an average lead time of 2 months compared with CT documented progress. But interestingly, there was no difference in progression-free survival (PFS) between these 5 patients and the others without HER2 amplification (p > 0.05). Conclusions: Plasma HER2 amplification detected by ddPCR was showed dynamic changing over time and would predict resistance to cetuximab-containing treatment. Average 2 months lead time was observed and need to validate in the further study.