Management Of Triple-negative Breast Cancer Research Articles

Androgen receptor: A new player in triple negative breast cancer management

Androgen receptor: A new player in triple negative breast cancer management

Circulating non‑coding RNA‑biomarker potential in neoadjuvant chemotherapy of triple negative breast cancer?

Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy-based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum- or urine-based analyses of non-coding RNA (ncRNA) expression may allow for fast, minimally-invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer-related ncRNAs [microRNA (miR)-7, -9, -15a, -17, -18a, -19b, -21, -30b, -222 and -320c, PIWI-interacting RNA-36743 and GlyCCC2] in triple positive BT-474 cells and three TNBC cell lines (BT-20, HS-578T and MDA-MB-231) treated with various chemotherapeutic agents using reverse transcription-quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy-driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two-sample t-tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT-474 cell line in intra- and extracellular compartments. Serum and urine-based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR-36743, miR-17, -19b and -30b expression levels and an NACT-driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy-based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.

Targeted Therapies for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as "one size fits all" approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

Know your enemy: Genetics, aging, exposomic and inflammation in the war against triple negative breast cancer.

Triple negative breast cancer (TNBC) is one of the most biologically aggressive and very often lethal breast disease. It is one of the most puzzling women malignancies, and it currently appears not to be a good candidate to a standardized, unanimously accepted and sufficiently active therapeutic strategy. Fast proliferating and poorly differentiated, it is histopathologically heterogeneous, and even more ambiguous at the molecular level, offering few recurrent actionable targets to the clinicians. It is a formidable and vicious enemy that requires a huge investigational effort to find its vital weak spots. Here, we provide a broad review of "old but gold" biological aspects that taken together may help in finding new TNBC management strategies. A better and updated knowledge of the origins, war-like tactics, refueling mechanisms and escape routes of TNBC, will help in moving the decisive steps towards its final defeat.

FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

Background: Triple negative breast cancers are aggressive, enriched with cancer stem cells, and lack effective targeted therapies with little side effects.Methods: We isolated cancer stem cells from two triple negative breast cancer cell lines via cell sorting following transcriptome sequencing, bioinformatics analysis, experimental and clinical validations, as well as functional investigations to explore genes capturing triple negative breast cancer features for improved diagnosis and therapeutics in clinics.Results: We found that FA2H is under-expressed in triple negative breast cancers both in vitro and in clinics, and FA2H suppresses cancer stemness via inhibiting the STAT3/IL6 axis and NFkB signaling.Conclusions: This study reports the tumor suppressive roles of FA2H on breast cancer cells through cancer stemness control. FA2H and other candidates unveiled in this study that capture the features of cancer stem cells may contribute as diagnostic marker and/or effective therapeutic targets for improved triple negative breast cancer management.

Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

BackgroundChemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported.MethodsCell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed.ResultsCisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo.ConclusionsMetformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Single peptides and combination modalities for triple negative breast cancer.

Unlike other types of breast cancers (BCs), no specific therapeutic targets have been established for triple negative breast cancer (TNBC). Therefore, chemotherapy and radiotherapy are the only available adjuvant therapeutic choices for TNBC. New emerging reports show that TNBC is associated with higher numbers of intratumoral tumor infiltrating lymphocytes. This is indicative of host anti-TNBC immune surveillance and suggesting that immunotherapy can be considered as a therapeutic approach for TNBC management. Recent progress in molecular mechanisms of tumor-immune system interaction and cancer vaccine development studies, fast discoveries and FDA approvals of immune checkpoint inhibitors, chimeric antigen receptor T-cells, and oncolytic virotherapy have significantly attracted attention and research directions toward the immunotherapeutic approach to TNBC. Here in this review different aspects of TNBC immunotherapies including the host immune system-tumor interactions, the tumor microenvironment, the relevant molecular targets for immunotherapy, and clinical trials in the field are discussed.

Utilizing the genomically adjusted radiation dose (GARD) to personalize adjuvant radiotherapy in triple negative breast cancer management.

BackgroundUtilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose.MethodsTN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy.FindingsIn cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1–7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1–29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy.InterpretationGARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.

Chromosomal radiosensitivity of triple negative breast cancer patients

Purpose: Based on clinical and molecular data, breast cancer is a heterogeneous disease. Breast cancers that have no expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are defined as triple negative breast cancers (TNBCs); luminal cancers have different expressions of ER, PR and/or HER2. TNBCs are frequently linked with advanced disease, poor prognosis and occurrence in young African women, and about 15% of the cases are associated with germline BRCA1/2 mutations. Since radiotherapy is utilized as a principle treatment in the management of TNBC, we aimed to investigate the chromosomal instability and radiosensitivity of lymphocytes in TNBC patients compared to luminal breast cancer patients and healthy controls using the micronucleus (MN) assay. The effect of mutations in breast cancer susceptibility genes on chromosomal radiosensitivity was also evaluated.Methods: Chromosomal radiosensitivity was evaluated in the G0 (83 patients and 90 controls) and S/G2 (34 patients and 17 controls) phase of the cell cycle by exposing blood samples from all patients and controls to 2 and 4 Gy ionizing radiation (IR).Results: In the G0 MN assay, the combined cohort of all breast cancer, TNBC and luminal patients’ exhibit significantly elevated spontaneous MN values compared to controls indicating chromosomal instability. Chromosomal radiosensitivity is also significantly elevated in the combined cohort of all breast cancer patients compared to controls. The TNBC patients, however, do not exhibit enhanced chromosomal radiosensitivity. Similarly, in the S/G2 phase, 76% of TNBC patients do not show enhanced chromosomal radiosensitivity compared to the controls. In both the G0 and S/G2 phase, luminal breast cancer patients demonstrate a shift toward chromosomal radiosensitivity compared to TNBC patients and controls.Conclusions: The observations of the MN assay suggest increased chromosomal instability and chromosomal radiosensitivity in South African breast cancer patients. However, in TNBC patients, the irradiated MN values are not elevated. Our results suggest that the healthy lymphocytes in TNBC patients could handle higher doses of IR.

Structure-based identification of novel sirtuin inhibitors against triple negative breast cancer: An in silico and in vitro study

Triple-negative breast cancer (TNBC) is an aggressive disease exemplified by a poor prognosis, greater degrees of relapse, the absence of hormonal receptors for coherent utilization of targeted therapy, poor response to currently available therapeutics and development of chemoresistance. Aberrant activity of sirtuins (SIRTs) has strong implications in the metastatic and oncogenic progression of TNBC. Synthetic SIRT inhibitors are effective, however, they have shown adverse side effects emphasizing the need for plant-derived inhibitors (PDIs). In the current study, we identified potential plant-derived sirtuin inhibitors using in silico approach i.e. molecular docking, ADMET and molecular dynamics simulations (MD). Docking studies revealed that Sulforaphane, Kaempferol and Apigenin exhibits the highest docking scores against SIRT1 & 5, 3 and 6 respectively. ADMET analysis of above hits demonstrated drug-like profile. MD of prioritized SIRTs-PDIs complexes displayed stability with insignificant deviations throughout the trajectory. Furthermore, we determined the effect of our prioritized molecules on cellular viability, global activity as well as protein expression of sirtuins and stemness of TNBC cells utilizing in vitro techniques. Our in vitro findings complements our in silico results. Collectively, these findings provide a better insight into the structural basis of sirtuin inhibition and can facilitate drug design process for TNBC management.

Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple‐negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.

Real-world data regarding the efficacy of neoadjuvant carboplatin-paclitaxel followed by dose-dense adriamycin-cyclophosphamide for triple-negative early breast cancer.

e12559 Background: Platinum based regimens in the neoadjuvant (NA) setting for triple negative breast cancer (TNBC) have resulted in a significant increase in the pathological response (pCR) rate but at the cost of worse hematological toxicities. Despite these data such NA regimens are not widely used as yet for TNBC. Currently, no real world evidence exist regarding the efficacy and toxicity of this treatment regimen. Methods: Patients treated with neoadjuvant carbo-pac-ddAC between December 2015 and May 2018 at Clatterbridge Cancer Centre NHS Foundation Trust were identified via pharmacy records. Clinical records were reviewed, and clinico-pathological information and toxicity data were recorded. Data lock was January 16, 2019. Results: 53 female patients were identified with a median age of 48 years (IQR: 40.0-55.5). At presentation: Median tumour size 29mm (IQR: 20.0-40.0), 45% (24/53) were LN +, 8% (4/53) were ER+. Of 30 patients tested for germ line susceptibility, 23% (7/30) were found to have a BRCA mutation (full details to be presented). Delivery of planned CT : 4% (2/53) discontinued early for progressive disease or patient choice; of the remaining patients there were a total of 36 deferrals and 8 dose reductions. Surgical details: Breast: 42% (22/53) mastectomy & 58% (31/53) WLE, Ax management: 37% (19/51) Ax clearance & 63% (32/51) sentinel node biopsy (2 patients underwent previous axillary treatment for prior BC). Of 24 patients LN+ at presentation 58% (14/24) underwent Ax clearance; of these 64% (9/14) had no Ax involvement. pCR rate (ypT0/is, N0) (cases with prior ipsilateral Ax surgery excluded) was 53% (27/51) & pCR breast alone: 60% (31/52). Radiotherapy: 90% (47/52) received radiotherapy post-surgery. Outcome: At a median follow up 42.4 wks (IQR: 34.2-54.4), 6% (3/52) patients had disease recurrence resulting in 2 deaths. Conclusions: These initial real world data confirm the efficacy of NA therapy with carbo-pac-ddAC, with pCR rates consistent with literature. These results support the use of platinum based chemotherapy in the NA management of TNBC. Updated outcomes will be presented based on pCR versus no pCR; and BRCA status.

Abstract QS12: Deferoxamine Diminishes Breast Cancer Proliferation and Enhances Irradiated Breast Reconstruction: An Antitumorigenic Mechanism Defined

PURPOSE: Radiation plays an essential role in the oncologic management of triple-negative breast cancer, but patients who undergo radiotherapy experience significantly more wound complications during the reconstructive process. Deferoxamine is an FDA-approved iron chelator with immense potential to up-regulate angiogenesis and improve reconstructive outcomes. More specifically, the ability of deferoxamine to mitigate the deleterious effects of radiation on skin and soft tissue has been shown to enhance expander-based irradiated breast reconstruction, increase fat graft retention, and facilitate irradiated transverse rectus abdominis myocutaneous flap survival. The purpose of this study is to determine the impact of deferoxamine on breast cancer cell proliferation in-vitro, in order to delineate oncologic safety concerns regarding the utilization of deferoxamine as a regenerative therapeutic. METHODS: Triple-negative breast cancer cells, which do not respond to hormone or HER2 blocking therapy, were utilized in this study as patients with triple-negative breast cancer commonly receive chemoradiation and are potential candidates to receive deferoxamine as a regenerative therapeutic during the reconstructive process. The effect of radiation and deferoxamine on two triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468) and one female fibroblast control cell line was determined via MTS (percent cell viability) analysis. Radiation (0, 5, 10 Gy) and deferoxamine (0, 25, 50, 75, 100 µM) were delivered individually and jointly, and all experiments were completed in triplicate. Intracellular iron concentration was determined via QuantiChromTMassay, NF-κB localization was determined via dual-luciferase reporter assay, and apoptosis/necrosis was determined via annexin V assay in order to delineate mechanism. ANOVA statistical analysis was performed using SPSS (p<0.05). RESULTS: Both triple-negative breast cancer cell lines exemplified a significant decrease in percent viability following exposure to 10 Gy of radiation (p<0.05) or 25 µM deferoxamine (p<0.01). The administration of radiation (10 Gy) in combination with deferoxamine (100 µM) to triple-negative breast cancer cells resulted in significant reduction of percent cell viability compared to the administration of radiation alone (p<0.05). Fibroblasts exemplified no significant response to individually administered radiation (10 Gy) or deferoxamine (100 µM), while joint administration of radiation (10Gy) and deferoxamine (25µM) resulted in a significant increase in percent cell viability compared to the administration of radiation alone (p<0.05). In both triple-negative breast cancer cell lines, individual administration of deferoxamine (100µM) significantly decreased intracellular iron concentration (p<0.05). Joint administration of radiation and deferoxamine suppressed NF-κB activation indicating a cessation of cell proliferation and amplified cellular apoptosis (p<0.01) with no notable increase in cellular necrosis. CONCLUSIONS: The administration of radiation and/or deferoxamine imparts a significant decrease in triple-negative breast cancer cell proliferation, without significantly impeding growth of female fibroblast control cells in-vitro. Mechanistically, deferoxamine administration decreases intracellular iron concentration leading to decreased cell proliferation and increased cell death via apoptosis. Taken together, these findings suggest deferoxamine may be safely utilized to facilitate improved reconstructive outcomes among triple-negative breast cancer survivors and warrant future investigations to quantify in-vivoeffects.

Prolactin modulates TNBC aggressive phenotype limiting tumorigenesis.

Triple-negative breast cancer (TNBC) accounts for ~20% of all breast cancer cases. The management of TNBC represents a challenge due to its aggressive phenotype, heterogeneity and lack of targeted therapy. Loss of cell differentiation and enrichment with breast cancer stem-like cells (BCSC) are features of TNBC contributing to its aggressive nature. Here, we found that treatment of TNBC cells with PRL significantly depletes the highly tumorigenic BCSC subpopulations CD44+/CD24- and ALDH+ and differentiates them to the least tumorigenic CD44-/CD24- and ALDH- phenotype with limited tumorsphere formation and self-renewal capacities. Importantly, we found PRL to induce a heterochromatin phenotype marked by histone H3 lysine 9 trimethylation (H3K9me3) and accompanied by ultra-structural cellular architecture associated with differentiation and senescence rendering the cells refractory to growth signals. Crucially, we found PRL to mediate these effects in vivo in a pre-clinical animal xenograft of TNBC controlling tumor growth. These results reveal that the lactogenic hormone PRL may exert its anti-tumorigenic effects on TNBC through cellular reprogramming indicative of differentiation resulting in the depletion of BCSCs and restricting tumorigenesis.

Raloxifene nano-micelles effect on triple-negative breast cancer is mediated through estrogen receptor-β and epidermal growth factor receptor

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that differs in progression, recurrence, and prognosis from other forms of breast cancer. The heterogeneity of TNBC has remained a challenge as no targeted therapy is currently available. Previously, we and others have demonstrated that raloxifene, a selective oestrogen receptor modulator, was also acting independently of the oestrogen receptor-α. However, raloxifene is characterised by a low bioavailability in vivo. Thus, we encapsulated raloxifene into a styrene-maleic acid (SMA) micelle to improve its pharmacokinetics. The micellar raloxifene had higher cytotoxicity when compared to the free formulation, promoted a higher cellular uptake and affected critical signalling pathways. Furthermore, SMA-raloxifene reduced TNBC tumour growth more efficiently than free raloxifene. Finally, we showed that this effect was partially mediated through oestrogen receptor-β. In conclusion, we have provided new insight into the role of raloxifene nanoformulation in improving the management of TNBC.

Nottingham Prognostic Index is an Applicable Prognostic Tool in Non-Metastatic Triple-Negative Breast Cancer

Introduction:Triple-negative breast cancer (TNBC) is characterized by a poor prognosis due to high mortality and early relapse, requiring the study of its prognostic factors. Tumor size, histological grade and lymph node status represent important parameters that are widely studied in breast cancer, and are retained as prognostic factors by several international guidelines. The Nottingham team combined these parameters into a prognostic score called the Nottingham prognostic index (NPI). In this study, we investigated the influence of NPI on outcomes in non metastatic TNBC.Methodology:This retrospective cohort study included all female patients with non metastatic TNBC who received treatment at the Regional Oncology Center Hassan II Oujda - Morocco, between January 2009 and December 2011. The prognostic impact of the NPI on the survival curves at 5 years was studied using multivariate Cox proportional hazards models.Results:The analysis of the data involved 98 patients, 39 patients (39.8%) were classed in the poor prognosis group with a NPI > 5.4. The Overall survival (OS) and Disease free survival (DFS) rates at 5 years, in this group, were 70 and 55.6 % respectively. After adjusting for clinic-pathological variables, a NPI > 5.4 was associated with mortality (HR: 2.598, 95% CI: 1.423 – 4.744, p = 0.002) and disease progression (HR: 2.512, CI to 95%: 1.496 – 4.219, p <0.001) in patients with non-metastatic TNBC.Conclusion:This retrospective cohort analysis showed that NPI was an independent prognostic factor for OS and DFS at 5 years in women with non metastatic TNBC. Once validated, the impact of this score on survival outcomes could be considered in the clinical management of TNBC.

Real-life clinical pattern, management, and survival in Thai patients with early-stage or metastatic triple-negative breast cancer.

ObjectivesTo characterize the clinical pattern and evaluate real-life practices in the management of patients with triple-negative breast cancer (TNBC) in Thailand.MethodsIn this multicenter, prospective, observational cohort, females (aged ≥18 years) with histologically and immunohistochemically confirmed TNBC were enrolled. Patient data was collected at four study visits–an inclusion visit (for enrollment), and three subsequent follow-up visits at 12±1, 24±1, and 36±1 months after completion of first day of any planned chemotherapy.ResultsOf the 293 enrolled patients, 262 (89.4%) had early-stage TNBC (Stage I: 46 patients, Stage II: 151 patients, and Stage III: 65 patients) and 31 (10.6%) had metastatic TNBC (mTNBC). Chemotherapy was prescribed to 95.4% of the early-stage patients and to 100.0% of the mTNBC patients; most commonly as anthracycline-based in combination with cyclophosphamide and other agents. Patients’ performance status and consensus guidelines were the major factors affecting choice of treatment. In early-stage patients, median disease-free survival (DFS) and overall survival (OS) had not been reached for Stage I and II patients, and were calculated to be 37.0 months and 40.0 months, respectively, in Stage III patients. In mTNBC patients, progression-free survival (PFS) and OS were found to be 10.0 months and 14.0 months, respectively. In Stage III patients, anthracycline-based regimens were found to be associated with increase in DFS (p = 0.0181) and OS (p = 0.0027) compared to non-anthracycline-based regimens. In mTNBC patients, non-taxane-based regimens were associated with an increase in PFS (p = 0.0025). The 3-year survival rates in early-stage and mTNBC patients were 85.0% and 21.0%, respectively.ConclusionClinical management of TNBC in Thailand follows the general guidelines for treatment of TNBC. However, prognosis and survival outcomes are suboptimal, especially in progressive disease. This study is the first assessment in the existing practices in which the results could pave to way to improve the treatment outcome of TNBC in Thailand.

Nano-delivery of RAD6/Translesion Synthesis Inhibitor SMI#9 for Triple-negative Breast Cancer Therapy.

The triple-negative breast cancer (TNBC) subtype, regardless of their BRCA1 status, has the poorest outcome compared with other breast cancer subtypes, and currently there are no approved targeted therapies for TNBC. We have previously demonstrated the importance of RAD6-mediated translesion synthesis pathway in TNBC development/progression and chemoresistance, and the potential therapeutic benefit of targeting RAD6 with a RAD6-selective small-molecule inhibitor, SMI#9. To overcome SMI#9 solubility limitations, we recently developed a gold nanoparticle (GNP)-based platform for conjugation and intracellular release of SMI#9, and demonstrated its in vitro cytotoxic activity toward TNBC cells. Here, we characterized the in vivo pharmacokinetic and therapeutic properties of PEGylated GNP-conjugated SMI#9 in BRCA1 wild-type and BRCA1-mutant TNBC xenograft models, and investigated the impact of RAD6 inhibition on TNBC metabolism by 1H-NMR spectroscopy. GNP conjugation allowed the released SMI#9 to achieve higher systemic exposure and longer retention as compared with the unconjugated drug. Systemically administered SMI#9-GNP inhibited the TNBC growth as effectively as intratumorally injected unconjugated SMI#9. Inductively coupled mass spectrometry analysis showed highest GNP concentrations in tumors and liver of SMI#9-GNP and blank-GNP-treated mice; however, tumor growth inhibition occurred only in the SMI#9-GNP-treated group. SMI#9-GNP was tolerated without overt signs of toxicity. SMI#9-induced sensitization was associated with perturbation of a common set of glycolytic pathways in BRCA1 wild-type and BRCA1-mutant TNBC cells. These data reveal novel SMI#9 sensitive markers of metabolic vulnerability for TNBC management and suggest that nanotherapy-mediated RAD6 inhibition offers a promising strategy for TNBC treatment.

TNBC Challenge: Oligonucleotide Aptamers for New Imaging and Therapy Modalities.

Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) technique holds great promise to the search for novel targetable biomarkers, and aptamer-based molecular approaches have the potential to overcome obstacles of current imaging and therapy modalities. In this review, we highlight recent advances in oligonucleotide aptamers used as imaging and/or therapeutic agents in TNBC, discussing the potential options to discover, image and hit new actionable targets in TNBC.

Curcumin⁻Copper Complex Nanoparticles for the Management of Triple-Negative Breast Cancer.

Breast cancer is the most common cancer diagnosed among females worldwide. Although breast cancer survival has largely improved in the past 30 years, it remains highly heterogeneous in its response to treatment. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor-2 (Her2). While TNBC may initially be responsive to chemotherapy, recurrence and subsequent high mortality rates are frequently reported. Studies have shown curcumin and its derivatives to be effective against TNBC cell lines in vitro. To improve its anti-cancer effects, we have synthesized Fe3+–curcumin (Fe–Cur3) and Cu2+–curcumin (CD) complexes and investigated them experimentally. Further, CD was encapsulated into a poly(styrene)-co-maleic acid (SMA) micelle to enhance its stability. We assessed the cytotoxicity of these formulations both in vitro and in vivo. SMA–CD demonstrated dose-dependent cytotoxicity and abolished TNBC tumor growth in vivo. The encapsulation of the curcumin–copper complex improved its anti-cancer activity without overt adverse effects in a murine model of TNBC. These results provide evidence and insights into the value of nanoformulations in enhancing drug-delivery and increasing the potential therapeutic efficacy of curcumin derivatives.