Role Of Tamoxifen Research Articles

Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-β to Overcome Photodynamic Immunotherapy Resistance.

Currently, limited photosensitizers possess the capacity to reverse tumor hypoxia and reduce programmed death ligand-1 (PD-L1) and transforming growth factor-β (TGF-β) expression simultaneously, hindering the perfect photodynamic therapy (PDT) effect due to acquired immune resistance and the tumor hypoxic microenvironment. To tackle these challenges, in this research, we demonstrated that mitochondrial energy metabolism depression can be utilized as an innovative and efficient approach for reducing the expression of PD-L1 and TGF-β simultaneously, which may offer a design strategy for a more ideal PDT nanosystem. Through proteomic analysis of 5637 cells, we revealed that tamoxifen (TMX) can incredibly regulate PD-L1 expression in tumor cells. Then, to selectively deliver clinically used mitochondrial energy metabolism depressant TMX to solid tumors as well as design an ideal PDT nanosystem, we synthesized MHI-TMX@ALB by combining a mitochondria-targeted heptamethine cyanine PDT-dye MHI with TMX through self-assembly with albumin (ALB). Interestingly enough, the MHI-TMX@ALB nanoparticle demonstrated effective reversion of tumor hypoxia and inhibition of PD-L1 protein expression at a lower dosage (7.5 times to TMX), which then enhanced the efficacy of photodynamic immunotherapy via enhancing T-cell infiltration. Apart from this, by leveraging the heptamethine dye's targeting capacity toward tumors and TMX's role in suppressing TGF-β, MHI-TMX@ALB also more effectively mitigated 4T1 tumor lung metastasis development. All in all, the MHI-TMX@ALB nanoparticle could be used as a multifunctional economical PD-L1 and TGF-β codepression immune-regulating strategy, broadening the potential clinical applications for a more ideal PDT nanosystem.

Beneficial Effects of Tamoxifen Treatment in Type 1 Diabetes

Type 1 diabetes (T1D) results from the destruction of pancreatic β-cell through the β-cell specific autoimmune process. β-cell autoantigens, macrophages, dendritic cells (DC), B lymphocytes, and T lymphocytes have been implicated in the pathogenesis of autoimmune diabetes. Tamoxifen is a selective estrogen receptor modulators (SERM), used in the treatment of breast cancer. Research reports have shown that tamoxifen might decrease the strength of immune responses through modulation of DC differentiation and activation, and it may depress immunity. In NOD/ShiLtJ mice (female), which is a polygenic model for T1D, we found that tamoxifen exerts antidiabetic effects through acting on the immune system, leading to the suppression of insulitis and systemic inflammatory cytokine production in the in-vivo model. Tamoxifen therapy preserved the β-cell mass and prevented the development of T1D. Tamoxifen providing β-cell protection and immunoinhibitory effects offer a novel insight into the possible role of tamoxifen in the regulation of islet cell function and glucose homeostasis. These findings are significant and useful for clinical application. Disclosure J. Zheng: None. M. Zafar: None. L. Chen: None. X. Guo: None. X. Li: None.

Abstract P3-04-16: Steroid receptor co-activator 1 mediation of cancer cell reprogramming in endocrine resistant breast cancer

Abstract Cancer cells undergo dynamic and frequently reversible modifications and this cellular plasticity permits reprogramming in response to long term endocrine treatment. A well-established theory, the cancer stem cell theory; suggests that within an ER positive tumour cell population are a small number of stem cells which are capable of infinite self-renewal and are insensitive to treatment with standard endocrine regimes. However, emerging reports that pluripotent cells can be generated from adult somatic cells (Takahashi, 2007) alludes to an alternate mechanism for cancer cells to reprogramme and evade endocrine treatment. To investigate the role of tamoxifen in promoting cellular reprogramming and endocrine resistance in breast cancer, we isolated single luminal A breast cancer CD24+CD44- clones from endocrine sensitive MCF-7 cells. The clones were expanded in the presence and absence of tamoxifen. Extensive profiling of cells following long-term exposure to tamoxifen revealed a resistant phenotype similar to that reported in other established models. Steroid receptor co-activator 1 (SRC-1) is a master regulatory protein which has been shown to be central to the development of endocrine resistance. The mechanisms of which are still poorly understood (Walsh et al., 2012). Utilising genome-wide transcriptomic sequencing this study investigated whether SRC-1 can regulate transcriptional networks which mediate reprogramming in individual cells to induce survival adaptability and drug resistance in breast cancer. RNA-sequencing was carried out in a model of endocrine resistance (shNon-Targeting versus shSRC-1). There were 1,731 genes up-regulated by SRC-1, of which 153 were identified as transcription factors (TFs)/chromatin remodellers. Combining the transcriptomic profiling with ChIP-sequencing we identified a transcriptional network pertinent to SRC-1. Molecular characterisation identified E2F7, NFIA, DEK, SMAD2, SMARCA1, ASCL1 and TRPS1 as key drivers of SRC-1 mediated endocrine resistance. Each TF was confirmed as a direct target of SRC-1, via promoter specific binding and were found to be drivers of endocrine resistant cell migration. Furthermore, all TFs were necessary in mammosphere formation and their promotion of cellular de-differentiation was observed by 3D acinar organisation and flow cytometry. To elucidate the core TFs required for cancer cell reprogramming, their effect on the pioneer reprogramming TFs (OCT4, SOX2, cMYC and KLF4) was investigated. SMAD2, SMARCA1, ASCL1 and TRPS1 have emerged as pivotal regulators of endocrine resistant cell reprogramming. This study has unravelled an SRC-1-mediated TF network responsible for promoting the cellular reprogramming of breast cancer cells. Concerted activity of this network is responsible for driving de-differentiation of cells and enhancing their stem-like, highly migratory and proliferative tumour initiation population. This study provides important information regarding the mechanism of cellular reprogramming in ER positive endocrine resistant cancer and may lead to potential novel therapeutic targets. Citation Format: Browne A, Fagan A, Vareslija D, Ward E, Hill A, Young L. Steroid receptor co-activator 1 mediation of cancer cell reprogramming in endocrine resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-16.

Abstract P1-09-06: Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: The prognostic abilities of most gene expression signatures in breast cancer are often due to detection of proliferative activity measured from expression of genes regulated as a function of cell cycle progression. Cell Cycle Progression (CCP) score is an important prognostic factor in prostate cancer, and has shown promising results for renal and lung cancer; its role in ductal carcinoma in situ (DCIS) has not been explored. We investigated the prognostic and predictive relevance of CCP Score in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy (RT) or both as adjuvant treatment in DCIS. mRNA expression of 25 S- and M-phase CCP genes was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. CCP score is an un-weighted average of the expression values of CCP genes after normalisation with 14 housekeeping genes. CCP score was analysed as a continuous variable and also as an ordinal variable using tertile-based cut-offs. Exploratory analyses with subgroups defined by HER2 status by immunohistochemistry were performed. Results: CCP scores were evaluable in 521 (134 recurrence events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Increase in CCP score (median 1.15; IQR 0.71-1.74) was associated with increased risk of ipsilateral breast event (IBE) [Hazard ratio (HR) = 1.28; 95% Confidence Interval (95%CI) 1.08-1.51; p = 0.0049]. CCP score however was not an independent predictor in multivariate analyses [HR = 1.16; 95%CI 0.95-1.42; p = 0.14]. CCP scores were categorised as CCP low (<0.87), CCP intermediate (>/= 0.87 to < 1.52) and CCP high (>/= 1.52) by tertiles. The benefit of RT in reducing IBE was significant when CCP score was low [HR = 0.35; 95%CI 0.14-0.87; p = 0.024] or intermediate [HR = 0.23; 95%CI 0.09-0.59; p = 0.0023], however, those with high CCP score did not derive significant RT benefit [HR = 0.59; 95%CI 0.31-1.13; p = 0.11]. In exploratory subgroup analyses, HER2 negative DCIS with high CCP score (20.9% of all DCIS cases) did not derive RT benefit and the largest RT benefit was seen for DCIS that expressed HER2 and did not have a high CCP score (23.2% of all DCIS cases). Benefit of RT and 10-year IBE rates by CCP score (categorised) and HER2 status subgroups.SubgroupneventsHR (95%CI)p10-year IBE rates (%) - No RT10-year IBE rates (%) - RTCCP-high & HER2 neg106220.83 (0.35-1.97)0.6722.5 (14.0-35.0)20.0 (10.5-36.0)CCP-high & HER2 pos67210.43 (0.16-1.17)0.09840.6 (27.1-57.6)20.4 (8.9-42.9)CCP-non-High & HER2 neg217300.43 (0.18-0.99)0.04816.2 (10.7-24.0)8.1 (4.0-16.3)CCP- non-High & HER2 pos118330.14 (0.04-0.46)0.001239.5 (29.3-51.6)7.1 (2.3-20.4)CCP-non-High = low or intermediate CCP score Conclusions: CCP score is not independently associated with the risk of IBE but appears to be a predictor of RT benefit. Exploratory analyses suggest that combined with HER2 status, it may help in identifying a large DCIS subgroup where RT is highly indicated and another large subgroup where mastectomy may be merited. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-06.

