Prognostic Value of Progesterone Receptor in Estrogen Receptor-Positive, HER-2 Negative Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors (ER) and/or Progesterone Receptors (PR) and these patients are often treated with anti-estrogen therapy.

It has been well established that the detection of Estrogen, Progesterone and HER-2 neu receptors on the tumor cell expressed either alone or together, is a significant prognostic factor, and is associated with the conditional gene expression in the tumor cell itself. The St. Gallen International Expert Consensus in 2011 classified breast cancer into five molecular subtypes with prognostic significance, based on these genetically determined expressions in the tumor cell. The five molecular subtypes of breast cancer include 1) Luminal A (ER+ and/or PR+, HER-2 negative, Ki-67 less than 14%) constituting about 26% of patients 2) Luminal B with HER-2 negative (ER+ and/or PR+, HER-2 negative, Ki-67 14% or more) constituting about 32% 3) Luminal B with HER-2 positive (ER+ and/or PR+, HER-2+, any Ki-67) constituting about 25% 4) HER-2 enriched (ER-, PR-, HER-2+) accounting for about 8% of patients 5) Basal-like (triple negative) (ER-, PR-, HER-2 negative, CK5/6+ and/or EGFR+) constituting about 9% of all breast cancer patients. According to the 2015 St. Gallen guidelines, adjuvant chemotherapy can avoided in Luminal A patients, whereas patients with ER+ HER-2 negative tumors with low or no PR expression or with high Ki-67 expression are considered to have a high risk of relapse and adjuvant chemotherapy is often recommended. It should be noted however that low PR expression in Luminal A patients can carry a poor prognosis as well.

The Progesterone Receptor (PR) is a member of the nuclear receptor family and is regulated by the Estrogen Receptor. It is expressed in over two-thirds of ER-positive breast cancers and is more highly expressed in the Luminal A breast cancer subtype. Several studies have demonstrated improved prognosis among PR-positive breast cancer patients. Further, in ER+, HER-2 negative breast cancers, the Progesterone Receptor is an independent prognostic marker. However, the prognostic value of PR by tumor grade has been unclear.

The authors hypothesized that patient with high-grade tumors might do well if PR is positive. The objective of this study therefore was to study the prognostic value of PR in tumors with high tumor proliferative index, using tumor grade as a surrogate for the proliferative activity of ER+, HER-2 negative breast cancer. This retrospective study included women with primary operable, invasive, ER+ HER-2 negative breast cancer, diagnosed between 2000 and 2012, treated at University Hospitals Leuven. The association of PR status and subtype (Grade 1-2 versus Grade 3) was assessed with Distant Recurrence Free Interval (DRFI) and Breast Cancer specific survival. The data set from BIG 1-98 trial was used for validation. A total of 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. The median patient age was 58 years, 73% had Luminal A-like subtype, 27% had Luminal B-like subtype, lymph node status was predominantly negative (62%) and PR was positive in 89% of patients. Median tumor size was 2.1 cm and most of the patients received adjuvant endocrine therapy (96%) and/or radiotherapy (87%). Adjuvant chemotherapy was administered to 29% of the patients. The median follow up period was 8.6 years.

It was noted in this study that PR positive tumors were more strongly associated with better prognosis in Luminal B-like than in Luminal A-like breast cancer, suggesting that PR is more prognostic in Luminal B-like versus Luminal A-like tumors. Among the Luminal B-like tumors, the 5-year cumulative incidences of distant recurrence were 18.7% in PR negative and 9.2% in PR positive tumors. 

It was concluded PR positivity may be more protective against metastatic relapse in Luminal B-like versus Luminal A-like breast cancer. An absent PR is a clinically more important negative prognostic factor in tumors with a high proliferative index than in low proliferative ER+ HER-2 negative breast tumors. Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer. Van Astena K, Slembroucka L, Olbrecht S, et al. The Oncologist 2019;24:165-171