RT Journal Article
SR Electronic
T1 DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 1621
OP 1631
DO 10.1158/1078-0432.CCR-15-0561
VO 22
IS 7
A1 Nygård, Sune Boris
A1 Vainer, Ben
A1 Nielsen, Signe Lykke
A1 Bosman, Fred
A1 Tejpar, Sabine
A1 Roth, Arnaud
A1 Delorenzi, Mauro
A1 Brünner, Nils
A1 Budinska, Eva
YR 2016
UL http://clincancerres.aacrjournals.org/content/22/7/1621.abstract
AB Purpose: Prospective–retrospective assessment of the TOP1 gene copy number and TOP1 mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer.Experimental Design: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan. TOP1 copy number status was analyzed by fluorescence in situ hybridization (FISH) using a TOP1/CEN20 dual-probe combination. TOP1 mRNA data were available from previous analyses.Results: TOP1 FISH and follow-up data were obtained from 534 patients. TOP1 gain was identified in 27% using a single-probe enumeration strategy (≥4 TOP1 signals per cell) and in 31% when defined by a TOP1/CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent on TOP1 FISH status. TOP1 mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized by TOP1 mRNA expression ≥ third quartile (RFS: HRadjusted, 0.59; P = 0.09; OS: HRadjusted, 0.44; P = 0.03). The treatment by TOP1 mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasing TOP1 mRNA values appeared to be associated with increasing benefit of irinotecan.Conclusions: In contrast to the TOP1 copy number, a trend was demonstrated for a predictive property of TOP1 mRNA expression. On the basis of TOP1 mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer. Clin Cancer Res; 22(7); 1621–31. ©2015 AACR.