title: TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy.
abstract: Anthracycline is a DNA topoisomerase 2-α (TOP2A) inhibitor and its concomitant over expression with Human Epidermal Growth Factor Receptor 2 (HER2) was investigated of being predictive for the response to anthracycline-based chemotherapies in breast cancer. 309 early and local advanced breast cancer patients were treated with anthracycline-based neoadjuvant chemotherapies in intense dose dense (IDD) (CE, Cyclophosphamide + Epirubicin) or conventional (TE, Paclitaxel + Epirubicin) regimens. HER2 proteins were qualitatively analyzed by immunohistochemistry (IHC) of primary tumor core biopsies, and TOP2A gene amplification levels of HER2 over-expressing cases were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Overall pathological complete response rate (pCR) was achieved in 14.3 %. HER2 was over expressed in 80/309 (25.9 %) cases, of which 61/80 cases have been tested for their TOP2A status. Over expression of HER2 was significantly positively correlated with higher pCR rates compared to low HER2 expression (27.5 % vs. 9.6 %, P < 0.001). Concurrent high TOP2A amplification led to a significantly higher pCR rate compared to low or no TOP2A amplification (56.3 % vs. 13.8 %, P = 0.001). HER2 over expression was associated with a significantly higher pCR rate only when TOP2A was also amplified (56.3 % vs. 9.6 %, P < 0.001), but not when it was deleted or normal (13.8 % vs. 9.6 %, P = 0.183) compared to HER2 low-expressing tumors. The interaction between HER2 or TOP2A and anthracycline-based regimen was observed in IDD and conventional neoadjuvant chemotherapies. The TOP2A amplification is related to anthracycline-based neoadjuvant chemotherapy sensitivity, and TOP2A should be included in future studies in breast cancer as a predictive marker.
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 17 Panjiayuannanli, Chaoyang District, Beijing 100021, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wang
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.forename: Pin
authors.initials: P
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; 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; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D000075223:Poly-ADP-Ribose Binding Proteins; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D017239:Paclitaxel; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human