title: TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.
abstract: OBJECTIVE
  Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer.
  
  
  METHODS
  Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant.
  
  
  RESULTS
  Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC.
  
  
  CONCLUSIONS
  We identified biologic pathways and a novel gene signature in primary ER+breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755-64. ©2016 AACR.
authors.affiliation: Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts. myles_brown@dfci.harvard.edu rinath_jeseloshn@dfci.harvard.edu.|Center for Functional Caner Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rinath
authors.initials: R
authors.lastname: Jeselsohn
authors.affiliation: Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts.|Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Migliaccio
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.|"Sandro Pitigliani" Medica Oncology Unit, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Biagioni
authors.affiliation: Center for Functional Caner Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Functional Caner Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jonas
authors.initials: J
authors.lastname: De Tribolet-Hardy
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guarducci
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Bonechi
authors.affiliation: Astra Zeneca Pharmaceuticals, Macclesfield, United Kingdom.
authors.forename: Naomi
authors.initials: N
authors.lastname: Laing
authors.affiliation: Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts. myles_brown@dfci.harvard.edu rinath_jeseloshn@dfci.harvard.edu.|Center for Functional Caner Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.|"Sandro Pitigliani" Medica Oncology Unit, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Angelo Di
authors.initials: AD
authors.lastname: Leo
authors.affiliation: Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.|"Sandro Pitigliani" Medica Oncology Unit, Istituto Toscano Tumori, Prato, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Malorni
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004815:Epidermal Growth Factor / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling / Q000379:methods; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051541:Hepatocyte Nuclear Factor 3-alpha; D011960:Receptors, Estrogen; D050656:Transcription Factor AP-2; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor