Topoisomerase-1 gene copy aberrations are frequent in patients with breast cancer

TY - JOUR

T1 - Topoisomerase-1 gene copy aberrations are frequent in patients with breast cancer

AU - Kümler, Iben

AU - Balslev, Eva

AU - Poulsen, Tim S.

AU - Nielsen, Signe Lykke

AU - Nygård, Sune Boris

AU - Rømer, Maria Unni

AU - Christensen, Ib Jarle

AU - Høgdall, Estrid

AU - Moreira, José

AU - Nielsen, Dorte Lisbet

AU - Brünner, Nils

AU - Stenvang, Jan

N1 - © 2015 UICC.

PY - 2015/10/15

Y1 - 2015/10/15

N2 - Topoisomerase-1 (Top1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the Top1 protein and since no validated anti-Top1 antibodies for immunohistochemistry have been reported, we raised the hypothesis that TOP1 gene amplifications may serve as a proxy for the Top1 protein and thereby a biomarker of response to treatment with Top1 inhibitors in BC. The aim was to determine the prevalence of TOP1 gene copy gain in BC. The prevalence of TOP1 gene copy gain was investigated by fluorescence in situ hybridization with a TOP1/CEN-20 probemix in normal breast tissue (N-‰=-‰100) and in tissue from patients with metastatic BC in a discovery (N-‰=-‰100) and a validation cohort (N-‰=-‰205). As amplification of 20q including CEN-20 is common in BC a TOP1/CEN-2 probemix was applied to the validation cohort. More than 30% of the patients had gene copy numbers of-‰≥-‰4 and â20% of the patients had TOP1/CEN-20 ratios-‰≥-‰1.5. The CEN-2 probe did not add any information. Gain of the TOP1 gene appears to be common in BC making the gene a potential biomarker for response to treatment with Top1 inhibitors. As 20q amplification is a common finding in BC and as no other suitable reference gene has yet been identified, TOP1 copy number may be a more valid method of detecting gain than using a gene/centromere ratio. What's New? Inhibitors of topoisomerase 1 (TOP1) are merging as second or third line treatment options for breast cancer but predictive markers for their success are lacking. Here the authors show by fluorescence in situ hybridization using formalin-fixed, paraffin-embedded breast cancer tissue samples that gain of TOP1 gene copy number is frequent in breast cancer cells, thus serving as a potential biomarker to pre-select breast cancer patients for treatment with topoisomerase inhibitors in the future.

AB - Topoisomerase-1 (Top1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the Top1 protein and since no validated anti-Top1 antibodies for immunohistochemistry have been reported, we raised the hypothesis that TOP1 gene amplifications may serve as a proxy for the Top1 protein and thereby a biomarker of response to treatment with Top1 inhibitors in BC. The aim was to determine the prevalence of TOP1 gene copy gain in BC. The prevalence of TOP1 gene copy gain was investigated by fluorescence in situ hybridization with a TOP1/CEN-20 probemix in normal breast tissue (N-‰=-‰100) and in tissue from patients with metastatic BC in a discovery (N-‰=-‰100) and a validation cohort (N-‰=-‰205). As amplification of 20q including CEN-20 is common in BC a TOP1/CEN-2 probemix was applied to the validation cohort. More than 30% of the patients had gene copy numbers of-‰≥-‰4 and â20% of the patients had TOP1/CEN-20 ratios-‰≥-‰1.5. The CEN-2 probe did not add any information. Gain of the TOP1 gene appears to be common in BC making the gene a potential biomarker for response to treatment with Top1 inhibitors. As 20q amplification is a common finding in BC and as no other suitable reference gene has yet been identified, TOP1 copy number may be a more valid method of detecting gain than using a gene/centromere ratio. What's New? Inhibitors of topoisomerase 1 (TOP1) are merging as second or third line treatment options for breast cancer but predictive markers for their success are lacking. Here the authors show by fluorescence in situ hybridization using formalin-fixed, paraffin-embedded breast cancer tissue samples that gain of TOP1 gene copy number is frequent in breast cancer cells, thus serving as a potential biomarker to pre-select breast cancer patients for treatment with topoisomerase inhibitors in the future.

U2 - 10.1002/ijc.29556

DO - 10.1002/ijc.29556

M3 - Journal article

C2 - 25855483

SN - 0020-7136

VL - 137

SP - 2000

EP - 2006

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 8

ER -