The Prognosis and Predictive Value of Estrogen Negative/Progesterone Positive (ER−/PR+) Phenotype: Experience of 1159 Primary Breast Cancer from a Single Institute

Breast cancer is a serious worldwide public health problem and is currently the most common cancer overall. Its endocrine therapy is related to the expression of the steroid hormones, estrogen receptor (ER), and progesterone receptor (PR). Breast cancers can be presented under multiple profiles of steroid hormones: ER(−)/PR(+), ER(+)/PR(−), double-positive/negative ER, and PR. 2–8% of all breast cancers express only PR (ER−/PR+) which is an abnormal phenotype, with less known about their behaviors and outcomes. Our study was performed on a large and well-characterized database of primary breast cancer from 2012 to 2019, up to 1159 cases. These cases were divided according to ER and PR expression, as we put all of our focus on ER-negative/PR-positive group, more specifically ER−/PR+/HER2+ and ER−/PR+/HER2− gene expressions, to highlight their features and find a pattern that links HR (hormone receptors) profiles and breast cancer subtypes. Out of the informative cases, 94 patients (8%) had ER−/PR+ breast cancers, while 676 (58.4%) had ER+/PR+, 88 (7.6%) had ER+/PR−, and 164 (14.2%) had ER−/PR− tumors. The ER−/PR+ group was statistically correlated with a high risk of recurrence and death in midway between the double-negative and double-positive HR. According to HER2 status, a low DFS was observed in patients ER−/PR+/HER2−, which is closer to the DFS of TNBC cases but worse than ER+/PR any. On the other side, the ER−/PR+/HER2+ showed also a poorer DFS closer to the HER2+ subgroup in between TNBC and ER+/PR any. The clinicopathological features of the ER−/PR+/HER2− and ER−/PR+ HER2+ have distinguished the patients into two groups with a difference in some clinicopathological characteristics: both groups had closer OS estimation, which was worse than ER−/PR any and better than TNBC and HER2. The ER−/PR+/HER2− seems to increase the risk of recurrence than ER−/PR+/HER2+ when compared to ER+/PR any. On the other hand, the ER−/PR+/HER2+ seems to increase the risk of death more than ER−/PR+/HER2− in comparison with ER+/PR any. Our results support that ER−/PR+ tumors really exist and are rare and clinically and biologically distinct subtypes of breast cancer. In addition, our analysis, which was based on dividing the groups according to HER2 expression, has revealed the existence of two distinct groups; this gave the ER−/PR+ subgroup a heterogeneity characterization. Moreover, this breast cancer subtype should not be treated as a luminal tumor but rather according to the HER2 expression status.

1. Introduction
Breast cancer is a serious worldwide public health problem and is currently the most common cancer overall [1], causing the highest number of cancer-related deaths among women. Due to its complexity and heterogeneity, breast cancer presents veritable variation in clinical, morphological, and molecular management [2]. The molecular classification by immunohistochemical expression of estrogen receptor ER, progesterone receptor PR, human epidermal growth factor receptor 2 (HER2), and proliferation index Ki-67 established by St. Gallen surrogate for breast cancer subtypes reveals five main entities: luminal-A, luminal-B HER2-negative, luminal B HER2-positive, HER2 enriched, and TNBC (triple negative: lack of expression of ER, PR, and no overexpression of HER2) [3, 4].

Breast cancer endocrine therapy is actually related to the expression of the steroid hormones, estrogen receptor (ER), and progesterone receptor (PR). The estrogen receptor (ER) and progesterone receptor (PR) are expressed in more than 75% of breast cancers [5, 6]. They are one of the most powerful prognostic factors and predictive markers in hormonal treatment [7–9]. Therefore, breast cancers can be presented in multiple profiles of steroid hormones: ER(−)/PR(+), ER(+)/PR(−), double-positive/negative ER, and PR [3].

The treatment strategies decisions in cases of double-positive/negative steroid hormones can be taken easily [9]. Not to mention, hormone-receptor-positive breast tumors are qualified by less aggressive clinicopathological outcomes and a high prognosis in reason of the benefits from endocrine therapy [10].

Estrogen receptors (ER) status on its own is useful in predicting benefits from antiestrogenic treatment, but not from hormonal treatment. Thus, progesterone receptors are often tested in parallel with estrogen receptors, as studies have shown that PR expression is conditional on ER activity [3, 4, 11, 12]. Consequently, the luminal tumors are the most common breast cancer phenotypes, presenting more than 50% of all breast cancers [9]. Moreover, only 15–20% of all breast cancer cases have expressed one hormone receptor at a time, with a predominance of tumors expressing ER, but not PR (ER+/PR−) [13, 14].

The existence of breast cancer with ER-negative/PR-positive phenotype is still debated. The biological significance, prognosis, and predictive impact of ER−/PR+ breast cancers have been discussed; there are some hypotheses about considering this profile as a technical artifact. The HR status of breast cancer may be altered due to several factors, resulting in a false-negative ER and/or false-positive PR assay. Antibody selection for ER testing, improper tissue fixations, and different thresholds for reporting immunostaining or less sensitive immunohistochemistry, are some of these factors [15–17]. The American Society of Clinical Oncology/College of American Pathologists recommended that ER−/PR+ tumors should be tested repeatedly to avoid false negative ER results [7, 18].