title: DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6.
abstract: BACKGROUND
  There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases.
  
  
  METHODS
  Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan.
  
  
  RESULTS
  In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan.
  
  
  CONCLUSIONS
  Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.
authors.affiliation: Imaging Science, Proteomics and Genomics Research Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, UK. james.o'connor@manchester.ac.uk
authors.forename: J P B
authors.initials: JP
authors.lastname: O'Connor
authors.forename: C J
authors.initials: CJ
authors.lastname: Rose
authors.forename: A
authors.initials: A
authors.lastname: Jackson
authors.forename: Y
authors.initials: Y
authors.lastname: Watson
authors.forename: S
authors.initials: S
authors.lastname: Cheung
authors.forename: F
authors.initials: F
authors.lastname: Maders
authors.forename: B J
authors.initials: BJ
authors.lastname: Whitcher
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.forename: G A
authors.initials: GA
authors.lastname: Buonaccorsi
authors.forename: G
authors.initials: G
authors.lastname: Thompson
authors.forename: A R
authors.initials: AR
authors.lastname: Clamp
authors.forename: G C
authors.initials: GC
authors.lastname: Jayson
authors.forename: G J M
authors.initials: GJ
authors.lastname: Parker
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D003287:Contrast Media; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D019786:Gadolinium DTPA; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000556:secondary; D008279:Magnetic Resonance Imaging; D008297:Male; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003287:Contrast Media; D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D019786:Gadolinium DTPA; D002955:Leucovorin; D005472:Fluorouracil