title: Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy.
abstract: BACKGROUND
  In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM.
  
  
  METHODS
  Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM.
  
  
  RESULTS
  Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2-32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity.
  
  
  CONCLUSIONS
  Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling.
authors.affiliation: AP-HP Hôpital Paul Brousse, Department of Pathology, Villejuif, France.|Inserm U1193, Paris-Sud University, Villejuif, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Sebagh
authors.affiliation: AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.|Inserm U935, Paris-Sud University, Villejuif, France.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Allard
authors.affiliation: Inserm U1193, Paris-Sud University, Villejuif, France.|AP-HP Hôpital Paul Brousse, Department of Oncogenetics, Villejuif, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Bosselut
authors.affiliation: AP-HP Hôpital Paul Brousse, Department of Pathology, Villejuif, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Dao
authors.affiliation: Inserm U1193, Paris-Sud University, Villejuif, France.|AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vibert
authors.affiliation: AP-HP Hôpital Paul Brousse, Radiology, Villejuif, France.
authors.forename: Maïté
authors.initials: M
authors.lastname: Lewin
authors.affiliation: Inserm U1193, Paris-Sud University, Villejuif, France.|AP-HP Hôpital Paul Brousse, Department of Oncogenetics, Villejuif, France.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
authors.affiliation: Inserm U1193, Paris-Sud University, Villejuif, France.|AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cherqui
authors.affiliation: AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.|Inserm U935, Paris-Sud University, Villejuif, France.
authors.forename: René
authors.initials: R
authors.lastname: Adam
authors.affiliation: AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.|Inserm U935, Paris-Sud University, Villejuif, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sa Cunha
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D057234:Preoperative Period; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: colorectal liver metastases; intermetastatic tumor heterogeneity; pathological response; somatic gene profile