Effect of Continuous Relatively High Dose Tamoxifen on Survival of Patients with Recurrent Glioblastoma Multifome

Background: Currently, there is no standard treatment for recurrent glioblastoma multiforms (GBM). The majority of cases recur after standard primary treatment.The role of tamoxifen as antineoplastic agent is evaluated in both preclinical and experimental studies. The usage of tamoxifen in the treatment of malignant gliomas was investigated with encouraging results. This study was conducted to evaluate the safety and efficacy of tamoxifen for patients with recurrent GBM. Patients and methods: Twenty-two patients with recurrent GBM after standard primary therapy were included in this study. They were selected according to the inclusion and exclusion criteria below. All patients were subjected to receive daily tamoxifen 80mg/m2 in 3 to 4 divided doses according patient compliance continuously until disease progression or development of intractable toxicity e.g DVT. Other supportive treatment as analgesics, neuro-tonics and physiotherapy were included if indicated. The cases were followed by full neurological examination weekly and brain MRI every two to three months during treatment. Results: This study included 13 males (59.1%) and nine females (40.9 %), the median age was 52.50 years, regarding KPS, there were nine patients (40.9%) with KPS 60 -70%, 11 patients(50%) with KPS 70-80% and two patients (9.1%) with KPS 80-90%. The median follow-up was 8 months after tamoxifen therapy, there were six patients (27.3%) showed partial response, three patients (13.6%) still in stable disease, and 13 patients (59.1%) had progressive disease with overall response rate 27.3%, the median TTP was three months with six months progression free survival rate 13.6% and median overall survival (OS) was eight months with one-year overall survival rate 20.5%. There is no treatment-related toxicity. Conclusion: Tamoxifen was well tolerated and had a modest efficacy for patients with recurrent GBM and its effect should be evaluated in the future studies

Abstract P3-07-02: Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: As compared to invasive breast cancer (IBC), HER2 is much more frequently overexpressed in ductal carcinoma in situ (DCIS). Unlike IBC, the prognostic significance of HER2 overexpression remains to be established in DCIS and large studies to investigate its predictive role are lacking. We investigated the prognostic and predictive relevance of HER2 protein and ERBB2 mRNA expression in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. ERBB2 mRNA expression was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. ERBB2 mRNA expression was analysed as a continuous variable and also as a binary variable using a cut-off to reproduce HER2 expression distribution similar to that observed with immunohistochemistry (IHC). HER2 protein expression was evaluated by IHC using HercepTest™ and scored as per ASCO-CAP 2013 recommendations; HER2 equivocal (IHC2+) were grouped with HER2 negative (IHC 0 or 1+) for main analyses. Additional analyses using binary ERBB2 mRNA expression as a reflex test for HER2 IHC2+ were also performed. Results: HER2 protein expression was evaluable in 713 (181 events) of 755 available samples (DCIS absent or lost during assay in 42). ERBB2 mRNA expression was evaluable in 521 (134 events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Both results were available in 508 cases (130 events). Increase in ERBB2 mRNA expression (median 0.62; range 0.07-36.76) was associated with increased risk of in situ ipsilateral breast event (DCIS-IBE) [Hazard ratio (HR) = 1.07; 95% Confidence Interval (95%CI) 1.04-1.10; p < 0.0001] but not with increased risk of invasive ipsilateral breast event (I-IBE) [HR = 1.03; 95%CI 0.97-1.10; p = 0.3209]. HER2 positivity by IHC was similarly associated with increased risk of DCIS-IBE [HR = 2.90; 95%CI 1.91-4.40; p < 0.0001] but not with increased risk of I-IBE [HR = 1.40; 95%CI 0. 0.81-2.42; p = 0.2313]. Reclassification of HER2 IHC2+ cases using binary ERBB2 mRNA expression (46 as negative, 16 as positive; 18 expression data unavailable) further improved prognostic discrimination of HER2 IHC [ΔX2 (1d.f.) 5.51; p = 0.0189] for any recurrence. The effect of radiotherapy (RT) for reducing I-IBE was greater in HER2 positive (by ERBB2 mRNA expression) cases [HR = 0.24; 95%CI 0.07-0.83; p = 0.0237] as compared with HER2 negative cases [HR = 0.60; 95%CI 0.23-1.55; p = 0.2925]. Kaplan-Meier estimates of 10-year I-IBE rates with and without RT were 4.5% (2.5%-1.4%) and 15.8% (9.6%-25.3%) in HER2 positive DCIS; rates in HER negative DCIS were 5.2% (2.1%-2.4%) and 7.3% (4.3%-12.2%) respectively. The differential benefit of RT by HER2 status was also seen for reduction in DCIS-IBE. Conclusions: HER2 overexpression is associated with increased risk of DCIS-IBE but not of I-IBE. HER2 status is predictive of radiotherapy response with larger reductions in both I-IBE and DCIS-IBE seen in HER2 positive DCIS. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [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 P3-07-02.

Abstract P3-07-01: Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: Majority of studies investigating prognostic role of ER and PgR expression in ductal carcinoma in situ (DCIS) have failed to show a significant relationship with recurrence. Branched evolutionary tumour growth and resulting intratumour heterogeneity is now increasingly acknowledged in a variety of cancers. DCIS offers the opportunity to investigate relevance of clonal populations in different ducts that may have evolved differently and may impact outcome differently. We investigated prognostic role of ER and PgR expression in DCIS and impact of clonal variation in ER/PgR expression using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. A nested case-control design was used; cases (patients with recurrence) were matched by treatment arm and age to 2 controls each (no recurrence). ER and PgR expression was evaluated on whole sections by immunohistochemistry using 1D5, PGR636 antibodies and EnVisionTM FLEX + detection system (Dako). Assays were scored by Allred method (positive if expression >1%) and clonal method. Clonal method documented presence of ducts with complete lack of ER or PgR expression in otherwise ER or PgR positive (Allred method) DCIS. Analyses categorising such multi-clonal DCIS as ER or PgR positive as per current practice (standard) and categorising these as ER or PgR negative DCIS (clonal method) were performed. Results: Of 540 samples (180 cases, 360 controls), ER and PgR status was evaluable in 504 and 498 patients respectively. ER expression was absent (ER-) in 148 (29.4%), 356 (70.6%) were ER positive (ER+) with 39 (7.7%) of these displaying multi-clonal expression (ERmulti-clonal). PgR expression was absent in 163 (32.7%), 335 (67.3%) were PgR positive with 84 (16.9%) of these displaying multi-clonal expression. ER- DCIS showed increased risk (Table) of in situ ipsilateral breast event (DCIS-IBE) and invasive ipsilateral breast event (I-IBE) (borderline significance). Prognostic discrimination was higher when ER status was determined by clonal method (ΔX2 1.57 for I-IBE and 9.05 for DCIS-IBE). Increases in the risk of I-IBE and DCIS-IBE were similar for ER- and ERmulti-clonal DCIS. TableEndpointComparisonScoring MethodHazard Ratio (95%CI)pI-IBEER- vs. ER+Standard1.75 (0.99-3.09)0.0544 ER- vs. ER+Clonal1.90 (1.10-3.30)0.0224 ER- vs. ER+*Clonal1.89 (1.05-3.41)0.0337 ERmulti-clonal vs. ER+*Clonal1.93 (0.74-5.03)0.1759DCIS-IBEER- vs. ER+Standard2.58 (1.68-3.94)<0.0001 ER- vs. ER+Clonal3.13 (2.02-4.85)<0.0001 ER- vs. ER+*Clonal3.11 (1.97-4.93)<0.0001 ERmulti-clonal vs. ER+*Clonal3.20 (1.62-6.34)0.0008* ER+ DCIS not exhibiting multi-clonal expression Lack of PgR expression was only associated with increased risk of DCIS-IBE and PgR status did not add to the prognostic information provided by ER status. Conclusions: ER expression is prognostic for recurrence in DCIS. ER+ DCIS with distinct ER- clones has a recurrence risk similar to ER- DCIS. ER scoring should take clonality of expression into account. Citation Format: Thorat MA, Jones LJ, Levey PM, Elia G, Evagora CA, Bundred NJ, Fentiman IS, Forbes JF, Cuzick J. Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [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 P3-07-01.

In vitro effects of tamoxifen on adipose-derived stem cells.

In breast reconstructive procedures, adipose-derived stem cells (ASCs) that are present in clinical fat grafting isolates are considered to play the main role in improving wound healing. In patients following chemotherapy for breast cancer, poor soft tissue wound healing is a major problem. However, it is unclear if tamoxifen (TAM) as the most widely used hormonal therapeutic agent for breast cancer treatment, affects the ASCs and ultimately wound healing. This study evaluated whether TAM exposure to in vitro human ASCs modulate cellular functions. Human ASCs were isolated and treated with TAM at various concentrations. The effects of TAM on cell cycle, cell viability and proliferation rates of ASCs were examined by growth curves, MTT assay and BrdU incorporation, respectively. Annexin V and JC-1 Mitochondrial Membrane Potential assays were used to analyze ASC apoptosis rates. ASCs were cultured in derivative-specific differentiation media with or without TAM (5 uM) for 3 weeks. Adipogenic and osteogenic differentiation levels were measured by quantitative RT-PCR and histological staining. TAM has cytotoxic effects on human ASCs through apoptosis and inhibition of proliferation in dose- and time-dependent manners. TAM treatment significantly down-regulates the capacity of ASCs for adipogenic and osteogenic differentiation (p<0.05 vs. control), and inhibit the ability of the ASCs to subsequently formed cords in Matrigel. This study is the first findings to our knowledge that demonstrated that TAM inhibited ASC proliferation and multi-lineage ASC differentiation rates. These results may provide insight into the role of TAM with associated poor soft tissue wound healing and decreased fat graft survival in cancer patients receiving TAM.

Abstract A31: Revisited use of tamoxifen for improving melanoma therapy

Abstract The rapid increase in the incidence of malignant melanoma, a highly aggressive, drug-resistant cancer, has not been accompanied by significant therapeutic breakthroughs for decades, despite the introduction of biochemotherapies. The Dartmouth regimen, of which tamoxifen is a standard component, has also had little impact on outcome. Therefore, examination of alternative melanoma vulnerabilities is essential. Sphingolipid (SL) metabolism is an area of cancer science that has recently risen to prominence. This is because ceramide, the aliphatic backbone of SL's, can act as a powerful tumor censor. However, cancer cells rapidly inactivate ceramide via two major metabolic routes: glycosylation to form glucosylceramide and hydrolysis, which generates sphingosine 1-phosphate, a mitogenic SL. These actions severely blunt ceramide anticancer properties, thwarting potential utility in treatment. Our previous work has shown that tamoxifen is a potent inhibitor of ceramide metabolism at glycosylation and hydrolysis. Herein, we exploit these unique actions and pair tamoxifen with a cell-permeable ceramide, C6-ceramide, and demonstrate that this novel drug duo, unlike the single agents, was highly effective in inhibiting melanoma cell (A375 and cell lines established from patients) proliferation, inducing caspase-dependent apoptosis, promoting cell cycle arrest, diminishing cellular adhesion and migration, reducing cell surface expression of integrins, and downregulating expression of the main source of drug resistance in melanoma, survivin, all essential elements of a drug regimen useful for limiting melanoma growth. Because integrin expression often correlates with conversion of melanoma growth from radial to vertical, we propose that tamoxifen can serve as an effective adjuvant to C6-ceramide for countering metastatic potential. Whereas the role of tamoxifen in the Dartmouth regimen has always remained elusive, its role as a ceramide sensitizer is clear and presents novel inroads for improving melanoma therapy. Citation Format: Samy A.F Morad, Lance C. Bridges, Myles C. Cabot. Revisited use of tamoxifen for improving melanoma therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A31.

Breast Cancer Prevention for BRCA1 and BRCA2 Mutation Carriers: Is There a role for Tamoxifen?

Breast Cancer Prevention for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Is There a role for Tamoxifen?

Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Has Practice Not Changed?

TO THEEDITOR: The editorial 1 regarding the publication by Soulos et al 2 stated that some older women with breast cancer are being clearly overtreated. Most clinicians will agree with this statement. However, the author also indicated that “offering radiation therapy to a woman with a good-prognosis tumor and a life expectancy of less than 5 years does not seem indicated.” 1(p1578) Although this statement represents a publicly shared standard, 3,4 it is not supported by facts. Several studies have evaluated the role of adjuvant radiotherapy, and all indicated a benefit of radiotherapy in reducing locoregional recurrence rates. 5-11 The Toronto Breast Cancer Study indicated that the relapse rate was 1.2% with tamoxifen alone and decreased to 0% when tamoxifen was given with whole-breast irradiation (WBI). There were no significant differences in the distant recurrence rates, questioning the role of tamoxifen alone in controlling systemic disease in this subgroup of patients. 7 The Cancer and Leukemia Group B 9343 trial published in the same issue of New England Journal of Medicine concurred with the results of the Toronto group. In this study, women age 70 years with tumors 2 cm were assigned to tamoxifen either with or without WBI. The locoregional control recurrence rates were lower in the combined WBI-tamoxifen group (1% v 4%; P .001). 6 These results were supported in a later update abstract presented in 2010, where the only significantly different outcome was local recurrence with a difference of 2% in the irradiated group and 9% in those women who did not receive adjuvant radiotherapy. 5 In view of these facts, it is not clear why omitting radiotherapy in older patients with low-risk disease has become a publicly shared standard. Maybe it is because there were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or 5-year rates of overall survival. 3,5-7,12 Giordano 1 commented that older women with low-risk breast cancer treated with adjuvant radiotherapy are at risk for unnecessary adverse effects, inconvenience of treatment, and possibly increased personal costs for a treatment unlikely to offer them any benefit. This could also be applied to the endocrine treatment, as both classes of endocrine agents have their own recognized adverse effects and

