title: HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer.
abstract: BACKGROUND
  Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
  
  
  METHODS
  HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
  
  
  RESULTS
  Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors.
  
  
  CONCLUSIONS
  Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
authors: Carsten
authors: C
authors: Denkert
authors: Jens
authors: J
authors: Huober
authors: Sibylle
authors: S
authors: Loibl
authors: Judith
authors: J
authors: Prinzler
authors: Ralf
authors: R
authors: Kronenwett
authors: Silvia
authors: S
authors: Darb-Esfahani
authors: Jan C
authors: JC
authors: Brase
authors: Christine
authors: C
authors: Solbach
authors: Keyur
authors: K
authors: Mehta
authors: Peter A
authors: PA
authors: Fasching
authors: Bruno V
authors: BV
authors: Sinn
authors: Knut
authors: K
authors: Engels
authors: Mattea
authors: M
authors: Reinisch
authors: Martin-Leo
authors: ML
authors: Hansmann
authors: Hans
authors: H
authors: Tesch
authors: Gunter
authors: G
authors: von Minckwitz
authors: Michael
authors: M
authors: Untch
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506487:ESR1 protein, human; C508053:ERBB2 protein, human
references: Clin Chem. 2009 Sep;55(9):1719-27
references: 19617290
references: Breast Cancer Res Treat. 2009 Jul;116(1):131-43
references: 18668363
references: J Clin Oncol. 2009 Jun 20;27(18):2962-9
references: 19364966
references: Ann Oncol. 2011 Aug;22(8):1736-47
references: 21709140
references: J Clin Oncol. 2009 Dec 1;27(34):5685-92
references: 19884557
references: J Clin Oncol. 2011 Sep 1;29(25):3351-7
references: 21788566
references: Ann Oncol. 2008 Jun;19(6):1090-6
references: 18296421
references: Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):865s-70s
references: 15701879
references: PLoS Med. 2012;9(5):e1001216
references: 22675273
references: Mod Pathol. 2007 May;20(5):584-91
references: 17396141
references: J Clin Oncol. 2006 Jul 1;24(19):3032-8
references: 16809727
references: Cancer Res. 2007 Aug 1;67(15):7256-65
references: 17671194
references: Lancet Oncol. 2012 Feb;13(2):135-44
references: 22257523
references: Clin Chem. 2010 Dec;56(12):1845-53
references: 20947696
references: J Clin Oncol. 2010 Apr 20;28(12):2015-23
references: 20308671
references: J Clin Oncol. 2010 Jan 1;28(1):105-13
references: 19917869
references: J Clin Oncol. 2012 May 20;30(15):1796-804
references: 22508812
references: Breast Cancer Res Treat. 2012 Apr;132(3):863-70
references: 21667238
references: J Clin Oncol. 2005 Dec 20;23(36):9067-72
references: 16172462
references: Biochem Biophys Res Commun. 2009 Mar 13;380(3):699-704
references: 19285025
references: Breast Cancer Res Treat. 2011 Feb;126(1):109-17
references: 21190079
references: Biostatistics. 2004 Jul;5(3):465-81
references: 15208206
references: Lancet Oncol. 2012 Jan;13(1):25-32
references: 22153890
references: J Natl Cancer Inst. 2002 Jun 5;94(11):852-4
references: 12048273
references: J Clin Oncol. 2011 Nov 10;29(32):4279-85
references: 21990395
references: Nature. 2008 Dec 4;456(7222):663-6
references: 19005469
references: Diagn Mol Pathol. 2011 Mar;20(1):1-10
references: 21326033
references: J Natl Cancer Inst. 2002 Jun 5;94(11):855-7
references: 12048274
references: Lancet. 2012 Feb 18;379(9816):633-40
references: 22257673
references: J Clin Oncol. 2011 May 20;29(15):e458
references: 21502545
references: Arch Pathol Lab Med. 2007;131(1):18-43
references: 19548375
references: J Clin Oncol. 2010 Oct 10;28(29):4539-44
references: 20837942
references: J Natl Cancer Inst. 2003 Jan 15;95(2):142-53
references: 12529347
references: N Engl J Med. 2005 Oct 20;353(16):1659-72
references: 16236737
references: Cancer Res. 2008 May 15;68(10):3697-706
references: 18483252
references: J Clin Oncol. 2009 Nov 20;27(33):5538-46
references: 19786658
references: J Clin Oncol. 2010 Apr 20;28(12):2024-31
references: 20308670
references: N Engl J Med. 2008 Mar 27;358(13):1409-11
references: 18367751
references: N Engl J Med. 2005 Oct 20;353(16):1673-84
references: 16236738
references: N Engl J Med. 2011 Oct 6;365(14):1273-83
references: 21991949
references: J Clin Oncol. 2010 Oct 1;28(28):4300-6
references: 20697093
references: Breast Cancer Res. 2012 Mar 14;14(2):R46
references: 22417870
references: Clin Cancer Res. 2011 Sep 15;17(18):6012-20
references: 21807638