Identification of the activated form of the progesterone receptor (PR) in breast cancer (BC).

Abstract

593 Background: Upon ligand binding, PRs dimerize and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of PR (APR). FDP and are observed in BC independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in BC and presence/absence of APR is hypothesized to predict anti-progestin activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 paraffin embedded/formalin fixed archival BC samples were processed with PR-A or PR- B isotype specific antibodies. Nuclear morphology was analyzed with standard microscopy at x1000, interpretation of the IHC slides was done by an experienced pathologist. Standard PR, estrogen receptor (ER), and Ki67 testing were done. Tumor grading/stage was obtained from the patients’ records. Results: Histology was ductal 85%, lobular 13%, other 2%. Consistent with prior research observations, tumors had two PR nuclear morphologies: 1. Diffuse pattern (D) where the PR was distributed evenly in a fine granular pattern or, 2. Aggregate pattern (A) where the PR is distributed in discrete clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A), D cells only (D), and a heterogenous mix of A+D cells (AD). The APRpos group is defined as the A and A+ D phenotypes. Tumors were PR positive in 76% for PRA and 80% for PRB. Tumors were APRpos for PRA in 23% and independent of PR intensity score, ER, Ki67, and HER2, but associated with higher PR % positivity and higher tumor grade. Tumors were APRpos for PRB in 22% and associated with lower PR intensity and higher tumor grade, independent of ERpos %, PRpos %, Ki67 and HER2. Conclusions: PR positive BC tumors can be grouped in two categories based on PR nuclear morphology: 1. a group with diffuse and homogenous nuclear staining, 2. a group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated PR (APR). The described IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy in patients with BC.