Abstract 4906: Tamoxifen-mediated apoptosis relationship with ERα36 in gastric cancer cell BGC823

Abstract Aim: The growth, apoptosis and estrogen receptor α36 (ERα36) expression and location changes in gastric cancer cell line BGC823 were observed, when dealt with different concentrations Tamoxifen (TAM), to characterize the role of TAM in gastric cancer growth and apoptosis and the mechanism of it. Materials and Methods: BGC823 cell was dealt with 10-6M and 10-5M TAM for 24h and 48h. Cell growth was assessed by WST1 assay. The mRNA and protein expressions of ERα36 were examined by RT-PCR and Western blot methods. Average optical densities were detected and processed using Student's t test analysis. Immunofluorescence assay was used to examine ER-α36 location in BGC823 cell. Hoechest33258 assay was used to examine apoptosis. Results: TAM could promote apoptosis and inhibit growth of BGC823 cell, and this effect had concentration dependant (P&amp;lt;0.05). TAM could promote ERα36 mRNA expression, and the increase level of ERα36 mRNA expression had concentration dependent of E2β(P&amp;lt;0.05). TAM could promote ERα36 protein expression, and the increase level of ERα36 protein expression had concentration dependent of E2β(P&amp;lt;0.05). The location of ERα36 had no change, when BGC823 cell dealt with TAM.Conclusions: TAM could promote apoptosis and inhibit growth of BGC823 cell, and the effect had concentration dependant. TAM could promote ERα36 expression in BGC823 cell, and the effect had concentration dependant. ERα36 may participate apoptosis mediated by Tamoxifen in Gastric Cancer Cell Line BGC823 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4906. doi:1538-7445.AM2012-4906

Expanded Prostate Cancer Index Composite for Clinical Practice: Development and Validation of a Practical Health Related Quality of Life Instrument for Use in the Routine Clinical Care of Patients With Prostate Cancer

Measuring the health related quality of life of patients with prostate cancer in routine clinical practice is hindered by the lack of instruments enabling efficient, real-time, point of care scoring of multiple health related quality of life domains. Thus, we developed an instrument for this purpose. The Expanded Prostate Cancer Index Composite for Clinical Practice is a 1-page, 16-item questionnaire that we constructed to measure urinary incontinence, urinary irritation, and the bowel, sexual and hormonal health related quality of life domains. We eliminated conceptually overlapping items from the 3-page Expanded Prostate Cancer Index Composite-26 and revised the questionnaire format to mirror the AUA symptom index, thereby enabling practitioners to calculate health related quality of life scores at the point of care. We administered the Expanded Prostate Cancer Index Composite for Clinical Practice to a new cohort of patients with prostate cancer in community based and academic oncology, radiation, and urology practices to evaluate instrument validity as well as ease of use in clinical practice. A total of 175 treated and 132 untreated subjects with prostate cancer completed the Expanded Prostate Cancer Index Composite for Clinical Practice. The domain scores of the Expanded Prostate Cancer Index Composite for Clinical Practice correlated highly with the respective domain scores from longer versions of the Expanded Prostate Cancer Index Composite (r≥0.93 for all domains). The Expanded Prostate Cancer Index Composite for Clinical Practice showed high internal consistency (Cronbach's α 0.64-0.84) and sensitivity to prostate cancer treatment related effects (p<0.05 in each of 5 health related quality of life domains). Patients completed the Expanded Prostate Cancer Index Composite for Clinical Practice efficiently (96% in less than 10 minutes and with 11% missing items). It was deemed very convenient by clinicians in 87% of routine clinical encounters and clinicians accurately scored completed questionnaires 94% of the time. The Expanded Prostate Cancer Index Composite for Clinical Practice is a valid instrument that enables patient reported, health related quality of life to be measured efficiently and accurately at the point of care, and thereby facilitates improved emphasis and management of patient reported outcomes.

