High Progesterone Receptor Expression Research Articles

How Progesterone Receptor Expression Impacts Platinum Sensitivity in Ovarian Clear Cell Carcinoma: Insights from Clinical and Experimental Perspectives.

Ovarian clear cell carcinoma (OCCC) is often considered a relatively platinum-resistant malignancy. The aim of this study was to explore the influence of progesterone receptor (PR) expression levels on platinum sensitivity and survival outcomes in people with OCCC. A retrospective analysis was conducted with 80 people with OCCC who underwent surgery followed by adjuvant chemotherapy. PR expression was assessed via immunohistochemical (IHC) staining and quantified using the H score. The platinum sensitivity and survival outcomes of patients with weak and strong PR expression were compared. Additionally, cisplatin viability and migration experiments were conducted with OCCC cell lines (ES-2 and TOV-21G) with varying PR isoform expressions. Among the 80 patients, 62 were classified as having platinum-sensitive disease, while 18 had platinum-resistant disease. The mean total PR H- score of platinum-sensitive tumors was significantly higher than that of platinum-resistant tumors (p = 0.002). Although no significant differences in progression-free and overall survival were observed between patients with high and low PR expression, those with high PR expression tended to have longer survival. While PR protein was only weakly detectable in ES-2 and TOV-21G cells, a transfection of the PR-A or PR-B gene resulted in a strong expression of PR-A or PR-B, which led to significantly reduced proliferation and migration in ES-2 and TOV-21G cells. Furthermore, overexpression of PR-A or PR-B enhanced cisplatin cytotoxicity in these cell lines. In conclusion, strong PR expression was associated with improved platinum sensitivity and survival outcomes, consistent with our experimental findings. The potential of PR as a tumor sensitizer to cisplatin in OCCC warrants further investigation.

Clinical, Histopathological, and Immunohistochemical Characteristics of Predictive Biomarkers of Breast Cancer: A Retrospective Study.

Breast cancer is a complex disease with variability in clinical manifestation, response to current therapy, and biochemical and histological features among various subgroups. Histologic grading and immuno-histochemical evaluation of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 proliferation index play a crucial role in increasing the differential diagnostic value among various types of breast carcinoma. The aim of this study was to determine the histopathological and immuno-histochemical characteristics of breast tumors from a University Laboratory of Pathology in Greece. The study included female patients over 18 years of age, whose histopathological and immunohistochemical reports were stored in the archives of the First Department of Pathology of National and Kapodistrian University of Athens. The study involved 197 female patients with a median age of 70 years and median tumor size of 2.6 cm. Most tumors were located at the left breast and ductal carcinoma was the most common histologic type (35.5%). Most tumors had histologic grade 2 (106, 53.8%), and were classified as TNM stage IIA (65, 33%). Most grade 1 and 2 tumors exhibited high expression of PR, whereas most grade 3 tumors had no PR expression. Moreover, patients with triple-negative cancer presented with grades 2 and 3 at a lower percentage compared to patients without a triple-negative phenotype (p=0.001). The study provided valuable insights into the histopathological and immuno-histochemical characteristics involved in the development and progression of breast cancer.

EPPK1 as a Prognostic Biomarker in Type I Endometrial Cancer and Its Correlation with Immune Infiltration.

Approximately 20% of patients with type I endometrial cancer (EC) of the uterus experience recurrence and metastasis. However, existing data do not provide sufficient evidence for the utility of protein levels as prognostic biomarkers in type I EC. This study aims to determine whether epiplakin1 (EPPK1) and progesterone receptor (PR) play a role in the recurrence and metastasis of type I EC. Following the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) for assessing the quality of biomarker research results, a retrospective analysis was conducted on clinical information and tissue samples of type I EC patients. Protein expression data and clinical data for type I EC were downloaded from The Cancer Proteome Atlas (TCPA) database. We utilized the Kaplan-Meier (K-M) method and Cox proportional hazards regression analyses to evaluate whether epiplakin1 (EPPK1), progesterone receptor (PR) and certain clinical parameters can serve as independent prognostic factors. The Immune Cell Abundance Identifier (ImmuCellAI) and Cancer Immunome Atlas (TCIA) were employed to predict responses to immunotherapy. Immunohistochemistry was carried out to assess the expression of EPPK1 in type I EC. Type I EC patients with high EPPK1 and low PR expression had higher International Federation of Gynecology and Obstetrics (FIGO) stage, recurrence, and metastasis rates. Furthermore, EPPK1 was identified as an independent prognostic factor, and low expression of EPPK1 was predominantly observed in the POLE ultramutated (POLEmut) group, indicating a favorable prognosis. Additionally, the high EPPK1 expression group had a lower Immune Prognostic Score (IPS), suggesting that the high-expression group may not benefit from immune checkpoint inhibitors. High expression of EPPK1 is an independent prognostic factor in type I EC patients with low PR expression. It can identify a subgroup of patients at high risk of recurrence. A more aggressive treatment approach is recommended for these patients.

