Efficacy Of Breast Cancer Therapy Research Articles

Biomarkers of everolimus efficacy in breast cancer therapy

Everolimus is an inhibitor of serine/ threonine kinase mTOR. The drug is approved for the treatment of metastatic ER positive, HER2 negative breast cancers and benefits a subset of patients with these breast cancers in combination with hormonal therapies. Despite extensive efforts, no additional predictive biomarkers to guide therapeutic decisions for everolimus have been introduced in clinical practice. This paper discusses predictive biomarkers for everolimus efficacy in breast cancer. A search of the medline and web of science databases was performed using the words "everolimus" and "biomarkers". References of retrieved articles were manually scanned for additional relevant articles. Everolimus benefits a subset of patients with metastatic ER positive, HER2 negative breast cancers in combination with hormonal therapies. Despite extensive efforts no additional predictive biomarkers to guide therapeutic decisions for everolimus therapy have been confirmed for use in clinical practice. However, promising biomarker leads for everolimus efficacy in breast cancer have been suggested and include expression of proteins in the mTOR pathway in ER positive, HER2 negative breast cancers. In HER2 positive cancers PIK3CA mutations, and PTEN expression loss are prognostic. Other clinical predictive biomarkers with more limited data include characteristics derived from whole genome sequencing, subsets of circulating leukocytes and changes in Standardized Uptake Values (SUV) of Positron Emission Tomography (PET) scans. Putative predictive biomarkers for everolimus efficacy in breast cancer patients, both genomic and clinical, deserve further study and could lead to a better selection of responsive patients.

Advances with metal oxide-based nanoparticles as MDR metastatic breast cancer therapeutics and diagnostics.

Metal oxide nanoparticles have attracted increased attention due to their emerging applications in cancer detection and therapy. This study envisioned to highlight the great potential of metal oxide NPs due to their interesting properties including high payload, response to magnetic field, affluence of surface modification to overcome biological barriers, and biocompatibility. Mammogram, ultrasound, X-ray computed tomography (CT), MRI, positron emission tomography (PET), optical or fluorescence imaging are used for breast imaging. Drug-loaded metal oxide nanoparticle delivered to the breast cancer cells leads to higher drug uptake. Thus, enhanced the cytotoxicity to target cells compared to free drug. The drug loaded metal oxide nanoparticle formulations hold great promise to enhance efficacy of breast cancer therapy including multidrug resistant (MDR) and metastatic breast cancers. Various metal oxides including magnetic metal oxides and magnetosomes are of current interests to explore cancer drug delivery and diagnostic efficacy especially for metastatic breast cancer. Metal oxide-based nanocarrier formulations are promising for their usage in drug delivery and release to breast cancer cells, cancer diagnosis and their clinical translations.

Development and Evaluation of Letrozole-Loaded Hyaluronic Acid/Chitosan-Coated Poly(d,l-lactide-co-glycolide) Nanoparticles

Letrozole (LTZ), an aromatase inhibitor with poor aqueous solubility, is used as the first line treatment for hormonal sensitive breast cancer in postmenopausal women. The purpose of the current study is to develop hyaluronic acid (HA)/chitosan (Cs)-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles for the delivery of LTZ to improve therapeutic efficacy, control release and minimize side effects of LTZ. PLGA nanoparticles were prepared, and the effect of various parameters on particle size, surface charge, and encapsulation efficiency was extensively studied. The morphology of nanoparticles was visualized using transmission electron microscopy (TEM), and drug-polymer interactions were studied using differential scanning calorimetry (DSC) and Fourier transform-infrared spectroscopy (FT-IR). The in vitro release kinetics and effect of freeze-drying process on the physicochemical characteristics of nanoparticles were also evaluated. Moreover, the in vivo acute toxicities of blank and drug-loaded nanoparticles were assessed. PLGA nanoparticles exhibited nanosized (464.3 ± 2.1 nm) spherical particles, negative surface charge (zeta-potential of − 10.5 ± 0.4 mV), and high drug encapsulation efficiency of 63.9 ± 3.7% and sustained drug release pattern over 48 h. The in vivo acute toxicity study revealed that the nanoparticles were well tolerated at a dose of 300 mg/kg. HA/Cs-coated PLGA nanoparticles might provide a promising system for LTZ delivery and further investigations could confirm their potential efficacy in breast cancer therapy.

Development and Characterization of Soy Lecithin Liposome as Potential Drug Carrier Systems for Codelivery of Letrozole and Paclitaxel

In the present work, a dual-drug-loaded soy lecithin liposomal system was developed by coencapsulation of Letrozole (LET) with Paclitaxel (PTX) to improve the efficacy in breast cancer therapy. Liposomes were synthesized by the thin film layer hydration. To sufficiently evaluate the characteristics of these liposomes, the particle size, zeta potential, morphology, drug encapsulation, in vitro drug release, and cytotoxicity were ascertained. Results showed promisingly anticancer potentials, as the following parameters indicated: nanosize diameter (around 193 nm) and negative surface charge. Data collected from the coloaded drug liposomes showed suitable encapsulation efficiency (50.56% for PTX and 31.13% for LET). Controlled and sustained releases were achieved up to 72 h for both the loaded drugs following the diffusion mechanism. In addition, the in vitro cytotoxicity study on the human breast cancer cell line (MCF-7) given the dual-drug-loaded liposome showed greater inhibition of cell growth than the single drug. Consequently, LET and PTX coloaded liposomes made from soy lecithin are expected to be an ingenious drug-delivery system for combination chemotherapy.

Breast cancer therapy affects the expression of antineonatal Nav1.5 antibodies in the serum of patients with breast cancer.

Neonatal Nav1.5 (nNav1.5) is the alternative splice variant of Nav1.5 and it has been widely associated with the progression of breast cancer. The immunological context of nNav1.5 with respect to breast cancer metastases remains unexplored. The presence of antibodies against nNav1.5 may highlight the immunogenicity of nNav1.5. Hence, the aim of the present study was to detect the presence of antineonatal Nav1.5 antibodies (antinNav1.5-Ab) in the serum of patients with breast cancer and to elucidate the effects of breast cancer therapy on its expression. A total of 32 healthy female volunteers and 64 patients with breast cancer were randomly recruited into the present study as the control and breast cancer group, respectively. Patients with breast cancer were divided equally based on their pre- and ongoing-treatment status. Serum samples were tested with in-house indirect enzyme-linked immunosorbent assay (ELISA) to detect antinNav1.5-Ab, CD25 (T regulatory cell marker) using an ELISA kit and Luminex assay to detect the expression of metastasis-associated cytokines, such as vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-10, IL-8, chemokine (C-C motif) ligand 2 and tumor necrosis factor-alpha (TNF-α) The mean difference in the expression of antinNav1.5-Ab among the three groups (control, pretreatment and ongoing-treatment) was significant (P=0.0005) and the pretreatment breast cancer group exhibited the highest expression. The concentration of CD25 was highest in the pretreatment breast cancer group compared with the control and ongoing-treatment groups. There was a significant positive correlation between antinNav1.5-Ab and IL-6 in the pretreatment group (r=0.7260; P=0.0210) and a significant negative correlation between antinNav1.5-Ab and VEGF in the ongoing-treatment group (r=−0.842; P-value=0.0040). The high expression of antinNav1.5-Ab in the pretreatment group was in accordance with the uninterrupted presence of metastasis and highlighted the immunogenicity of nNav1.5 whereas the low expression of antinNav1.5-Ab in the ongoing-treatment group reflected the efficacy of breast cancer therapy in eliminating metastases. The augmented manifestation of T regulatory cells in the pretreatment group highlighted the functional role of nNav1.5 in promoting metastasis. The parallel expression of antinNav1.5-Ab with the imbalanced expression of cytokines promoting metastasis (IL-8, IL-6 and TNF-α) and cytokines that prevent metastasis (IL-10) indicated the role of nNav1.5 in breast cancer growth. The expression of antinNav1.5-Ab in accordance to the metastatic microenvironment indicates the immunogenicity of the protein and highlights the influence of breast cancer therapy on its expression level.

Novel Tamoxifen Nanoformulations for Improving Breast Cancer Treatment: Old Wine in New Bottles

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications. Nanotechnology has emerged as one of the most important strategies to solve the issue of TAM toxicity, owing to the ability of nano-enabled-formulations to deliver smaller concentrations of TAM to cancer cells, over a longer period of time. Various TAM-containing-nanosystems have been successfully fabricated to selectively deliver TAM to specific molecular targets found on tumour membranes, reducing unwanted toxic effects. This review begins with an outline of breast cancer, the current treatment options and a history of how TAM has been used as a combatant of BC. A detailed discussion of various nanoformulation strategies used to deliver lower doses of TAM selectively to breast tumours will then follow. Finally, a commentary on future perspectives of TAM being employed as a targeting vector, to guide the delivery of other therapeutic and diagnostic agents selectively to breast tumours will be presented.

The Role of Breast Cancer Stem Cells as a Prognostic Marker and a Target to Improve the Efficacy of Breast Cancer Therapy

Breast cancer is the most common form of tumor in women and the leading cause of cancer-related mortality. Even though the major cellular burden in breast cancer is constituted by the so-called bulk tumor cells, another cell subpopulation named cancer stem cells (CSCs) has been identified. The latter have stem features, a self-renewal capacity, and the ability to regenerate the bulk tumor cells. CSCs have been described in several cancer types but breast cancer stem cells (BCSCs) were among the first to be identified and characterized. Therefore, many efforts have been put into the phenotypic characterization of BCSCs and the study of their potential as prognostic indicators and therapeutic targets. Many dysregulated pathways in BCSCs are involved in the epithelial–mesenchymal transition (EMT) and are found up-regulated in circulating tumor cells (CTCs), another important cancer cell subpopulation, that shed into the vasculature and disseminate along the body to give metastases. Conventional therapies fail at eliminating BCSCs because of their quiescent state that gives them therapy resistance. Based on this evidence, preclinical studies and clinical trials have tried to establish novel therapeutic regimens aiming to eradicate BCSCs. Markers useful for BCSC identification could also be possible therapeutic methods against BCSCs. New approaches in drug delivery combined with gene targeting, immunomodulatory, and cell-based therapies could be promising tools for developing effective CSC-targeted drugs against breast cancer.

Dual drug loaded PLGA nanospheres for synergistic efficacy in breast cancer therapy

Improved therapeutic effects can be achieved by the delivery of combination of drugs through multifunctional cell targeted nanocarrier systems. The present investigation reports the preparation of Poly (D,L-lactic-co-glycolic acid) (PLGA) nanospheres loaded with the novel combination such as Rutin (R) and Benzamide (B) as drugs using water-oil-water (w/o/w) emulsion method. Dual drug loaded PLGA nanospheres (R/B@PLGA) were stabilized by poly (vinyl alcohol) (PVA) coating and characterized in terms of morphology, size, surface charge, and structural chemistry by Scanning electron microscopy (SEM), Dynamic light scattering (DLS), Zeta potential analysis, UV–vis and Fourier transform infrared (FT-IR) spectroscopy. The inhibitory effects of rutin and benzamide on MDA-MB-231 (triple negative breast cancer-TNBC) cells using the drug loaded PLGA nanospheres as well as their non-toxic features were evaluated in vivo. The anticancer activity of the R/B@PLGA nanospheres through cell cycle disruption and apoptotic induction was assessed in vitro by flow cytometry analysis. Further, the in vitro antioxidant capacity, pH-based drug release and hemocompatible property were also investigated. It was shown that the R/B@PLGA nanospheres lacked genotoxic potential and they did not alter the antioxidant enzyme activities and histological features of zebrafish. Hence, this dual drug delivery system (DDS) not only actively targets multidrug-resistance (MDR) associated phenotype but also improves the therapeutic efficiency by its non-toxic nature towards enhanced cancer cell focused delivery and sustained release of therapeutic agents.

Polymer-lipid hybrid anti-HER2 nanoparticles for targeted salinomycin delivery to HER2-positive breast cancer stem cells and cancer cells.

PurposeBreast cancer stem cells (CSCs) are responsible for the initiation, recurrence, and metastasis of breast cancer. Sufficient evidence has established that breast cancer cells can spontaneously turn into breast CSCs. Thus, it is essential to simultaneously target breast CSCs and cancer cells to maximize the efficacy of breast cancer therapy. HER2 has been found to be overexpressed in both breast CSCs and cancer cells. We developed salinomycin-loaded polymer–lipid hybrid anti-HER2 nanoparticles (Sali-NP-HER2) to target both HER2-positive breast CSCs and cancer cells.MethodsThe antitumor activity of Sali-NP-HER2 constructed by conjugating anti-HER2 antibodies to polymer–lipid salinomycin nanoparticles was evaluated in vitro and in vivo.ResultsSali-NP-HER2 efficiently bound to HER2-positive breast CSCs and cancer cells, resulting in enhanced cytotoxic effects compared with non-targeted nanoparticles or salinomycin. In mice bearing breast cancer xenografts, administration of Sali-NP-HER2 exhibited superior efficacy in inhibiting tumor growth. Sali-NP-HER2 reduced the breast tumorsphere formation rate and the proportion of breast CSCs more effectively than non-targeted nanoparticles or salinomycin alone.ConclusionSali-NP-HER2 represents a promising approach in treating HER2-positive breast cancer by targeting both breast CSCs and cancer cells.

Initial experience of intraoperative radiotherapy as tumour bed boost after neoadjuvant chemotherapy in breast cancer patients

Background: Radiotherapy has shown high efficacy in breast cancer therapy; in recent years, benefits of its intraoperative application were demonstrated. The aim of our study is to report initial experience of intraoperative radiotherapy (IORT) during breast conserving surgery (BCS) followed by external beam whole breast radiotherapy (EBRT) in patients with breast cancer after completion of neoadjuvant chemotherapy (nCHT). Methods: We retrospectively analysed data of 13 consecutive women who had completed nCHT because of locally advanced breast cancer and subsequently underwent IORT during BCS between 2005 and 2012. Demographic, clinical/surgical and histological parameters were evaluated and follow-up assessment was performed (median follow-up: 37 months, range 3–41 months). Results: Thirteen women (one with bilateral malignancy) received nCHT followed by BCS with IORT. The most frequent acute side effect was erythema (GI/II), occurring in 4 cases (4/14; 29%). Late follow-up analysis could be performed in 10 patients (median FU 40 months, range 31–41 months). Six of these patients (6/10, 60%) presented with low/moderate tumour bed fibrosis. No grade III fibrosis was observed. Three patients (3/10, 30%) had developed skin retractions. Five patients (5/10, 50%) complained about pain during late follow-up. There was no case of severe toxicity after IORT treatment up to the time of final evaluation. Conclusions: No relevant increase in severe acute and late complications could be observed in this small group of breast cancer patients who had received a combination of IORT and BCS followed by EBRT after completion of nCHT. This pilot study raises hope that IORT and BCS may be a feasible and safe enhancement of treatment strategies in this subgroup of patients with locally advanced malignancy.

A Novel MPEG-PDLLA-PLL Copolymer for Docetaxel Delivery in Breast Cancer Therapy.

Satisfactory drug loading capacity and stability are the two main factors that determine the anti-cancer performance. In general, the stability of the micelles is reduced when the drug loading (DL) is increased. Therefore, it was a challenge to have high drug loading capacity and good stability. In this study, we introduced a hydrophilic poly (L-Lysine) (PLL) segment with different molecular-weights into the monomethoxy poly (ethylene glycol)-poly (D, L-lactide) (MPEG-PDLLA) block copolymer to obtain a series of novel triblock MPEG-PDLLA-PLL copolymers. We found that the micelles formed by a specific MPEG2k-PDLLA4k-PLL1k copolymer could encapsulate docetaxel (DTX) with a satisfactory loading capacity of up to 20% (w/w) via the thin film hydration method, while the stability of drug loaded micellar formulation was still as good as that of micelles formed by MPEG2k-PDLLA1.7k with drug loading of 5% (w/w). The results from computer simulation study showed that compared with MPEG2k-PDLLA1.7k, the molecular chain of MPEG2k-PDLLA4k-PLL1k could form a more compact funnel-shaped structure when interacted with DTX. This structure favored keeping DTX encapsulated in the copolymer molecules, which improved the DL and stability of the nano-formulations. The in vitro and in vivo evaluation showed that the DTX loaded MPEG2k-PDLLA4k-PLL1k (DTX/MPEG2k-PDLLA4k-PLL1k) micelles exhibited more efficiency in tumor cell growth inhibition. In conclusion, the MPEG2k-PDLLA4k-PLL1k micelles were much more suitable than MPEG2k-PDLLA1.7k for DTX delivery, and then the novel nano-formulations showed better anti-tumor efficacy in breast cancer therapy.

Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.

BackgroundThere is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors.MethodsPhospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model.ResultsThe average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle.ConclusionsThe Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.

Biomarkers indicate efficacy of breast cancer therapy

Biomarkers indicate efficacy of breast cancer therapy

A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationships to human breast cancer.

IntroductionGenomic variability limits the efficacy of breast cancer therapy. To simplify the study of the molecular complexity of breast cancer, researchers have used mouse mammary tumor models. However, the degree to which mouse models model human breast cancer and are reflective of the human heterogeneity has yet to be demonstrated with gene expression studies on a large scale.MethodsTo this end, we have built a database consisting of 1,172 mouse mammary tumor samples from 26 different major oncogenic mouse mammary tumor models.ResultsIn this dataset we identified heterogeneity within mouse models and noted a surprising amount of interrelatedness between models, despite differences in the tumor initiating oncogene. Making comparisons between models, we identified differentially expressed genes with alteration correlating with initiating events in each model. Using annotation tools, we identified transcription factors with a high likelihood of activity within these models. Gene signatures predicted activation of major cell signaling pathways in each model, predictions that correlated with previous genetic studies. Finally, we noted relationships between mouse models and human breast cancer at both the level of gene expression and predicted signal pathway activity. Importantly, we identified individual mouse models that recapitulate human breast cancer heterogeneity at the level of gene expression.ConclusionsThis work underscores the importance of fully characterizing mouse tumor biology at molecular, histological and genomic levels before a valid comparison to human breast cancer may be drawn and provides an important bioinformatic resource.

Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA

Monitoring the effectiveness of therapy early and accurately continues to be challenging. We hypothesize that determination of Human Epidermal Growth Factor Receptor 2 (HER2) mRNA in malignant breast cancer (BC) cells by positron emission tomography (PET) imaging, before and after treatment, would reflect therapeutic efficacy. WT4340, a peptide nucleic acid (PNA) 12-mer complementary to HER2 mRNA was synthesized together with -CSKC, a cyclic peptide, which facilitated internalization of the PNA via IGFR expressed on BC cells, and DOTA that chelated Cu-64. Mice (n = 8) with BT474 ER+/HER2+ human BC received doxorubicin (DOX, 1.5mg/kg) i.p. once a week for six weeks. Mice (n = 8) without DOX served as controls. All mice were PET imaged with F-18-FDG and 48 h later with Cu-64-WT4340. PET imaging were performed before and 72 h after each treatment. Standardized uptake values (SUVs) were determined and percent change calculated. Animal body weight (BW) and tumor volume (TV) were measured. SUVs for Cu-64-WT4340 after DOX treatment declined by 54% ± 17% after the second dose, 41% ± 15% after the fourth dose, and 29% ± 7% after the sixth dose, compared with 42% ± 22%, 31% ± 18%, and 13% ± 9% (p<0.05) for F-18-FDG. In untreated mice, the corresponding percent SUVs for Cu-64-WT4340 were 145% ± 82%, 165% ± 39%, and 212% ± 105% of pretreatment SUV, compared with 108% ± 28%, 151% ± 8%, and 152% ± 35.5%, (p<0.08) for F-18-FDG. TV in mice after second dose was 114.15% ± 61.83%, compared with 144.7% ± 64.4% for control mice. BW of DOX-treated mice was 103.4% ± 7.6% of pretreatment, vs. 100.1% ± 4.3% for control mice. Therapeutic efficacy was apparent sooner by molecular PET imaging than by determination of reduction in TV.

Can estrogen receptor overexpression in normal tissues due to previous estrogen deprivation explain the fulvestrant efficacy in breast cancer therapy?

Fulvestrant is a down-regulator of estrogen receptors (ERs) with still evolving optimal dosage for ER-positive breast cancer patients. The CONFIRM phase III trial in women with advanced breast cancer proved fulvestrant 500-mg to be associated with a longer time till progression (TTP) than the 250-mg schedule. Detailed results suggest that the fulvestrant in both schedules depended on the previous endocrine therapy. All complete responses and the only significant TTP difference between the two schedules was found among women previously treated with tamoxifen (TAM) and not in women after aromatase inhibitors (AIs).Noting that TAM competes with estrogen binding to ERs is important, so the optimal TAM dosage produces drug concentrations comparable to concentrations of available ER ligands. All AIs diminish production of the main ER ligand, so the optimal AI dosage depends on the overall pool of aromatase molecules in the body. Both treatments are not directly related to the pool of available ERs in the body.Here proposed interpretation is that estrogen deprivation due to years of endocrine breast cancer therapy increases ER expression in breast cancer cells and in other healthy estrogen target tissues. The breast cancer exposure to fulvestrant depends on the presence of all ERs in the body. Only when this overall pool is sufficiently saturated with fulvestrant, we can expect to achieve some breast cancer response due to down-regulation of ER in cancer tissue.The CONFIRM data suggest that among patients switching from TAM to fulvestrant, only the 500-mg schedule could down-regulate the moderately enlarged total body ER pool and thus induce breast cancer regression. In patients switching from previous AI treatments, both 250 and 500-mg schedules were unable to prolong the TTP, suggesting that in both doses, fulvestrant showed no efficacy since the overall ER pool was more enlarged after AIs.Fulvestrant might be more effective before TAM and AIs, in the first line endocrine therapy of metastatic breast cancer, since an unaltered ER pool in normal tissues is expected in this setting.

264. A Stem Cell Gene Therapy Approach for Enhancing the Efficacy of Breast Cancer Therapy by Trastuzumab (Herceptin)

264. A Stem Cell Gene Therapy Approach for Enhancing the Efficacy of Breast Cancer Therapy by Trastuzumab (Herceptin)

BRCA1-associated complexes: new targets to overcome breast cancer radiation resistance

Since BRCA1 was cloned a decade ago, significant progress has been made in defining its biochemical and biological functions, as well as its role in breast and ovarian cancers. BRCA1 has been implicated in many cellular processes, including DNA repair, cell cycle checkpoint control, protein ubiquitination and chromatin remodeling. This review examines the role(s) of BRCA1 in mediating these cellular processes, and discusses its potential involvement in the resistance of breast cancer to radiation-based therapies. Finally, the possibility that BRCA1-associated proteins may serve as new targets for breast cancer radiation therapy is explored. The activation or inactivation of these BRCA1-associated proteins may modify both the risk of developing cancers in BRCA1 mutation carriers and the efficacy of breast cancer therapy, including radiation.

Activation of Akt correlates with resistance to endocrine therapy for metastatic breast cancer

9500 Background: In breast cancer, the PI3K/Akt pathway can be activated by membrane receptors, including the HER family of growth factor receptors. Akt promotes breast cancer cell survival and it has been suggested that Akt promotes resistance to chemotherapy, trastuzumab, and tamoxifen. This suggests that targeting the PI3K/Akt pathway may increase the therapeutic efficacy of breast cancer therapy. Methods: 1. We analyzed the activation of Akt by immunohistochemical analyses of expression of phosphorylated Akt (pAkt) in breast cancer, from 253 patients who underwent surgery at our department. We also evaluated the expression of HER2, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemistry. 2. Thirty-five patients with metastatic breast cancer received 44 endocrine therapies. We evaluated the correlation of pAkt expression with effect of the endocrine therapy in those patients. Results: 1. Expression of pAkt was positive in 85 samples (33.6%). Expression of pAkt significantly correlated with overexpression of HER2 (p<0.0001) and inversely correlated with PR expression (p<0.05). There was no correlation between of ER expression and pAkt expression. 2. Endocrine therapies for recurrent cases were as follows; Aromatase inhibitor for 21 cases, LH-RH agonist for 7 cases, SERM for 15 cases and MPA for one case. We defined CR, PR, and SD as effective and PD as not effective. High expression of pAkt and HER2 in primary tumor well correlated with resistance of endocrine therapy (p=0.0045 and p=0.0229) (Table). Conclusion: Activation of Akt correlated with HER2 overexpression and inversely correlated with PR expression. Activation of Akt correlated with endocrine therapies for metastatic breast cancer. This study suggets that pAkt may be used as a predictor of resistance of endocrine therapy for breast cancer and that inhibition of Akt may increase the efficacy of endocrine therapy. No significant financial relationships to disclose.

New targets for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists.

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biologic functions such as transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In breast cancer this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. There is evidence suggesting that Akt promotes breast cancer cell survival and resistance to chemotherapy, trastuzumab, and tamoxifen. Rapamycin is a specific mTOR antagonist that targets this pathway and blocks the downstream signaling elements, resulting in cell cycle arrest in the G1 phase. Targeting the Akt/PI3K pathway with mTOR antagonists may increase the therapeutic efficacy of breast cancer therapy.