Treatment Options For Breast Cancer Research Articles

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.

Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing. We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

EXTH-63. FOCUSED ULTRASOUND HYPERTHERMIA MEDIATED CONTROL OF THERMAL RESPONSIVE CAR T CELL ACTIVITY IN BREAST CANCER BRAIN METASTASIS

Abstract HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), observed in up to 50% of HER2-positive breast cancer patients, remains a clinical challenge. While Chimeric Antigen Receptor (CAR) T cell therapy is promising therapeutic strategy to address the unmet need in treating BCBM, improving its effectiveness and safety is critical for clinical translation. We hypothesized that spatially and temporally controlled activity of CAR-T cells with a thermal gene switch (TS) under MRI-guided focused ultrasound (MRgFUS) would potentiate anti-tumor responses in difficult-to-treat BCBM. To test our hypothesis, we developed a closed-loop controlled MR-thermometry (MRTI) based FUS system (MRgFUS) and αHER2 CAR-T cells engineered with TS expressing the reporter gene firefly luciferase (TS.Fluc) or bi-specific engager on NKG2D ligands (TS.BTE) upon MRgFUS-hyperthermia (41.5°C). In vivo quantification of TS activity from intratumorally delivered TS.Fluc αHER2 CAR-T cells in HER2+ BCBM mice model (HER2+ MDA-MB-468 in NSG mice with primary human CAR-T cells) followed by pulsed MRgFUS-hyperthermia resulted in a ~10-fold increase in luminescent activity compared to unheated mice. To assess longitudinal activation, we quantified TS activity with a second sonication 4 days post the initial FUS treatment. Prior to the second sonication, TS.Fluc expression had returned to baseline levels, while following it robust TS.Fluc expression was observed again, demonstrating that MRgFUS can activate engineered T cells with TS in brain tumors with high spatiotemporal control. Subsequently we investigated the therapeutic efficacy of intratumorally delivered TS.BTE αHER2 CAR T cells in mixed tumor model of heterogeneous HER2 MDA-MB-468 (75% HER2+) and observed significant tumor regression of HER2- tumor cells in the treated group compared to controls, demonstrating the potential of the proposed strategy to noninvasively drive the local production of key transgenes and potentiate anti-tumor responses in difficult-to-treat BCBM.

Novel Benzohydrazide Derivative as a Potential Anticarcinogenic Agent for Breast Cancer: Synthesis, Crystal Structure, In Vitro and In Silico Assessments

Polycyclic aromatic compounds (PACs) are a class of organic molecules known for their significant biological activity, including anticancer properties. These compounds often interact with biological macromolecules, making them crucial in the development of new therapeutic agents. In this study, we report a new benzohydrazide derivative, (E)-4-(hexyloxy)-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide (2), which incorporates a naphthalene ring, a typical PAC, as a core structural element. The structure of the compound was analyzed using FTIR, 1H NMR, 13C NMR and elemental analysis. Moreover, single crystal X-ray crystallography studies demonstrated that the compound adapted monoclinic crystal system with C 2/c space group. In the crystal structure, the intermolecular N–H···O hydrogen bonds link the molecules into infinite chains along the b-axis direction. The dominant interactions formed in the crystal packing were found to be hydrogen bonding and van der Waals interactions according to the Hirshfeld surface (HS) analysis. The evaluation of energy frameworks showed that stabilization of the compound was dominated by dispersion energy contribution. The anticancer activity of the compound was tested by employing several cellular assays. The compound showed strong anticancer effects, with IC50 values of 85 µM for MCF7 cells and 115 µM for MDA-MB-231 cells, indicating dose-dependent suppression of cell viability, migration, and colony formation. Computational analyses indicated favorable binding of compound 2 to ERRγ and predicted good oral availability of the generated compound. Pathway analysis using KEGG pathways identified significant enrichment in pathways related to cancer. These results highlight the compound's promise as a potential treatment option for breast cancer, prompting further exploration in future studies.

Impact of fetal umbilical cord blood CD34+ cells on breast cancer cell lines: a mechanism of fetal microchimerism?

Introduction Fetal microchimerism could be involved in the regulation of breast cancer oncogenesis. CD34+ cells could be of a particular interest as up to 12% of the CD34+ population in maternal blood are of fetal origin. The aim of this research was to analyze the impact of umbilical cord blood (UCB) CD34+ on MCF-7 and MDA-MB-231 breast cancer cell lines, in order to uncover novel biological mechanisms and suggest novel treatment options for breast cancer. Methods UCB CD34+ cells were obtained from healthy women at full-term delivery. Direct cultures were grown with MCF-7 and MDA-MB-231 cells. Proliferation, migration, invasion, and transcriptomic analysis of breast cancer cells were compared between cultures exposed and non-exposed to UCB CD34+ cells. Interactions between UCB CD34+ and breast cancer cells were analyzed under fluorescent microscopy. Functional analyses were generated with QIAGEN's Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Results Direct contact between UCB CD34+ and breast cancer cell lines induced a reduction in the proliferative capacities of MCF-7 and MDA-MB-231 and diminished the migration abilities of MDA-MB-231 cells. In 3D co-culture, UCB CD34+ cells were attracted by tumor spheroids and incorporated into tumor cells. These cell-to-cell interactions were responsible for transcriptome modifications coherent with observed functional modifications. Among the cytokines secreted by UCB CD34+, IFN was identified as a potential upstream regulator responsible for the molecular modifications observed in transcriptomic analysis of MCF-7 breast cancer cells exposed to UCB CD34+ cells, as was IL-17A in MDA-MB-231 cells. Conclusion Direct cell-to-cell contact induced functional modifications in breast cancer cells. Interactions between UCB CD34+ and breast cancer cells could induce cell fusion and signal transmission via cytokines. Further analysis of direct cell-to-cell interactions should be performed at a molecular level to further understand the potential role of fetal CD34+ cells in breast cancer.

Could macrocytosis predict survival In advanced breast cancer patients that were treated with CDK 4–6 inhibitors?

IntroductionCyclin Dependent Kinase (CDK) 4–6 inhibitors are the recommended first-line treatment option for hormone-positive metastatic breast cancer (MBC). They show their effects by causing cell cycle arrest in G1-S phase. Neutropenia is the most common haematological side effect. In the literature, data on the association between CDK 4–6 inhibitors and macrocytosis are limited. We aimed to investigate the effect of macrocytosis on survival. MethodsWe retrospectively analysed 133 patients with de novo hormone positive MBC using CDK 4–6 inhibitors in first line treatment. Mean Corpuscular Volume (MCV) > 100 was considered macrocytosis and patients were divided into two groups; MCV<100 and MCV >100. The association of macrocytosis with clinicopathological features, Progression Free Survival (PFS) and Overall Survival (OS) were evaluated. Results42 patients were receiving palbociclib and 81 patients were receiving ribociclib. Median OS was determined as 33 months and median PFS was determined as 22 months. Macrocytosis ever rate was 45.8 % during follow-up. Macrocytosis was observed in 4.2 % of the patients in the first month, 16.7 % in the third month, 41.6 % in the sixth month and 42.2 % in the twelfth month. ER receptor level, ki-67, macrocytosis at 6–12 months and macrocytosis-ever which were found to affect OS as a result of univariate Cox regression analysis, were evaluated with multivariate Cox regression models and it was observed that they had significant effect on PFS and OS. ConclusionMacrocytosis may be a useful biomarker for the prediction of PFS and OS in MBC patients receiving CDK 4–6 inhibitors.

Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases.

The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases. Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety. The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed. Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment.

Preparation and Formulation of a New Therapeutic Supplement by the Combination of Dendritic Cells and IPI-549 (Eganelisib) for the Treatment of Breast Cancer in BALB/c Mice

: Dendritic cell-based cancer immunotherapy is considered an innovative and promising approach aimed at enhancing the host's immune response to combat tumors. Additionally, IPI-549 has been identified as a first-line therapeutic option for breast cancer treatment. The objective of this research was to develop and formulate a novel therapeutic supplement by combining dendritic cells with IPI-549 (Eganelisib) for breast cancer treatment. The concurrent administration of dendritic cells and IPI-549 (DC-IPI) was utilized to treat mice and elicit immunological responses triggered by vaccination. Tumor regression and overall survival rates were evaluated across five distinct experimental groups. The administration of tumor cell lysate alongside DC-IPI resulted in a significant reduction in tumor growth and a two- to three-fold increase in the survival duration of treated mice. DC-IPI, whether decorated with mannan or not, elicited stronger responses in terms of delayed-type hypersensitivity, lymphocyte proliferation, and CD107a expression. Moreover, our findings demonstrated a reduction in IL-4 production in the supernatants of splenocyte cultures. A significant reduction in BRCA1 mRNA levels was also observed following treatment with DC-IPI. In conclusion, our results suggest that the DC-IPI antigen delivery system exhibited substantial anti-tumor efficacy in a breast cancer mouse model, representing a potential advancement in immunotherapy for human breast cancer.

Xanthine negatively regulates c-MYC through the PI3K/AKT signaling pathway and inhibits the proliferation, invasion, and migration of breast cancer cells.

Breast cancer is a prevalent and aggressive malignancy associated with elevated mortality rates worldwide. Dysregulation of the c-MYC oncogene and aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway are common features in breast cancer progression, rendering them attractive therapeutic targets. Here, we assessed the effects of the plant derivative, xanthine, on breast cancer cells and explored the molecular mechanisms underlying its activity. Breast cancer cell lines were treated with xanthine, followed by assessment of c-MYC expression levels. Cell proliferation, invasion, and migration were analyzed to assess the effects of xanthine treatment on breast cancer cell behavior. Xanthine treatment induced a decrease in c-MYC expression, resulting in significant inhibition of breast cancer cell proliferation, invasion, and migration. Mechanistic investigations revealed that these effects were mediated by suppression of the PI3K/AKT signaling pathway. Xanthine shows great potential for breast cancer treatment by targeting c-MYC via the PI3K/AKT signaling pathway. Our findings indicate that development of xanthine as a novel treatment option for breast cancer, which acts by influencing key oncogenic pathways involved in tumor progression, may be warranted.

Knowledge-map and research trends of circulating tumor cells in breast cancer: a scientometric analysis

Assessing circulating tumor cells (CTCs) in early-stage breast cancer patients can help identify relapse risk for timely interventions. Molecular analysis of CTCs can reveal vulnerabilities for personalized treatment options in metastatic breast cancer. This study aims to summarize CTCs in breast cancer research understanding and evaluate research trends. Extracted from the Web of Science Core Collection, publications on CTCs in breast cancer studies spanning from January 1, 2008, to December 21, 2023, were included. Co-authorships, references, and keywords were analyzed using Bibliometrix R packages and VOSviewer software. References and keywords burst detection were conducted with CiteSpace, and BICOMB was utilized to generate high-frequency keyword layouts. Biclustering analysis of the binary co-keyword matrix was performed using gCLUTO. 1747 articles focusing on CTCs in breast cancer were identified. The USA and the University of Texas MD Anderson Cancer Center demonstrated the highest productivity at the national and institutional levels, respectively. The journal “CANCERS” had the highest publication outputs on this subject. Pantel K emerged as the foremost author with the highest publication and co-citation counts. Analysis of co-keywords unveiled five prominent research areas concerning CTCs in breast cancer. The prognostic and predictive roles of CTCs in breast cancer have substantial implications for clinical practice. Nevertheless, precise assessment of CTCs, encompassing its quantities and attributes through advanced technologies, and its role in detecting minimal residual disease in breast cancer, continue to pose notable challenges. In conclusion, recent advancements and trends in CTCs research in breast cancer are examined through scientometric analysis in this study. The results provide valuable insights for the formulation of novel approaches in CTCs research, emphasizing the current research frontiers.

Study protocol: Optimising patient positioning for the planning of accelerated partial breast radiotherapy for the integrated magnetic resonance linear accelerator: OPRAH MRL

BackgroundAccelerated partial breast irradiation (APBI) is an accepted treatment option for early breast cancer. Treatment delivered on the Magnetic Resonance integrated Linear Accelerator (MRL) provides the added assurance of improved soft tissue visibility, important in the delivery of APBI. This technique can be delivered in both the supine and prone positions, however current literature suggests that prone treatment on the MRL is infeasible due to physical limitations with bore size. This study aims to investigate the feasibility of positioning patients on a custom designed prone breast board compared with supine positioning on a personalised vacuum bag. Geometric distortion, the relative position of Organs at Risk (OAR) to the tumour bed and breathing motion (intrafraction motion) will be compared between the supine and prone positions. The study will also investigate the positional impact on dosimetry, patient experience, and position preference.MethodsUp to 30 patients will be recruited over a 12-month period for participation in this Human Research Ethics Committee approved exploratory cohort study. Patients will be scanned on the magnetic resonance imaging (MRI) Simulator in both the supine and prone positions as per current standard of care for APBI simulation. Supine and prone positioning comparisons will all be assessed on de-identified MRI image pairs, acquired using appropriate software. Patient experience will be explored through completion of a short, anonymous electronic survey. Descriptive statistics will be used for reporting of results with categorical, parametric/non-parametric tests applied (data format dependent). Survey results will be interpreted by comparison of percentage frequencies across the Likert scales. Thematic content analysis will be used to interpret qualitative data from the open-ended survey questions.DiscussionThe results of this study will be used to assess the feasibility of treating patients with APBI in the prone position on a custom designed board on the MRL. It may also be used to assist with identification of patients who would benefit from this position over supine without the need to perform both scans. Patient experience and technical considerations will be utilised to develop a tool to assist in this process.Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN1262400067583. Registered 28th of May 2024. https://www.anzctr.org.au/ACTRN12624000679583.aspx

A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind.

Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an "evolutionary double-bind", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.

Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang inhibits the progression of triple negative breast cancer though the activation inhibition of NF-κB triggered by CAFs-derived IL6

Ethnopharmacological relevanceThe treatment options for triple-negative breast cancer (TNBC) are limited. Traditional Chinese Medicine (TCM) plays an important role in the treatment of TNBC. The herb pair Scutellaria barbata D.Don and Scleromitrion diffusum (Willd.) R.J.Wang (SH) is commonly used in clinical practice for its anti-tumor properties. It has been proven to have good therapeutic effects on tumor-related diseases, but the underlying molecular mechanisms are not yet fully explained. Aim of studyThrough bioinformatics, it was validated that IL6, primarily derived from cancer-associated fibroblasts (CAFs), is associated with poor prognosis. Additionally, cell and animal experiments confirmed that SH inhibits tumor proliferation, migration, and growth in an orthotopic tumor model by suppressing the IL6/NF-κB pathway. Materials and methodsGEO, TCGA and HPA databases were used to analyze the prognostic value of CAFs and IL6, then IL6 resource was detected. After the bioinformatics, the influence of CAFs and CAFs-derived IL6 on TNBC was verified by experiments both in vitro and in vivo. Cell clone formation assay, wound-Healing assay, and Transwell assay were used to detect the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vitro. TNBC model in mice was used to prove the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vivo. The biological pathway of NF-κB was explored by western blotting through detecting unique molecules. ResultsBioinformatics analysis revealed that higher proportion of CAFs and elevated level of IL6 were significantly associated with poor prognosis in TNBC. At the same time, IL6 was proved predominantly derived from CAFs. After the indication of bioinformatics, experiments in vitro demonstrated that both CAFs and IL6 could enhance the clone formation and migration ability of MDA-MD-231 cells (231), furthermore, the promotion of CAFs was related with the level of IL6. Based on these data, mechanism was detected that CAFs-derived IL6 enhancement was closely related to the activation of NF-κB signaling pathway, while the activation can be reduced by SH. In the end, the promotion of CAFs/CAFs-derived IL6/NF-κB and the efficacy of SH inhibition were both confirmed by experiments in vivo. ConclusionsBioinformatics data indicates that higher proportion of CAFs and higher level of CAFs-derived IL6 are significantly related to poorer survival of TNBC. CAFs and CAFs-derived IL6 were proved to promote the progression of TNBC both in vitro and in vivo, and the process of which was significantly related to the activation of NF-κB. SH inhibited the progress of TNBC, which was proved to be closely related to CAFs/CAFs-derived IL6/NF-κB.

The Antioxidant and HDAC-Inhibitor α-Lipoic Acid Is Synergistic with Exemestane in Estrogen Receptor-Positive Breast Cancer Cells.

Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1-3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC50 value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou-Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer.

Unique Profile of Post Mastectomy Pain Syndrome in Breast Cancer Patient in an Oncologic Center Surabaya, Indonesia

Background: Post Mastectomy Pain Syndrome (PMPS) is chronic neurophatic pain that is localized around the surgical site and can occur immediately or some time after surgery and lasts up to more than three months. Breast cancer is the most malignancy in women worldwide. Mastectomy is one of the treatment options for breast cancer that is often performed. Goal: This research aims to provide an overview of the profile of breast cancer patients who experience PMPS at the Oncology Clinic at RSUD dr. Soetomo Surabaya in Desember 2023. Method: This research uses a cross sectional to all breast cancer patients who experience PMPS. Samples were taken by consecutive sampling based on inclusion and exclusion criteria. We present our data descriptively in the tabulation of diagrams and tables. Results: Based on the quality of pain, most patients complained of radiating pain (52.7%), followed by stinging (33.33%), and dullness (14%). Pain was mainly felt at the surgical area (94%) with the remaining 6% feeling pain in ipsilateral arm. A total 108 samples (60%) answered that they felt pain continously, and most of samples (86.7%) had a history of taking anti-pain medication to reduce complaints. Only about 36% of the samples said that pain improved over time. Conclusion: At the Tertiary Oncologic Centre in Surabaya, most post-mastectomy pain syndrome patients were older, with luminal A type, and at higher TNM stages. The majority reported pain radiating from the surgery site, typically manifesting more than six months after the surgery.

Expanding the treatment options for HER2-low metastatic breast cancer: Experience with trastuzumab deruxtecan in aggressive luminal HER2-low breast cancer

Expanding the treatment options for HER2-low metastatic breast cancer: Experience with trastuzumab deruxtecan in aggressive luminal HER2-low breast cancer

Plasma Metabolome Signatures to Predict Responsiveness to Neoadjuvant Chemotherapy in Breast Cancer.

Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification.

GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer

Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6–30% of breast cancer patients achieved a pathological complete response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.

Tanshinone I improves TNBC chemosensitivity by suppressing late-phase autophagy through AKT/p38 MAPK signaling pathway

The inhibition of autophagy is a potential therapeutic strategy to improve the chemosensitivity of triple-negative breast cancer (TNBC). In this study, we demonstrated that a natural terpenoid tanshinone I (TAN) enhanced the effectiveness of paclitaxel (PTX), at least in part, through an autophagy-dependent mechanism against TNBC. In vitro validation demonstrated that the combined therapy resulted in a synergistic decrease in the growth of TNBC cells. The chemosensitizing impact of TAN might be attributed to its inhibition of PTX-induced autophagy in the late phase by obstructing the fusion of autophagosomes and lysosomes, rather than by inhibiting lysosomal function. The findings from KEGG pathway analysis and molecular docking suggested that TAN might impact breast cancer chemoresistance primarily through the PI3K-Akt and MAPK signaling pathways. The non-canonical AKT/p38 MAPK signaling was further validated as the primary mechanism responsible for the inhibition of autophagy by TAN. In vivo study showed that the combined administration of TAN and PTX demonstrated a more significant suppression of tumor growth and autophagic activity compared to PTX monotherapy in the MDA-MB-231 xenograft nude mouse model. The safety evaluation of TAN in a zebrafish model, along with in vitro and in vivo validation, provided experimental and pre-clinical data supporting its potential as a natural adjunctive therapy in TNBC. Overall, this study suggests that the combination of TAN with PTX could provide an effective treatment option for advanced breast cancer, and targeting the AKT/p38 MAPK/late-autophagy signaling axis may be a promising approach for developing therapeutic interventions against TNBC.

Nanosuspensions in Breast Cancer Therapy: A Comprehensive Overview

Nanosuspensions offer a promising avenue for enhancing breast cancer treatment through improved drug delivery, solubility, and targeting. These colloidal dispersions contain submicron drug particles, significantly increasing surface area and enhancing drug solubility and dissolution rates. This improvement can lead to increased drug bioavailability, enabling lower doses and reduced side effects. It is also possible to engineer nanosuspensions so that they are controlled-release drugs, providing sustained therapeutic levels at the tumor site. Nanosuspensions facilitate targeted drug delivery, which is one of their key advantages. In order to minimize systemic toxicity, nanosuspensions contain targeting ligands or antibodies that adhere to the surface of nanoparticles in order to deliver drugs specifically to breast cancer cells. The nanosuspension platform also allows a combination therapy approach to be used, allowing multiple drugs to be delivered simultaneously in order to achieve synergistic effects and combat drug resistance. Nanosuspension treatments can be beneficial both therapeutically and for imaging and diagnostic purposes. Using nanoparticles labeled with imaging agents, it is possible to visualize tumors and monitor treatment responses. Nanosuspensions may reduce side effects associated with traditional chemotherapy by improving drug targeting and reducing systemic exposure. A nanosuspension represents a promising treatment option for breast cancer. Nanosuspensions must be fully exploited for their full potential to improve outcomes and quality of life for patients.

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.

Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drug targets, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drug repurposing, but also to highlight shared etiology explaining repurposing. We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways, and similarly for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 76 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known risk factors. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.