Application value of circulating tumor DNA monitoring effect of epithelial growth factor receptor monoclonal antibody therapy for metastatic colorectal cancer

Abstract

Objective To investigate the application value of circulating tumor DNA (ctDNA) monitoring effect of epithelial growth factor receptor (EGFR) monoclonal antibody therapy for metastatic colorectal cancer (mCRC). Methods The retrospective cross-sectional study was conducted. The clinicopathological data of 9 mCRC patients who were admitted to the Peking University Cancer Hospital between March 2012 and December 2013 were collected. Patients received single EGFR monoclonal antibody treatment (cetuximab or parni monoclonal antibody). The ctDNA concentration and variations of 22 genes in EGFR pathway of ctDNA were analyzed using high-throughput sequencing and ctDNA. Observation indicators: (1) treatment situations; (2) ctDNA concentration in plasma before and after treatment; (3) related gene mutations of EGFR pathway of ctDNA; (4) follow-up and survival situations. Follow-up using outpatient examination and telephone interview was performed to detect survival up to August 2015. Results (1) Treatment situations: of 9 patients, 6 and 3 underwent respectively single drug treatment using cetuximab monoclonal antibody or parni monoclonal antibody. After EGFR monoclonal antibody treatment, best response was partial remission in 1 patient, stable disease in 6 patients and disease progression in 2 patients. (2) CtDNA concentration in plasma before and after treatment: ctDNA concentration of 9 patients was 1.7-25.0 μg/L before treatment, showing a significantly individual difference. There were some changes in ctDNA concentration of 9 patients during treatment: ctDNA concentration was increased in 1 patient during partial remission; of 6 patients during stable disease, ctDNA concentration was decreased in 5 patients and increased in 1 patient; of 9 patients during disease progression, ctDNA concentration was decreased in 4 patients and increased in 5 patients. (3) Related gene mutations of EGFR pathway of ctDNA: ① Of 9 patients, 2 possessed RAS/RAF genetic mutations after treatment during disease progression, NRAS Q61H and BRAF V600E mutations were found in 1 patient, and mutation abundances were respectively 17.8% and 5.2%; 1 possessed KRAS G13D genetic mutation, a mutation abundance was 5.1% before treatment and then was increased to 16.7% during disease progression. ② Seven patients possessed TP53 genetic mutation before treatment, 5 had partial response or stable disease after treatment, including 4 with a reduced mutation abundance and 1 with an increased mutation abundance. Of 5 patients with partial response or stable disease to disease progression, mutation abundance of TP53 gene was increased in 4 patients and reduced in 1 patient; 2 patients had disease progression after treatment and mutation abundances of TP53 gene were reduced. ③ Two patients possessed SMAD4 genetic mutation. ④ The intron mutations were found in EGFR, PIK3CA, AKT1, ERBB2, PTEN, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, FBX7, FGFR3, NOTCH1, ERBB4、FGFR1 and FGFR2 genes, without changes of amino acids, these were not included in analysis. (4) Follow-up and survival situations: 9 patients were followed up for 1-31 months after treatment, with a median time of 7 months, and died at end of follow-up. Conclusion RAS/RAF gene mutations are detected by monitoring ctDNA when mCRC patients underwent EGFR monoclonal antibody therapy. Key words: Colonic neoplasms; Rectal neoplasms; Metastatic colorectal neoplasms; Translational medicine; Epithelial growth factor receptor; Circulating tumor DNA