Clinical outcome and global gene expression data support the existence of the estrogen receptor-negative/progesterone receptor-positive invasive breast cancer phenotype

Abstract

The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER-/PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients.

Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors

“…The existence of ER À /PGR þ tumors has been questioned, investigated, and confirmed. [95][96][97][98] Itoh et al 75 suggested the use of ESR1 mRNA expression to help stratify ER À /PGR þ patients, and approximately 25% of these patients' tumors had the molecular profile of ER þ tumors with similar relapse-free survival to that of ER þ /PGR þ patients. 75 Shen et al 99 also showed that patients who were ER À / PGR þ had a relapse-free survival similar to that of ER þ /PGR þ patients and had a better response to endocrine therapy than ER þ / PGR À patients.…”

“…Multimodal assessments of tumors using a PC of estrogen signaling and ESR1 and/or PGR mRNA expression, together with IHC ER/PGR status, would be extremely useful in stratifying breast cancer patients for endocrine treatment. Schroth et al 97 showed that in ER À /PGR þ patients, 59 unique mRNAs were differentially regulated, including ESR1 and GATA3. 97 It is reasonable to assume that PGR status and ER status both correlate with our PC of estrogen pathway activity across our breast tumors.…”

“…Schroth et al 97 showed that in ER À /PGR þ patients, 59 unique mRNAs were differentially regulated, including ESR1 and GATA3. 97 It is reasonable to assume that PGR status and ER status both correlate with our PC of estrogen pathway activity across our breast tumors. However, further patient stratification is required to investigate these multiple parameters robustly.…”

Estrogen Receptor-negative/progesterone Receptor-positive and Her-2 Negative Breast Cancer Might No Longer Be Classified as Hormone Receptor Positive Breast Cancer

“…There are four hormone-receptor status (HoR status) phenotypes, and the ER-negative/PR-positive (sPR positive) phenotype is infrequent, accounting for 1.0%-4.10% of all types of malignant breast cancer [11][12][13][14][15][16]. The existence of the sPR positive breast cancer used to be controversial.…”

“…The existence of the sPR positive breast cancer used to be controversial. Then, the sPR positive phenotype was proved by re-evaluating ER and PR status through immunohistochemical staining (IHC) [13,17] or analyzing PAM50 expression signature and mRNA level of ESR1 [11,18]. Besides, Borras and his co-authors established the sPR positive Evsa-T cell line, which also demonstrated the presence of sPR positive breast cancer [19].…”