Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status.
OBJECTIVE
Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C).


METHODS
TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533).


RESULTS
An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size.


CONCLUSIONS
In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.
Tubbs
Raymond
R
Department of Molecular Pathology, Cleveland Clinic, Cleveland, OH 44195, USA. TubbsR@ccf.org
Barlow
William E
WE
Budd
G Thomas
GT
Swain
Eric
E
Porter
Peggy
P
Gown
Allen
A
Yeh
I-Ten
IT
Sledge
George
G
Shapiro
Charles
C
Ingle
James
J
Haskell
Charles
C
Albain
Kathy S
KS
Livingston
Robert
R
Hayes
Daniel F
DF
D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D002886:Chromosomes, Human, Pair 17; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human