FAS/FAS ligand ratio: a marker of oxaliplatin-based intrinsic and acquired resistance in advanced colorectal cancer.
OBJECTIVE
Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown.


METHODS
Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses.


RESULTS
We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P=0.0001; 0.07 versus 0.14 ng/mL; P=0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P=0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001).


CONCLUSIONS
These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.
Medical Oncology, Institut Malalties Hemato-Oncologiques, Gastroenterology Department, Hospital Clinic Barcelona, Institut d'Investigacions Bimédiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Cristina
C
Nadal
Joan
J
Maurel
Rosa
R
Gallego
Antoni
A
Castells
Raquel
R
Longarón
Maribel
M
Marmol
Sergi
S
Sanz
Rafael
R
Molina
Marta
M
Martin-Richard
Pere
P
Gascón
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D015999:Multivariate Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D012044:Regression Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D048069:Tumor Necrosis Factors / Q000097:blood*; D019014:fas Receptor / Q000097:blood*
D014408:Biomarkers, Tumor; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009944:Organoplatinum Compounds; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D000077150:Oxaliplatin; D005472:Fluorouracil