Endocrinal Therapy Research Articles

62P Combination of chemotherapy with endocrinal therapy as upfront treatment of metastatic breast cancer in hormone receptor- positive, HER2 -negative disease: A phase II randomised clinical trial

62P Combination of chemotherapy with endocrinal therapy as upfront treatment of metastatic breast cancer in hormone receptor- positive, HER2 -negative disease: A phase II randomised clinical trial

16P The prognostic value of androgen receptor expression in triple-negative breast cancer patients

Triple negative breast cancer (TNBC) is a distinct subtype of BC that is characterized by frequent recurrence and metastasis. Patients with TNBC have significantly worse prognosis compared to other subtypes of BC due to lack of well-defined targeted and endocrinal therapy. Androgen receptor (AR) expression is an emerging prognostic marker that has been observed in 10% to 50% of TNBC.The aim was to assess the relation between AR and clinicopathological features. Also, assessing the survival outcome in relation to AR expression in TNBC patients.

Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression

Breast cancer is common worldwide, and the estrogen receptor-positive subtype accounts for approximately 70% of breast cancer in women. Tamoxifen and fulvestrant are drugs currently used for endocrinal therapy. Breast cancer exhibiting endocrine resistance can undergo metastasis and lead to the death of breast cancer patients. Drug repurposing is an active area of research in clinical medicine. We found that nafamostat mesylate, clinically used for patients with pancreatitis and disseminated intravascular coagulation, acts as an anti-cancer drug for endocrine-resistant estrogen receptor-positive breast cancer (ERPBC). Epigenetic repression of CDK4 and CDK6 by nafamostat mesylate induced apoptosis and suppressed the metastasis of ERPBC through the deacetylation of Histone 3 Lysine 27. A combination of nafamostat mesylate and CDK4/6 inhibitor synergistically overcame endocrine resistance in ERPBC. Nafamostat mesylate might be an essential adjuvant or alternative drug for the treatment of endocrine-resistant ERPBC due to the low cost-efficiency of the CDK4/6 inhibitor.

Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance

BackgroundOrganoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells.MethodsIn this study, we conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. Furthermore, we performed in silico functional analysis on 3D-growth-specific looping genes and to compare patient outcomes with or without endocrinal therapy. Finally, we performed 3C/RT-qPCR validations in 3D spheroids and 3D-FISH confirmations in organoids of breast cancer patient tissues.ResultsWe found that chromatin structures have experienced drastic changes during the 3D culture growth of BC cells although there is not much change in the quantity of chromatin domains. We also observed that the strengths of looping genes were statistically different between 2D monolayers and 3D spheroids. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected genes in Hippo relevant pathways with enhanced looping in organoids of breast cancer patient tissues.ConclusionsHence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer. Our analyses suggest that the strengthened looping-mediated Hippo relevant pathways may contribute to endocrine therapy resistance in breast cancer patients.

CLINICAL SIGNIFICANCE OF ESTROGEN RECEPTOR 1 GENE PROMOTOR METHYLATION IN HORMONAL THERAPY RESISTANT BREAST CANCER PATIENTS

Breast cancer (BC) remains the most common malignancy in women worldwide, and is the leading cause of female cancer-related mortality. This warrants early diagnosis and the improvement of specific subtype treatments, thus leading to significant improvements of the 5-year survival rates. However metastatic breast cancer (MBC) still remains incurable. About 70% of breast cancer patients express estrogen receptor alpha (ERα) and are considered estrogen dependent. Thus these hormone receptor positive patients are candidates for endocrinal therapy. Unfortunately, the efficacy of endocrine therapy is limited by the development of BC endocrine resistance which is considered a major challenge in both the adjuvant and metastatic settings, and nearly half of ER+ve BC patients treated with hormonal therapy become unresponsive to treatment over time. This warrants the need for investigating markers that reflect hormonal resistance mechanisms, such as epigenetic alterations including aberrant DNA methylation and chromatin remodeling. An epigenetic marker like the ESR1 promoter methylation might eventually be a one promising tool that help clinicians make the right decisions, since ESR1 gene promotor methylation might potentially affect the response to endocrine treatment.

Endocrine Therapy Versus Chemotherapy as First Line Treatment in Metastatic Hormone Receptor Positive Breast Cancer

Introduction: The standard treatment of hormone receptor positive Her2 negative metastatic breast cancer is endocrine therapy with or without targeted therapy (e.g.CDK4/6inhibitors and mTOR inhibitors). Chemotherapy is indicated only in visceral crisis and the presence of visceral metastases is not indication for chemotherapy Aim of study The retrospective study aimed to characterize treatment and outcomes for patients with hormone receptor positive metastatic breast cancer in Alexandria clinical oncology department to review change in treatment trend during the last 10 years. Physician questionnaire to determine their preferences in choosing treatment. Methods Retrospective study using patient files of adult female diagnosed and treated at Clinical Oncology and Nuclear Medicine Department, Alexandria Main University Hospitals during the period from January 2010 to December 2019. Physician questionnaire was done by physician recruitment via online survey & scientific meetings. Results: The study identified 611 women with hormone receptor positive metastatic breast cancer, median age was 50years, 48.9% were postmenopausal, 56.7% of hormone receptor positive, Her2 negative patients received chemotherapy as first line systemic treatment, 69.5% of these patients received chemotherapy as first line treatment in the first 5years. But, 48.8% of these patients received chemotherapy as first line in the last 5years and the study showed that median overall survival for all studied patients was 34 months. In contrast, the physician questionnaire showed that 75% of physicians prefer endocrinal therapy as first line treatment for hormone receptor positive, Her2 negative metastatic breast cancer. Conclusion: There is significant change in practice pattern in choosing the first line treatment between the first and last 5 years. Also, there is a discrepancy between practice pattern and physician preferences in choosing the first line systemic treatment for hormone receptor positive, Her2 negative metastatic breast cancer. The reason is the unavailability of most targeted agents (e.g; CDK4/6 inhibitors and mTOR inhibitors) and some hormonal agents such as fulvestrant.

Anti-hyperplasia Effects of Total Saponins From Phytolaccae Radix in Rats With Mammary Gland Hyperplasia via Inhibition of Proliferation and Induction of Apoptosis.

Mammary gland hyperplasia (MGH) is a pathological condition that affects the majority of women at the child-bearing stage. The hormone and endocrinal therapy are typically used to treat MGH. Nevertheless, there are still some certain side effects accompanied with the benefits, which negatively affect the life quality of patients. Therefore, plant-derived agents that are effective against MGH development and with fewer side effects should be developed. The aim of this study was to investigate the protective effects and underlying mechanism of total saponins of Phytolaccae (TSP) against MGH in vivo. The results showed that treatment with TSP could significantly correct the disorder of serum sex hormones levels in rats with MGH, and eliminate the formation of MGH. Moreover, TSP significantly protected estrogen and progesterone-induced MGH histological changes, inhibited the swelling of the nipple, and improved the organ coefficient of uterus in rats with MGH. Mechanistically, TSP treatment not only effectively suppressed the mRNA and protein expression of ERα and PR in mammary gland, but also simultaneously up-regulated ERβ expression, and thus blocked sex hormones from interacting with their receptors. TSP treatment markedly suppressed mammary phosphorylation levels of ERK1/2, as well as reduced the mRNA and protein overexpression of VEGF and bFGF in mammary of rats. In addition, TSP treatment substantially down-regulated the expression of Bcl-2 and Ki-67, as well as elevated the expression of Bax. These findings indicated that TSP could potentially be used for effective treatment of MGH.

Cell death by gold nanoparticles in MDA‐MB‐231 cells involves different epigenetic alterations: role of surface charge

