10O_PR Prognostic Significance of Progesterone Receptor-Positive Tumor Cells Within Immunohistochemically-Defined Luminal A Breast Cancer

ABSTRACT Background Current immunohistochemical (IHC)-based definitions of the breast intrinsic subtypes of Luminal A (LumA) and B (LumB) are imperfect when compared to multi-gene subtyping assays. In this study, we sought to improve the IHC-subtyping by examining the clinical-pathological characteristics of genomically defined LumA and B subtypes, and then selecting IHC markers to represent these genomic classes. Methods Differences in global and single gene expression patterns between LumA and B tumors were first identified from the PAM50 microarray training data set. Clinical-pathological features were also collected from 2,950 primary tumors across 4 independent studies: Nielsen et al. (n = 701), GEICAM/9906 (n = 542), BCCA (n = 619) and a combined publicly available microarray dataset (n = 1,088). Optimal cutoffs to predict distant relapse-free survival (DRFS) were independently tested. Multivariable Cox-models were used to test the independent prognostic significance. Results Gene expression analyses identified PGR, but not ESR1, as one of the most discriminatory genes of LumA tumors. Clinical-pathological comparisons of LumA and B subtypes consistently identified higher rates of PR-positivity, HER2-negativity, and histological grade 1 in LumA tumors. No differences were observed in estrogen receptor (ER) status or IHC scoring of ER+ tumor cells. Interestingly, IHC-defined LumA tumors with a low percentage of PR+ tumor cells were more likely to be identified as non-LumA by PAM50, and were independently associated with lower DRFS compared to IHC-defined LumA tumors with high percentage of PR+ tumor cells. A score of u003e20% PR+ tumor cells was statistically chosen and validated for predicting survival differences within IHC-defined LumA tumors. Finally, little additional prognostic value was seen with the use of the recently reported IHC4 score when IHC-based intrinsic subtypes are known. Conclusions Semi-quantitative IHC expression of PR adds prognostic value within the current IHC-based LumA definition by improving the identification of good outcome breast cancers. This newest IHC-based definition of LumA would now be HR + /HER2-/Ki67 20%. Disclosure P.S. Bernard, T.O. Nielsen and C.M. Perou: Equity stock holder of University Genomics and BioClassifierLLC Patent inventor of PAM50. All other authors have declared no conflicts of interest.