Current Breast Cancer Treatment Research Articles

Abstract 1820: Investigating the role of estrogen receptor β agonists in the prevention and treatment of breast cancer

Abstract Breast Cancer is the primary cause of cancer-associated mortality worldwide. In the United States alone, more than 250,000 women are diagnosed every year. Asian women have the lowest incidence rates. However, their rates increase to those of the US within one generation after migration. Suggesting that diet and lifestyle are major contributing factors in breast cancer risk. Since Asian women consume high amount of soy when compared to other populations, perhaps compounds found in soy may have a protective effect that is lost once they adopt a western diet. Recent studies have identified plant-derived compounds from soy and licorice that activate Estrogen Receptor β. Unlike previous ERβ agonists, these novel compounds are selective for ERβ and have been tested for safety in clinical trials. Current breast cancer treatment strategies focus on Estrogen Receptor α signaling, given that the majority of cases diagnosed are ERα positive. These treatment strategies include endocrine therapies; such as anti-estrogens or aromatase inhibitors. However, in the last decade, the importance of ERβ has emerged. Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. The objective of this study was to investigate the utility of using ERβ agonists in the prevention and treatment on breast cancer. To investigate the significance of ERβ activation in the prevention of breast cancer, we used an immunocompetent transgenic mouse model of breast cancer. Specifically, HER2/neu overexpressing mice develop premalignant lesions at 4-5 months and tumors starting at month 7. HER2/neu mice were treated with ERβ agonists for 3 months and subsequently mammary glands were analyzed using whole mount and IHC. When compared to controls, ERβ agonist treated mice showed a decrease in branching and ductal hyperplasia, with no change in body weight. These results suggest that ER β agonist treatment is chemopreventive and provided protection against premalignant lesion in the mammary gland. To investigate the utility of ERβ agonists in the treatment of breast cancer, we used in-vitro and in-vivo models systems. Our results demonstrated that treatment with the agonists was able to inhibit the short-term and long-term growth of the breast cancer cell lines; MCF7aro and LTLT which represent post-menopausal breast cancer and letrozole resistant cells, respectively. In addition to growth inhibition, treatment with ERβ agonists also decreased cell migration and invasion. In addition to activating ERβ, we also found that the agonists are also able to increase the expression of ERβ without increasing ERα levels. Our studies also demonstrated that treatment with ERβ agonists modulated key signaling molecules involved in cell death and cell cycle. Our studies suggest that activation of ERβ signaling is a valuable strategy in the treatment and chemoprevention of breast cancer. Citation Format: Cathy Samayoa, Naveen K. Krishnegowda, Ratna K. Vadlamudi, Rajeshwar R. Tekmal. Investigating the role of estrogen receptor β agonists in the prevention and treatment of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1820.

Seroma Cytology in Breast Cancer: An Underappreciated Issue

BackgroundThe presence of malignant cells in postoperative seroma has been ignored in current breast cancer treatment. We aimed to assess the presence of malignant seroma cytology and to evaluate its relationship with the known prognostic factors for breast cancer. Patients and MethodsThe solution from irrigation of the operation field and postoperative drainage fluid from 68 patients were prospectively collected and examined for malignant cytology. The results were evaluated according to the tumor characteristics and patient demographics. ResultsMalignant cytology was found in none of the intraoperative samples but was found in the postoperative samples from 4 patients. Of these 4 patients, 3 were free of axillary metastasis. None of the common risk factors for breast cancer was associated with the finding of malignant cytology. ConclusionMalignant cells can be seen in the drainage fluids from breast cancer patients independent of any contamination occurring during surgery, even in those without axillary metastasis.

23 Surveillance and Incidence of Chemotherapy-Induced Cardiotoxicity in Breast Cancer: A Long Term Observational Study

Introduction Recent advances in chemotherapy have transformed breast cancer from a fatal disease to a survivable condition. However, many patients who survive their cancer, succumb to the unintended adverse effects of therapy. Chemotherapy-induced cardiotoxicity is now among the most feared adverse effects and has been reported in up to 50% of patients up to twenty years later, the majority of which occurring after completion of therapy. Consequently, current breast cancer treatment guidelines recommend assessment of LV function before, during and after chemotherapy. Methods We conducted a retrospective cohort study of 1263 breast cancer patients who received either anthracyclines alone or combined with the monoclonal antibody trastuzumab at Ninewells Hospital, Dundee between January 2003 and December 2014. Imaging modalities such as MUGA scans were extracted from the CHEMOCARE database which allowed us to identify whether cardiac assessments were carried out at baseline and during treatment as per recommendations. LVEF at baseline and during routine follow-up was also calculated to determine if patients had developed left ventricular systolic dysfunction (LVSD) during chemotherapy. Results Of 1262 patients, 1260 patients (99.8%) were female, with an mean age of 59.3 years. 82.2% of the patients had received anthracyclines alone and 17.8% received a combination of an anthracycline and trastuzumab. 900 patients (71.3%) received adjuvant radiotherapy, 311 (24.6%) received chemotherapy only and 51 (4.0%) had an unknown type of therapy. 1101 (87.2%) of patients were on epirubicin with an average cumulative dose of 570.7 mg/m 2 , making it the most used anthracyline as it is less cardiotoxic compared to doxorubicin. 683 (54.0%) underwent screening for baseline cardiac function using MUGA scans. Of these, only 290 (42.5%) had follow up scans during the course of their treatment as mandated by guidelines. Among patients who had adequate follow up, 32 (11%) developed LVSD during chemotherapy, corresponding to a rate of 6.7% (n = 5) among those on anthracyclines alone and 12.5% (n = 27) among patients on combination therapy. Conclusion Despite recommendations to monitor cardiac function, our data shows in all chemotherapy patients, only half of them were monitored in our cohort. Although LVSD is usually a late sequel of cancer treatment, we have shown its occurrence even when chemotherapy is being delivered, thus highlighting the importance of surveillance to ensure early detection and management. This may reflect physicians’ opinion, contrary to guideline recommendations, that single chemotherapy is associated with less cardiotoxicity.

Abstract P6-01-01: Impact of imaging surveillance on the risk of radiation induced malignancies in breast cancer survivors

Abstract Introduction: After curative treatment of breast cancer (BC), relevant clinical guidelines recommend against the use of imaging procedures other than yearly mammography for surveillance, based on the lack of survival benefit for intensive surveillance strategies. Nevertheless, use of non-recommended imaging tests occurs frequently in this context. Most BC surveillance studies have focused on the potential benefit of detection of early relapse, on financial burden, and risk of false positives with different follow-up regimens. No study has analyzed the risk of imaging radiation induced malignancies (IRIM) in BC survivors exposed to repeated body imaging during surveillance. We previously reported on the IRIM risk in the BC clinical trials setting (Fresco R. The Oncologist 2015). In this current study we report on this risk during surveillance in clinical practice in BC survivors. Objective: To estimate IRIM risk in patients curatively treated for BC undergoing imaging tests during surveillance. Methodology: We defined 6 surveillance strategies with differing imaging requirements, from a non imaging-intensive one (yearly mammography only) to intensive ones (mammography + CT, Bone scan, PET-CT and/or MUGA) (Table 1). For each strategy we calculated the imaging dose and excess lifetime attributable cancer risk (LAR) for a 60 year-old BC survivor, using NCI's Radiation Risk Assessment Tool (RadRat). Results: Total effective imaging radiation dose received by a 60 year-old BC survivor during surveillance was 8.4 miliSieverts (mSv) when only yearly mammography is performed to 199.9 mSv when CT, MUGA and bone scan are added. Mean IRIM LAR ranges from 37.2/100,000 with the first strategy to 1,330/100,000 with the latter. Performing MUGA scans increased IRIM risk 31% compared to not performing it. The addition of any additional radiating imaging procedure to yearly mammography significantly increases LAR. Imaging effective dose and LAR in different surveillance strategiesFollow-up strategyImaging effective dose (mSv)Excess lifetime attributable cancer risk: mean (90% uncertainty range) (/100,000)Yearly mammography only8.437.2 (21.4-60.3)Yearly mammography + Chest/abdomen CT q6mo for 3y, then annually for 2y128.4857.0 (503.0-1,350.0)Yearly mammography + Chest/abdomen CT q6mo for 3y, then annually for 2y + Bone scan q12mo for 5y159.91,060.0 (603.0-1,640.0)Yearly mammography + Chest/abdomen CT q6mo for 3y, then annually for 2y + MUGA q6mo for 2y168.41,130.0 (642.0-1,800.0)Yearly mammography + Chest/abdomen CT q6mo for 3y, then annually for 2y + MUGA q6mo for 2y + Bone scan q12mo for 5y199.91,330.0 (792.0-2,080.0)Yearly mammography + PET-CT q6mo for 3y, then annually for 2y184.41,310.0 (802.0-1,990.0) Conclusions: A number of incremental second cancers could be derived from imaging performed during BC surveillance after curative treatment. Addition of non-recommended imaging for relapse detection increases IRIM risk compared to performing only mammography. This, in addition to the lack of proven benefit in BC endpoints, emphasizes the need to follow recommendations for surveillance clinical guidelines, and forgo imaging studies other than annual mammography to detect relapses. Substituting MUGA with echocardiogram for cardiac assessment could also reduce IRIM risk. Citation Format: Spera G, Gonzalez V, Meyer C, Fung H, Mackey JR, Fresco R. Impact of imaging surveillance on the risk of radiation induced malignancies in breast cancer survivors. [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 P6-01-01.

Fostering positive experiences of group-based exercise classes after breast cancer: what do women have to say?

Purpose: The adverse side effects of current treatments for breast cancer highlight the need for rehabilitative programmes. Group-based exercise programmes have been found to be effective in reducing symptoms and treatment side effects and improving physical and psychological health in cancer survivors. To assist programme administrators and instructors in the ongoing design and delivery of optimal group-based exercise programmes, we conducted a longitudinal qualitative study to explore breast cancer survivors’ perceptions of the instructor and the climate the instructor created within the context of a group-based exercise programme, and how this contributes to women’s motivational experiences. Method: Seven women participating in an eight-week group-based exercise programme were interviewed at the start and end of the programme. Data were analysed using thematic analysis. Results: The instructor’s attributes (energy, enthusiasm, approachability, knowledge, experience) and her focus on promoting self-improvement, personal progress, skill development and task mastery contributed to participants’ positive experiences, which served to enhance their motivation to remain involved in the programme. Conclusions: Instructors play an essential role in creating a supportive climate and fostering positive experiences in group-based exercise programmes for breast cancer survivors. Hiring caring and knowledgeable instructors who are able to create a supportive climate may enhance breast cancer survivors’ experiences in group-based exercise programmes and promote sustained participation.Implications for RehabilitationPromoting self-improvement, personal progress, skill development and task mastery can enhance breast cancer survivors’ adherence to group-based exercise programmes, which can help mitigate the effects of cancer and its treatment.In addition to training leaders to run safe and effective programmes, hiring instructors who have high energy, and who are enthusiastic, approachable, knowledgeable and experienced can promote breast cancer survivors’ adherence to group-based exercise programmes.Training in breast cancer management is required to allow instructors to understand the complexities of this disease and develop tailored exercise programmes.Future research needs to identify training techniques that can effectively promote exercise instructors’ competence in working with breast cancer survivors.

Biomarker assessment and molecular testing for prognostication in breast cancer.

Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single-molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single-molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures.

Specific targeting and noninvasive imaging of breast cancer stem cells using single-walled carbon nanotubes as novel multimodality nanoprobes.