Triple negative breast cancer represents an important clinical challenge, as these tumours do not respond to endocrinal therapy. Nanotechnology offers a solution to overcome these clinical challenges. Gold nanoparticles (AuNPs) have been used in multiple ways for the prevention of breast cancer due to their unique physicochemical properties, therapeutic payload efficiency of drugs, biological compatibility, theranostic applications and radiation sensitizer effects. Here, we elucidate the molecular mechanism by which AuNPs selectively cause death in triple negative breast cancer (MDA‐MB‐231) cells. Both citrate capped (negatively charged) and cysteamine capped (positively charged) AuNPs significantly decreased the proliferation of MDA‐MB‐231 cells in a dose‐dependent manner and were less toxic to MCF‐10A cells. For the first time, we provide evidence that AuNPs can be used to prevent the progression of triple negative breast cancer by altering Wnt/β‐catenin signalling. AuNPs significantly decreased the protein expressions of β‐catenin, GSK‐3β, Cyclin D1, p53 and increased the protein expressions of phospho‐GSK‐3β, acetyl‐p53 and p‐p38. HR‐TEM was used to study the localisation of AuNPs. It is interesting to report that both AuNPs caused cell death but (−ve charged) AuNPs significantly increased the expression of MKP‐1, dephosphorylated and deacetylated histone H3 at Ser10 and K9/K14 residues respectively. However, (+ ve charged) AuNPs decreased the expression of MKP‐1, phosphorylated and acetylated histone H3 at Ser10 and K9/K14 residues respectively in MDA‐MB‐231 cells. Although both the nanoparticles have almost similar size (between 25–40 nm), the surface charge of AuNPs might contribute to the different patterns of histone modifications. Phosphorylation of histone H3 at ser 10 has been shown to be involved in chromatin condensation during mitosis and increase in phosphorylation of histone H3 suggests that cells might be undergoing mitotic catastrophy with (+ ve charged) AuNPs. This was reflected in lower IC50 values (655 μg/mL) with (+ ve charged) AuNPs in comparison to (−ve charged) AuNPs (720 μg/mL). To the best of our knowledge, we report for the first time that AuNPs potentiates the cell death of MDA‐MB‐231 cells to 5‐fluorouracil (5‐FU). Studies are in progress to gain insights on the sensitization effect of AuNPs on MDA‐MB‐231 cells to 5‐Fluorouracil. This study further warrants the usage of AuNPs either alone or in combination in cancer therapeutics.Support or Funding InformationThe authors are thankful to NIPER, SAS NAGAR, MOHALI, PUNJAB for funding the current experimental workThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Bone structure after two sequential regimens of tamoxifen and Arimidex in an ovariectomized rat model

Background Tamoxifen and Arimidex are two standard drugs for endocrinal therapy in breast cancer patients. However, it is not well established as to which of the two drugs should be prescribed first in the sequential regimens. Aim The present study was designed to investigate bone structure characteristics after two alternative sequential regimens of tamoxifen and Arimidex to determine the superior regimen conserving bone in postmenopausal rats. Materials and methods Adult female rats were divided into six groups: group I included control rats; group II included ovariectomized (ovx) nontreated rats; group III included ovx rats treated with tamoxifen; group IV included ovx rats treated with Arimidex; group V included ovx rats treated sequentially with tamoxifen plus Arimidex; and group VI included ovx rats treated sequentially with Arimidex plus tamoxifen (tamoxifen→Arimidex vs. Arimidex→tamoxifen). Daily oral drug treatments were given for 1 month for each drug. Tamoxifen was administered at a dose of 60 μg/day/ rat. Arimidex was administered at a dose of 40 μg/rat/day. At the end of the experiment, all rats were sacrificed, and the tibias were extracted and processed for paraffin block embedding or scanning electron microscopic examination. Cortical and trabecular bone thickness were measured by means of image analysis. Results Histological and scanning electron microscopic observations revealed widening of the haversian canals, with marked loss of cancellous bone trabeculae following ovariectomy. This was confirmed by a significant decrease in bone thickness on histomorphometry. Single drug treatment with Arimidex revealed extensive cavitation and widening of the haversian canals with severe erosion cavities. The tamoxifen-treated group showed apparently preserved bone structure compared with the Arimidex group. Group of the first sequential therapy (group V) demonstrated histologically few cancellous bone trabeculae. However, the second sequential regimen (group VI) showed severe rarefaction, thinning, and bone fractures. Scanning microscopy and bone measurements confirmed the histological findings. Conclusion Sequential hormonal treatment starting with tamoxifen followed by Arimidex is likely to preserve bone structure compared with the other sequential regimen. Single drug treatment with tamoxifen gave best bone preservation. To our knowledge, this is the first experimental report in this regard.

Response of Subcutaneous Xenografts of Endometrial Cancer in Nude Mice to Inhibitors of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase (MAPK) Pathways: An Effective Therapeutic Strategy for Endometrial Cancer

