DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
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DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer. / Nygård, Sune Boris; Vainer, Ben; Nielsen, Signe L; Bosman, Fred T; Tejpar, Sabine; Roth, Arnaud; Delorenzi, Mauro; Brunner, Nils; Budinska, Eva.
In: Clinical Cancer Research, Vol. 22, No. 7, 2016, p. 1621-1631.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
AU - Nygård, Sune Boris
AU - Vainer, Ben
AU - Nielsen, Signe L
AU - Bosman, Fred T
AU - Tejpar, Sabine
AU - Roth, Arnaud
AU - Delorenzi, Mauro
AU - Brunner, Nils
AU - Budinska, Eva
N1 - Copyright © 2015, American Association for Cancer Research.
PY - 2016
Y1 - 2016
N2 - 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 (CC).EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant CC 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 ≥ 3rd quartile (RFS: HRadjusted, 0.59; P = .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 CC.
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 (CC).EXPERIMENTAL DESIGN: Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant CC 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 ≥ 3rd quartile (RFS: HRadjusted, 0.59; P = .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 CC.
U2 - 10.1158/1078-0432.CCR-15-0561
DO - 10.1158/1078-0432.CCR-15-0561
M3 - Journal article
C2 - 26542057
VL - 22
SP - 1621
EP - 1631
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -
ID: 147543091