title: Intratumor Heterogeneity Affects Gene Expression Profile Test Prognostic Risk Stratification in Early Breast Cancer.
abstract: OBJECTIVE
  To examine the effect of intratumor heterogeneity (ITH) on detection of genes within gene expression panels (GEPs) and the subsequent ability to predict prognostic risk.
  
  
  METHODS
  Multiplexed barcoded RNA analysis was used to measure the expression of 141 genes from five GEPs (Oncotype Dx, MammaPrint, PAM50, EndoPredict, and Breast Cancer Index) in breast cancer tissue sections and tumor-rich cores from 71 estrogen receptor (ER)-positive node-negative tumors, on which clinical Oncotype Dx testing was previously performed. If the tumor had foci of high Ki67 (n = 26), low/negative progesterone receptor (PR; n = 13), or both (n = 5), additional cores were obtained. In total, 181 samples were processed. Oncotype Dx recurrence scores were calculated from NanoString nCounter gene expression data.
  
  
  RESULTS
  Hierarchical clustering using all GEP genes showed that majority (61 of 71) of tumor samples clustered by patient, indicating greater interpatient heterogeneity (IPH) than ITH. We found a strikingly high correlation between Oncotype Dx recurrence scores obtained from whole sections versus tumor-rich cores (r = 0.94). However, high Ki67 and low PR cores had slightly higher but not statistically significant recurrence scores. For 18 of 71 (25%) patients, scores were divergent between sections and cores and crossed the boundaries for low, intermediate, and high risk.
  
  
  CONCLUSIONS
  Our study indicates that in patients with highly heterogeneous tumors, GEP recurrence scores from a single core could under- or overestimate prognostic risk. Hence, it may be a useful strategy to assess multiple samples (both representative and atypical cores) to fully account for the ITH-driven variation in risk prediction. Clin Cancer Res; 22(21); 5362-9. ©2016 AACR.
authors.affiliation: Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Rekha
authors.initials: R
authors.lastname: Gyanchandani
authors.affiliation: Department of Biostatistics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Kristine
authors.initials: K
authors.lastname: Cooper
authors.affiliation: Department of Biostatistics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.affiliation: Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.affiliation: Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Fastuca
authors.affiliation: Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Whitney
authors.initials: W
authors.lastname: Crosson
authors.affiliation: Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dabbs
authors.affiliation: Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania. leeav@upmc.edu.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D018570:Risk Assessment
chemical_list: D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone