ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction.
OBJECTIVE
The prognostic and predictive relevance of epidermal growth factor receptor 2 (ERBB2) and topoisomerase II alpha (TOP2A) have long been a matter of debate. However, the correlation of DNA amplification, RNA levels, and protein expression and their prognostic role and association with anthracycline responses in node-negative breast cancer have not yet been evaluated.


METHODS
We first analyzed TOP2A and ERBB2 at the levels of gene amplification, and RNA and protein expression, and studied their correlations. Additionally, TOP2A and ERBB2 were analyzed in 782 node-negative breast carcinomas in patients who did not receive systemic therapy and in 80 patients treated with epirubicin and cyclophosphamide (EC) prior to surgery.


RESULTS
TOP2A gene amplification did not correlate with protein expression (P = 0.283) and showed an association with gene expression with only borderline significance (P = 0.047). By contrast, TOP2A RNA levels correlated with protein expression (P < 0.001). TOP2A gene expression was significantly associated with the metastasis-free interval (MFI; P < 0.001) and was associated with complete remission in patients treated with EC (P = 0.002). In contrast to TOP2A, ERBB2 gene amplification correlated with RNA level (P < 0.001) and protein expression (P < 0.001). ERBB2 gene expression was associated with the MFI only in estrogen receptor-positive carcinomas, whereas ERBB2 protein expression (P = 0.032) was associated with MFI in the entire cohort.


CONCLUSIONS
Overall, our study indicates that the TOP2A RNA level is a good prognostic marker and is also associated with a favorable response to anthracyclin-based therapy. By contrast, ESR1 was associated with poorer responses to anthracyclin-based therapy, whereas the association with ERBB2 RNA was not significant.
Brase
Jan C
JC
Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany. j.brase@dkfz.de
Schmidt
Marcus
M
Fischbach
Thomas
T
Sültmann
Holger
H
Bojar
Hans
H
Koelbl
Heinz
H
Hellwig
Birte
B
Rahnenführer
Jörg
J
Hengstler
Jan G
JG
Gehrmann
Mathias C
MC
D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D010865:Pilot Projects; D000075223:Poly-ADP-Ribose Binding Proteins; D012334:RNA, Neoplasm / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human