Résumé
Malignant tumors shed cell free DNA into the blood stream. Analyzing this new biological source may have important implications in a shift towards personalized medicine for diagnosing and/or monitoring malignancies. We recently showed the first clinical validation and clinical utility of circulating DNA (cfDNA) analysis in oncology by testing RAS/BRAF hotspot mutations in plasma from metastatic colorectal cancer patients (mCRC) (Nat Med. 2014 Apr;20(4):430-5). In addition, liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. We evaluated under blinded conditions the ability of cfDNA to detect RAS/BRAF mutations in the plasma of 42 mCRC patients treated on a phase Ib/II trial of FOLFOX and dasatnib, with or without cetuximab. Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay was able to detect mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 22 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (50%) developed a second mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) developed new mutations. Patients may harbor mutations at very low frequency down to 0.01% before initiation or during treatment revealing the need of a high sensitive technique to detect mutant subclones. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Combined qualitative and quantitative cfDNA analysis allows tracking acquired resistance by studying the real-time clonal evolution of the tumor and might help physicians to adjust patient treatment. Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.
Note: This abstract was not presented at the meeting.
Citation Format: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2017-2924