ArticleLiterature Review

Triple-Negative Breast Cancer: An Unmet Medical Need

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Abstract

Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease. Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.

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... Treatment of choice for TNBC molecular subtype includes anthracycline/taxol or cisplatin based chemotherapy, or survival pathway based PARP, AKT and m-TOR selective small molecule inhibitor mediated targeted therapy. 4,5,20,21 These treatment options are associated with systemic toxicity, acquired tumor resistance and emergence of drug resistant cancer stem cells, leading to therapyresistant disease progression. 6,[20][21][22] Published studies on cellular models for Luminal A and TNBC molecular subtypes have provided evidence that several Chinese nutritional herbs with distinct mechanisms of action display growth inhibitory effects. ...
... 4,5,20,21 These treatment options are associated with systemic toxicity, acquired tumor resistance and emergence of drug resistant cancer stem cells, leading to therapyresistant disease progression. 6,[20][21][22] Published studies on cellular models for Luminal A and TNBC molecular subtypes have provided evidence that several Chinese nutritional herbs with distinct mechanisms of action display growth inhibitory effects. [11][12][13][14][15][16][17] The present study utilizes the MDA-MB-231 model for TNBC to examine the growth inhibitory effects of the Chinese nutritional herb DA, and to identify relevant molecular mechanisms for its efficacy. ...
... 25 These pathways are susceptible to small molecule inhibitors and exhibit demonstrable clinical efficacy. 4,5,20,21 Specifically, down-stream effectors BRAF, MEK and ERK represent more effective targets for selective small molecule inhibitors of oncogenic functions of RAS, since the gain of function oncogenic RAS remains essentially an intractable pharmacologic target. However, recent evidence on the efficacy of mutant RAS selective small molecule inhibitor suggests that downregulation of RAS-mediated MAPK signaling is due to the persistence of GDP bound Ras-p21. ...
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Background: Triple negative breast cancer (TNBC) lacks expressions of estrogen receptor-α (ER-α), progesterone receptor (PR) and amplified human epidermal growth factor receptor-2 (HER-2). Current treatment for TNBC includes anthracyclin, taxol and cisplatin-based conventional chemotherapy and survival pathway PARP, PI3K, AKT and mTOR selective targeted therapy. These treatments exhibit dose-limiting systemic toxicity and presence of drug resistant cancer stem cells, which highlight the need for identification of efficacious testable alternatives that are not toxic to non-tumorigenic cells. Dipsacus asperoides (DA) is a Chinese nutritional herb and its root represents a common ingredient in Chinese herbal formulations used in women for estrogen related health issues, osteoporosis and breast diseases. This study aims to investigate the growth inhibitory effects of DA, and to detect mechanisms for its efficacy. Methods: Human mammary carcinoma derived triple negative MDA-MB-231 cell line represented the TNBC model. Non-fractionated aqueous extract from DA represented the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation and cell cycle progression quantified growth inhibition. Western blot-based analysis for inhibition of RAS, PI3K and AKT and RB signaling identified mechanistic leads. Results: Treatment with DA induced a dose dependent cytostatic growth arrest (IC50:15 µg/ml; IC90: 30 µg/ml), reduced AI growth and inhibited cell cycle progression via G2/M arrest. DA affected the RAS, PI3K, AKT and RB signaling pathways, and functioned as a natural inhibitor of cyclin dependent kinase 4/6. Cellular apoptosis paralleled increase in pro-apoptotic Caspase 3/7 activity. Conclusion: These results demonstrate that DA inhibited growth, affected cell cycle progression, induced apoptosis and inhibited cancer cell survival pathways. This study validates a mechanism-based approach to identifying testable substitutes for secondary prevention/therapy of TNBC.
... Currently, surgery, radiotherapy and chemotherapy are the three main therapeutic tools. These treatments contribute to the recovery of many patients, but they are also associated with risks of injury or toxicity to normal tissues [4]. Despite constant improvements in cancer treatment, current therapeutics are not always effective in preventing the progression of the disease and the high mortality rate among cancer patients, as well as severe side effects during anti-neoplastic treatment, thus reinforcing the importance of developing more effective and safer therapies [4]. ...
... These treatments contribute to the recovery of many patients, but they are also associated with risks of injury or toxicity to normal tissues [4]. Despite constant improvements in cancer treatment, current therapeutics are not always effective in preventing the progression of the disease and the high mortality rate among cancer patients, as well as severe side effects during anti-neoplastic treatment, thus reinforcing the importance of developing more effective and safer therapies [4]. ...
Article