Objective: This study was designed to explore whether inhibition of the extracellular-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways can inhibit the growth of xenografts of endometrial cancer cell lines with different estrogen receptors (ER) profiles in vivo and to provide preliminary laboratory basis for the probability of endometrial adenocarcinoma treatment with blockage of the two pathways, especially to endometrial cancer with low ER status. Methods: Human endometrial cancer Ishikawa bearing ER and HEC-1Awith low ER status cells were subcutaneously injected into BALB/c nude mice to establish endometrial cancer xenograft tumor models. The effects of PI3K/Akt inhibitor LY294002, MAPK/ERK1/2 inhibitor PD-98059 and their combinations on the growth of the xenograft tumors and apoptotic state of Ishikawa and HEC-1Acells were tested in vivo using the inhibitory rate, the terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, H/E-stain. Western blot analysis was used to detect the alterations of activated ERK (P-ERK) and AKT (P-AKT) during this process. Results: LY294002, a PI3K/Akt pathway inhibitor, induced significant suppression in the growth of both Ishikawa and HEC-1Acell xenograft tumors, concomitant with increased apoptosis in xenografts as evidenced by TUNEL. A similar effect was also observed when the MAPK/ERK1/2 signaling pathway was inhibited by PD98059. Concurrent inhibition of the PI3K/Akt and MAPK/ERK1/2 pathways showed enhanced anti-tumor effects in vivo as indicated by increased apoptosis. At the same time, the levels of P-ERK and P-AKT in both xenograft tumors decreased, and their levels in combination group was the lowest. Conclusions: PD98059, LY294002 and their combinations showed remarkable inhibitory effects on xenograft tumors of endometrial carcinoma cell lines with different expression status of ER in vivo through blockage of PI3K/Akt and MAPK/ERK1/2 signaling pathways. This suggests that targeting these pathways may be an effective therapeutic strategy against endometrial carcinomas, especially for ER-negative cancers which show poor response to endocrinal therapy.

A combination of castration with (125)I brachtherapy in middle and late period prostate cancer

Objective To investigate the therapeutic efficacy of castration with 125I brachtherapy in middle and late stage prostate cancer. Methods Sixty-six patients with prostate cancer from 2004 to 2009 were analyzed, 40 were at clinical stage C and 26 were at clinical stage D, 42 had a pathologic grade G2 and 24 had a pathologic grade G3. The first endocrinal therapy used was total androgen blockade (chemical castration and anti-androgen drugs). The therapeutic time was three months before bilateral orchidectomy and brachtherapy. A 3D radiotherapy planning system was used for brachtherapy with transrectal ultrasound-guided radioactive 125I seed uniform implantation. Follow-up endocrinal therapy was decided according to a monthly check of serum PSA (prostate specific antigen) levels. After six months, serum PSA, IPSS and volume of the prostate before and after treatment were compared. Results The operations were completed successfully in all cases. The mean number of 125I seeds implanted was 55. The mean follow-up was 10 to 62 months, with an average of 49 months. Serum PSA, IPSS and the volume of the prostate was reduced significantly six months after operation (P<0.05). Conclusions Castration with 125I brachtherapy is an effective approach in combination therapy for treating middle and late stage prostate cancer. Key words: Prostatic neoplasms; Carcinoma; 125I brachtherapy; Castration

Review of medical management of prostate cancer

The procedure of treating prostate cancer is as the following: After local prostatectomy or radiotherapy or local palliative therapy, androgen-dependent prostate cancer(ADPC) should be given first-line endocrinal therapy. Almost all patients will be developed from ADPC to hormone independent prostate cancer (HIPC) after 14 ～ 30 months, including androgen-independent prostate cancer(AIPC) and hormone-refractory prostate cancer(HRPC). Second-line endocrinal therapy and chemotherapy should be given, respectively. Antibone metastasis therapy is given when bone metastasis occurred. All medical methods should be used rationally and comprehensively to improve the management of prostate cancer. Key words: Prostate Neoplasms ; Drug therapy ;

17β-Estradiol activates PI3K/Akt signaling pathway by estrogen receptor (ER)-dependent and ER-independent mechanisms in endometrial cancer cells

Cellular response to estrogen is mediated both by estrogen receptor (ER) binding to estrogen response element (ERE) and by non-nuclear actions like activation of signal transducing pathways. The main aims are to study if PI3K/Akt signaling pathway can be activated by 17β-estradiol (E2) via non-nuclear action and to investigate the relationship of the action of E2 and ER in endometrial cancer cells expressing with different status of ER. The levels of phosphorylated Akt (Ser 473) (P-Akt) and total Akt were examined by western blot and Akt kinase activity was measured in cells after stimulation with 1 μM E2 at different time points. Inhibitory role of LY294002 on activation of Akt induced by E2 and its estrogen antagonist, ICI182 780 were also tested. P-Akt/Akt was used as a measure of activation of Akt. We found that maximum P-Akt/Akt and Akt kinase activity took place at 30 min in Ishikawa cells and 15 min in HEC-1A cells and the activation persisted for at least 2 h after stimulation with 1 μM E2. The activation of Akt elicited gradually with increasing doses of E2. PI3K inhibitor, LY294002, stopped the activating Akt in a dose-dependent manner and 50 μM LY294002 completely blocked the activation of Akt induced by E2. ICI182 780 could block the activation of PI3K/Akt in ER-positive Ishikawa cells but not in HEC-1A cells with poor-expressed ER. This study demonstrated that E2 is able to promptly activate PI3K/Akt signal pathway in Ishikawa cells in an ER-dependent manner and ER-independent in HEC-1A cells. Blockage of PI3K/Akt cascade may become a potential and effective way to control endometrial carcinoma, especially in ER-negative cancers, which show no response to endocrinal therapy.

Aromatasehemmer riskant für das Gehirn?

Impressive successes have been achieved with the possibilities offered by the endocrinal treatment of metastasizing breast cancer. Adjuvant endocrinal therapy is presently undergoing a change. Should we continue to prescribe tamoxifen as we have been doing for the past 30 years, or should we resort to administering aromatase inhibitors for up to five or more years? Before initiating a large-scale change we should make every effort to find out whether there would be any long-term adverse effects on the central nervous system. The enzyme aromatase safeguards elementary oestrogen supply to the neurons in the brain region. If an aromatase inhibitor completely blocks oestrogen synthesis, there will be an decline of synapsis plasticity in the hippocampus. This can be explained neurologically by absence of neuroprotective effects exercised by the oestrogens and may trigger neurodegenerative changes associated with difficulties of learning and memory. Hence, it is mandatory to clarify multi-centrically whether long-term administration of aromatase inhibitors involves brain risks. So far there has been no indication of a definitely longer survival due to administration of aromatase inhibitors than with tamoxifen. Aromatase research indicates possible neurodegeneration, possibly with long-term effects leading finally to Alzheimer's disease.

Better Prognosis of Many Cancers in Female: A Phenomenon Not Explained by Study of Steroid Receptors

Experimental evidence indicates that specific sex hormonal imbalance, deficiency, and excess may be causes of tumors or at least contribute in some way to their development. Clinical observations show that the prognoses of patients with various malignancies differ among males and females, and some cancers can be alleviated and partially controlled by altering the accustomed hormonal environment. Although beneficial effects usually are only temporary, there is no doubt that some cancers are hormone-dependent to a degree. A significant number of prostatic carcinoma in males and breast carcinoma in both sexes have been treated with various additive or ablative endocrine manipulations. The detection and quantitation of specific steroid binding proteins in hormone-sensitive tumors have enhanced our understanding of the mechanism of endocrinal therapy. Excluding carcinoma of the breast and of the sex organs (ovary and uterus in females, testis and prostate in males), many other solid tumors have been tested for the presence of estrogen and other steroid receptors. A fair number of solid cancers contains estrogen and progesterone receptors (ER, PR), even those from male patients. Thus, the better prognosis of females with sarcoma, melanoma, liver, colorectal and other cancers cannot simply be explained by the presence or absence of estrogen or progesterone receptors. This review attempts to summarize clinical reports of this interesting phenomenon, including therapeutic results with estrogenic, antiestrogenic, and other hormonal approaches.

Better prognosis of many cancers in female: a phenomenon not explained by study of steroid receptors.

Experimental evidence indicates that specific sex hormonal imbalance, deficiency, and excess may be causes of tumors or at least contribute in some way to their development. Clinical observations show that the prognoses of patients with various malignancies differ among males and females, and some cancers can be alleviated and partially controlled by altering the accustomed hormonal environment. Although beneficial effects usually are only temporary, there is no doubt that some cancers are hormone-dependent to a degree. A significant number of prostatic carcinoma in males and breast carcinoma in both sexes have been treated with various additive or ablative endocrine manipulations. The detection and quantitation of specific steroid binding proteins in hormone-sensitive tumors have enhanced our understanding of the mechanism of endocrinal therapy. Excluding carcinoma of the breast and of the sex organs (ovary and uterus in females, testis and prostate in males), many other solid tumors have been tested for the presence of estrogen and other steroid receptors. A fair number of solid cancers contains estrogen and progesterone receptors (ER, PR), even those from male patients. Thus, the better prognosis of females with sarcoma, melanoma, liver, colorectal and other cancers cannot simply be explained by the presence or absence of estrogen or progesterone receptors. This review attempts to summarize clinical reports of this interesting phenomenon, including therapeutic results with estrogenic, antiestrogenic, and other hormonal approaches.