Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive Breast Cancer.
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SUBMITTER: Fowler AM
PROVIDER: S-EPMC7152560 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Obesity is one of the most important health risks in postmenopausal women. Molecular pathways that are connected with obesity are believed to interact with the pathogenesis of breast cancer (BC). The aim of this research was to study the polymorphisms of two obesity-associated genes ADIPOQ and FTO that are also related to the pathogenesis of BC. Obesity-associated gene polymorphisms ADIPOQ rs1501299 and rs2241766, and FTO rs1477196, rs7206790, rs8047395, and rs9939609 were studied in 101 Turkish postmenopausal estrogen receptor-positive BC patients and 100 healthy control individuals. ADIPOQ rs1501299 was detected to be associated with protection against BC. The ADIPOQ rs1501299 TT genotype, the rs2241766 GT genotype and the G allele were found to be significantly higher in the control group. In addition, ADIPOQ rs1501299 polymorphism was protective in the recessive model and rs2241766 polymorphism was protective in the dominant model. While none of the FTO gene polymorphisms were found to be associated with BC, the frequencies of rs9939609 A allele and rs7206790 G allele were correlated with body mass index (BMI) in BC patients. ADIPOQ rs1501299 TT genotype, rs2241766 GT genotype, and G allele might be protective against BC in the Turkish population but this conclusion needs to be further verified.
| S-EPMC8326496 | biostudies-literature
Project description:IntroductionEstrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.MethodsWe integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses' Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.ResultsIn a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.ConclusionER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.
| S-EPMC3978610 | biostudies-literature
Project description:Background: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. Methods: We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. Results: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. Conclusions: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.
| S-EPMC6691389 | biostudies-literature
Project description:Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies.SignificanceEstrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.
| S-EPMC10883292 | biostudies-literature
Project description:The majority of breast cancer tumors are estrogen receptor-positive (ER+) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER+ breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER+ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER+) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28-0.72; P=0.001)]. It was also more pronounced in the ER+/PR- subgroup (HR, 0.15; 95% CI, 0.05-0.46; P=0.001). In the second cohort, patients of the ER+/PR- subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05-0.60; P=0.006). However, this was not identified among ER+/PR+ tumors (HR, 1.31; 95% CI, 0.69-2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER+/PR- tumor.
| S-EPMC6923975 | biostudies-literature
Project description:BackgroundProgesterone receptor (PR)-negative tumors have been shown to have worse prognosis and were underrepresented in recent trials on patients with estrogen receptor (ER)-positive breast cancer. The role of PR-negative status in the context of 21-gene recurrence score (RS) and nodal staging remains unclear.MethodsThe National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-3N0-1a breast cancer. Logistic and Cox multivariable analyses (MVA) were performed to identify association of PR status with high RS (> 25) and overall survival (OS), respectively.ResultsAmong 143,828 women, 130,349 (90.6%) and 13,479 (9.4%) patients had PR-positive and PR-negative tumors, respectively. Logistic MVA showed that PR-negative status was associated with higher RS (> 25: aOR 16.15, 95% CI 15.23-17.13). Cox MVA showed that PR-negative status was associated with worse OS (adjusted hazards ratio [aHR] 1.20, 95% CI 1.10-1.31). There was an interaction with nodal staging and chemotherapy (p = 0.049). Subgroup analyses using Cox MVA showed the magnitude of the chemotherapy benefit was greater among those with pN1a, PR-negative tumors than pN1a, PR-positive tumors (PR-positive: aHR 0.57, 95% CI 0.47-0.67; PR-negative: aHR 0.31, 95% CI 0.20-0.47). It was comparable among those with pN0 tumors regardless of PR status (PR-positive: aHR 0.74, 95% CI 0.66-0.82; PR-negative: aHR 0.63, 95% CI 0.51-0.77).ConclusionPR-negative tumors were independently correlated with higher RS and were associated with greater OS benefits from chemotherapy for pN1a tumors, but not pN0 tumors.
| S-EPMC10088125 | biostudies-literature
Project description:Simple Summary Most breast cancers co-express estrogen receptor α (ERα) and progesterone receptor (PgR). These cancers are sensitive to endocrine therapy and, in general, have superior outcomes. However, a subset of tumors expresses ERα but loses expression of PgR in various mechanisms. The processes driving the loss of PgR may cause resistance to hormonal treatment and a more aggressive clinical course. The current review summarizes current knowledge on the biology of ERα-positive PgR(−)negative breast cancer and discusses the associations between molecular mechanisms and clinical characteristics. Abstract Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12–24% of BCs present ERα(+)/PgR(−) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(−) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(−) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(−) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g., by microRNAs), and post-translational modifications (e.g., phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.
| S-EPMC8507533 | biostudies-literature
Project description:Estrogen receptor (ER) and progesterone receptor (PR) have been used as indicators of endocrine system status since the mid-1970s in the clinical management of breast cancer. The predictive role of ER in endocrine therapy is undisputed, but the prognostic value of PR is still debated. The aim of this study was to investigate the clinical characteristics and prognosis of ER positive breast cancer with different PR expression levels.A population cohort of 3,030 primary invasive ER positive breast cancer patients from a single cancer center underwent surgery and received adjuvant endocrine therapy from 2004 to 2010. The clinical and biological features of these patients with high PR-expressing tumors were compared with those of patients with low PR-expressing tumors. The follow-up data for disease-free survival (DFS), overall survival (OS), and breast cancer specific survival (BCSS) was obtained from 2,778 patients. Cox regression analysis was used to correlate biomarkers and tumor characteristics with DFS, OS, and BCSS.Tumors with low PR expression had more invasive pathological features and biological indexes than those with high PR expression. Low PR expression was an independent poor prognostic factor for DFS (p=0.014; hazard ratio [HR], 0.781; 95% confidence interval [CI], 0.641-0.950), OS (p=0.002; HR, 0.699; 95% CI, 0.560-0.873), and BCSS (p=0.005; HR, 0.714; 95% CI, 0.566-0.902). Furthermore, in low PR expressing tumors, patients who received chemotherapy had better DFS (p=0.002; HR, 0.449; 95% CI, 0.268-0.751), OS (p<0.001; HR, 0.341; 95% CI, 0.192-0.606), and BCSS (p<0.001; HR, 0.292; 95% CI, 0.156-0.549) than patients who did not received chemotherapy.Patients with ER positive invasive breast cancer with low PR expressing tumors have a worse prognosis than those with high PR expressing tumors, and these patients can benefit from chemotherapy.
| S-EPMC5500399 | biostudies-other
Project description:The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype.Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n?=?67,932) and Fudan University Shanghai Cancer Center (n?=?2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated.Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P?=?0.61 for sufficient versus insufficient endocrine therapy).The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.
| S-EPMC4595063 | biostudies-literature
Project description:Purpose of reviewMetastatic breast cancer (MBC) remains a major clinical challenge, necessitating the development of innovative therapeutic strategies. Estrogen receptor (ER) degradation using proteolysis-targeting chimeras (PROTAC) has emerged as a promising approach for overcoming acquired resistance to endocrine therapy. This review will summarize recent findings, highlighting the role of ER degradation by PROTAC in patients with MBC.Recent findingsThe application of PROTAC technology for ER degradation has demonstrated initial success in preclinical and early clinical studies. PROTACs, consisting of an ER-targeting moiety, an E3 ubiquitin ligase-recruiting moiety, and a linker, facilitate ER ubiquitination and subsequent proteasomal degradation. Yet, significant challenges persist in the clinical translation of ER degradation by PROTAC. These include the optimization of PROTAC design, elucidation of mechanisms underlying resistance to PROTAC-induced ER degradation, and identification of predictive biomarkers for patient stratification. Additionally, addressing potential off-target effects and toxicity profiles remains a critical aspect of developing PROTAC-based therapies.SummaryRecent data demonstrate the potential of ER degradation by PROTAC as a therapeutic strategy for patients with MBC. Continued research efforts and development of synergistic combinations are crucial for further advancing PROTAC-based therapies and improving outcomes in patients with MBC.
| S-EPMC10566586 | biostudies-literature