Therapy In Treatment Of Breast Cancer Research Articles

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Exemestane (EXE) is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway is incomplete, with ambiguity existing in the identity of enzymes driving the production of its key metabolite, 17β-dihydroexemestane (17β-DHE). The impact of genetic variation on EXE metabolism is also unknown. This study aims to describe cytosolic reductase involvement in hepatic EXE metabolism and to assess the impact of functional polymorphisms on metabolite production. Phase I metabolites were identified in incubations of EXE with pooled human liver cytosol or recombinant protein for AKR1Cs and CBR1. Kinetic parameters characterizing EXE reduction were measured for purified wild-type enzymes, and nonsynonymous variants occurring at greater than 1% minor allele frequency using UPLC/MS/MS. Human liver cytosol, CBR1, AKR1C1, AKR1C2, AKR1C3, and AKR1C4 reduce EXE to active primary metabolite 17β-DHE. The formation of a novel metabolite, 17α-DHE, was catalyzed by recombinant AKR1C4 and CBR1 in addition to hepatic cytosol. Variants AKR1C3 Arg258Cys and AKR1C4 Gly135Glu had significantly decreased affinity for EXE relative to their respective wild types. Five common AKR1C3 polymorphisms were associated with decreased rates of catalysis, whereas AKR1C4 Gly135Glu increased the velocity of EXE reduction. AKR1Cs and CBR1 catalyze EXE reduction in vitro. These results imply that cytosolic ketosteroid reductases may participate in the EXE metabolic pathway in vivo. In addition, several common variants were associated with altered enzymatic activity, suggesting that functional polymorphisms could play an important role in overall EXE metabolism and activity by altering the extent and duration of 17β-DHE exposure.

HER2-positive breast cancer, how far away from the cure?-on the current situation of anti-HER2 therapy in breast cancer treatment and survival of patients.

With the diagnosis and treatment of tumor enter into the area of precision medical, based on selected targeted molecular typing of patients with individualized diagnosis and treatment play an important role. HER gene encoded epidermal growth factor receptor 2 (HER2) leading to increased early distant metastasis of breast cancer in patients and poor prognosis. However, a number of clinical studies provided evidence-based anti-HER2 targeted therapy and confirmed the benefit of anti-HER2 targeted therapy in patient survival. In recent years, through the tireless efforts of scholars in the field of breast cancer in our country, the whole diagnosis and treatment of breast cancer has accomplished an international standard. But based on a variety of factors, the anti-HER2 targeted therapy between China and the developed countries, and between different areas in China still exists certain gaps, is now a problem need to be solved. This article will analyzing the diagnostic and treatment on HER2-positive breast cancer in the United States and China, exploring reasons and looking for answers to narrow down the gap in the treatment of HER2-positive breast cancer between China and the United States. Improve the anti-HER2 targeted therapy in our country, let the patients get maximum benefit from anti-HER2 targeted therapy.

A novel long non-coding RNA FGF14-AS2 is correlated with progression and prognosis in breast cancer

Breast cancer is diverse in their natural history and in their responsiveness to treatments. It is urgent to generate candidate biomarkers for the stratification of patients and personalization of therapy to avoid overtreatment or inadequate treatment. Long noncoding RNAs (lncRNAs) have been found to be pervasively transcribed in the genome and played critical roles in cancer progression. A lot of lncRNAs have been reported as potential prognostic biomarkers and therapeutic targets in multiple cancers. In this study, we demonstrated that FGF14 antisense RNA 2 (FGF14-AS2), a novel long non-coding RNA, was significantly down-regulated in breast cancer tissue compared with adjacent normal tissue both in validated cohort and TCGA cohort. Reduced expression of FGF14-AS2 was correlated with larger tumor size, more lymph node metastasis and advanced clinical stage in both cohorts. Kaplan–Meier analysis indicated that patients with lower FGF14-AS2 expression had a worse overall survival. Moreover, multivariate analysis revealed that decreased expression of FGF14-AS2 was an independent predictor of overall survival. Together, these results suggested that FGF14-AS2 involved in the progress of breast cancer and might act as a tumor suppressor gene. To the best of our knowledge, it was firstly reported that FGF14-AS2 was involved in cancer. This study provided a potential new marker and a target for gene therapy in breast cancer treatment.

Crosstalk events in the estrogen signaling pathway may affect tamoxifen efficacy in breast cancer molecular subtypes

Steroid hormones are involved on cell growth, development and differentiation. Such effects are often mediated by steroid receptors. One paradigmatic example of this coupling is the estrogen signaling pathway. Its dysregulation is involved in most tumors of the mammary gland. It is thus an important pharmacological target in breast cancer. This pathway, however, crosstalks with several other molecular pathways, a fact that may have consequences for the effectiveness of hormone modulating drug therapies, such as tamoxifen. For this work, we performed a systematic analysis of the major routes involved in crosstalk phenomena with the estrogen pathway – based on gene expression experiments (819 samples) and pathway analysis (493 samples) – for biopsy-captured tissue and contrasted in two independent datasets with in vivo and in vitro pharmacological stimulation. Our results confirm the presence of a number of crosstalk events across the estrogen signaling pathway with others that are dysregulated in different molecular subtypes of breast cancer. These may be involved in proliferation, invasiveness and apoptosis-evasion in patients. The results presented may open the way to new designs of adjuvant and neoadjuvant therapies for breast cancer treatment.

Abstract 5124: Identification and characterization of novel regulators of TRAIL-induced apoptosis in breast cancer cells

Abstract TNF-related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor super family and can induce apoptotic cell death upon binding to its cognate receptors, TRAIL Receptor 1 (TRAIL-R1) and TRAIL Receptor 2 (TRAIL-R2). TRAIL has been found to induce selectively cell death in triple negative breast cancer (TNBC) cell lines (so called because the breast cancer cells lack estrogen and progesterone receptor expression and Her-2 amplification). Other subtypes of breast cancer are relatively resistant to TRAIL-induced apoptosis. However, the mechanisms that underlie the sensitivity of TNBCs to TRAIL-induced apoptosis are not yet understood. To identify regulators of TRAIL-induced apoptosis in the TNBC/mesenchymal cell line MB231, an siRNA screen of the kinome, phosphatome, and other potential regulators (∼1,300 genes) of the TRAIL pathway was carried out to measure the effects of loss of function of these genes on TRAIL-induced caspase-3/7 activation, capase-8 activation, and cell death. One hundred fifty negative regulators of the TRAIL pathway were identified, including 83 kinases, 4 phosphatases, and 63 non-kinases. The identified regulators were involved in diverse cell processes, including apoptosis, transcriptional regulation, growth factor receptor signaling, DNA repair, cell metabolism, and cell cycle regulation. Interestingly, no positive regulators were identified. A subset of the 150 candidates were rescreened in MB231 and three additional cell lines representative of other subytpes of breast cancer, including MB468 (TNBC/basal), SKBR3 (Her-2 amplified), and T47D (estrogen receptor positive). Interestingly, the TNBC/basal cell line MB468 was sensitized to TRAIL-induced caspase-3/7 activation by all of the candidates, whereas T47D and SKBR3 were sensitized to TRAIL by only two and three of the candidates, respectively. These findings demonstrate that breast cancer cell lines are varyingly sensitized to the effects of TRAIL. The anti-apoptotic protein Bcl-xL and the tyrosine kinase Src were also identified as negative regulators of TRAIL-induced apoptosis. We have further shown that pharmacologic inhibition of Bcl-xL or Src sensitize a wide range of breast cancer cell lines to TRAIL-induced apoptosis. These findings lend further support to the screen. Overall, the siRNA screen has identified many regulators of TRAIL-induced apoptosis in the TNBC cell line MB231 and a smaller subset of regulators in breast cancer cell lines representative of other subtypes. These findings suggest targets for the rational development of combination therapy in breast cancer treatment. Citation Format: Jennifer Dine, Sireesha Garimella, Kristie Gehlhaus, Magda Grandin, Natasha Caplen, Stanley Lipkowitz. Identification and characterization of novel regulators of TRAIL-induced apoptosis in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5124. doi:10.1158/1538-7445.AM2014-5124

Evaluation of lymphocyte infiltrate composition in triple-negative mammary carcinomas and its association with clinical-pathologic and demographic data.

1131 Background: Triple-negative breast cancer corresponds to 15-20% of cases. Despite the advances in development of therapies for breast cancer treatment, this subtype still have a dismal prognos...

Aberrant PTPRO methylation in tumor tissues as a potential biomarker that predicts clinical outcomes in breast cancer patients.

BackgroundAberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer.ResultsWe screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines.ConclusionsHere, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.

