title: Subtype-Specific Metagene-Based Prediction of Outcome after Neoadjuvant and Adjuvant Treatment in Breast Cancer.
abstract: OBJECTIVE
  In spite of improvements of average benefit from adjuvant/neoadjuvant treatments, there are still individual patients with early breast cancer at high risk of relapse. We explored the association with outcome of robust gene cluster-based metagenes linked to proliferation, ER-related genes, and immune response to identify those high-risk patients.
  
  
  METHODS
  A total of 3,847 publicly available gene-expression profiles were analyzed (untreated, N = 826; tamoxifen-treated, N = 685; chemotherapy-treated, N = 1,150). Genes poorly performing in formalin-fixed samples were removed. Outcomes of interest were pathologic-complete response (pCR) and distant metastasis-free survival (DMFS). In ER(+)HER2(-), the proliferation and ER-related metagenes were combined to define three risk groups. In HER2(+) and ER(-)HER2(-) risk groups were defined by tertiles of an immune-related metagene.
  
  
  RESULTS
  The high-proliferation/low-ER group of ER(+)HER2(-) breast cancer had significantly higher pCR rate [OR, 5.01 (1.76-17.99), P = 0.005], but poorer outcome [HR = 3.73 (1.63-8.51), P = 0.0018] than the low-proliferation/high-ER. A similar association with outcome applied to patients with residual disease (RD) after neoadjuvant chemotherapy (P = 0.01). In ER(-)HER2(-) and HER2(+) breast cancer, immune metagene in the high tertile was linked to higher pCR [33.7% vs. 11.6% in high and low tertile, respectively; OR, 3.87 (1.79-8.95); P = 0.0009]. In ER(-)HER2(-), after adjuvant/neoadjuvant chemotherapy, 5-year DMFS was 85.4% for high-tertile immune metagene, and 43.9% for low tertile. The outcome association was similar in patients with RD (P = 0.0055). In HER2(+) breast cancer treated with chemotherapy the association with risk of relapse was not significant.
  
  
  CONCLUSIONS
  We developed metagene-based predictors able to define low and high risk of relapse after adjuvant/neoadjuvant therapy. High-risk patients so defined should be preferably considered for trials with investigational agents.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Callari
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Cappelletti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Aiuto
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Musella
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lembo
authors.affiliation: Tumor Identity Cards Programme (CIT), Research Department, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Petel
authors.affiliation: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karn
authors.affiliation: Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy. Center for Translational Genomics and Bioinformatics, Ospedale San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. bianchini.giampaolo@hsr.it mariagrazia.daidone@istitutotumori.mi.it.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Department of Medical Oncology, Ospedale San Raffaele, Milan, Italy. bianchini.giampaolo@hsr.it mariagrazia.daidone@istitutotumori.mi.it.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bianchini
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D054892:Metagenome / Q000235:genetics*; D020360:Neoadjuvant Therapy / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen