Journal
ANNALS OF ONCOLOGY
Volume 26, Issue 8, Pages 1715-1722Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdv177
Keywords
circulating tumor DNA; metastatic colorectal cancer; biomarker; treatment response
Categories
Funding
- Victorian Cancer Agency Translational Research Grant
- Hilton Ludwig Cancer Prevention Initiative - Conrad N. Hilton Foundation
- Ludwig Institute for Cancer Research
- National Institutes of Health [CA152753, CA57345, CA62924]
- Victorian Cancer Agency Clinical Research Fellowship
- NATIONAL CANCER INSTITUTE [R37CA043460, U01CA152753, P50CA062924, P30CA006973, R37CA057345, R01CA057345] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007309] Funding Source: NIH RePORTER
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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 before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out 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 before 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 precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 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.
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