title: Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy.
abstract: BACKGROUND
  Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up.
  
  
  METHODS
  Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score.
  
  
  RESULTS
  Increased Mammostrat scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients.
  
  
  CONCLUSIONS
  This is the fifth independent study providing evidence that Mammostrat can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.
authors.affiliation: Endocrine Cancer Group, Edinburgh Cancer Research Centre, Edinburgh University, Carrington Crescent, Edinburgh EH4 2XU, UK. john.bartlett@ed.ac.uk
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thomas
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Ross
authors.forename: Robert S
authors.initials: RS
authors.lastname: Seitz
authors.forename: Brian Z
authors.initials: BZ
authors.lastname: Ring
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Beck
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Pedersen
authors.forename: Alison
authors.initials: A
authors.lastname: Munro
authors.forename: Ian H
authors.initials: IH
authors.lastname: Kunkler
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Campbell
authors.forename: Wilma
authors.initials: W
authors.lastname: Jack
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Kerr
authors.forename: Laura
authors.initials: L
authors.lastname: Johnstone
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.forename: Udi
authors.initials: U
authors.lastname: Chetty
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D003955:Diagnostic Tests, Routine / Q000379:methods*; D018572:Disease-Free Survival; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013629:Tamoxifen / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D027283:Large Neutral Amino Acid-Transporter 1; D011960:Receptors, Estrogen; D013629:Tamoxifen; D016159:Tumor Suppressor Protein p53; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C527875:CEACAM5 protein, human