title: Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases.
abstract: OBJECTIVE
  We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC).
  
  
  BACKGROUND
  It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy.
  
  
  METHODS
  We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993-2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients.
  
  
  RESULTS
  Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011).
  
  
  CONCLUSIONS
  Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Andreou
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.forename: Su S
authors.initials: SS
authors.lastname: Chen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zimmitti
authors.forename: Antoine
authors.initials: A
authors.lastname: Brouquet
authors.forename: Junichi
authors.initials: J
authors.lastname: Shindoh
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
authors.forename: Christopher
authors.initials: C
authors.lastname: Garrett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Aloia
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Vauthey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D004252:DNA Mutational Analysis; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005500:Follow-Up Studies; D006498:Hepatectomy; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011183:Postoperative Complications; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil