title: Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.
abstract: BACKGROUND
  Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.
  
  
  RESULTS
  We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.
  
  
  CONCLUSIONS
  We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.
authors.affiliation: Functional Genomics Unit, Jules Bordet Institute, Brussels, Belgium. sherene.loi@petermac.org
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Pratyaksha
authors.initials: P
authors.lastname: Wirapati
authors.forename: Françoise
authors.initials: F
authors.lastname: Lallemand
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tutt
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gillet
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ryder
authors.forename: James F
authors.initials: JF
authors.lastname: Reid
authors.forename: Maria G
authors.initials: MG
authors.lastname: Daidone
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: Els Mjj
authors.initials: EM
authors.lastname: Berns
authors.forename: Maurice Phm
authors.initials: MP
authors.lastname: Jansen
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bontempi
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen