Prognostic Significance of Progesterone Receptor-Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer.

Prat A, Cheang MC, Martín M, Parker JS, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO, Perou CM.

Source

Aleix Prat, Joel S. Parker, and Charles M. Perou, University of North Carolina, Chapel Hill, NC; Aleix Prat, Vall d'Hebron Institute of Oncology and Universitat Autònoma de Barcelona, Barcelona; Miguel Martín, Instituto de Investigacion Sanitaria Hospital Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense; Miguel Martín, Eva Carrasco, and Rosalía Caballero, Grupo Español de Investigación en Cáncer de Mama, Madrid, Spain; Maggie Chon U. Cheang, Scott Tyldesley, Karen Gelmon, and Torsten O. Nielsen, British Columbia Cancer Agency; Maggie Chon U. Cheang, Scott Tyldesley, Karen Gelmon, and Torsten O. Nielsen, University of British Columbia, Vancouver, British Columbia, Canada; and Philip S. Bernard, University of Utah Health Sciences Center, Salt Lake City, UT.

Abstract

PURPOSECurrent immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. PATIENTS AND METHODSGene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance.ResultsClinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. CONCLUSIONSemiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.