A novel role for tamoxifen in the inhibition of human platelets

Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), is widely used therapeutically for the treatment and prevention of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism of this adverse effect is still unclear. Arterial thromboses mostly consist of platelets that are adherent to ruptured endothelial surfaces. Several lines of evidence reported that tamoxifen stimulates platelet activation using different methodologies. In our preliminary study, tamoxifen exhibited potent antiplatelet activity in washed human platelets. The aim of this study was to examine the signal transduction pathways of tamoxifen in platelet activation. In this study, tamoxifen (3∼7 μmol/L) exhibited more potent activityin inhibiting platelet aggregation stimulated by collagen than other agonists (ie, thrombin). Tamoxifen inhibited collagen-stimulated platelet activation accompanied by relative Ca(+2) mobilization, thromboxane A(2) (TxA(2)) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) phosphorylation (ie, p38 MAPK and extracellular signal-regulated kinase 1/2), but not hydroxyl radical (OH(•)) formation. However, tamoxifen did not increase nitric oxide (NO) release or vasodilator-stimulated phosphoprotein (VASP) phosphorylation in washed platelets. Furthermore, neither ICI 182,780, a pure ER antagonist, nor ODQ, an inhibitor of guanylate cyclase, significantly reversed the tamoxifen-mediated inhibition of platelet aggregation. In conclusion, this study demonstrates for the first time that tamoxifen possesses potent antiplatelet activity, the mechanism of which may be involved in the inhibition of the PLCγ2-PKC-p38 MAPK-TxA(2) cascade, thereby leading to the inhibition of platelet activation. In our study, the direct inhibition of platelet activation by tamoxifen possibly may provide new insights into understanding its cardiovascular effects.

Tamoxifen Affects the Toxicokinetics of o,p′-DDT in Male Nile Tilapia (Oreochromis niloticus)

The goal of the present study was to evaluate the role of Tamoxifen (TAM), in the distribution and/or elimination kinetics of o,p'-DDT, in male tilapias. A non-compartmental analysis was chosen to describe the time course of o,p'-DDT plasma concentrations. Mean plasma concentration of o,p'-DDT following IP administration indicates a very complex kinetic profile. Tamoxifen decreased the o,p'-DDT mean half-life (t½) from 20.38 to 16.11days, the Mean Residence Time (MRT) from 28.7 to 23.23days, and clearance (CL) from 0.0031 to 0.001mL/min. The distribution pattern of o,p'-DDT in tissues and the clearance in plasma suggest that storage points mediated through the membrane-receptor lipophilicity can be involved.

Fifth Alon Dembo Memorial Workshop: Case 3

OVO5/EORTC 55855, a study punitively refuting the value of CA-125 in the follow-up of ovarian cancer patients, has many deficiencies, including a heterogeneous ovarian cancer patient population, no control of initial treatment regimens, and no control of subsequent surgery or chemotherapeutic management for recurrence. Recent studies suggest a role for prompt surgery in selected cases of recurrent ovarian cancer with CA-125 elevations, a role for tamoxifen in managing rising CA-125 levels in patients without evidence of disease and the use of platinum doublets for treating recurrent platinum-sensitive disease, none of which were incorporated into OVo5/EORTC 55955. A patient with advanced stage ovarian cancer presenting with a CA-125 level of 2000 U/mL, who is initially treated with surgery followed by chemotherapy and has a normal CT scan and normal CA-125 at completion of her initial chemotherapy. This patient remains at a very high risk for recurrence. I would continue to monitor this patient with serial CA-125 levels to identify recurrent cancer and consider initiating treatment before it is clinically obvious.

Nephrogenic systemic fibrosis (NSF): the role of tamoxifen.

Dear Sir, Nephrogenic systemic fibrosis (NSF) is exclusively found in patients with marked renal impairment who have been exposed to gadolinium (Gd) through its use as a contrast agent in magnetic resonance imaging (MRI) studies [1]. The main clinical feature of NSF is thickening and hardening of the skin, and joint contractures are common. There is no confirmed effective treatment for NSF and no current evidence in the literature that spontaneous improvement occurs. Improvement in renal function, either by recovery after an acute kidney injury or through transplantation, is thought to be the most beneficial therapy [1–3], although relapses following re-exposure have been described [3]. We describe the case of a patient who we have successfully managed with tamoxifen. A 57-year-old male developed end-stage chronic renal failure (ESCRF) secondary to biopsy-proven IgA nephropathy and was commenced on haemodialysis. He was diagnosed with an epidural abscess and required surgical decompression, with good results. A cerebellar abscess was later noted, thought to have originated from the primary site. This was treated conservatively and monitored with regular MRI scans to assess progress. Overall, the patient underwent eight separate MRI examinations in a 12-month period, accumulating a total dose of 105 mL gadoteridol (ProHance®). There are no records detailing the timing of post-MRI haemodialysis, but at that time, it was not a routine practice to reschedule haemodialysis sessions to minimize Gd exposure. Around a year later, he complained of progressive stiffness of his hands and feet. Examination revealed symmetrical thickening of the skin in his distal extremities with marked limitation of joint movement. NSF was confirmed on skin biopsy. Physiotherapy was commenced but proved ineffectual, and he refused any further input from services, including any formal assessment from the occupational therapy team. He required admission to hospital due to pain, severe enough to require opiate analgesia, and markedly deteriorating mobility resulting in his being virtually immobile. While an inpatient, he was commenced on oral steroids and tamoxifen, which lead to a dramatic improvement of his condition. He left hospital opiate-free and mobile using only a walking stick, and has successfully coped at home since then. To date, there are no validated treatments for NSF. The natural history of NSF is of progressive fibrosis, leading to contractures and immobility. In 5% of patients, the disease has an aggressive course that results in death—either directly due to respiratory compromise from pleural or diaphragmatic involvement, or by patients electing to discontinue dialysis due to deteriorating quality of life [4,5]. We suggest that this observation should prompt the need for further, randomized controlled trials into the potential benefit of tamoxifen in this situation. Conflict of interest statement. None declared.

Fertility and Reproductive Considerations in Premenopausal Patients with Breast Cancer

Approximately 10% of all new breast cancer diagnoses occur in young women. Although lacking medical comorbidities, these patients often have unique issues with regard to their reproductive health that merit special consideration. As breast cancer outcomes continue to improve, quality of life for patients and their families after breast cancer treatment has come to the forefront of cancer research, particularly in the growing field of oncofertility. This article reviews the literature on the singular situations and controversies faced by premenopausal breast cancer patients. Data on amenorrhea and the effects of modern chemotherapeutic agents on amenorrhea are limited, although the role of tamoxifen in amenorrhea is more clearly defined as increasing the rate of amenorrhea across several studies. At the forefront of studies on fertility and premenopausal breast cancer patients are investigations on fertility preservation via ovarian protection and on assisted reproductive technologies. The use of gonadotropin-releasing hormone analogs for ovarian protection remains controversial and continues to be investigated. Early integration of assessment and counseling regarding fertility preservation is part of the multidisciplinary approach in the care of the premenopausal breast cancer patient and is key to optimizing both cancer treatment and fertility plans for the future. Because of the many ongoing biological, practical, and ethical controversies surrounding oncofertility, eligible patients should be strongly encouraged to participate in clinical trials and studies to further increase our knowledge in this growing field.

Hormone Receptor Positive Early Breast Cancer: What Role for Aromatase Inhibitors?

Breast cancer is a significant problem worldwide. Five years of Tamoxifen has been the established endocrine adjuvant therapy for both pre- and post-menopausal women for several decades, until the more recent introduction of AI’s for use in post-menopausal ER-positive EBC. There are three third generation AI’s currently available commercially these include non steroidal (anastrozole and letrozole) and steroidal inhibitors (exemestane). Anastrozole, letrozole and exemestane have all been compared against tamoxifen in randomised phase III studies as upfront monotherapy and all show a significant improvement in disease free survival (DFS). However there has been no overall survival (OS) benefit seen with AI’s in any of the upfront trials. The question of upfront AI versus switch is complicated and is highly debated. Evidence from randomised phase III trials shows an improvement in DFS for all three AI’s in the switch setting. The only trial to show a significant survival benefit is the IES trial where patients were switched to exemestane. More data is required to directly compare the AI’s in the upfront setting and study the most appropriate duration of the AI’s. There does still appear to be a role for tamoxifen in low risk patients and for intermediate risk patients when used in combination with aromatase inhibitors in the switch setting.

Anastrozole Use in Early Stage Breast Cancer of Post-Menopausal Women

The majority of breast cancers express the estrogen receptor and depend on estradiol (E2) for their growth. Hormonal therapy aims at depriving estrogen signaling either by using selective estrogen receptor modulators (SERM)-that interfere with the binding of E2 to its receptor (ER)-or aromatase inhibitors (AI)-that block the aromatase-dependent synthesis of E2. While SERMs are recommended for both pre- and post-menopausal patients, AIs are indicated only for post-menopausal patients. For the past 20 years, the SERM tamoxifen has been considered the "gold standard" for the treatment of hormone receptor positive breast cancers. However, tamoxifen's role is now challenged by third generation AIs, such as anastrozole, which exhibit greater efficacy in the adjuvant setting in several recently reported trials. This review will focus on anastrozole's mechanism of action, dosing, pharmacology, pharmacokinetics, and clinical applications. It will briefly discuss the clinical trials that determined anastrozole's efficacy in the treatment of advanced breast cancer (ABC) and in the neoadjuvant setting. Finally, it will present the clinical trials that established anastrozole as a frontline agent in the treatment of post-menopausal women with hormone receptor positive early breast cancer.