Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer.
BACKGROUND
TOP2A gene encodes topoisomerase II alpha, the direct molecular target of anthracyclines. This gene is frequently coamplified with HER2. The aims of this study were to analyse the pattern of TOP2A amplification and protein expression in relation to the molecular subgroups of breast cancers; and to define the impact of TOP2A amplification on the outcome of a series of patients homogeneously treated with adjuvant anthracyclines.


METHODS
A cohort of 245 patients with early breast cancer homogeneously treated with anthracyclines in the adjuvant setting was selected. A tissue microarray containing these cancers was used to determine HER2 and TOP2A gene copy number by means of chromogenic in situ hybridization. Immunohistochemical staining of topoisomerase II alpha was also performed using a monoclonal antibody (Ki-S1). TOP2A amplification and protein expression were correlated with classical prognostic parameters, expression of immunohistochemical markers and with a gene expression profiling classification using surrogate immunohistochemical markers. Kaplan-Meier method was used to construct survival curves and results were compared with log-rank test.


RESULTS
TOP2A amplification was restricted to tumours with HER2 amplification and was significantly associated with ER positivity. In the subgroup of patients with HER2 amplified tumours, TOP2A amplification predicted a better overall survival and disease free survival (P = 0.028 and 0.026, respectively). On multivariate analysis, TOP2A amplification maintained its predictive value for DFS.


CONCLUSIONS
TOP2A amplification is likely to be a useful marker to predict the subset of patients who will benefit from anthracyclines.
Arriola
Edurne
E
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Rodriguez-Pinilla
Socorro Maria
SM
Lambros
Maryou B K
MB
Jones
Robin L
RL
James
Michelle
M
Savage
Kay
K
Smith
Ian E
IE
Dowsett
Mitch
M
Reis-Filho
Jorge S
JS
D018943:Anthracyclines / Q000008:administration & dosage*; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D008207:Lymphatic Metastasis / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D016896:Treatment Outcome
D018943:Anthracyclines; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C000618811:TOP2A protein, human