title: Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.
abstract: 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.
  
  
  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 naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, Western Hospital, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia jeanne.tie@mh.org.au.
authors: J
authors: J
authors: Tie
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: I
authors: I
authors: Kinde
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: Y
authors: Y
authors: Wang
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Eastern Health Clinical School, Melbourne.
authors: H L
authors: HL
authors: Wong
authors: MIA Radiology, Melbourne.
authors: J
authors: J
authors: Roebert
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors: M
authors: M
authors: Christie
authors: Melbourne EpiCentre, Department of Medicine, The University of Melbourne, Melbourne.
authors: M
authors: M
authors: Tacey
authors: Faculty of Medicine, Nursing and Health Sciences, Monash University, Eastern Health Clinical School, Melbourne.
authors: R
authors: R
authors: Wong
authors: Andrew Love Cancer Centre, Barwon Health, Geelong.
authors: M
authors: M
authors: Singh
authors: Department of Medical Oncology, Flinders University, Adelaide, Australia.
authors: C S
authors: CS
authors: Karapetis
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors: J
authors: J
authors: Desai
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, Western Hospital, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.
authors: B
authors: B
authors: Tran
authors: Ludwig Institute for Cancer Research, New York, USA.
authors: R L
authors: RL
authors: Strausberg
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: L A
authors: LA
authors: Diaz
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: N
authors: N
authors: Papadopoulos
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: K W
authors: KW
authors: Kinzler
authors: Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, USA.
authors: B
authors: B
authors: Vogelstein
authors: Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne Department of Medical Oncology, Western Hospital, Melbourne Department of Medical Oncology, The Royal Melbourne Hospital, Melbourne Faculty of Medicine Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia Ludwig Institute for Cancer Research, New York, USA Ludwig Institute for Cancer Research, Melbourne, Australia.
authors: P
authors: P
authors: Gibbs
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002277:Carcinoma / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004247:DNA / Q000097:blood*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011446:Prospective Studies
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077146:Irinotecan; D004247:DNA; D002166:Camptothecin
keywords: biomarker; circulating tumor DNA; metastatic colorectal cancer; treatment response