title: Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.
abstract: BACKGROUND
  We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients.
  
  
  METHODS
  The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and β-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature.
  
  
  RESULTS
  A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and β-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like.
  
  
  CONCLUSIONS
  We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information. CLINICALTRIALS.GOV: This is the translational part of the Swedish multicenter and randomized trial TEX, clinicaltrials.gov identifier nct01433614 (http://www.clinicaltrials.gov/ct2/show/nct01433614).
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: N P
authors.initials: NP
authors.lastname: Tobin
authors.affiliation: Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Harrell
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Lövrot
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Egyhazi Brage
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Frostvik Stolt
authors.affiliation: Department of Oncology, Sundsvall General Hospital, Sundsvall.
authors.forename: L
authors.initials: L
authors.lastname: Carlsson
authors.affiliation: Department of Oncology, Sahlgrenska University Hospital, Gothenburg.
authors.forename: Z
authors.initials: Z
authors.lastname: Einbeigi
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Oncology, Sahlgrenska University Hospital, Gothenburg.
authors.forename: B
authors.initials: B
authors.lastname: Linderholm
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund.
authors.forename: N
authors.initials: N
authors.lastname: Loman
authors.affiliation: Department of Oncology, Skåne University Hospital, Helsingborg.
authors.forename: M
authors.initials: M
authors.lastname: Malmberg
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden; Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping.
authors.forename: T
authors.initials: T
authors.lastname: Walz
authors.affiliation: Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Hatschek
authors.affiliation: Department of Surgery, University of California at San Francisco (UCSF), San Francisco, USA; Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden. Electronic address: linda.lindstrom@ki.se.
authors.forename: L S
authors.initials: LS
authors.lastname: Lindström
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D051176:beta Catenin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D018631:ras Proteins
keywords: TEX randomized trial; biopsy at relapse; breast cancer metastases; gene expression; gene modules; metastasis characteristics