To Measure or not Measure the Progesterone Receptor, that is the Question

The regulation of progesterone receptor (PR) expression is governed by the estrogen receptor (ER), while PR, in turn, affects ER expression. The presence of PR in a tumor indicates that the ERα pathway is active and functioning normally, and PR plays a critical role in maintaining cell integrity, growth, and proliferation. However, only ER is currently used as a predictor of endocrine therapy responsiveness in clinical practice. While the American Society of Clinical Oncology and the College of American Pathologists recommends the assessment of PR in all tumors, the Royal College of Pathologists considers it optional due to its lesser predictive significance when compared to ER expression. Almost all PR-positive tumors are also ER-positive, while ER-negative, PR-positive tumors are rare. A recent study published in the journal Cancer by Lashen et al. analyzed a large cohort (n=1924) of breast cancer patients with ER-positive and HER-2-negative tumors who presented at Nottingham University hospitals between 1999 and 2006. The study examined and analyzed both PR expression and Ki67 expression levels.

The authors found that 10% (negative PR≤10 and positive PR>10) achieved the best association with patient outcomes, including those who had received endocrine therapy. In this cohort, the PR percentage was bimodal, with 20% of patients being PR negative (<10%) and 69% highly expressed (> 70%). Examining the entire cohort revealed a strong association between PR negativity and postmenopausal status as well as grade 3 tumors. In those patients who had undergone endocrine therapy, negative PR status was associated with parameters characteristic of aggressive tumors. There was also an association between PR negativity and high Ki-67 expression.

Outcomes
PR-negative patients showed a significant association with poor outcomes in terms of shorter breast cancer-specific survival (BCSS) and distant metastases-free survival (DMFS). PR negativity also showed a strong association with poor outcomes in those patients who have received endocrine therapy in both DMFS and BCSS. Ki-67 also showed a strong association with worse outcomes in those patients who have received endocrine therapy. There was, however, no difference in outcomes between PR-negative and PR-positive patients who had received both endocrine and chemotherapy.

Using multivariate analysis, PR was found to be a prognostic factor independent of histologic grade, tumor size, nodal stage, and Ki-67. In patients receiving endocrine therapy, PR remained an independent prognostic factor, but Ki-67 had lost its significance. In a direct comparison of PR and Ki-67 status, PR status maintained its significance with patient outcome, whereas Ki-67 lost its significance in the entire cohort and those receiving endocrine therapy.

Summary
PR positivity is seen in 65 to 75% of breast cancer cases and approximately 80 to 90% of ER-positive cases. This, of course, depends on the cutoff of positivity that is used. The authors examined multiple cutoffs and found that 10% in this large cohort achieved the best association with patient outcomes. The authors found in this study that PR-positive cases in the range of 1%-10% behave similarly to cases with <1%. They found that PR can categorize luminal breast cancer (ER-positive breast cancer) into high and low groups comparable and even superior to the Ki-67 index. The researchers showed that negative PR expression exhibited a strong association with features characteristic of aggressive tumors. It also showed that ER-positive/PR-negative breast cancer has a similar prognosis to hormone receptor-negative breast cancer. Finally, PR negativity was associated with a poor outcome in this cohort.

Dr. Alan Stolier, MD, FACS, clinical breast oncologist, shares his expert medical perspective with a series of educational and scientific articles.