PR in Breast Cancer: ESMO Biomarker Factsheet

Definition of PR

The progesterone receptor (PR) is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. Steroid hormones such as progesterone and oestrogen can bind and activate PR which leads to the transcription of genes involved in several cellular processes, including proliferation, evasion of apoptosis, invasion, and angiogenesis.

PR is an upregulated target gene of the oestrogen receptor (ER) and expression of PR is strongly dependent on oestrogen,^1,2 thus it is rare that normal PR-positive cells do not also express ER. In normal cells PR exists in two isoforms, PR-α and PR-β that regulate different but overlapping subsets of target genes.²

PR is an upregulated target gene of the oestrogen receptor (ER) and expression of PR is strongly dependent on oestrogen,^1,2 thus it is rare that normal PR-positive cells do not also express ER. In normal cells PR exists in two isoforms, PR-α and PR-β that regulate different but overlapping subsets of target genes.²

PR Expression in Breast Cancer

PR is a biomarker used routinely at diagnosis to characterise breast cancer. PR is expressed in >50% of ER-positive breast tumours but rarely seen in ER-negative breast tumours.^1,3

A small sub-group of patients are recorded as having PR expression in the absence of detectable ER. This is largely attributable to false-negative ER or false-positive PR status, although this does not account for all cases.³

PR-status is also useful in defining the triple negative breast cancer subtype, which is negative for PR, ER, and HER2 (triple negative) and accounts for 15% of breast cancers.

PR as a Prognostic Biomarker in Breast Cancer

PR is a valuable prognostic biomarker in breast cancer, with overall survival, time to treatment failure/progression, and time to recurrence positively related to PR levels.⁴

Low/absent expression of PR in ER-positive breast tumours is associated with more proliferative and aggressive disease, poorer prognosis and recurrence, whilst PR-positive/ER-positive tumours have more favourable clinico-pathological parameters and prognosis.³

PR as a Predictive Biomarker in Breast Cancer

The predictive value of PR status is controversial.⁴ Some reports suggest that PR-positive patients are more responsive to hormonal therapy;⁵ however, a more recent meta-analysis suggests that given ER status, PR status is not significantly predictive of response to tamoxifen.⁶

PR Testing Recommendations in Breast Cancer

Immunohistochemistry (IHC) is the standard assay platform to determine PR status with a number of clinically validated antibodies available. IHC can be applied to core biopsy and surgical resection specimens.

Scoring Recommendations

The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline for IHC testing of ER and PR in breast cancer recommend the cut-off to define PR-positive from PR-negative cases as ≥1% PR-positive tumour cells.⁴ Cases in which <1% tumour cell nuclei are immune-reactive should be considered PR-negative.

When defining intrinsic subtypes of breast cancer (e.g. luminal A versus luminal B tumours), the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines recommend a cut-off value of 20% to distinguish between high and low values for PR.⁷

Ensuring Quality and Timely PR Testing Results

The ASCO/CAP guidelines provide a comprehensive set of recommendations to improve the accuracy of ICH testing of PR.⁴ Variables within the IHC method that should be standardised to ensure accurate and reliable PR staining include:

• Tissue handling: time from tissue acquisition to fixation should be standardised and as short as possible. Storage of slides for more than 6 weeks before analysis is not recommended.
• Type of fixative: only 10% neutral buffered formalin should be used as the fixative for breast tissue.
• Duration of tissue fixation: breast tissue specimens must be fixed in 10% neutral buffered formalin for no less than 6 hours and for not more than 72 hours before processing.
• Antibody selection: the selection of antibodies for PR IHC testing should be restricted to those reagents that have well-established specificity and sensitivity and have been clinically validated, demonstrating good correlation with patient outcomes in published reports.
• Control samples: positive and negative controls should be included with every PR IHC assay batch run.
• Interpretation of assay: the interpretation of PR assays should include an evaluation of both the percentage of positive tumour cell nuclei and the intensity of the staining reaction.
• Internal quality control and validation: a comprehensive quality control programme for PR IHC analyses should include all aspects of the test to help ensure an appropriate and expected number of PR-positive breast cancers in the patient population served by the laboratory.

Which Technique and Which Algorithm Should be Used for the Analysis of the PR Status in Breast Cancer?

Evaluation of PR status should be performed using a clinically validated IHC assay or an assay that has been tested for and shows high concordance with a clinically validated assay.⁴ Quality assurance programmes are essential for laboratories reporting PR-status results.⁷

Patient Selection

PR status should be determined in all patients with invasive breast cancer or breast cancer recurrence.^4,7 PR-negativity is a determining factor in the decision to use systemic adjuvant therapies.⁷

References

1. Leong AS-Y and Zhuang Z. The Changing Role of Pathology in Breast Cancer Diagnosis and Treatment. Pathobiology 2011;78(2):99–114.
2. Obr A and Edwards DP. The Biology of Progesterone Receptor in the Normal Mammary gland and in Breast Cancer. Mol Cell Endocrinol 2012;357(1-2):4–17.
3. Patani N, Martin LA, Dowsett M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer 2013;133(1):1-13.
4. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28(16):2784-95.
5. Dowsett M, Houghton J, Iden C, et al. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol 2006;17:818-826.
6. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378(9793):771-84.
7. Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi7-23.