title: Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer.
abstract: OBJECTIVE
  Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.
  
  
  METHODS
  Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.
  
  
  RESULTS
  We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27-17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52-4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of "luminal-like" genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.
  
  
  CONCLUSIONS
  We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed.
authors.affiliation: Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute of Fudan University, Shanghai, China.
authors.forename: Ke-Da
authors.initials: KD
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhan
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rodriguez
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Stephen
authors.initials: S
authors.lastname: Wong
authors.forename: Andreas
authors.initials: A
authors.lastname: Makris
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mayer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D000328:Adult; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D053536:Keratin-16 / Q000235:genetics; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D018365:Neoplasm, Residual / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011944:Receptors, Androgen / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D047629:Estrogen Receptor beta; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C084958:GBX2 protein, human; D018398:Homeodomain Proteins; C507431:KRT16 protein, human; D053536:Keratin-16; D011944:Receptors, Androgen; D051153:Wnt Proteins; C540523:Wnt11 protein, human; C424663:MMP28 protein, human; D053505:Matrix Metalloproteinases, Secreted
references.citation: JAMA. 2011 May 11;305(18):1873-81
references.pmid: 21558518
references.citation: Med Oncol. 2012 Jun;29(2):406-10
references.pmid: 21264529
references.citation: Cancer Res. 2005 Dec 15;65(24):11259-64
references.pmid: 16357129
references.citation: Clin Cancer Res. 2007 Apr 15;13(8):2329-34
references.pmid: 17438091
references.citation: J Biol Chem. 2010 Apr 30;285(18):14042-51
references.pmid: 20189993
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references.pmid: 19666588
references.citation: Clin Cancer Res. 2009 Apr 1;15(7):2472-8
references.pmid: 19276248
references.citation: J Clin Oncol. 2010 Sep 20;28(27):4111-9
references.pmid: 20697068
references.citation: J Clin Oncol. 2007 Oct 1;25(28):4414-22
references.pmid: 17785706
references.citation: Breast Cancer Res Treat. 2011 Apr;126(2):407-20
references.pmid: 20490655
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: BMC Bioinformatics. 2005 Nov 04;6:265
references.pmid: 16271137
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):31-6
references.pmid: 11134512
references.citation: J Clin Invest. 2011 Jul;121(7):2750-67
references.pmid: 21633166
references.citation: Breast Cancer Res. 2007;9(5):R65
references.pmid: 17910759
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):365-73
references.pmid: 18268121
references.citation: Dev Cell. 2009 Jul;17(1):9-26
references.pmid: 19619488
references.citation: Oncogene. 2004 Oct 7;23(46):7669-78
references.pmid: 15361840
references.citation: PLoS Med. 2010 May 25;7(5):e1000279
references.pmid: 20520800
references.citation: BMC Bioinformatics. 2009 Oct 28;10:358
references.pmid: 19863798
references.citation: Oncogene. 2012 Apr 19;31(16):2017-27
references.pmid: 21892208
references.citation: Oncogene. 2009 Jul 23;28(29):2634-42
references.pmid: 19483726
references.citation: Breast Cancer Res. 2011 Oct 06;13(5):R97
references.pmid: 21978456
references.citation: J Clin Oncol. 2012 May 20;30(15):1879-87
references.pmid: 22454417
references.citation: J Clin Oncol. 2001 Mar 15;19(6):1688-97
references.pmid: 11250998
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1160-7
references.pmid: 19204204
references.citation: Nature. 2012 Apr 04;486(7403):395-9
references.pmid: 22495314
references.citation: J Clin Oncol. 2005 Feb 20;23(6):1169-77
references.pmid: 15718313
references.citation: J Steroid Biochem Mol Biol. 2002 Feb;80(2):175-89
references.pmid: 11897502
references.citation: J Natl Cancer Inst. 2006 Sep 6;98(17):1183-92
references.pmid: 16954471
references.citation: Oncologist. 2011;16(8):1101-10
references.pmid: 21680575
references.citation: J Clin Oncol. 2006 Sep 10;24(26):4236-44
references.pmid: 16896004
references.citation: J Clin Oncol. 1995 Jul;13(7):1564-71
references.pmid: 7541448
references.citation: Breast Cancer Res Treat. 2009 Sep;117(1):91-8
references.pmid: 19112615
references.citation: Breast Cancer Res Treat. 2011 Nov;130(2):477-87
references.pmid: 21837479
references.citation: J Clin Oncol. 2008 Mar 10;26(8):1275-81
references.pmid: 18250347