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, Ben VAINER, Signe Lykke NIELSEN, Fred BOSMAN, Sabine TEJPAR, Arnaud ROTH, Mauro DELORENZI, Nils BRÜNNER and Eva BUDINSKÁ. DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer. Clinical Cancer Research. Philadelphia: American Association for Cancer Research Inc., 2016, vol. 22, No 7, p. 1621-1631. ISSN 1078-0432. Available from: https://dx.doi.org/10.1158/1078-0432.CCR-15-0561.

Basic information

• Original name: DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
• Authors: NYGÅRD, Sune Boris (208 Denmark), Ben VAINER (208 Denmark), Signe Lykke NIELSEN (208 Denmark), Fred BOSMAN (756 Switzerland), Sabine TEJPAR (56 Belgium), Arnaud ROTH (756 Switzerland), Mauro DELORENZI (756 Switzerland), Nils BRÜNNER (208 Denmark) and Eva BUDINSKÁ (703 Slovakia, guarantor, belonging to the institution).
• Edition: Clinical Cancer Research, Philadelphia, American Association for Cancer Research Inc. 2016, 1078-0432.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30200 3.2 Clinical medicine
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 9.619
• RIV identification code: RIV/00216224:14110/16:00091498
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1158/1078-0432.CCR-15-0561
• UT WoS: 000373360600011
• Keywords in English: ADVANCED COLORECTAL-CANCER; III RANDOMIZED-TRIAL; DRUG-SENSITIVITY; VERSION 3.2013; CELL-LINES; CHEMOTHERAPY; FLUOROURACIL; FEASIBILITY; MULTICENTER; RESISTANT
• Tags: EL OK
• Tags: International impact, Reviewed

Abstract

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.