In Vitro and In Vivo Imaging of Peptide-Encapsulated Polymer Nanoparticles for Cancer Biomarker Activated Drug Delivery

Gelatin nanoparticles coated with Cathepsin D-specific peptides were developed as a vehicle for the targeted delivery of the cancer drug doxorubicin (DOX) to treat breast malignancy. Cathepsin D, a breast cancer cell secretion enzyme, triggered the release of DOX by digesting the protective peptide-coating layer of nanoparticles. Fabricated nanoparticles were successfully detected with ultrasound imaging in both in vitro conditions and in vivo mouse cancer models. Cell viability experiments were conducted to determine the efficacy of biomarker activation specific to breast cancer cell lines. These experimental results were compared with the outcome of a viability experiment conducted on noncancerous cells. Viability decreased in human MCF7 mammary adenocarcinoma and mouse 4T1 mammary carcinoma cells, while that of noncancerous 3T3 fibroblast cells remained unaffected. Next, a real-time video of nanoparticle flow in mouse models was obtained using in vivo ultrasound imaging. The fluorescent profile of DOX was used as a means to examine nanoparticle localization in vivo. Results show the distribution of nanoparticles concentrated primarily within bladder and tumor sites of subject mice bodies. These findings support the use of biomarker coated nanoparticles in target specific therapy for breast cancer treatment.

Abstract P2-04-03: A robust transgenic mouse model to study male breast cancer.

Abstract Male breast cancer accounts for about 1% of all breast cancers and even though it is a rare disease, the incidence rate has increased steadily during the past 20 years. Study of the male form of the disease has been hampered by a lack of relevant animal models as it is commonly believed that male mammary glands do not contain ducts. Female FVB C3(1)-SV40Tag transgenic mice spontaneously develop hyperplastic mammary lesions that progress to invasive mammary tumors, whereas most of the transgenic males develop prostatic hyperplasia that progresses to adenocarcinoma. However, upon closer examination, we discovered that approximately 45% of transgenic males develop mammary tumors by 40 weeks of age, often prior to developing prostate tumors. The course of male mammary development is similar to that observed in the females but with a later onset. Hyperplastic ducts form as early as 15 weeks of age and progress into DCIS-resembling tumors before developing into invasive tumors that invade locally into adipose tissue and muscle and occasionally form metastases to lung and other organs. We then examined male mammary development in the FVB background strain (wild type) and showed that all males develop mammary ducts that continue to grow and branch throughout adulthood. The morphology of these ducts was similar to that of females with a central lumen surrounded by concentric layers of luminal epithelium, myoepithelium, a basement membrane and surrounding stroma. A study of CD1 male mice confirmed that male mammary development was not specific to the FVB strain but rather, CD1 males showed similar mammary ductal development. Male mammary development in FVB wild type animals and tumor progression in the transgenic males was characterized in terms of cell proliferation, apoptosis and expression of various markers of differentiation including hormone receptor status. In summary, our results demonstrate that FVB C3(1)-SV40Tag transgenic males represent a highly robust and reproducible model for the study male breast cancer. Our long-term goal is to leverage the information we uncovered through this effort to design novel therapies for breast cancer treatment in men. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-03.

Combining Notch inhibition with current therapies for breast cancer treatment

Over recent years, there has been an increasing interest in targeting Notch signalling for the treatment of breast cancer. This has stemmed from the realization that many Notch pathway components display altered expression in breast cancer, and that Notch signalling impacts on many of the cellular properties associated with tumour initiation and progression. Consequently, Notch pathway inhibitors are now entering the initial stages of clinical trials. However, there is a definite need to consider how best to use these inhibitors and therefore which treatment strategies are likely to yield the most promising results. In particular, recent studies suggest that the greatest success will come from combining Notch pathway inhibitors with current breast cancer therapies.

Abstract 3273: A robust transgenic mouse model to study male breast cancer

Abstract Male breast cancer accounts for about 1% of all breast cancers and even though it is a rare disease, the incidence rate has increased steadily during the past 20 years. Study of the male form of the disease has been hampered by a lack of relevant animal models as it is commonly believed that male mammary glands do not contain ducts. Female FVB C3(1)-SV40Tag transgenic mice spontaneously develop hyperplastic mammary lesions that progress to invasive mammary tumors, whereas most of the transgenic males develop prostatic hyperplasia that progresses to adenocarcinoma. However, upon closer examination, we discovered that approximately 55% of transgenic males develop mammary tumors by 40 weeks of age, often prior to developing prostate tumors. The course of male mammary development is similar to that observed in the females but with a later onset. Hyperplastic ducts form as early as 15 weeks of age and progress into DCIS-resembling tumors before developing into invasive tumors that invade locally into adipose tissue and muscle and occasionally form metastases to lung and other organs. We then examined male mammary development in the FVB background strain (wild type) and showed that all males develop mammary ducts that continue to grow and branch throughout adulthood. The morphology of these ducts was similar to that of females with a central lumen surrounded by concentric layers of luminal epithelium, myoepithelium, a basement membrane and surrounding stroma. A study of CD1 male mice confirmed that male mammary development was not specific to the FVB strain but that CD1 males showed similar mammary ductal development. Male mammary development in FVB wild type animals and tumor progression in the transgenic males was characterized in terms of cell proliferation, apoptosis and expression of various markers of differentiation including hormone receptor status. In summary, our results demonstrate that FVB C3(1)-SV40Tag transgenic males represent a highly robust and reproducible model for the study male breast cancer. Our long-term goal is to leverage the information we uncovered through this effort to design novel therapies for breast cancer treatment in men. 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 3273. doi:1538-7445.AM2012-3273

Meta-analysis confirms achieving pathological complete response after neoadjuvant chemotherapy predicts favourable prognosis for breast cancer patients

Neoadjuvant chemotherapy (NAC) has become a widely accepted method of sequencing systemic therapy for breast cancer treatment. While ‘response to chemotherapy’ in the neoadjuvant setting has been utilised to predict prognosis, the published data are inconsistent. The present meta-analysis was conducted to determine whether the pathologic response to NAC predicts for outcomes. Papers were selected from the PubMed database based on defined inclusion and exclusion criteria. Parameters such as number/percentage of patients having pCR and outcome statistics (i.e. overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS)) were collected. The analysis included 16 studies with 3776 patients. The summary odds ratio (OR) estimating the association of OS with pCR was 3.44 (95% confidence interval [95%CI]: 2.45–4.84), with similar findings for DFS (OR=3.41, 95%CI: 2.54–4.58) and RFS (OR=2.45, 95%CI: 1.59–3.80). No obvious statistical heterogeneity was detected. Funnel plots and Egger’s tests did not reveal publication bias. This meta-analysis confirms that pathologic response is a prognostic indicator for RFS, DFS and OS and suggests that patients achieving pCR after NAC have favourable outcomes.

Liposomal M-V-05: Formulation development and activity testing of a novel dihydrofolate reductase inhibitor for breast cancer therapy

In the management of metastatic breast cancer, fewer recognized therapeutic standards are available as compared to the early stages of the disease. Thus, it is pertinent to search for new, effective therapy to improve survival, tolerability and quality of life of patients. In this study, a liposomal formulation was developed for a novel dihydrofolate reductase (DHFR) inhibitor, M-V-05. Drug encapsulation into liposomes was achieved by the citrate-based, pH gradient loading technique, with a final drug-to-lipid weight ratio of 0.1:1. The liposome formulation exhibited a sustained release profile of the encapsulated drug that followed first order release kinetics. Liposomal M-V-05 was found to be more effective than the standard DHFR inhibitor, methotrexate, and its activity was comparable to liposomal doxorubicin, with IC50 values of 37 and 59 microM achieved in MDA-MB-231 and JIMT-1 cells, respectively. Similar cytotoxicity was observed in primary patient samples of invasive ductal carcinoma of the breast. The combination of liposomal M-V-05 and liposomal doxorubicin in fixed molar ratio of 3:1 was additive in cytotoxicity, allowing the concentrations of liposomal doxorubicin and liposomal M-V-05 to be reduced by 62 and 46%, respectively. Taken together, liposomal M-V-05 represents a promising agent and offers a potential new adjuvant therapy for breast cancer treatment.

The rapamycin-regulated gene expression signature determines prognosis for breast cancer

BackgroundMammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer.ResultsColony formation and sulforhodamine B (IC50 < 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In the Wang dataset, RMI predicted time to disease relapse (P = 0.009).ConclusionRapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment.

S20 Combined ER and HER-targeted therapy in breast cancer treatment

S20 Combined ER and HER-targeted therapy in breast cancer treatment

Rapamycin-regulated gene expression signature determines prognosis in breast cancer.