The limitation of current breast cancer treatments was elucidated by the presence of cancer stem cells (CSCs) that play essential role in cancer initiation, progression, resistance, recurrence and metastasis. Materials& methods: Biocompatible multimodality single-walled carbon nanotube (SWCNT) nanoprobes were developed. The biodistribution and preferential homing of CD44 antibody-conjugated SWCNTs toward the tumor site were monitored using MRI, single-photon emission computed tomography and near-infrared fluorescence imaging noninvasive imaging modalities. Quantification of SWCNTs by sensitively measuring iron content in sorted CSC populations using inductively coupled plasma-mass spectrometry confirmed the enhanced selective targeting of anti-CD44 SWCNT and immunohistochemistry analyses revealed enhanced colocalization with areas rich in CD44 receptors. This preclinical study provided encouraging results for efficient targeting of breast CSCs and perspectives for further clinical studies to confirm the efficacy and safety of the designed nanocarriers.

Abstract 4493: Ironing out breast cancer: investigation of a novel iron chelator

Abstract Introduction: Breast cancer is the second leading cause of cancer-related death in women. Current breast cancer therapy is hindered by dose-limiting toxicities, demonstrating the need for less toxic alternatives. As cancer cells have an increased requirement for iron, we hypothesized that iron withdrawal using a highly selective iron chelator (DIBI) developed by Chelation Partners Incorporated (CPI) would enhance breast cancer cell killing by chemotherapeutic drugs and ionizing radiation. Results: DIBI inhibited the growth of a panel of breast cancer cell lines while similar doses had limited effects on the growth of normal fibroblasts. In breast cancer cells, DIBI-mediated iron chelation increased transferrin receptor 1 mRNA expression and decreased the expression of ferroportin1 mRNA, which is indicative of decreased intracellular iron stores. Iron citrate reversed the inhibitory effect of DIBI, confirming the iron-specific activity of the compound. On the basis of iron-binding capacity, a comparison between DIBI and two conventional iron chelators demonstrated that DIBI was more effective at inhibiting breast cancer cell proliferation. DIBI-treated breast cancer cells showed a dose-dependent reduction in rounds of cell division, as well as arrest in the S-phase of the cell cycle. Higher doses of DIBI also induced apoptosis in breast cancer cells. In addition, DIBI treatment of breast cancer cells induced double-stranded DNA breaks, which are likely important for its anticancer activity. Pretreatment of breast cancer cells with DIBI enhanced the grow-inhibitory effects of ionizing radiation and conventional chemotherapeutic agents, suggesting that DIBI may increase the effectiveness of current breast cancer therapies. Combination treatment with cisplatin and DIBI demonstrated that DIBI enhanced both the cytotoxic and cytostatic anticancer effects of cisplatin. Conclusion: These findings suggest that selective sequestration of iron from the tumor microenvironment may prevent or diminish tumor progression. In the future, treating patients with this novel iron chelator in combination with conventional therapies may increase the effectiveness of current breast cancer treatments. Citation Format: Anna Greenshields, David Hoskin, Melanie Coombs, Taryn Grant. Ironing out breast cancer: investigation of a novel iron chelator. [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 4493. doi:10.1158/1538-7445.AM2015-4493

MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2.

The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer.

The triterpenoids of Hibiscus syriacus induce apoptosis and inhibit cell migration in breast cancer cells

BackgroundBreast cancer-related mortality increases annually. The efficacy of current breast cancer treatments is limited, and they have numerous side effects and permit high recurrence. Patients with estrogen receptor (ER)-negative or triple-negative breast cancer are particularly difficult to treat. Treatment for this type of cancer is lacking, and its prognosis is poor, necessitating the search for alternative treatments.MethodsThis study screened Chinese herb Hibiscus syriacus extracts and identified a novel anti-cancer drug for patients with ER-negative breast cancer. The inhibitory effects on cell viability and migration were evaluated for each compound, and the molecular regulatory effects were evaluated on both mRNA and protein levels.ResultWe found several triterpenoids including betulin (K02) and its derivatives (K03, K04, and K06) from H. syriacus inhibited human triple-negative breast cancer cell viability and migration but revealed smaller cytotoxic effects on normal mammalian epithelial cells. Betulin and its derivatives induced apoptosis by activating apoptosis-related genes. In addition, they activated p21 expression, which induced cell cycle arrest in breast cancer cells. Betulin (K02) and betulinic acid (K06) had stronger inhibitory effects on cell viability and migration than K03 and K04.ConclusionsH. syriacus extracts might inhibit breast cancer cell viability and induce apoptosis by activating p53 family regulated pathways and inhibiting AKT activation. H. syriacus extracts may provide important insight into the development of novel alternative therapies for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-015-0592-9) contains supplementary material, which is available to authorized users.

A Comparison of IHC and FISH Cytogenetic Methods in the Evaluation of HER2 Status in Breast Cancer

The HER2 gene is responsible for the formation of the HER2 receptor on the surface of epithelial cells. Increased numbers of this receptor are associated with aworse prognosis in cancer. Increased numbers of copies of the HER2 gene occur in about 20-30% of breast cancer patients, so determining HER2 receptor levels is important in the current diagnosis and treatment of breast cancer. One diagnostic technique is the immunohistochemical (IHC) method, which permits indirect measurement of overexpression of HER2 receptors, based on subjective determination of the intensity of the color reaction. Another technique is the use of fluorescent in situ hybridization (FISH), which permits the exact number of copies of the HER2 gene to be specified. Based on the results of FISH tests, patients can be qualified for treatment with antibodies that partially block HER2 receptors. This treatment causes inhibition of tumor growth signals. Determining the HER2 status in breast cancer with the FISH method allows the further progress of the disease to be predicted, the right treatment to be chosen and the response to the treatment to be foreseen. Because of the widespread use of the FISH and IHC methods, comparing the advantages and disadvantages of these two methods seems to be relevant.

Current medical treatment of estrogen receptor-positive breast cancer.

Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

PCN279 - Systemic Treatment of Metachronous Metastases After Curative Treatment of Breast Cancer

PCN279 - Systemic Treatment of Metachronous Metastases After Curative Treatment of Breast Cancer

Current treatment of early breast cancer: adjuvant and neoadjuvant therapy.

Breast cancer is the most commonly diagnosed cancer in women. The latest world cancer statistics calculated by the International Agency for Research on Cancer (IARC) revealed that 1,677,000 women were diagnosed with breast cancer in 2012 and 577,000 died. The TNM classification of malignant tumor (TNM) is the most commonly used staging system for breast cancer. Breast cancer is a group of very heterogeneous diseases. The molecular subtype of breast cancer carries important predictive and prognostic values, and thus has been incorporated in the basic initial process of breast cancer assessment/diagnosis. Molecular subtypes of breast cancers are divided into human epidermal growth factor receptor 2 positive (HER2 +), hormone receptor positive (estrogen or progesterone +), both positive, and triple negative breast cancer. By virtue of early detection via mammogram, the majority of breast cancers in developed parts of world are diagnosed in the early stage of the disease. Early stage breast cancers can be completely resected by surgery. Over time however, the disease may come back even after complete resection, which has prompted the development of an adjuvant therapy. Surgery followed by adjuvant treatment has been the gold standard for breast cancer treatment for a long time. More recently, neoadjuvant treatment has been recognized as an important strategy in biomarker and target evaluation. It is clinically indicated for patients with large tumor size, high nodal involvement, an inflammatory component, or for those wish to preserve remnant breast tissue. Here we review the most up to date conventional and developing treatments for different subtypes of early stage breast cancer.

Glabridin attenuates the migratory and invasive capacity of breast cancer cells by activating microRNA-200c.

Current treatments for breast cancer, a common malignancy in human females, are less than satisfactory because of high rates of metastasis. Glabridin (GLA), which acts through the FAK/ROS signaling pathway, has been used as an antioxidant and anti-metastatic agent. However, little is known regarding the effect of microRNA (miRNA) on GLA's anti-metastatic activity. The miRNA-200 family, which is frequently expressed at low levels in triple negative breast cancers, inhibits metastasis by blocking the epithelial–mesenchymal transition. Here, we found that GLA attenuated the migratory and invasive capacity of breast cancer cells by activating miR-200c. GLA induced the mesenchymal–epithelial transition in vitro and in vivo, as determined by increased expression of the epithelial marker, E-cadherin, and decreased expression of the mesenchymal marker, vimentin. Overexpression of miR-200c enhanced the expression of E-cadherin and decreased the expression of vimentin. Furthermore, in MDA-MB-231 and BT-549 breast cancer cells exposed to GLA, knockdown of miR-200c blocked the GLA-induced mesenchymal–epithelial transition and alleviated the GLA-induced inhibition of migration and invasion. Thus, elevation of miR-200c by GLA has considerable therapeutic potential for anti-metastatic therapy for breast cancer patients.

1α,25-Dihydroxyvitamin D3 inhibits cell growth and NFκB signaling in tamoxifen-resistant breast cancer cells

Resistance to antiestrogens is a major clinical problem in current breast cancer treatment and development of new treatment strategies for these tumors is highly prioritized. In this study, we have investigated the effects of 1α,25-dihydroxyvitamin D3 on the proliferation of tamoxifen-resistant cells. Further, we have investigated on a molecular level the effects of vitamin D on NFkB signaling in tamoxifen-resistant breast cancer cells. Parental human breast cancer MCF-7 cells and four tamoxifen-resistant sublines have been used to investigate the effects of 1α,25-dihydroxyvitamin D3 on cell proliferation using a colorimetric method, gene expression using quantitative PCR, protein phosphorylation using Western blot analysis and cellular localization of proteins using immunofluorescence microscopy. We found that 1α,25-dihydroxyvitamin D3 is able to strongly decrease the growth of both tamoxifen-sensitive and -resistant breast cancer cells and that this antiproliferative effect of 1α,25-dihydroxyvitamin D3 might be mediated via inhibition of the NFκB pathway. We found that 1α,25-dihydroxyvitamin D3 stimulates the gene expression of IkB, an NFκB-inhibiting protein, and that cells pretreated with 1α,25-dihydroxyvitamin D3 have a decreased sensitivity to TNFα stimulation. Further, we show that 1α,25-dihydroxyvitamin D3 treatment strongly decreases the TNFα-induced translocation of p65 into the nucleus. This manuscript reports novel findings regarding the effects of 1α,25-dihydroxyvitamin D3 on NFκB signaling in tamoxifen-resistant breast cancer cells and suggests that vitamin D might be interesting for further evaluation as a new strategy to treat antiestrogen-resistant breast cancers.

Living with the Consequences of Curative Treatment of Breast Cancer

Living with the Consequences of Curative Treatment of Breast Cancer

Cost Implications of the SSO-ASTRO Consensus Guideline on Margins for Breast-Conserving Surgery with Whole Breast Irradiation in Stage I and II Invasive Breast Cancer

Over $125 billion is spent annually in the United States for cancer treatment. Among women in this country, breast cancer remains the most common nondermatologic cancer diagnosis and the second leading cause of cancerrelated death. In 2010, breast cancer treatment costs were estimated at $16.5 billion, comprising 13 % of the burden of total cancer-related costs. Health care spending varies throughout the phases of breast cancer treatment, with *23 % of total expenditures allocated during the initial episode of treatment (diagnosis and management during the first year), 41 % during continuing care, and 36 % during the last year of life. It has been estimated that surgical costs account for 25 % of breast cancer treatment expenditure among Medicare patients. An important contributor to health care costs includes deviations from the standard of care and variations in clinical practice that are not supported by evidence. Moreover, dramatic regional variations in health care spending are not associated with the quality of delivered care or with improved patient outcomes. In contrast, studies have consistently shown that adherence to clinical pathways and guidelines, and reductions in unintended practice variations are linked to improvement in clinical outcomes at lower costs. In the current treatment of early-stage breast cancer, management of surgical margins after lumpectomy is a prime example of wide variation in clinical practice. Consensus exits on the importance of removing all microscopically evident disease; however, there has historically been little agreement on what constitutes a pathologically acceptable distance from tumor cells to ink. Definitions of margin adequacy have ranged from ‘‘no tumor on ink’’ in the original NSABP B-06 trial, to the Milan trials requiring quadrantectomy with 2–3 cm of grossly normal tissue around the tumor including overlying skin and underlying fascia. Taghian et al. demonstrated this lack of consensus in defining close and negative margins in a survey of North American and European practicing radiation oncologists, with only 46 % of North American respondents considering ‘‘no tumor on ink’’ as adequately negative margins. A survey of surgeons treating breast cancer again demonstrated wide variation in defining margin adequacy, with only 3 % endorsing ‘‘no tumor on ink’’ as negative margins. The debate of what constitutes a negative margin has continued at a national level and has widespread implications for patients and cancer-related treatment costs. The meta-analysis included in this issue by Moran et al. may finally put rest to this issue. In the United States, 60–75 % of women diagnosed with early-stage breast cancer are treated with breast-conservation therapy (lumpectomy and radiotherapy) based on long-term followup and contemporary data demonstrating equivalent survival to mastectomy. The ‘‘SSO-ASTRO consensus guidelines on margins for breast-conserving surgery with whole breast irradiation in stage I–II invasive breast cancer’’ included 33 studies with 28,162 patients reviewed by an expert panel. Evidence-based consensus guidelines on Society of Surgical Oncology 2014

Application of tissue microarrays for receptor immunohistochemistry in breast carcinoma

The current treatment of breast cancer, the most frequent malignancy found in females, requires the study of biomarkers. The standard set of these includes at least an estrogen receptor, a progesterone receptor and a HER2 receptor, although many other factors have been shown to contribute to the prognosis. Tissue microarrays have been introduced to decrease costs and workload of immunohistochemistry applied to large collections of samples. The aim of the study was to test the performance of this technology on three basic biomarkers of breast carcinoma in 106 cases of invasive breast carcinoma. Tissue microarrays composed of 3 cores sized 0.6 mm per case were constructed and stained by standard immunohistochemistry. The results were assessed on virtual slides created with an Aperio scanner. A sensitivity and specificity of 0.83 and 0.88 was obtained for the estrogen receptor, 0.76 and 0.88 for the progesterone receptor, 0.69 and 0.96 for HER2. In conclusion, TMA technology may give results comparable to the diagnosis based on whole sections, and the clinicopathologic correlations for the immunohistochemistry performed by both methods are fairy similar.

PREVENTION OF ERYSIPELAS IN THE EARLY POSTOPERATIVE PERIOD AFTER THE IMPOSITION MIKROLIMFOVEIN ANASTOMOSIS IN PATIENTS AFTER BREAST CANCER LYMPHEDEMA

The aim of work is valuation of the effectiveness of autologous lymphocytes activated by complex of cytokines to prevent erysipelas of patients with after breast cancer syndrome.The estimate of influence of activated autologous lymphocytes to erysipelas. The treatment results of 128 patients with secondary lymphedema of the upper limb II–III stage after curative treatment of breast cancer are included in the work.Activated roncoleukin auto lymphocytes injections were performed in the forearm of the affected limb to the main group’s patients.17.4% faces relapses were recorded in the comparison group. while the group with the usage of activated roncoleukin autologous lymphocytes had achieved significant reductions in recurrent of erysipelas up to 5%.