Chromosome 17 centromere duplication and responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer.
Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis.
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
Ariadna
A
Tibau
Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain ; Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Laura
L
López-Vilaró
Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
Maitane
M
Pérez-Olabarria
Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
Tania
T
Vázquez
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Cristina
C
Pons
Department of Epidemiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Ignasi
I
Gich
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Carmen
C
Alonso
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Belén
B
Ojeda
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Teresa
T
Ramón y Cajal
Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain ; Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain.
Enrique
E
Lerma
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain ; Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain.
Agustí
A
Barnadas
Institut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
Daniel
D
Escuin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D002503:Centromere / Q000187:drug effects*; D058674:Chromosome Duplication; D002886:Chromosomes, Human, Pair 17; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human
CEP17, chromosome 17 centromere enumeration probe; CI, confidence interval; CISH, chromogenic in situ hybridization; DFS, disease-free survival; EC-D, epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by docetaxel (100 mg/m2); ER, estrogen receptor; FEC75, fluorouracil (600 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (600 mg/m2); FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OR, odds ratio; OS, overall survival; PR, progesterone receptor; TOP2A, topoisomerase II alpha; pCR, pathologic complete response