Progesterone Receptor (PR/PgR) Testing in Breast Cancer: An Educational Overview

Introduction

The progesterone receptor (PR, also abbreviated PgR) is one of the core hormone-receptor biomarkers assessed in every newly diagnosed invasive breast carcinoma. The 2020 ASCO/CAP guideline treats PR primarily as a prognostic marker reported alongside the estrogen receptor (ER); it is not an independent predictor of endocrine-therapy benefit over ER alone [1]. Reported alongside the estrogen receptor (ER) and HER2, PR helps characterize a tumor's hormone-receptor biology and refines the picture of how a cancer may behave and which broad categories of therapy it may respond to. This article explains what PR testing measures, how it is performed and scored, what each result means, and how the result informs treatment eligibility, while flagging areas that remain in flux.

What the Test Measures

The progesterone receptor is a nuclear hormone receptor: a protein that, when activated, translocates to the cell nucleus and regulates gene transcription. In the breast, PR expression is itself driven in large part by estrogen signaling through the estrogen receptor. For this reason, PR is often thought of as a downstream marker of an intact and functional ER pathway. When a tumor expresses PR, it suggests that the estrogen-signaling axis is present and transcriptionally active.

This biological relationship is central to interpreting PR results. PR is measured not in isolation but as a complement to ER, because together the two receptors give a more complete portrait of a tumor's endocrine (hormone-driven) biology than either does alone.

How It Is Tested

PR is assessed by immunohistochemistry (IHC) performed on formalin-fixed, paraffin-embedded (FFPE) tissue, the same tissue-processing platform used for routine histology. The assay applies antibodies against the progesterone receptor protein, and bound antibody is visualized as a colored reaction product localized to tumor cell nuclei.

Because IHC signal integrity depends heavily on how tissue is handled before staining, PR testing carries the same preanalytic constraints as ER [1]. These include controlling the time from tissue removal to fixation (cold ischemic time), achieving adequate and appropriate formalin fixation, and validating the assay against standardized criteria. Deviations in fixation can degrade the antigen and produce falsely low or false-negative results, a critical consideration given that a single percentage point can change the reported result category.

Scoring is based on the percentage of invasive tumor cell nuclei that show staining, at any intensity. Under the current framework, a tumor is considered PR positive at ≥1% of nuclei staining and PR negative when <1% stain [1]. The pathologist evaluates only the invasive component and reports the estimated percentage.

What Each Result State Means

• PR positive (≥1%): At least 1% of the invasive tumor nuclei express the progesterone receptor. Combined with ER status, this supports the interpretation that the tumor has an active endocrine pathway.

• PR negative (<1%): Fewer than 1% of invasive tumor nuclei express PR. In an ER-positive tumor, loss of PR (the ER-positive/PR-negative phenotype) is associated with a less favorable endocrine-response profile than the ER-positive/PR-positive phenotype [1]. In other words, PR adds prognostic and predictive nuance that ER alone does not fully capture.

It is important to emphasize that PR is interpreted in the context of ER, not as a standalone determinant. The combination of the two receptors, rather than PR by itself, guides how the endocrine biology of the tumor is understood.

What It Determines for Treatment Eligibility

PR testing is used primarily for its prognostic value. Per the 2020 ASCO/CAP guideline, PR is not an independent predictor of endocrine-therapy benefit over ER; eligibility for endocrine therapy is driven by ER status, while PR adds prognostic nuance within ER-positive disease [1].

Framed at the level of drug classes rather than individual patient recommendations: ER positivity is what informs eligibility for endocrine (anti-hormonal) therapy; PR is reported alongside it. According to the 2020 ASCO/CAP guideline, lower or absent PR in an ER-positive tumor is associated with a comparatively less favorable prognosis, a prognostic signal clinicians factor into their overall assessment [1].

This article does not and cannot advise any individual on whether to take a specific medication. The role of PR in the diagnostic report is to characterize the tumor's biology and thereby inform the broader clinical discussion about categories of therapy for which a patient may or may not be a candidate. Those decisions are made by the treating team in the full clinical context.

Caveats and What Is Evolving

Several points stand out for a mixed audience:

1. The 1% cutoff is a convention, not a sharp biological boundary. The ASCO/CAP guideline established ≥1% as the threshold for positivity for both ER and PR [1]. The formal "ER-low positive" 1, 10% category with its required interpretive comment is, in the 2020 guideline, an ER construct, it is not defined as a separate category for PR [1]. More generally, hormone-receptor results near the low end occupy a biologically ambiguous zone, and this remains an area where the evidence continues to evolve.

2. Preanalytics can drive the result. Because a difference of a single percentage point changes the category, rigorous adherence to fixation and handling standards is essential [1]. A false-negative caused by poor tissue handling has real consequences for how a tumor is classified.

3. PR does not stand alone. Its meaning is anchored to ER status and, more broadly, to the full biomarker panel including HER2. The emergence of the HER2-low category, an evolving and actively debated classification within HER2 testing, illustrates how breast cancer biomarker thresholds are being continually refined. While HER2-low pertains to HER2 rather than PR, it is a reminder that the categorical cutoffs used across breast biomarkers are subject to ongoing reassessment as evidence accumulates.

4. Standardized protocols apply. Reporting should follow validated, standardized examination protocols to ensure reproducibility across laboratories [2].

Summary

PR testing by IHC on FFPE tissue, scored as the percentage of invasive tumor nuclei staining with a ≥1% positivity threshold, provides primarily prognostic information; per ASCO/CAP it does not independently predict endocrine-therapy benefit over ER [1]. Interpreted alongside ER, it refines the assessment of a tumor's endocrine biology and informs eligibility for endocrine therapy classes. The ER-positive/PR-negative phenotype flags a less favorable prognosis. As with all breast biomarkers, attention to preanalytics is critical, and the field continues to refine how thresholds and categories are defined.

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References

1. Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol / Arch Pathol Lab Med. 2020. doi:10.1200/JCO.19.02309. PMID 31928354.

2. College of American Pathologists. Protocol for the Examination of Specimens From Patients With Invasive Carcinoma of the Breast. CAP Cancer Protocols (current version). Available at cap.org cancer protocols.