title: Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial.
abstract: BACKGROUND
  Chromosomal instability (CIN) has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer we have previously demonstrated that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on tumour fitness and growth. The aim of this current study was to validate this finding using previously defined CIN thresholds in a much larger prospective cohort from a randomised, controlled, clinical trial.
  
  
  METHODS
  As a surrogate measurement of CIN, dual centromeric fluorescence in situ hybridisation was performed for both chromosomes 2 and 15 on 1173 tumours from the breast cancer TACT trial (CRUK01/001). Each tumour was scored manually and the mean percentage of cells deviating from the modal centromere number was used to define four CIN groups (MCD1-4), where tumours in the MCD4 group were defined as having extreme CIN.
  
  
  RESULTS
  In a multivariate analysis of disease-free survival, with a median follow-up of 91 months, increasing CIN was associated with improved outcome in patients with ER-negative cancer (P trend = 0.03). A similar pattern was seen in ER-negative/HER2-negative cancers (Ptrend = 0.007).
  
  
  CONCLUSIONS
  This prospective validation cohort study further substantiated the association between extreme CIN and improved outcome in ER-negative breast cancers. Identifying such patients with extreme CIN may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification in this aggressive breast cancer subtype.
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London.
authors.forename: M
authors.initials: M
authors.lastname: Jamal-Hanjani
authors.affiliation: ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, London.
authors.forename: R
authors.initials: R
authors.lastname: A'Hern
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London The Francis Crick Institute, 44 Lincoln's Inn Fields, London.
authors.forename: N J
authors.initials: NJ
authors.lastname: Birkbak
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London.
authors.forename: P
authors.initials: P
authors.lastname: Gorman
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London.
authors.forename: E
authors.initials: E
authors.lastname: Grönroos
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London.
authors.forename: S
authors.initials: S
authors.lastname: Ngang
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London.
authors.forename: P
authors.initials: P
authors.lastname: Nicola
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London.
authors.forename: L
authors.initials: L
authors.lastname: Rahman
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London.
authors.forename: E
authors.initials: E
authors.lastname: Thanopoulou
authors.affiliation: The Francis Crick Institute, 44 Lincoln's Inn Fields, London.
authors.forename: G
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Guy's and St Thomas' NHS Trust, London.
authors.forename: P
authors.initials: P
authors.lastname: Ellis
authors.affiliation: Velindre NHS Trust, Cardiff.
authors.forename: P
authors.initials: P
authors.lastname: Barrett-Lee
authors.affiliation: Royal Marsden NHS Foundation Trust, London.
authors.forename: S R D
authors.initials: SR
authors.lastname: Johnston
authors.affiliation: ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, London.
authors.forename: J
authors.initials: J
authors.lastname: Bliss
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK r.roylance@qmul.ac.uk charles.swanton@crick.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Roylance
authors.affiliation: Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London The Francis Crick Institute, 44 Lincoln's Inn Fields, London.
authors.forename: C
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D043171:Chromosomal Instability; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; C508053:ERBB2 protein, human
keywords: breast cancer; chromosomal instability; intratumour heterogeneity; modal centromere deviation; prognostic biomarker