title: Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil.
abstract: BACKGROUND
  Different 5-fluorouracil (5-FU) schedules and/or biochemical modulators may result in different mechanisms of cytotoxicity, potentially affecting the correlation between thymidylate synthase (TS) expression and the clinical response to the fluoropyrimidine.
  
  
  METHODS
  TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 124 patients homogeneously treated in a series of clinical trials at our institutions with: (A) leucovorin (LV)-modulated infusional 5-FU (n = 48); (B) LV-modulated bolus 5-FU (n = 41); (C) methotrexate (MTX)-modulated bolus 5-FU (n = 35).
  
  
  RESULTS
  A statistically significant correlation between TS levels and the clinical response was observed with the regimens involving continuous infusion and/or LV modulation (response rate in patients with low and high TS: 66% versus 24%, P = 0.003, and 50% versus 0%, P = 0.0001, in group A and B, respectively). Conversely, TS levels failed to predict the clinical response within the group of patients treated with MTX-modulated bolus 5-FU (response rate 21% versus 13%, P = 0.50, with low and high TS, respectively). Consistently, the median time to progression/overall survival time in patients with low and high TS were 9 versus 6 months/19 versus 14 months (P = 0.009/0.035, group A), 8 versus 2 months/12 versus 6 months (P = 0.002/0.0006, group B) and 3 versus 2 months/12 versus 13 months (P = 0.14/0.74, group C).
  
  
  CONCLUSIONS
  The correlation between intratumoral TS levels and the clinical response to 5-FU depends strongly on the schedule of administration/biochemical modulators that are used in different 5-FU regimens. These data strengthen the notion that different 5-FU schedules have different mechanisms of cytotoxicity.
authors.affiliation: Department of Medical Oncology, EO Ospedali Galliera, Genoa, Italy. carlo.aschele@galliera.it
authors.forename: C
authors.initials: C
authors.lastname: Aschele
authors.forename: D
authors.initials: D
authors.lastname: Debernardis
authors.forename: R
authors.initials: R
authors.lastname: Bandelloni
authors.forename: S
authors.initials: S
authors.lastname: Cascinu
authors.forename: V
authors.initials: V
authors.lastname: Catalano
authors.forename: P
authors.initials: P
authors.lastname: Giordani
authors.forename: S
authors.initials: S
authors.lastname: Barni
authors.forename: D
authors.initials: D
authors.lastname: Turci
authors.forename: G
authors.initials: G
authors.lastname: Drudi
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.forename: L
authors.initials: L
authors.lastname: Gallo
authors.forename: F
authors.initials: F
authors.lastname: Maley
authors.forename: S
authors.initials: S
authors.lastname: Monfardini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D016009:Chi-Square Distribution; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005069:Evaluation Studies as Topic; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011336:Probability; D011379:Prognosis; D012680:Sensitivity and Specificity; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000032:analysis / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate