PCA-PAM50 improves consistency between breast cancer intrinsic and clinical subtyping reclassifying a subset of luminal A tumors as luminal B

Sci Rep. 2019 May 28;9(1):7956. doi: 10.1038/s41598-019-44339-4.

Abstract

The PAM50 classifier is widely used for breast tumor intrinsic subtyping based on gene expression. Clinical subtyping, however, is based on immunohistochemistry assays of 3-4 biomarkers. Subtype calls by these two methods do not completely match even on comparable subtypes. Nevertheless, the estrogen receptor (ER)-balanced subset for gene-centering in PAM50 subtyping, is selected based on clinical ER status. Here we present a new method called Principle Component Analysis-based iterative PAM50 subtyping (PCA-PAM50) to perform intrinsic subtyping in ER status unbalanced cohorts. This method leverages PCA and iterative PAM50 calls to derive the gene expression-based ER status and a subsequent ER-balanced subset for gene centering. Applying PCA-PAM50 to three different breast cancer study cohorts, we observed improved consistency (by 6-9.3%) between intrinsic and clinical subtyping for all three cohorts. Particularly, a more aggressive subset of luminal A (LA) tumors as evidenced by higher MKI67 gene expression and worse patient survival outcomes, were reclassified as luminal B (LB) increasing the LB subtype consistency with IHC by 25-49%. In conclusion, we show that PCA-PAM50 enhances the consistency of breast cancer intrinsic and clinical subtyping by reclassifying an aggressive subset of LA tumors into LB. PCA-PAM50 code is available at ftp://ftp.wriwindber.org/ .

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / classification
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Cohort Studies
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / genetics*
  • Ki-67 Antigen / metabolism
  • Principal Component Analysis
  • Prognosis
  • Protein Array Analysis
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Survival Analysis
  • Terminology as Topic

Substances

  • Biomarkers, Tumor
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Ki-67 Antigen
  • MKI67 protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2