Abstract
IntroductionEstrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.MethodsWe integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.ResultsIn a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.ConclusionER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.
Highlights
Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer
These results suggested that evaluation of PR status in ER+ breast cancer might be used to help guide clinical management, as high levels of PR expression may identify a subset of ER+ patients most likely to benefit from hormonal therapy [7]
Progesterone receptor mRNA tends to be expressed at low-levels in ER- breast cancer and the ER-/PR+ subtype is extremely rare We performed a genome-wide analysis to determine the relative level of progesterone receptor (PGR) expression and variability of PGR expression in ER- and ER+ breast cancer (Figure 2)
Summary
Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. The biologic, prognostic and predictive importance of assessment of estrogen receptor (ER) expression in breast cancer is well established; the added value of progesterone receptor (PR) assessment is controversial [2,3,4] Despite this uncertainty, the American Society of Clinical Oncology and the College of American Pathologists recommend testing for both ER and PR on all newly diagnosed cases of invasive breast cancer [1]. Analyses from observational studies showed that loss of PR expression was associated with worse overall prognosis among ER+ breast cancers [9,10,11,12,13] These results suggested that evaluation of PR status in ER+ breast cancer might be used to help guide clinical management, as high levels of PR expression may identify a subset of ER+ patients most likely to benefit from hormonal therapy [7]
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