Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy.
Current clinical algorithms are unable to precisely predict which colorectal cancer patients would benefit from adjuvant chemotherapy, and there is a need for novel biomarkers to improve the selection of patients. The metastasis-promoting protein S100A4 predicts poor outcome in colorectal cancer, but whether it could be used to guide clinical decision making remains to be resolved. S100A4 expression was analyzed by immunohistochemistry in primary colorectal carcinomas from a consecutively collected, population-representative cohort and a randomized phase III study on adjuvant 5-fluorouracil/levamisole. Sensitivity to treatment with 5-fluorouracil in S100A4 knockdown cells was investigated using 2D and 3D cell culture assays. Strong nuclear expression of S100A4 was detected in 19% and 23% of the tumors in the two study cohorts, respectively. In both cohorts, nuclear immunoreactivity was associated with reduced relapse-free (P < 0.001 and P = 0.010) and overall survival (P = 0.046 and P = 0.006) in univariate analysis. In multivariate analysis, nuclear S100A4 was a predictor of poor relapse-free survival in the consecutive series (P = 0.002; HR 1.9), but not in the randomized study. Sensitivity to treatment with 5-fluorouracil was not affected by S100A4 expression in in vitro cell culture assays, and there was no indication from subgroup analyses in the randomized study that S100A4 expression was associated with increased benefit of adjuvant treatment with 5-fluorouracil/levamisole. The present study confirms that nuclear S100A4 expression is a negative prognostic biomarker in colorectal cancer, but the clinical utility in selection of patients for adjuvant fluoropyrimidine-based chemotherapy is limited.
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Kjetil
K
Boye
Section for Oncology, Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
Havjin
H
Jacob
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Kari-Anne M
KA
Frikstad
Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Medical Faculty, University of Oslo, Oslo, Norway.
Jahn M
JM
Nesland
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
Gunhild M
GM
Maelandsmo
Section for Oncology, Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.|Department of Oncology and Radiophysics, Haukeland University Hospital, Bergen, Norway.
Olav
O
Dahl
Medical Faculty, University of Oslo, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Gastroenterological Surgery, Ullevål Hospital, Oslo University Hospital, Oslo, Norway.
Arild
A
Nesbakken
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Medical Faculty, University of Oslo, Oslo, Norway.|Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Kjersti
K
Flatmark
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D000066491:Clinical Decision-Making; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D007978:Levamisole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000071999:S100 Calcium-Binding Protein A4; C077591:S100A4 protein, human; D007978:Levamisole; D005472:Fluorouracil
5-fluorouracil; S100A4; adjuvant chemotherapy; colorectal cancer; prognostic factor