Abstract Abstract #3072 Background: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer.&amp;#x2028; Methods: MDA-MB-468 breast cancer cell line is triple negative and PTEN null. Sensitivity of MDA-MB-468 breast cancer cell line to rapamycin was determined by in vitro growth assays and in vivo tumor studies. Total RNA was extracted from cell lines treated with rapamycin or DMSO for 24 hours and xenografts treated with DMSO or rapamycin for 1 or 22 days. Total RNA was used for expression profiling and hybridized to Affymetrix HG-U133 Plus 2.0 arrays. We used two well-described primary breast cancer datasets of 251 (Miller et al, Proc. Natl. Acad. Sci. USA 2005;102:13550) and 286 (Wang et al, Lancet. 2005;365:671) patients from the public domain and assessed the prognostic capability of rapamycin-regulated gene expression signatures.&amp;#x2028; Results: Colony formation and sulforhodazine B (IC50 &amp;lt; 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a 31-gene expression signature that was up- regulated by rapamycin treatment in vitro as well as in vivo (FDR of 0.1). From the 31 genes on HG-U133 Plus 2.0 array, 20 that were included on HG-U133A array were used for analysis. In the Miller dataset, rapamycin metagene index (RMI) did not correlate with tumor size or lymph node status. High (0.75 percentile) RMI was significantly associated with longer survival (P=0.015). On multivariate analysis, RMI (P=0.029), tumor size (P=0.015) and lymph node status (P=0.001) were prognostic. In the Wang dataset, RMI predicted time to disease relapse (P=0.009).&amp;#x2028; Conclusion: Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3072.

Molecular targeted therapies for breast cancer treatment

Targeting the oestrogen receptor, HER2 (human epidermal growth factor receptor 2) and vascular endothelial growth factor has markedly improved breast cancer therapy. New targeted therapeutic approaches to induction of apoptosis or inhibition of anti-apoptosis, cell cycle progression, signal transduction and angiogenesis are described. The molecular pathways and their inhibitory or repair mechanisms are discussed in the preclinical and clinical settings.

Poster - Thurs Eve-30: Investigation of a patient immobilization system for breast tomotherapy.

Using tomotherapy to deliver adjuvant radiation therapy for breast cancer treatment requires more precise immobilization than can be achieved using gravity alone. We evaluated the use of a thermoplastic shell to immobilize the patient's torso during breast cancer treatment. To measure intrafraction breathing motion, 4DCT scans were performed for eight post-lumpectomy or post-mastectomy breast cancer patients with the thermoplastic shell in place. The 4DCT scans were then analyzed to determine the magnitude of motion of the breast surface, chest wall, and heart over the breathing cycle. Maximum surface motion was typically less than 2mm, with a maximum of 4mm. Maximum displacement of the chest wall was less than 3mm with a maximum of 5mm in a single patient. Comparison with the setup errors recorded prior to repositioning the patients suggests that, with the thermoplastic shell in place, patient setup error will be a more significant source of uncertainty in patient position than breathing motion.

Metabolic approaches to breast cancer treatment and prevention

Standard systemic therapy for breast cancer treatment and prevention are generally directed at reduction in cell growth and increase in apoptosis by direct inhibition of DNA synthesis or signalling pathways that control cell proliferation and cell death. Data are accumulating that calorie restriction (CR) and/or exercise, or agents that target metabolic pathways may have antitumour effects either alone or in combination with standard therapies for cancer prevention and treatment, and merit further investigation. Here, we outline

Mortality following development of breast cancer while using oestrogen or oestrogen plus progestin: a computer record-linkage study

The literature on the relationship between breast cancer mortality and postmenopausal oestrogen and combined oestrogen/progestin therapy is seemingly contradictory. This study explored survival after exposure to oestrogen or oestrogen plus progestin at or in the year prior to breast cancer diagnosis. Information on patients first diagnosed with invasive breast cancer between 1993 and 1998 was linked with outpatient pharmacy data from 1992 to 2000. Patients were classified according to use of oestrogen alone or oestrogen plus progestin at or in the year prior to diagnosis. Compared to nonusers, and adjusting for age at diagnosis, race/ethnicity, tumour size and grade, oestrogen receptor status, surgery status, and chemotherapy and hormone therapy for breast cancer treatment, oestrogen plus progestin users had lower all-cause mortality (stage I hazard ratio (HR)=0.69, 95% confidence interval (CI)=0.48–0.99; stage II HR=0.53, 95% CI=0.39–0.72) and breast cancer mortality (stage I HR=0.52, 95% CI=0.26–1.04; stage II HR=0.69, 95% CI=0.48–0.98). Oestrogen users experienced little or no survival benefit for all-cause mortality (stage I HR=1.04, 95% CI=0.77–1.42; stage II HR=0.86, 95% CI=0.65–1.14) or breast cancer mortality (stage I HR=1.23, 95% CI 0.72–2.10; stage II HR=1.01, 95% CI 0.72–1.41). Our findings suggest, relative to nonusers, a lower risk of death from all causes and from breast cancer in patients who were diagnosed with breast cancer while exposed to oestrogen plus progestin, but not in patients exposed to oestrogen only.