Journal Article

Association of emergence of new mutations in circulating tumuor DNA during chemotherapy with clinical outcome in metastatic colorectal cancer

Gao, Xin, Zhou, Yanping, Chang, Lianpeng, Dou, Xuelin, Ying, Hongyan, Shi, Xiaohua, Zhao, Lin, Li, Ningning, Bai, Chunmei, Guan, Mei, Shao, Yajuan, Sun, Zhao, Jia, Ning, Zhou, Jianfeng, Cheng, Yuejuan

2021

Overview

Background The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC). Methods Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8–10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA. Results A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6–26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70–50.69; P  = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29–15.70; P  = 0.0008). Conclusions Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 5-Fluorouracil / Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biomarker / Biomarkers / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer / Cancer Research / Cancer therapies / Care and treatment / Chemotherapy / Circulating Tumor DNA / Circulating tumour DNA / Clinical outcomes / Colorectal cancer / Colorectal Neoplasms - diagnosis / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - mortality / Computed tomography / Deoxyribonucleic acid / DNA / Female / Gene mutations / Genetic aspects / Genomics / Health aspects / Health Promotion and Disease Prevention / High-Throughput Nucleotide Sequencing / Humans / Irinotecan / Kaplan-Meier Estimate / Male / Medical prognosis / Medicine/Public Health / Metastases / Metastasis / Metastatic colorectal cancer / Middle Aged / Mutation / Neoplasm Staging / New mutation / Next generation sequencing / Oncology / Oncology, Experimental / Oxaliplatin / Patient outcomes / Patients / Plasma / Prognosis / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins p21(ras) - genetics / Risk assessment / Software / Solid tumors / Surgical Oncology / Tomography, X-Ray Computed / Tumors / Variables