Clinicopathological Analysis of GATA3 Positive Breast Cancers with Molecular Subtypes: A Cross-sectional Study

Introduction: In breast carcinoma, a panel of various marker proteins are used to characterise tumour subtypes, confirm tissue of origin, distinguish metastatic tumours from primary tumours, and provide additional information that may be important for prognosis, predicting response to therapy, or evaluating residual tumours post-treatment. Aim: To investigate the immunohistochemical expression of GATA binding protein 3 (GATA3) in breast carcinoma. Materials and Methods: This cross-sectional study was conducted in the Department of Pathology in collaboration with the Department of Surgery at Pt. BD Sharma, PGIMS, Rohtak, Haryana, India over the period of one year from April 2023 to March 2024. Tumour specimens (n=60) were obtained after modified radical mastectomy. All clinicopathological parameters were noted. Histological tumour grading was performed using the Nottingham Modification of the Bloom-Richardson (MBR) grading system, and representative sections were subjected to immunohistochemical analysis for Oestrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2/Neu (HER2/Neu), and Ki-67 for molecular subtyping, as well as GATA3 expression. The association between GATA3 expression and clinicopathological parameters and different breast cancer molecular subtypes was calculated using the Chi-square and Fisher’s exact Test. The collected data were analysed using the software package Statistical Package for the Social Sciences (SPSS) version 24.0. Results: The age of patients ranged from 28 to 75 years, with a median age of 50.0 years. Triple-negative/basal-like was the most common molecular subtype 20 (33.33%) among all cases. Sixteen cases (26.67%) were of the luminal A subtype. Other molecular subtypes included 12 cases (20%) each of luminal B and HER2-enriched types. GATA3 was positive in 45 of 60 cases, constituting 75% of all cases. A statistically significant relationship was observed between GATA3-positive tumours and histological grade (p-value=0.024), ER status (p-value<0.001), PR status of the tumour (p-value=0.001), and the luminal A and B molecular subtypes (p-value<0.001). No association was found between GATA3 expression and patient age, side of the breast involved, tumour size, histologic subtype, lymph node status, Nottingham Prognostic Index (NPI), or HER2/Neu status of the tumour. Conclusion: GATA3 is a sensitive marker of breast carcinoma and exhibits nuclear expression that aids in better interpretation. It can be especially useful in metastatic breast carcinoma when considered in conjunction with other immunohistochemical markers. GATA3-positive breast cancers demonstrate luminal differentiation and are characterised by high ER and PR expression.

Progesterone Enhances Niraparib Efficacy in Ovarian Cancer by Promoting Palmitoleic-Acid-Mediated Ferroptosis.

Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi) are increasingly important in the treatment of ovarian cancer. However, more than 40% of BRCA1/2-deficient patients do not respond to PARPi, and BRCA wild-type cases do not show obvious benefit. In this study, we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status. This synergy was validated in an ovarian cancer organoid model and invivo experiments. Furthermore, we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage. In clinical cohort, it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy, and high progesterone receptor expression combined with low glutathione peroxidase 4 (GPX4) expression predicted better efficacy of PARPi in patients with ovarian cancer. These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.

Expression of Sex Hormone Receptors in Canine Osteosarcoma.

Simple SummaryOsteosarcoma is a bone tumor that arises from normal bone cells that become malignant. This is a disease that is relatively common in dogs and also affects humans. Dogs are a useful model for human osteosarcoma as they share many similarities including genetic changes, manner of spread and how they respond to treatment. In dogs, the tumors are frequently seen in large breeds and may be caused by environmental and genetic factors. Sex steroids have been shown to regulate bone metabolism directly and indirectly through receptors on bone. The aim of this study was to investigate the expression levels of sex hormone receptors in canine osteosarcoma tissue and cell lines. Our results demonstrate varying levels of receptors in tissue and a high expression of progesterone receptors in the canine osteosarcoma cell lines. Low oxygen levels further increased progesterone receptor expression. Lastly, estradiol decreased the expression of progesterone receptor in one of the cell lines, and progesterone decreased cell proliferation in the same cell line. Further investigation is recommended to determine whether or not sex steroid receptor levels and sensitivity to hormones are related.Sex steroids regulate bone metabolism directly and indirectly through receptors on bone. Estrogen receptors (ER-∝, ER-β), progesterone receptor (PR), and androgen receptor (AR), have been previously identified on human osteosarcoma (OSA) cells, and are considered to influence tumor growth, but their expression and role in canine OSA is unknown. The aim of this study was to characterize sex hormone receptor expression levels in naturally occurring OSA tissue and in three canine OSA cell lines. The expression of ER-α, ER-β, PR, and AR was investigated using RT-PCR. PR expression levels were also quantified in OSA cells cultured under hypoxic conditions or in the presence of estradiol. The effects of progesterone on cell proliferation were quantified. Results demonstrated varying expression levels of these receptors in five OSA subtypes. OSA cell lines demonstrated high gene expression levels of PR and low gene expression levels of ER-α and ER-β and no gene expression of AR. PR expression was increased in OSA cells cultured under hypoxic conditions in a HIF-∝ independent manner. Interestingly, one cell line expressed very high levels of PR, expression of which decreased in response to estradiol. In addition, progesterone decreased OSA cell proliferation in this particular cell line. Further investigation of the role of sex steroids, particularly PR and its ligands, in regulation of canine OSA is recommended.

P-336 Progesterone receptor is not downregulated in the endometrial epithelial compartment of women without embryo implantation during frozen thawed embryo transfer cycles

Abstract Study question Is the mean endometrial progesterone receptor (PGR) expression in the endometrial epithelial compartment different between women with and without embryo implantation failure? Summary answer PGR expression is higher in epithelial endometrial compartment of women with embryo implantation failure, during mock hormonal endometrial preparation preceding frozen thawed embryo transfer cycles. What is known already PGR downregulation is critical for embryo implantation. Downregulation takes place during the window of implantation in the EEC, while, in stromal cells, it is highly expressed. Embryos are unable to attach to the maternal surface when PGR expression remains expressed in epithelial endometrial compartment (EEC). Limited information is available whether PGR is downregulated during hormonal endometrial preparation for frozen thawed embryo transfer cycles. Study design, size, duration In this cohort study, 47 endometrial biopsies were obtained between 2016-2017 Participants/materials, setting, methods Infertile women (n = 47) submitted to frozen thawed embryo transfer (FET) cycles had an endometrial biopsy after 5 days of intravaginal progesterone supplementation during mock hormonal endometrial preparation (HEP) preceding FET and prospectively followed until confirmation of an intrauterine pregnancy. PGR immunostaining was performed using standard immunohistochemical technique (clone BSB2 - BS2126, BIO SB). PRG expression was quantified using the histologic score (HScore, range from 0 - 4). Ethical approval was obtained from local ethical committee. Main results and the role of chance Age, body mass index, endometrial thickness, and the number of embryos transferred were not significantly different between women who became or not pregnant. PGR Hscore (mean ± SD) in EEC was significantly lower in pregnant women (1.2 ± 0.8; n = 14 ) compared to women without pregnancy (2.8 ± 0.6; n = 33 ) Student t-test p < 0.0001. The AUC was 0.90 ± 0.05 (95% CI: 0.7-1) p < 0.0001 displaying 94.2 % sensitivity and 80.4% specificity for a 1.65 PGR cut-off value. Limitations, reasons for caution This is an observational study to determine if a difference in PGR expression was identified in these cases Wider implications of the findings The mean PGR expression is abnormally higher in EEC of women with embryo implantation failure using HEP for FET cycles. The 1.65 cut-off may be used in future studies to investigate whether high PGR expression is a risk factor for failure of blastocyst implantation in HEP for FET. Trial registration number not applicable

Abstract 649: Targeting progesterone receptor (PR) with the antiprogestin onapristone in patient-derived xenograft (PDX) models of estrogen receptor positive (ER+), PR positive (PR+) bone metastasis of breast cancer

Abstract Background: Onapristone (ONA) is a progesterone receptor (PR) antagonist that prevents PR-mediated DNA transcription. ONA is currently being evaluated in metastatic breast cancers (MBC), as well as other hormone-dependent cancers. Recently, therapeutic options for metastatic estrogen receptor (ER) positive breast cancers have been expanded by the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), administered in combination with endocrine treatments, as first line therapy. Moreover, the selective PI3K inhibitor alpelisib (ALP) has been approved for the treatment of PIK3CA-mutated endocrine resistant MBC. The objective of this study was to evaluate the efficacy of ONA in combination with fulvestrant (FUL) and palbociclib (PAL) or ALP in different PDX models established from ER and PR positive breast cancers. Methods: PDX models were established from primary tumors or biopsies from bone metastases from endocrine therapy patients with progressing tumors. ER and PR expression were analyzed by immunohistochemistry (IHC) and western blot (WB) analysis in 17 PDX models. The anti-tumor activity of onapristone alone or combined with FUL and PAL was tested in 2 ER+/PR+ PDX studies, while the combination with ALP+FUL was tested in one PIK3CA-mutated PDX study. Phosphorylation of both PR and ER-PR interactions were analyzed in treated tumors by WB and by the in situ Proximity Ligation Assay (PLA), respectively. Results: PR expression was found in 1/9 PDX established from primary breast tumors and 4/8 PDX established from bone metastases. ONA in vivo activity was tested in 2 PDX of bone metastases: PDX BC1101 (PR low) and BC1117 (PR high). BC1101 showed amplification of FGFR1 and CCND1 genes, while BC1117 has an activating mutation of PIK3CA gene. In the low PR PDX BC1101, treatment with ONA was ineffective in both the monotherapy and combination setting. Conversely, in the PDX with high expression of PR, BC1117, ONA treatment, given as monotherapy, decreased tumor growth. The anti-tumor activity of ONA+FUL+PAL combination was significantly increased as compared to FUL+PAL, with the majority of xenografts showing tumor regression. Expression of PR and phospho-PR were inhibited in the tumors treated by FUL, ONA+FUL, and ONA+FUL+PAL. Interaction between ER and PR, analyzed by the in situ PLA assay, was inhibited in the ONA+FUL treated xenografts ±PAL. Finally, treatment with the triple combination of ONA+FUL+ALP was also highly effective and significantly greater than the combination of FUL+ALP. RNAseq analysis of treated xenografts is ongoing to identify transcriptomic changes in the different treatment arms. In conclusion, our study demonstrates that ONA improved the response to endocrine treatment using CDK4/6 or PI3K inhibitors in a MBC-derived PDX model with high PR expression. Citation Format: Martin Lehr, Ahmed Dahmani, Léa Huguet, Rania El-Botty, Charlène Thiebaut, Muriel Romancer, Paul Cottu, Elisabetta Marangoni. Targeting progesterone receptor (PR) with the antiprogestin onapristone in patient-derived xenograft (PDX) models of estrogen receptor positive (ER+), PR positive (PR+) bone metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 649.

Pathobiologic Stratification of Oncotype DX Recurrence Scores and Comparative Validation of 3 Surrogate Models.

The Oncotype DX Recurrence Score (RS) predicts recurrence and chemotherapy benefit in early-stage estrogen receptor-positive breast cancer patients. Cost and unavailability are 2 major disadvantages of the assay. Multiple models have been developed to predict the RS. To predict RS based on histopathologic and biomarker features, and to measure concordance and correlation with RS of the following 3 algorithms: breast cancer prognostic score, Magee0, and Magee2. Breast cancer cases with available RSs were reviewed (n = 442). RS categories were stratified by pathologic and biomarker variables. Histopathologic and biomarker data were abstracted from pathology reports, and RS was calculated by each model. Correlation and concordance between models and RS were calculated. Less than 5% of breast cancers with lobular features, low-grade tumors, carcinomas with high progesterone receptor content, or luminal A tumors had an RS greater than 25. Breast cancer prognostic score, Magee0, and Magee2 demonstrated correlation coefficients with RS of 0.63, 0.61, and 0.62, respectively. Two-step discordances were uncommon. When an RS of 25 was used to separate high-risk from non-high-risk cases, concordance rates of 86% to 88% were achieved. High RS was observed only in a small percentage of pure or mixed lobular carcinomas, low-grade or luminal A tumors, and tumors with high progesterone receptor expression, suggesting that these cancers may not require Oncotype testing. All 3 surrogate models demonstrated comparable correlation and high concordance with the RS when a cutoff of 25 was used, suggesting their utility in cases where the actual RS is unavailable.

High expression of progesterone receptor may be an adverse prognostic factor in oestrogen receptor-negative/progesterone receptor-positive breast cancer: results of comprehensive re-evaluation of multi-institutional case series

Oestrogen receptor (ER)-negative (-) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER-/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER-/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER-/PgR+ breast cancer were collected from 11 institutions from the period 2006-2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER-/PgR+ phenotype, including 21 HER2+ and 55 HER2- tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2- cohort, confirmed ER-/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER-/PgR+/HER2- breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3-19.2, p=0.019). We performed one of the largest validation studies so far on ER-/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor.

Prognostic Role of Androgen Receptor Expression in HER2+ Breast Carcinoma Subtypes.

HER2+ breast cancer (BC) is an aggressive subtype representing a genetically and biologically heterogeneous group of tumors resulting in variable prognosis and treatment response to HER2-targeted therapies according to estrogen (ER) and progesterone receptor (PR) expression. The relationship with androgen receptors (AR), a member of the steroid hormone’s family, is unwell known in BC. The present study aims to evaluate the prognostic impact of AR expression in HER2+ BC subtypes. A total of 695 BCs were selected and reviewed, AR, ER, PR and HER2 expression in tumor cells were examined by immunohistochemical method, and the SISH method was used in case of HER2 with equivocal immunohistochemical score (2+). A high prevalence of AR expression (91.5%) in BC HER+ was observed, with minimal differences between luminal and non-luminal tumor. According to steroid receptor expression, tumors were classified in four subgroups, including BC luminal and non-luminal HER2+ expressing or not AR. The luminal BC HER2 + AR+ was associated with lower histological grade, lower tumor size, higher PR expression and lower HER2 intensity of expression (2+). Also, the non-luminal tumors AR+ showed lower tumor size and lower prognostic stage but frequently higher grade and higher HER2 intensity of expression (3+). These findings should suggest a different progression of luminal and non-luminal tumors, both expressing AR, and allow us to speculate that the molecular mechanisms of AR, involved in the biology of BC HER2 + AR+, differ in relation to ER and PR expression. Moreover, AR expression may be a useful predictor of prognosis for overall survival (OS) in HER2+ BC subtypes. Our findings suggest that AR expression evaluation in clinical practice could be utilized in clinical oncology to establish different aggressiveness in BC HER2+ subtypes.

The Role of Progesterone Receptors in Breast Cancer.

The progesterone receptor (PR) modulates estrogen receptors α (ERα) action in breast cancer; it is an upregulated target gene of ER, and its expression is dependent on estrogen. PR is also a valuable prognostic biomarker in breast cancer, especially in hormone-positive breast cancer. High expression of PR is more frequently observed in tumors with a better baseline prognosis (ie, luminal A) than tumors with a poor baseline prognosis (ie, luminal B). In the following review, we present the role of PR in breast cancer, including the genomic characteristics and pathways in breast cancer, PR and endocrine therapy.

Neoadjuvant Endocrine Therapy for Operable Breast Cancer: A Retrospective Analysis of Real-World Use.

A retrospective study of the real-world use of neoadjuvant endocrine therapy (NET) is important for standardizing the role of NET in breast cancer care. In a consecutive series of women with operable breast cancer who received NET for ≥28 days, associations of NET objectives, NET outcomes, adjuvant chemotherapy use after NET, and survival with clinicopathological factors were examined. NET objectives were reduction in surgical extent in 49 patients, avoidance of surgery in 31, and treatment until scheduled surgery in 8. The mean duration of NET was 349.5 (range, 34-1,923), 869.8 (range, 36-4,859), and 55.8 (range, 39-113) days, respectively, in these cohorts (success rate: 79.6%, 64.5%, and 100%, respectively), and the differences were significant. Among patients in the former two cohorts, progression-free survival was significantly better in patients with stage 0 or I disease, ductal carcinoma in situ or invasive ductal carcinoma, ≥71% estrogen receptor (ER) positivity, and the surgical extent reduction cohort than the other counterparts. Postoperative chemotherapy use was significantly associated with lymph node metastasis, a high Ki67 labeling index, lymphovascular invasion, and a high preoperative endocrine prognostic index at the time of surgery after NET. Better recurrence-free survival after surgery was significantly associated with high ER expression after NET or high progesterone receptor expression before or after NET. NET can help reduce surgical extent or avoid surgery in women with early breast cancer, ductal carcinoma, or high ER expression. NET may also aid in decisions related to postoperative systemic therapy to improve survival.

The surgical effect on overactive bladder symptoms in women with pelvic organ prolapse

This study aimed to explore the effect of pelvic reconstruction surgery on the relation of pelvic organ prolapse (POP) and overactive bladder (OAB) and the impact of preoperative vaginal oestrogen supplement on vaginal tissue. A total of 100 postmenopausal women with symptomatic POP who underwent pelvic reconstruction surgery (laparoscopic sacrocolpopexy or transvaginal mesh) were enrolled in this study. Preoperative vaginal oestrogen was prescribed in 28 cases. The evaluation tools consisted of POP-Q, urodynamic study, Overactive Bladder Symptom Score (OABSS), and urinary NGF. Vaginal maturation index and vaginal specimens for hormone receptors study were investigated during operation to evaluate the effect of topical oestrogen. Follow-up assessments were performed at 1, 3, and 6 months after surgery. Preoperatively, 58 (58%) were POP with OAB. After reconstruction surgery, the OABSS decreased significantly (6.87 ± 0.85 vs 3.77 ± 0.61, p < 0.001) at postoperative 6 months in the group. Remarkable increasing trends of urinary NGF levels are noted till 3 months postoperatively, then decreasing to the baseline level at 6 months postoperative follow-up. Remarkable decrease of mRNA of the androgen receptor and significant higher expression of progesterone receptor (PR) were noted after use of the vaginal oestrogen cream. The severity of OAB in the POP women shows moderate degree according to OABSS. Pelvic reconstruction surgery can significantly improve the OAB symptoms. The surgery induced inflammation effect lasts for about 6 months. Short-term preoperative supplement of topical oestrogen brings alterations of the vaginal epithelium.

A validated model to predict low recurrence risk distinguished by 21-gene recurrence score in hormone receptor-positive invasive breast cancer patients.

532 Background: In the prospective TAILORx and RxPONDER trials, the 21-gene Recurrence Score (RS) showed endocrine therapy alone was non-inferior to chemo-endocrine therapy in the analysis of invasive disease-free survival in postmenopausal hormone-receptor (HR)-positive breast cancer patients with RS &lt; = 25. They also indicated chemotherapy was associated with benefit for women 50 years or younger with RS 11 to 25. However, in Japan, the test is not conventionally available because of non-coverage by national insurance. We aimed to develop and validate a model to predict RS using clinicopathological factors that identify patients who would have low risk shown by testing the 21-gene RS and can avoid chemotherapy. Methods: Four hundred patients, including 187 N0/1 postmenopausal, and 213 N0 premenopausal women who underwent surgery and had the RS from St. Luke’s International Hospital, Tokyo, Japan, were included in derivation cohort. Derivation cohort was divided into 2 groups by RS 25; patients with RS of 0 to 25 (n = 321) and with RS over 26 (n = 79). Multivariate logistic regression analysis was performed using candidate factors for all patients and pre- or postmenopausal patients. The prediction model was validated using an external cohort of 70 patients from Showa University School of Medicine, Tokyo, Japan. Results: Nuclear grade (NG) (adjusted OR, 5.28, 95% CI, 2.47–11.30), high Progesterone receptor (PgR) expression (Allred score 7-8) (adjusted OR, 10.62, 95% CI, 5.34–21.13) and low Ki67 level ( &lt; = 20%) (adjusted OR, 5.29, 95% CI, 2.33-12.01) were significant independent predictors of RS of 0 to 25. With these factors could predict RS of 0 to 25 (AUC of 0.848, 95% CI, 0.803-0.893) with the highest probability of low-RS for 100%. The prediction model of the validation cohort had same discriminatory ability having an AUC of 0.812 (95% CI, 0.701-0.923). In postmenopausal patients, NG (adjusted OR, 4.81, 95% CI, 1.72–13.42), high PgR expression (adjusted OR, 10.62, 95% CI, 4.52–37.72), and low Ki67 level (adjusted OR, 4.94, 95%CI, 1.87-13.04) were significantly associated with RS of 0 to 25 in multivariate analysis. A regression model with these 4 factors could predict RS of 0 to 25 (AUC of 0.842, 95%CI, 0.782-0.902). In premenopausal patients, NG (adjusted OR, 8.76, 95% CI, 1.14–67.40), high PgR expression (adjusted OR, 3.22, 95% CI, 1.61–6.43), and low Ki67 level (adjusted OR, 2.87, 95% CI, 1.20–6.87) were significantly associated with RS of 0 to 10 in multivariate analysis. These factors could predict RS of 0 to 10 (AUC of 0.811, 95% CI, 0.731-0.891). However, the highest probability of low-RS provided this model for premenopausal women was 46.8%. Conclusions: Our validated model could provide useful information to distinguish low-RS especially for postmenopausal patients with high reproducibility. However, for premenopausal women, the 21-gene RS is warranted.

Invasive Papillary Carcinoma of the Breast: Clinicopathological Features and Hormone Receptor Profile.

IntroductionPapillary neoplasms are a heterogeneous group of breast lesions, ranging from benign to in situ and invasive malignant tumors. The term invasive papillary carcinoma (IPC) is reserved for rare invasive breast tumors showing greater than 90% papillary morphology. The clinical, epidemiological and pathological characteristics of IPC are not widely described in the existing literature; therefore, in this study, we evaluated the clinicopathological features and biomarker profile of IPC and compared it with invasive ductal carcinoma (IDC) diagnosed in the same study duration.MethodsA retrospective study was conducted in the Department of Histopathology, Liaquat National Hospital and Medical College, from January 2013 to December 2020. During the study period, 44 cases of IPC and 1,268 cases of IDC were diagnosed. Slides and blocks of all cases were retrieved and histopathological diagnosis was reviewed. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2/neu), and Ki67 immunohistochemical (IHC) stains were applied on representative tissue blocks.ResultsThe mean age of the patients with IPC was 58.77±8.38 years, and the mean Ki67 index was 19.95±21.12%. The mean tumor size was 32.41±17.39 mm, and most tumors (59.1%) were tumor (T)-stage T2. Axillary metastasis was present in 13.6% cases, and 86.4% cases had nodal (N)-stage N0. ER and PR expression was noted in 72.7% cases, and HER2/neu positivity was seen in 13.6% cases. IPC cases had a higher mean age than IDC. Conversely, IPC had a lower mean Ki67 index than IDC. Similarly, IPC cases were found to have a lower frequency of axillary metastasis than IDC. IPC was noted to have a lower frequency of T3-stage and lymphovascular invasion than IDC. A higher expression of PR and lower frequency of HER2/neu expression was noted in IPC than IDC.ConclusionIPC is a rare malignant papillary breast tumor with a wide differential diagnosis and therefore poses a significant diagnostic challenge. We found that IPC had a favorable pathological profile than IDC, in terms of T-stage, Ki67 index, axillary metastasis, PR and HER2/neu expression.

Unfavorable Prognostic Effects of the Stem Cell Pluripotency Factor Sox2 in Feline Invasive Mammary Carcinomas.

Background: Sex-determining Region Y (SRY)-box transcription factor-2 (Sox2) belongs to the “Yamanaka's factors,” necessary and sufficient to convert somatic cells into pluripotent stem cells. In breast cancers, Sox2 expression has been associated with poor prognosis, and resistance to therapy. The aims of this study were to determine the frequency of Sox2 positivity in feline invasive mammary carcinomas (FMCs), its relationships with other clinical-pathologic variables, and with patient outcomes.Materials and Methods: This study relies on a previously described retrospective cohort of 180 FMCs, diagnosed in female cats treated by mastectomy alone, with 2-year follow-up. Sox2 (clone SP76), Estrogen Receptor alpha (ER), Progesterone Receptor (PR), Ki-67, Human Epidermal growth factor Receptor 2 (HER2), Androgen Receptor (AR), Bcl-2, Forkhead box protein A1 (FOXA1), basal markers and FoxP3-positive regulatory T cells (Tregs) were detected by automated immunohistochemistry. Sox2 expression was quantitated as an index (percentage of neoplastic cells demonstrating a positive nuclear signal). The FMCs were considered Sox2-positive at threshold >42%.Results: Sox2 was not expressed in the normal mammary gland or in mammary hyperplasia without atypia, but was occasionally detected in atypical hyperplasia. In FMCs, the mean Sox2 index was 38 ± 30%, and 79/180 FMCs (44%) were Sox2-positive. Sox2 expression was associated with older age at diagnosis, lymphovascular invasion, high Ki-67 proliferation indexes, low PR and FOXA1 expression, and increased numbers of tumor-associated Tregs, but was not significantly associated with the clinical stage, histological types, and histological grade. By multivariate survival analysis, Sox2 was associated with poor cancer-specific survival (Hazard Ratio = 1.48, 95% confidence interval 1.04–2.11, p = 0.0292), independently of the pathologic tumor size, pathologic nodal stage, distant metastasis, and AR expression. A rare subgroup of FMCs characterized by an AR+Sox2–phenotype (19/180 cases, 11%) was associated with very favorable outcomes.Conclusion: Sox2 expression was associated with poor cancer-specific survival of female cats with invasive mammary carcinomas, as previously reported in human breast cancer, but was more commonly expressed in cats than reported in breast cancers. Sox2 showed complementarity with AR in FMC prognostication.

Association of estrogen and progesterone receptors with clinicopathological prognostic factors in breast cancer

Background: The detection of the estrogen receptor (ER) and progesterone receptor (PgR) in women with breast cancer (BC) is considered a crucial step for prognostic evaluation and treatment choice in clinical practice. Objectives: This study aimed to evaluate the expression of the hormonal receptors (ER and PgR), their distribution, and their association with clinicopathologic prognostic parameters in a sample of Iraqi women with BC. Materials and Methods: The paraffin-embedded blocks from a total of 80 women diagnosed with primary invasive breast carcinomas with BC were examined by immunohistochemistry to assess the expression of ER and PgR status. Demographic and clinical data were collected from each patient in the preformed questionnaire. The association of steroid receptor expression with clinicopathologic parameters was assessed using binary logistic regression. Results: Among 80 BC women involved in the study, 54 (67.5%) and 39 (48.75%) had high expression of ER and PgR, respectively. High ER expression was significantly associated with older age (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.16-19.81, P = 0.03), postmenopausal status (OR = 3.6, 95% CI = 1.25–10.33, P = 0.015), smaller tumor (OR = 0.27, 95% CI = 0.09–0.75, P = 0.01), and with noninvolvement of lymph node (OR = 0.11, 95% CI = 0.02–0.51, P = 0.005). High PgR expression, on the other hand, was significantly associated with older age (OR = 4.44, 95% CI = 1.02–19.39) and postmenopausal status (OR = 3.13, 95% CI = 1.24–7.88, P = 0.016). Concomitant overexpression of both receptors was significantly associated with postmenopausal status and noninvolvement of lymph nodes. Conclusion: High expression of ER and PgR seems to be a good prognostic indicator because it was associated with less aggressive tumors.

Suppressed estrogen supply via extra-ovarian progesterone receptor membrane component 1 in menopause.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a Pgrmc1 heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve Pgrmc1 hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, Pgrmc1 hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but PGRMC1 knockdown increased PR and STS expression. Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.

Hormone Receptor Expression on Endocrine Therapy in Patients with Breast Cancer: A Meta-Analysis

To evaluate the role of hormone receptor expression on endocrine therapy in patients with breast cancer. The databases were used to collect the effect of high expression and low expression of hormone receptors on the efficacy of endocrine therapy in breast cancer. Two evaluators independently screened the literature based on preset inclusion and exclusion criteria. The quality of the article was evaluated using a modified Newcastle-Ottawa Scale (NOS) system. The survival data included in the literature were extracted and the ln(hazard ratio (HR)) and se[ln(HR)] of the overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) rates were calculated according to different level of hormone receptors. The RevMan 5.3 software was used to evaluate the meta-analysis. A total of 13 relevant literature were included in the study. There were 8318 estrogen receptor (ER)-positive and 7926 progesterone receptor (PR)-positive patients. Overall survival, DFS, and RFS rates in high expression of ER(+) patients were significantly higher in low expression of ER(+) patients (OS HR = .59, 95% confidence interval (CI): .46-.76, P < .0001; DFS HR = .62, 95%CI: .50-.76, P < .00001; RFS HR = .44, 95% CI: .33-.58, P < .00001). In patients with high expression of PR(+), OS, DFS, and RFS rates were significantly higher than those with low expression of PR(+) (OS HR = .66, 95% CI: .57-.78, P < .00001; DFS HR = .52, 95% CI: .42-.65, P < .00001; RFS HR = .24, 95% CI: .11-.53, P = .0004). The expression of ER and PR are powerful predictors of adjuvant endocrine therapy response. Breast cancer patients with high expression of hormone receptors benefit more from endocrine therapy and have better prognosis.