Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer
- Tie, J; Kinde, I; Wang, Y; Wong, HL; Roebert, J; Christie, M; Tacey, M; Wong, R; Singh, M; Karapetis, CS; Desai, J; Tran, B; Strausberg, R; Diaz, LA, Jr; Papadopoulos, N; Kinzler, KW; Vogelstein, B; Gibbs, P;
Publication Year 2015-04-07, Volume 26, Issue #8, Page 1715-22
- Journal Title
- Annals of Oncology
- Publication Type
- Journal Article
- BACKGROUND: Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. PATIENTS AND METHODS: This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected prior to treatment, 3 days after treatment and prior to cycle 2. CT scans were performed at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. RESULTS: Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P <0.001) levels were observed prior to cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio=5.25 with a 10-fold ctDNA reduction; P=0.016). Major reductions (>/=10-fold) versus lesser reductions in ctDNA pre-cycle 2 were associated with a trend for increased progression-free survival (median 14.7 months v 8.1 months; HR=1.87; P=0.266). CONCLUSIONS: ctDNA is detectable in a high proportion of treatment naive mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.
- WEHI Research Division(s)
- Systems Biology And Personalised Medicine
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-20 10:11:27Last Modified: 2016-02-05 12:25:51