Abstract P3-05-06: A better clinical cutpoint for progesterone receptor expression in tamoxifen treated breast cancer
Authors: Kornaga EN , Paterson AHG , Morris DG , Magliocco AM , Klimowicz AC 
Published: August 2014

INTRODUCTION: Hormone receptors are routinely measured by immunohistochemistry (IHC) to classify breast cancers (BC) and guide treatment decisions. Both estrogen receptor (ER) and progesterone receptor (PR) are measured yet “the precise role of PR in patient management has not been strongly established” (ASCO/CAP; JCO 2010 28(16)). PR expression is under the transcriptional control of ER, and its been suggested that BC with high PR expression are more estrogen-dependent and thus more sensitive to endocrine therapy. We hypothesized that using a higher PR threshold would be prognostic in hormone therapy (HT) treated ER+/HER2- BC patients compared to the current PR cutpoint (Allred Score≥3).

METHODS: We analyzed PR expression using the Calgary Tamoxifen BC Cohort (Cal-TBCC), a retrospective database that has a clinically annotated tissue microarray (TMA) series of 532 BC patients treated with HT. The NCI Stage I BC TMA set (N = 590) was obtained for validation. ER was visualized by staining with Dako ER pharmDx, and HER2 with Dako HercepTest. We visualized PR expression using ready-to-use PR assays from 3 commercial IHC vendors (Dako, Leica, Ventana) for the Cal-TBCC. The NCI validation set was stained only using the Dako assay. Allred scores were generated, capturing intensity and percentage coverage of PR expression. Only patients receiving HT that were ER+/HER2- by IHC were included for study.

RESULTS: We found that ER+/HER2- patients from the Cal-TBCC stratified using a newly defined PR Allred cutpoint to capture only PR-High BC had significantly better disease free survival (DFS) compared to the current cutpoint (PR+≥3), regardless of platform used (Table 1). Multivariate analysis - adjusting for tumor grade, size and lymph node status - confirmed the improved prognostic significance of the new PR cutpoint (Table 2A). We next validated the prognostic power of the newly defined cutpoint using the NCI series. This set also has a group of ER+/HER2- BC patients who were not treated with HT, allowing us to evaluate the ability of ER+/HER2-/PR-High to predict DFS in patients treated with or without HT. We found that in patients who weren't treated with HT, PR was not prognostic using either cutpoint (Logrank p = 0.952; p = 0.611); but in the HT group, the new cutpoint was predictive of treatment response (p = 0.343; p = 0.047) (Cox Table 2B).

Table 1 Current CutpointNew CutpointDako PRp = 0.024p = 0.0002Leica PRp = 0.102p = 0.0002Ventana PRp = 0.058p = 0.0001

CONCLUSIONS: We have identified a new cutpoint for PR expression in BC that is prognostic within a tamoxifen treated BC cohort, and that maintained significance across 3 commercial PR assays. Moreover, this new cutpoint seems to be predictive of HT, as the untreated NCI controls did worse than the HT treated group. We intend to continue to evaluate the clinical role for the new PR cutpoint by re-analyzing PR data from completed clinical trials.

Table 2 Current Cutpoint New Cutpoint 2A: Cal-TBCCHR95% CIp-valueHR95% CIp-valueDako PR0.7020.295-1.6700.420.6390.369-1.1060.11Leica PR0.7590.301-1.9130.560.5020.283-0.8880.018Ventana PR0.4480.201-0.9980.0490.4620.253-0.8440.0122B: NCI      No HT0.9690.349-2.6910.9520.8530.461-1.5770.61HT0.5980.204-1.7510.3490.4340.185-1.0150.054

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-06.