Low Progesterone Receptor Research Articles

Prognostic differences of phenotypes in pT1-2N0 invasive breast cancer: a large cohort study with cluster analysis

To find phenotypic subgroups of patients with pT1-2N0 invasive breast cancer by means of cluster analysis and estimate the prognosis and clinicopathological features of these subgroups. From 1999 to 2013, 4979 patients with pT1-2N0 invasive breast cancer were recruited for hierarchical clustering analysis. Age (≤40, 41-70, 70+ years), size of primary tumor, pathological type, grade of differentiation, microvascular invasion, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) were chosen as distance metric between patients. Hierarchical cluster analysis was performed using Ward's method. Cophenetic correlation coefficient (CPCC) and Spearman correlation coefficient were used to validate clustering structures. The CPCC was 0.603. The Spearman correlation coefficient was 0.617 (P<0.001), which indicated a good fit of hierarchy to the data. A twelve-cluster model seemed to best illustrate our patient cohort. Patients in cluster 5, 9 and 12 had best prognosis and were characterized by age >40 years, smaller primary tumor, lower histologic grade, positive ER and PR status, and mainly negative HER-2. Patients in the cluster 1 and 11 had the worst prognosis, The cluster 1 was characterized by a larger tumor, higher grade and negative ER and PR status, while the cluster 11 was characterized by positive microvascular invasion. Patients in other 7 clusters had a moderate prognosis, and patients in each cluster had distinctive clinicopathological features and recurrent patterns. This study identified distinctive clinicopathologic phenotypes in a large cohort of patients with pT1-2N0 breast cancer through hierarchical clustering and revealed different prognosis. This integrative model may help physicians to make more personalized decisions regarding adjuvant therapy.

Biological differences between functionalis and basalis endometria in women with and without adenomyosis

ObjectiveEndometriosis is commonly believed to originate from functionalis endometrium and adenomyosis from basalis endometrium. Due to the lack of enough information, we investigated the biological differences between these two layers of endometrium in women with and without adenomyosis. Study designThis was a case-controlled study with 12 control women and 17 women with adenomyosis undergoing hysterectomy. Full thickness (extending from the endometrium to the myometrium) biopsy specimens were obtained after the hysterectomy. Based on the phases of the menstrual cycle, the expression patterns of estrogen receptor (ER), progesterone receptor (PR), Ki-67, and activated Caspase-3 were analyzed by immunohistochemistry in the functionalis and basalis endometria. Apoptotic cells were evaluated by TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assay. ResultsA similar pattern of ER and PR expression was found in the functionalis and basalis endometria during the proliferative phase. In contrast, a significantly lower ER and PR expression was found in the basalis endometria than in the functionalis endometria during the secretory phase and the menstrual phase. This was equally observed in control women and in women with adenomyosis. Except Ki-67 indices, TUNEL-positive cells, and expression of activated Caspase-3 were significantly lower in the basalis endometria than in the functionalis endometria during the secretory phase. ConclusionA significant biological difference was found between the functionalis and the basalis endometria derived from women with adenomyosis.

MP57-18 EXPRESSION OF STEROID HORMONE RECEPTORS IN RESIDUAL CANCER AND STROMAL CELLS AFTER NEOADJUVANT CHEMOHORMONAL THERAPY WITH DOCETAXAL FOR HIGH-RISK LOCALIZED PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy III1 Apr 2016MP57-18 EXPRESSION OF STEROID HORMONE RECEPTORS IN RESIDUAL CANCER AND STROMAL CELLS AFTER NEOADJUVANT CHEMOHORMONAL THERAPY WITH DOCETAXAL FOR HIGH-RISK LOCALIZED PROSTATE CANCER Shintaro Narita, Taketoshi Nara, Mingguo Huang, Koichiro Takayama, Kazuyuki Numakura, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Hiroshi Nanjo, Shigeru Satoh, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Koichiro TakayamaKoichiro Takayama More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Atsushi MaenoAtsushi Maeno More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Hiroshi NanjoHiroshi Nanjo More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.672AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent studies suggest that activation of steroid hormone receptors (SHRs) is associated with PCa progression and resistance to chemohormonal therapy. In this study, we investigated SHR expressions in human PCa tissues in patients who underwent radical prostatectomy (RP) with and without neoadjuvant chemohormonal therapy. METHODS A tissue microarray with 210 cores from 70 high-risk localized PCa patients who underwent RP without neoadjuvant therapy (NNA), with neoadjuvant hormonal therapy (NHT), or with neoadjuvant chemohormonal therapy with docetaxel (CHT) was used to assess the epithelial and stromal expressions of four SHRs including androgen receptor (AR), glucocorticoid receptor (GR), estrogen receptor (ER) alpha, and progesterone receptor (PR). Expression levels of SHRs between the three groups were statistically assessed. Multivariate analyses were performed to investigate the prognostic factors of BCR in patients who underwent surgery with CHT. RESULTS AR and GR were expressed in both residual cancer and stromal cells, whereas ER alpha and PR were mainly expressed in stromal cells. The mean nuclear AR immunoreactivity score in residual cancer cells was significantly higher in the NNA group than in the NHT and CHT groups. The mean nuclear GR immunoreactivity score in residual cancer cells and mean nuclear ER alpha and PR in stromal cells were significantly higher in the CHT group than in the NNA and NHT groups. The patients with a low PR immunoreactivity score in stromal cells had a significantly higher BCR rate than those with a high nuclear immunoreactivity score (p = 0.011). In multivariate analysis, the number of risk factors constituting the classification of high-risk, a preoperative PSA level, pathological chemotherapy effect, and low nuclear PR immunoreactivity score in stromal cells were independent prognostic factors for BCR. CONCLUSIONS Stromal PR expression may be a potential prognostic marker for BCR in high-risk PCa patients who underwent radical prostatectomy after neoadjuvant chemohormonal therapy. The expression of SHRs in both residual cancer and stromal cells may play an important role in PCa resistance to chemohormonal therapy. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e759-e760 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Shintaro Narita More articles by this author Taketoshi Nara More articles by this author Mingguo Huang More articles by this author Koichiro Takayama More articles by this author Kazuyuki Numakura More articles by this author Hiroshi Tsuruta More articles by this author Atsushi Maeno More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Norihiko Tsuchiya More articles by this author Hiroshi Nanjo More articles by this author Shigeru Satoh More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract P3-04-05: Prognostic effect of semiquantitative measurement of PgR in luminal type breast cancer

Abstract Background: The identification of prognostic factors for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative breast cancer is an important issue for the accurate determination of the indications for chemotherapy. The progesterone receptor(PgR) is a downstream molecule induced by transcriptional activation of estrogen signaling. In recent report, quantitatively low PgR expression was significantly associated with a poorer prognosis for patients treated with anastrozole and/or tamoxifen. These findings seem to suggest that the clinically used Ki-67-based IHC classification of luminal subtypes is inaccurate and that semiquantitative measurement of PgR expression can improve the IHC-based classification. Method: 1327 consecutive patients with ER and/or PgR-positive HER2-negative invasive breast cancer treated with surgery and adjuvant treatment at the Seoul National University Hospital from January 2009 to December 2011 were reviewed. All patients had been pathologically diagnosed with breast cancer, and patients who had received chemotherapy or endocrine therapy before surgery were included. ER, PgR, HER2, and Ki-67 were determined from surgically resected, formalin-fixed, paraffin-embedded tumor tissue. The RFS and OS in Kaplan-Meier plots for the PgR high and low expression groups was compared using the log-rank test. Univariate and multivariate analyses of DFS and OS in relation to various factors were performed with a Cox proportional hazards model, which yielded the HR and 95% of CI for each variable. Results: Based on pathology data of semiquantitative measurement of the percentage of PgR-positive cells, patients were separated into two groups with PgR percentage cutoff 20%. Among 1372 patients, 665(48.5%) showed high PgR expression, 707(51.5%) showed low PgR expression. PgR expression was relatively high in younger age(&amp;lt;50 years, p&amp;lt;0.001). Higher PgR expression was related to low Ki-67 expression(&amp;lt;10%, p=0.003), and low cancer stage(p&amp;lt;0.001). The DFS and OS of patients in the high PgR subset were significantly better than the low PgR subset only in patients under 50years old.(p=0.005 and 0.037) Cox analysis showed that low PgR expression(HR, 3.06; 95% CI, 1.44-6.47) and negative ER expression(HR, 19.68; 95% CI, 5.89-65.80) were significant independent risk factors for DFS. Low PgR expression(HR, 5.66; 95% CI 1.62-19.74) and high Ki-67 expression(HR 1.06; 95% CI 1.01-1.17) were significant independent risk factors for OS. Conclusion: We were able to demonstrate that high PgR expression is associated with a better prognosis for luminal type breast cancer. The semiquantitative determination of PgR expression might thus improve the accuracy of the IHC-based classification of luminal A and luminal B breast cancer, especially for premenopausal patients. Citation Format: Kim MK, Han W. Prognostic effect of semiquantitative measurement of PgR in luminal type breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-05.

Abstract P5-08-23: Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive breast cancer

Abstract Background Immunohistochemistry markers are recognized as a predictive prognostic factor for women with breast cancer. Ki-67 and progesterone receptor (PgR) expression are reported to be independently associated with breast cancer prognosis. Some studies report high Ki-67 expression as a negative predictive marker. Whereas other studies report tendency of similar survival between high and low Ki67 cancers when PgR expression is high. In this study, we examined the prognostic significance of Ki-67 expression under PgR expression status. Methods The records of 2,366 patients were retrospectively reviewed. The patients underwent surgery for primary breast cancer from July 2009 to December 2012 at a single institution. We studied the prognostic significance of Ki-67 expression under PgR expression. We used 20% and 10% as the cut-off value for PgR and Ki-67, respectively. The end point was recurrence-free survival (RFS) evaluated by use of Kaplan-Meier analysis. Result Of the 2,366 analyzed patients, the median follow-up time was 43 months. During follow-up, 44 patients had recurrence, loco-regional recurrence developed in 23 patients and distant recurrence developed in 21 patients. In patients with low PgR expression, high Ki-67 expression group showed significantly worse prognosis compared to low Ki-67 expression group (p=0.005). On the other hand, no significant difference was shown between low and high Ki-67 expression group when PgR expression was high (p=0.637). Also multivariate analysis demonstrated that high Ki-67 expression was an independent prognostic factor only when PgR expression was low. (95% confidence interval [CI], 1.35-10.48; p=0.011) Conclusion This is the largest reported study that prognostic significance of Ki-67 expression is defined by PgR expression. Our study presents that high Ki-67 expression is inversely correlated with recurrence risk in early breast cancer patients only under low PgR expression. At high PgR expression, Ki-67 expression has no influence on breast cancer prognosis. Therefore, attention should be paid to correlation between PgR and Ki-67 expression. Citation Format: Han JH, Kang YJ, Han W, Lee H-B, Kim Y, Yoo T-K, Moon H-G, Noh D-Y. Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-23.

Abstract A43: Context-dependent growth effects of progestins in estrogen receptor-positive breast cancer patient-derived xenografts (PDX)

Abstract Introduction: Progesterone (P4) and progesterone receptors (PR) play elusive roles in breast cancer. Synthetic progestins in hormone replacement therapy increase breast tumorigenesis, yet these same progestins at high doses can be an effective therapy for some advanced breast tumors. The literature supports that progestins can either stimulate or inhibit breast cancer cell growth, and an increasing body of evidence supports P4 promotes expansion of breast cancer stem cells. Interplay between PR and estrogen receptors (ER) is emerging as important in dictating growth and response to treatment. There is historical precedence for PR interference of ER dependent gene transcription; recent reports identify that PR modulate ER DNA binding events. Given the importance of PR as a biomarker and potential therapeutic target, and the uncertainty surrounding its context-dependent actions, we aimed resolve this using breast cancer PDX models. The purpose of this study was to evaluate the effects of natural and synthetic progestins on growth and estrogen-dependent gene expression in luminal breast tumors, and to define contexts that dictate their divergent effects. Experimental procedures: Six luminal breast cancer PDX developed at UCD-AMC were used for these studies. Most profiled as Luminal B subtype. Tumors generally fell into two types: a pure luminal phenotype and a mixed luminal/basal phenotype based on cytokeratin expression. Tumors varied in expression of ER, PR, and androgen receptors (AR) from low (&amp;lt;10% positive cells), moderate (30-50%), to high (&amp;gt;90%). Tumors were grown in vivo under conditions of continuous placebo, 17β-estradiol (estrogen), estrogen plus progesterone (P4), or estrogen plus the synthetic progestin medroxyprogesterone acetate (MPA) for several months and growth parameters monitored. Receptor content was measure by immunohistochemistry and western blots. Gene expression profiles of select tumors were determined using Affymetrix® GeneChip human gene microarrays and/or RNAseq and results analyzed using Partek Genomics Suite™ software, and Metacore™ pathway analysis. Summary: In two pure luminal PDX with high receptor levels (ER, PR, AR) both P4 and MPA significantly inhibited estrogen-dependent growth (growth-inhibited, GI). Two PDX (one pure luminal, one mixed) with moderate ER and low PR and AR showed no significant effect of P4 or MPA on estrogen-dependent growth (growth neutral, GN). One mixed luminal/basal PDX with low ER and PR and moderate AR showed no effect with P4, whereas MPA simulated tumor growth above that with estrogen alone (growth stimulated, GS). Study of one PDX is ongoing. In the GI tumors both P4 and MPA reversed expression of ~30% of estrogen regulated genes. In particular these tumors had high estrogen-dependent expression of the Notch pathway, which was blocked by both P4 and MPA. Progestins did not alter estrogen-dependent genes in the GN or GS tumors, which did not include the Notch pathway. MPA stimulated a unique set of genes in the GS tumor, and was able to mobilize AR to the nucleus whereas P4 did not. Conclusion: Progestins have mixed effects on breast cancer PDX tumor growth. Tumors that have high ER and PR and are highly estrogen-dependent are more likely to exhibit strong growth inhibition by progestins (both P4 and MPA). Tumors with mixed luminal/basal phenotype that have less ER and PR and are moderately estrogen-dependent are less likely to be progestin-inhibited. In tumors with low ER and PR but high AR content MPA can act as an AR agonist to stimulate growth. Tumor-specific downstream estrogen-dependent pathways such as Notch may indicate whether progestins are therapeutic. Additional tumors are needed to confirm these results with the long term goal of developing a molecular assay to define those tumors that may benefit from progestin treatment. Citation Format: Jessica Finlay-Schultz, Heather M. Brechbuhl, Rachel B. Rosen, Austin E. Gillen, Britta M. Jacobsen, Peter Kabos, Carol A. Sartorius. Context-dependent growth effects of progestins in estrogen receptor-positive breast cancer patient-derived xenografts (PDX). [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A43.

Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18% immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane+ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane+OFS versus tamoxifen+OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

Mechanisms of chorioamnionitis-associated preterm birth: interleukin-1β inhibits progesterone receptor expression in decidual cells.

In chorioamnionitis (CAM), a major cause of preterm birth (PTB), maternal-fetal inflammation of the decidua and amniochorion cause the release of cytokines that elicit cervical ripening, fetal membrane rupture and myometrial activation. We posit that this inflammatory milieu triggers PTB by inhibiting progesterone receptor (PR) expression and increasing decidual prostaglandin (PG) production. Immunohistochemical staining of decidua detected significantly lower PR levels in decidual cells (DCs) from CAM-complicated PTB. Incubation of DCs with IL-1β decreased PR expression and significantly increased PGE2 and PGF2α production and COX-2 expression. The addition of PGF2α to DC cultures also suppressed PR expression. However, the COX inhibitor, indomethacin, did not reverse IL-1β suppression of PR expression in DC cultures. Although IL-1β treatment activated the NF-KB, ERK1/2 and p38 MAPK signalling cascades in DCs, inhibition of ERK1/2 MAPK signalling alone was sufficient to completely reverse the suppression of PR levels by IL-1β. These findings suggest that CAM-associated PTB is induced at least in part by IL-1β-mediated functional progesterone withdrawal.

Abstract 1861: Estrogen modulation of fibroblast growth factor signaling in non-small cell lung cancer

Abstract The estrogen signaling pathway induces proliferation in non-small cell lung cancer (NSCLC) and represents a novel therapeutic target for lung cancer. Estrogen receptor β (ERβ) is the predominant ER isoform in lung cancer and we have previously shown that high cytoplasmic ERβ combined with low progesterone receptor (PR) expression is a poor prognostic marker for NSCLC patients. To further elucidate the biological differences between ERβ high/PR low versus ERβ low/PR high expressing lung tumors, a mRNA microarray analysis using the Illumina HT-12 V4 Bead Chip platform was performed using RNA extracted from 64 cases. 165 genes were differentially expressed between these two groups at P&amp;lt;001. Fibroblast growth factor receptor 1 (FGFR1) was a highly over-expressed gene associated with ERβ high tumors (2.1-fold, P&amp;lt;0.004), while the decoy receptor for FGFR ligands, fibroblast growth factor receptor like-1 (FGFR5), was down-regulated (0.54-fold, P&amp;lt;0.0001). Ingenuity Pathway analysis revealed a network among the 165 differentially expressed genes that linked FGFR1 and FGFR5 to the ER. To analyze cross-talk between the FGF and E2 pathways, we determined the FGF/FGFR profile in a panel of three FGFR1 amplified and five non-amplified NSCLC cell lines. FGF2, 3, 10, and 19 were the most highly secreted FGFs in the cell line panel. FGFR1 amplified cells secreted statistically more FGF3, 6 and 10 compared to non-amplified cells. β-estradiol (E2) induced secretion of FGF2 in a cell line without FGFR1 amplification. FGFR3 and 5 were ubiquitously expressed across all cell lines while FGFR1, 2 and 4 expression was higher in amplified cell lines. There was no relationship between ERβ protein expression and FGFR1 amplification status or FGFR1-5 protein expression. Because FGF signaling has been shown to increase stem cell-like phenotypes in breast cancer, we determined basal and E2-stimulated expression of the stem cell markers, SOX2 and OCT4. Basal SOX2 and OCT4 were more highly expressed in FGFR1 amplified cells compared to non-amplified cells. SOX2 and OCT4 protein expression were increased by E2 treatment in FGFR1 non-amplified cells, with lesser effects in FGFR1 amplified H520 cells. SOX2 expression was also down-regulated in lung sections from mice treated with a combination of the anti-estrogen fulvestrant and the aromatase inhibitor anastrozole. Finally, we have shown that in FGFR1 non-amplified cells, the anti-proliferative effect of a pan-FGFR inhibitor, AZD4547, can be enhanced in the presence of the anti-estrogen fulvestrant. These results suggest that there is an interaction between the estrogen and FGF signaling pathways in lung cancer and provides a rationale for combination treatment of NSCLC tumors. Further characterization of the molecular types of NSCLC that will benefit from joint therapy is warranted. This work was supported by P50 CA090440. Citation Format: Laura P. Stabile, Natalie J. Rothenberger, Marjorie Romkes, Lisa Koodie, Mariya Farooqui, Sanja Dacic, Jill M. Siegfried. Estrogen modulation of fibroblast growth factor signaling in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1861. doi:10.1158/1538-7445.AM2015-1861

Abstract 2774: Androgen receptor is an independent prognostic marker of breast cancer in ethnically diverse women from Chicago

Abstract Androgen receptor (AR) has been demonstrated to be a prognostic marker in invasive breast cancer; higher expression levels of AR is associated with better prognosis among breast cancer patients. The goal of this analysis was to examine the extent to which AR was associated with specific breast cancer subtypes, and whether it could serve as an additional prognostic marker above and beyond breast cancer subtype, in an ethnically diverse sample of 287 patients (86 Non-Hispanic White, 84 Hispanic and 116 African American). Immunohistochemical analysis was performed on tissue microarrays constructed from invasive breast cancer samples obtained from the Breast Cancer Care in Chicago study. Tissue samples were tested for the expression of estrogen receptor (ER), progesterone receptor (PR), HER2. From these results, breast cancers were classified as Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), HER2 enriched (ER-/PR-/HER2+), and triple negative (TN) (ER-/PR-/HER2-). Tumor tissues were also analyzed for the expression of other proliferative and apopototic markers (i.e. Ki67, P53 and bcl2) as well as BRCA1 protein expression. AR expression was evaluated based on the percentage of positive tumor cells and staining intensity using the H-score. The H score is a product of the percentage of cells (0-100%) in each intensity category (0, 1+, 2+ and 3+). The final score is on a continuous scale between 0 and 300. AR expression was then classified as low (&amp;lt;60%) or high (≥60%) using the mean of the AR score as a cutoff. Among the 287 breast cancer cases, 59% were expressing low levels of AR while 41% were expressing high AR. The percentage of tumor samples with high AR expression was much higher for luminal A (52%) than for luminal B, HER2, and TN subtypes (43, 29, and 9%, respectively(P&amp;lt;0.0001). High AR expression significantly correlated with early stage (P = 0.01), lower nuclear grade (P&amp;lt;0.0001), ER and PR positivity (P&amp;lt;0.0001), bcl2 positivity(P&amp;lt;0.0001), higher levels of BRCA1 expression (P&amp;lt;0.0001), lower Ki67 index (P&amp;lt;0.0001), and lower P53 expression (P&amp;lt;0.0001). A hormone receptor expression score (HRES) with a high internal reliability (Cronbach's alpha = 0.7035) was created based on standardized variables for ER, PR and AR expression. Using an ordinal logistic regression model, the HRES was a highly significant predictor of tumor grade (P&amp;lt;0.0001). In conclusion, in this multi-ethnic sample of breast cancer patients, we found that AR was a significant independent predictor of less aggressive, lower grade disease, even after accounting for molecular subtype. AR might serve as a useful additional marker for the classification of breast cancer into molecular subtypes. Citation Format: Abeer M. Mahmoud, Umaima Al-alem, Virgilia Macias, Jacob K. Kresovich, Andre Kajdacsy-Balla, Elizabeth L. Wiley, Garth H. Rauscher. Androgen receptor is an independent prognostic marker of breast cancer in ethnically diverse women from Chicago. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2774. doi:10.1158/1538-7445.AM2015-2774

Prognostic Value of Preoperative Serum Levels of Periostin (PN) in Early Breast Cancer (BCa).

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients.

Enhanced Human Decidual Cell–Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal

Sustained plasma progesterone (P4) levels suggest initiation of human term labor by functional P4 withdrawal, reflecting reduced progesterone receptor (PR) and/or glucocorticoid receptor (GR) expression or activity. The steroid-induced immunophilin cochaperone FKBP51 inhibits PR- and GR-mediated transcription, suggesting a labor-initiating role. Gestational age-matched decidual sections were immunostained for FKBP51 and decidual cell (DC) and interstitial trophoblast (IT) markers, vimentin and cytokeratin, respectively. Term DC cultures were incubated with vehicle (control), estradiol (E2) with or without medroxyprogesterone acetate, dexamethasone (Dex), or Organon 2058. FKBP51 histologic scoring was significantly higher in DC nuclei during labor versus prelabor decidua, whereas FKBP51 immunostaining was undetected in interstitial trophoblasts (P < 0.05). In term DC cultures, E2 + medroxyprogesterone acetate or E2 + Dex enhanced FKBP51 expression (P < 0.01), whereas E2 + Organon 2058 inhibited PR expression (P < 0.05), and E2 + Dex inhibited GR expression (P < 0.05). Unlike term DCs, FKBP51 was undetected in control or Dex-treated cultured third-trimester trophoblasts. Electrophoretic mobility shift assays revealed that FKPB51 overexpression or silencing in cultured DCs altered PR-DNA binding. Increased FKBP51 levels in term DCs during labor complement our prior in situ observations of significantly lower PR in labor versus prelabor DCs. In a milieu of sustained plasma P4 levels, these reciprocal changes will amplify functional P4 withdrawal in DCs via FKBP51-mediated PR resistance coupled with declining PR levels, whereas the lack of FKBP51 expression in interstitial trophoblasts suggests unopposed constitutive GR action.

Progesterone receptor modulates ERα action in breast cancer.

SummaryProgesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Evaluation of HER2/neu Status by Immunohistochemistry Using Computer-Based Image Analysis and Correlation With Gene Amplification by Fluorescence In Situ Hybridization Assay: A 10-Year Experience and Impact of Test Standardization on Concordance Rate.

The American Society of Clinical Oncology/College of American Pathologists proposed several recommendations for human epidermal growth factor receptor 2 (HER2) test standardization. One suggestion was that image analysis (IA) could be useful for scoring of HER2/neu immunohistochemistry. The utilization of IA in a real-world practice in a large cohort of cases has not been previously reported. To compare HER2/neu quantification by IA with gene amplification by fluorescence in situ hybridization (FISH); to determine sensitivity, specificity, and concordance rates with the FISH assay; and to determine association between HER2 status with estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression. We evaluated HER2 results performed by immunohistochemistry and FISH in conjunction with ER, PR, and Ki-67 in 3093 invasive breast cancer cases from 2002 to 2011. The overall concordance between immunohistochemistry and FISH was 87.3% (1768 of 2026). When analyzed by year, there was an improvement in the positive concordance rate from 49.4% (44 of 89) to 95.0% (57 of 60) (P < .001). The negative concordance rate was at least 95% with a median false-negative rate of 1.5%. In the FISH+ group, amplification ratio showed significant correlation with IA scores (P < .001). Positive versus negative HER2 status was associated with lower ER and PR levels (P < .001) and higher Ki-67 expression (P < .001). Scoring of HER2/neu by IA was associated with high false-positive rates before 2008. Improvement in concordance rate after 2008 may be due to proper tissue handling, improved HER2/neu scoring by IA, and assay standardization.

Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer.

We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response.

Abstract P4-11-27: Prospective comparison of conventional clinicopathological factors, uPA/PAI-1 and EndoPredict®-clin score (EPclin) for adjuvant clinical decision making in ER-positive, HER2-negative breast cancer: Progesterone receptor expression is strongly associat

Abstract Background: Recently, EPclin, a second generation multigene test has been introduced into clinical practice. Aim of this prospective study is to compare conventional clinicopathological factors, uPA/PAI-1 and EPclin and to determine, how these parameters influence adjuvant treatment decisions. Methods: 217 consecutive cases of ER-pos, HER2neg, breast cancer cases were enrolled in this study. Conventional clinicopathological factors, uPA/PAI-1 and EPclin were obtained by central pathology assessment of the patients' surgical specimen. Decision for type of adjuvant treatment was made twice – once with and once without EPclin result- after case discussion in an interdisciplinary tumor conference. Results: 217 Patients (pt) have been evaluated. Tumor grading within the presented cohort was as follows: G1: 44 pt (20%), G2: 146 pt (68%), G3: 27 pt (12%). 59 pt (27%) had positive axillary lymph node involvement. 57 pt (26%) were pT1a/b. EPclin could be assessed in all patients. 85 pt (39%) were classified as "high risk" whereas 132 pt (61%) were classified as "low risk". uPA/PAI was obtained from 123 pt (57%). 64 pt (52%) out of these had high uPA/PAI-1 levels whereas 59 pt (48%) showed low uPA/PAI-1 levels. Level of progesterone receptor (PR) expression was obtained from 216 pt. 39 pt (18%) had low or absent PR expression (PR ≤ 20%). 26 pt (67%) of this low PR expression group were classified as EPclin high risk. Furthermore 118 pt (67%) of the high PR expression group (177 pt) were classified as "low risk" via EPclin (p&amp;lt;0,0001). In 89 cases (41%) treatment decision was influenced by EPclin: In 73pt (34%) adjuvant chemotherapy (ctx) was omitted whereas in 16 pt (7%) ctx was added following the EPclin result. Conclusions: This prospective study shows for the first time, that PR expression is strongly associated with risk score evaluated by EPclin testing. In comparison with uPA/PAI-1 and conventional clinicopathological factors EPclin is the more powerful tool to help reduce unnecessary adjuvant chemotherapy. Citation Format: Johannes Ettl, Kirsten Große Lackmann, Alexander Hapfelmeier, Evelyn Klein, Stefan Paepke, Christoph Petry, Katja Specht, Laura Wolff, Heinz Höfler, Marion Kiechle. Prospective comparison of conventional clinicopathological factors, uPA/PAI-1 and EndoPredict®-clin score (EPclin) for adjuvant clinical decision making in ER-positive, HER2-negative breast cancer: Progesterone receptor expression is strongly associat [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-27.

A Validated Model for Identifying Patients Unlikely to Benefit From the 21-Gene Recurrence Score Assay

BackgroundPredicting recurrence risk and chemotherapy benefit in early-stage breast cancer can be challenging, and Oncotype DX (ODX) is often used to gain insight. However, it is still unclear whether ODX can benefit in all cases. To clarify ODX's usefulness we sought to develop a model using readily available pathologic markers to help clinicians make that determination. Patients and MethodsClinical pathologic data from 221 hormone receptor-positive, HER2-negative invasive breast cancer patients was used to create a model. The model was then validated on a second institution's set of 319 patients. ResultsThe model has 2 simple rules: low grade and positive progesterone receptor tumors (LG+PR) are low risk, and high grade or low estrogen receptor (ER) (ER < 20%) tumors (HG/LER) are high risk. The TAILORx (Trial Assigning Individualized Options for Treatment (Rx)) trial thresholds of Recurrence Score (RS) ≤ 10, when chemotherapy is of little benefit, and RS ≥ 26 when chemotherapy might be beneficial were used to judge model performance. Impressively, the misclassifications of an HG/LER patient who has an RS ≤ 10 were 0% and 2%, and for LG+PR patients who had an RS ≥ 26 were 0% and 2.6%. In the validation set, 28% (66 of 232) of the indeterminate group (neither in the HG/LER nor the LG+PR groups) had an RS ≤ 10 or an RS ≥ 26; this group might clinically benefit from ODX. ConclusionA simple 2-rule model based on readily available pathologic data was developed and validated, which categorized patients into high and low risk for recurrence. Identification of patients who are unlikely to benefit from ODX testing could result in significant cost avoidance.

Effects of reproductive experience on central expression of progesterone, oestrogen α, oxytocin and vasopressin receptor mRNA in male California mice (Peromyscus californicus).

Fatherhood in biparental mammals is accompanied by distinct neuroendocrine changes in males, involving some of the same hormones involved in maternal care. In the monogamous, biparental California mouse (Peromyscus californicus), paternal care has been linked to changes in the central and/or peripheral availability of oestrogen, progesterone, vasopressin and oxytocin, although it is not known whether these endocrine fluctuations are associated with changes in receptor availability in the brain. Thus, we compared mRNA expression of oestrogen receptor (ER)α, progesterone receptor (PR), vasopressin receptor (V1a) and oxytocin receptor (OTR) in brain regions implicated in paternal care [i.e. medial preoptic area (MPOA)], fear [i.e. medial amygdala (MeA)] and anxiety [i.e. bed nucleus of the stria terminalis (BNST)] between first-time fathers (n = 8) and age-matched virgin males (n = 7). Males from both reproductive conditions behaved paternally towards unrelated pups, whereas fathers showed significantly shorter latencies to behave paternally and less time investigating pups. Furthermore, fathers showed significantly lower PR, OTR and V1a receptor mRNA expression in the BNST compared to virgins. Fathers also showed a marginally significant (P = 0.07) reduction in progesterone receptor mRNA expression in the MPOA, although fatherhood was not associated with any other changes in receptor mRNA in the MPOA or MeA. The results of the present study indicate that behavioural and endocrine changes associated with the onset of fatherhood, and/or with cohabitation with a (breeding) female, are accompanied by changes in mRNA expression of hormone and neuropeptide receptors in the brain.

High Ki-67 Expression and Low Progesterone Receptor Expression Could Independently Lead to a Worse Prognosis for Postmenopausal Patients With Estrogen Receptor-Positive and HER2-Negative Breast Cancer

BackgroundAccurate classification of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered clinically important for determining effective adjuvant treatment. Although Ki-67 expression has been identified as an essential constituent for this classification, the role of progesterone receptor (PgR) expression has yet to be fully elucidated. Because PgR expression is influenced by the estrogen milieu, we examined the prognostic significance of PgR expression in immunohistochemical (IHC)-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration. Materials and MethodsWe examined 327 surgically removed ER+ and HER2− breast cancer specimens. ER, PgR, and Ki67 expression was determined IHC for semiquantitative measurement. We used 1%, 20%, and 15% as the cutoff value for ER, PgR, and Ki-67, respectively. ResultsBreast cancer with low PgR (≤ 20%) expression was significantly associated with postmenopausal status, a large tumor size, and low ER expression. The low PgR expression subset had significantly worse distant relapse-free survival (DRFS) than the high PgR expression subset (P = .0067). This association was observed consistently in postmenopausal women but not in the premenopausal women. Multivariate analysis demonstrated that high Ki-67 expression (hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.57-10.58; P = .003) and low PgR expression (HR, 2.54; 95% CI, 1.08-6.40; P = .038) were significant independent factors affecting DRFS. ConclusionLow PgR expression was independently associated with a poorer prognosis for ER+ and HER2− breast cancer. Determination of PgR expression combined with that of Ki-67 could thus improve the accuracy of IHC-based classification of luminal A and luminal B breast cancer, especially for postmenopausal women.

Activation of mTOR/S6K But Not MAPK Pathways Might Be Associated With High Ki-67, ER+, and HER2− Breast Cancer

BackgroundEvaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear. Materials and MethodsWe determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER+, HER2− breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%. ResultsA significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset. ConclusionFrom our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER+/HER2− breast cancer with high Ki-67 expression.