Association between HER2, TOP2A, and response to anthracycline-based preoperative chemotherapy in high-risk primary breast cancer.
In breast cancer, recent studies suggest that the value of HER2 for predicting response to anthracycline-based chemotherapy may be more likely related to the concomitant amplification of the TOP2A gene. Here, we study the association between HER2 or TOP2A status and response to anthracycline-based preoperative chemotherapy and explore the interaction between HER2 or TOP2A status and intense dose-dense (IDD) chemotherapy. HER2 and TOP2A gene alterations were quantified by fluorescence in situ hybridization in primary tumor core biopsies from 373 high-risk primary breast cancer patients (tumors >/=3 cm or inflammatory) that received an IDD or conventionally scheduled anthracycline-based preoperative chemotherapy. HER2 was amplified in 94/350 tumors (27%) of which 40/94 (46%) demonstrated TOP2A amplification, and 17/94 (18%) TOP2A deletions. TOP2A gene alterations were not found in HER2 non-amplified cases. HER2 amplification was associated with a significantly higher pathologic complete response (pCR) rate only when TOP2A was co-amplified (30% vs. 11%, P = 0.002), but not when deleted (13% vs. 11%, P = 0.755), or normal (14% vs. 11%, P = 0.578) compared to HER2 non-amplified tumors. In multivariate analysis, TOP2A amplification (odds ratio [OR] 3.04, P = 0.021), but not HER2 amplification (OR 1.74, P = 0.170) was associated with a significantly higher pCR rate. No interaction was observed between HER2 or TOP2A status and IDD chemotherapy. TOP2A gene amplification may define a subset of HER2-amplified breast cancers that are responsible for the markedly improved chemosensitivity seen in HER2-positive breast cancer. However, added benefit of IDD chemotherapy itself was not associated with HER2 or TOP2A status.
Konecny
Gottfried E
GE
UCLA Translational Oncology Research Lab, David Geffen School of Medicine, University of California Los Angeles, 2825 Santa Monica Blvd, Suite 200, Santa Monica, CA, 90404-2429, USA. gkonecny@mednet.ucla.edu
Pauletti
Giovanni
G
Untch
Michael
M
Wang
He-Jing
HJ
Möbus
Volker
V
Kuhn
Walther
W
Thomssen
Christoph
C
Harbeck
Nadia
N
Wang
Ling
L
Apple
Sophia
S
Jänicke
Fritz
F
Slamon
Dennis J
DJ
D018943:Anthracyclines / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D020360:Neoadjuvant Therapy; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
D018943:Anthracyclines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; 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