title: 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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany. werner.schroth@ikp-stuttgart.de.|University of Tuebingen, Tuebingen, Germany. werner.schroth@ikp-stuttgart.de.
authors.forename: Werner
authors.initials: W
authors.lastname: Schroth
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Büttner
authors.affiliation: Institute of Stochastics and Applications, University of Stuttgart, Stuttgart, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Goletz
authors.affiliation: Onkologischer Schwerpunkt (OSP) Stuttgart, Stuttgart, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Faißt
authors.affiliation: Onkologischer Schwerpunkt (OSP) Stuttgart, Stuttgart, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Brinkmann
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Saladores
authors.affiliation: Onkologischer Schwerpunkt (OSP) Stuttgart, Stuttgart, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Heidemann
authors.affiliation: Department of Clinical Pathology, Robert Bosch Hospital Stuttgart, Stuttgart, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Gynecology, Robert Bosch Hospital Stuttgart, Stuttgart, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gerteis
authors.affiliation: Department of Internal Medicine, Division of General Medicine and Nephrology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: M D
authors.initials: MD
authors.lastname: Alscher
authors.affiliation: Institute of Stochastics and Applications, University of Stuttgart, Stuttgart, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dippon
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.|Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|Department of Clinical Pathology, Robert Bosch Hospital Stuttgart, Stuttgart, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Fritz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D010641:Phenotype; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D016019:Survival Analysis; D059467:Transcriptome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
keywords: Breast cancer; Endocrine treatment; Estrogen receptor subtype; Progesterone receptor subtype; TCGA