PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

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  • Bastien, Roy RL
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Rodríguez-Lescure, Álvaro
    • Other Affiliation: Department of Medical Oncology, Hospital Universitario de Elche, Elche, Spain
  • Ebbert, Mark TW
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Prat, Aleix
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Department of Genetics
    • Other Affiliation: Department of Medicine, Universitat Autónoma de Barcelona, Barcelona, Spain
  • Munárriz, Blanca
    • Other Affiliation: Department of Medical Oncology, Hospital Universitario La Fe, Valencia, Spain
  • Rowe, Leslie
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Miller, Patricia
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Ruiz-Borrego, Manuel
    • Other Affiliation: Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
  • Anderson, Daniel
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Lyons, Bradley
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Álvarez, Isabel
    • Other Affiliation: Department of Medical Oncology, Hospital de Donostia, San Sebastián, Spain
  • Dowell, Tracy
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Wall, David
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Seguí, Miguel
    • Other Affiliation: Department of Medical Oncology, Corporatiò Sanitaria Parc Taulí, Sabadell, Spain
  • Barley, Lee
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Boucher, Kenneth M
    • Other Affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA
  • Alba, Emilio
    • Other Affiliation: Department of Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain
  • Pappas, Lisa
    • Other Affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT, USA
  • Davis, Carole A
    • Other Affiliation: Department of Pathology, University of Utah Health Sciences Center/Huntsman Cancer Institute, Salt Lake City, UT, USA
  • Aranda, Ignacio
    • Other Affiliation: Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain
  • Fauron, Christiane
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Stijleman, Inge J
    • Other Affiliation: Department of Pathology, University of Utah Health Sciences Center/Huntsman Cancer Institute, Salt Lake City, UT, USA
  • Palacios, José
    • Other Affiliation: Department of Pathology, Hospital Virgen del Rocio, Sevilla, Spain
  • Antón, Antonio
    • Other Affiliation: Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain
  • Carrasco, Eva
    • Other Affiliation: Spanish Breast Cancer Research Group, GEICAM, Madrid, Spain
  • Caballero, Rosalía
    • Other Affiliation: Spanish Breast Cancer Research Group, GEICAM, Madrid, Spain
  • Ellis, Matthew J
    • Other Affiliation: Department of Oncology, Washington University, St. Louis, MO, USA
  • Nielsen, Torsten O
    • Other Affiliation: Department of Anatomical Pathology, University of British Columbia, Vancouver, Canada
  • Perou, Charles
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, School of Medicine, Department of Genetics
  • Astill, Mark
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
  • Bernard, Philip S
    • Other Affiliation: The ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Department of Pathology, University of Utah Health Sciences Center/Huntsman Cancer Institute, Salt Lake City, UT, USA
  • Martín, Miguel
    • Other Affiliation: Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain
Abstract
  • Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) ≥ 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis. Conclusions The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Roy RL Bastien et al.; licensee BioMed Central Ltd.
License
Journal title
  • BMC Medical Genomics
Journal volume
  • 5
Journal issue
  • 1
Page start
  • 44
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1755-8794
Bibliographic citation
  • BMC Medical Genomics. 2012 Oct 04;5(1):44
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • July 16, 2016

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