Cancer immunotherapy is the most promising trend in oncology, focusing on helping or activating the patient's immune system to identify and fight against cancer. In the last decade, interest in metabolic reprogramming of tumor-associated macrophages from M2-like phenotype (promoting tumor progression) to M1-like phenotypes (suppressing tumor growth) as a therapeutic strategy against cancer has increased considerably. Iron metabolism has been standing out as a target for the reprogramming of tumor-associated macrophages to M1-like phenotype with therapeutic purposes against cancer. Due to the importance of the iron levels in macrophage polarization states, iron oxide nanoparticles can be used to change the activation state of tumor-associated macrophages for a tumor suppressor phenotype and as an anti-tumor strategy.
... Based on specific biomarkers, BC is further categorized into subtypes, such as luminal A, B, and basal-like. TNBC is the basal-like and most severe form (see Figure 1) [39]. ...
... Based on specific biomarkers, BC is further categorized into subtypes, such as luminal A, B, and basal-like. TNBC is the basal-like and most severe form (see Figure 1) [39]. The initiation and progression of BC by obese breast adipose-derived factors. ...
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Citation: Naeem, M.; Iqbal, M.O.; Khan, H.; Ahmed, M.M.; Farooq, M.; Aadil, M.M.; Jamaludin, M.I.; Hazafa, A.; Tsai, W.-C. A
... Based on specific biomarkers, BC is further categorized into subtypes, such as luminal A, B, and basal-like. TNBC is the basal-like and most severe form (see Figure 1) [39]. ...
... Based on specific biomarkers, BC is further categorized into subtypes, such as luminal A, B, and basal-like. TNBC is the basal-like and most severe form (see Figure 1) [39]. The initiation and progression of BC by obese breast adipose-derived factors. ...
Article
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Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radio-therapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current chal-lenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their ef-ficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.
... The extreme heterogeneity of TNBC has led to difficulties in finding suitable molecular targets and has been reflected in the limited benefit from targeted therapies observed in clinical trials for unselected TNBC patients 4 . Therefore, most TNBC patients are still treated with chemotherapy, despite the fact that it is effective in a proportion of cases and only slightly improves the outcome 5 . ...
... • At least 1 genomic region with amplification/deletion > 12.5 Mb • Sum of amplification/deletion of different genomic regions > 37. 5 Informed consent statement. Informed consent was obtained from all subjects involved in the study. ...
Article
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Triple negative breast cancer (TNBC) is characterized by clinical aggressiveness, lack of recognized target therapy, and a dismal patient prognosis. Several studies addressed genomic changes occurring during neoadjuvant chemotherapy (NAC) focusing on somatic variants, but without including copy number alterations (CNAs). We analyzed CNA profiles of 31 TNBC primary tumor samples before and after NAC and of 35 single circulating tumor cells (CTCs) collected prior, during and after treatment by using next-generation sequencing targeted profile and low-pass whole genome sequencing, respectively. In pre-treatment tissue samples, the most common gains occurred on chromosomes 1, 2 and 8, and SOX11 and MYC resulted the most altered genes. Notably, amplification of MSH2 ( 4/4 versus 0/12, p < 0.01) and PRDM1 and deletion of PAX3 (4/4 versus 1/12, p < 0.01) significantly characterized primary tumors of patients with pathological complete response. All patients with paired pre- and post-NAC samples reported a change in post-treatment CNAs compared to baseline, despite they showed at least one common alteration. CNAs detected after treatment involved genes within druggable pathways such as EGFR, cell cycle process and Ras signaling. In two patients, CTCs shared more alterations with residual rather than primary tumor involving genes such as MYC, BCL6, SOX2, FGFR4 . The phylogenetic analysis of CTCs within a single patient revealed NAC impact on tumor evolution, suggesting a selection of driver events under treatment pressure. In conclusion, our data showed how chemoresistance might arise early from treatment-induced selection of clones already present in the primary tumor, and that the characterization of CNAs on single CTCs informs on cancer evolution and potential druggable targets.
... Triple-negative breast cancer (TNBC) is associated with a higher metastatic potential and shorter median time to relapse and death than other breast cancer subtypes (Hudis and Gianni, 2011). First, we examined whether the dosages used in this study influence cell viability in all cell lines. ...
Article
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Background: Metastasis represents an advanced stage of cancers, and matrix metalloproteinases are critical regulators. Calcium signal is crucial for appropriate cell behaviors. The efficacy and effects of calcium channel blockers in treating cancers are individually differ from each other. Here, we attempt to investigate the effects of nicardipine, a FDA-approved calcium channel blocker, in advanced breast cancers. Methods: We analyzed the influence of nicardipine on the colony-forming ability of triple negative breast cancer cell lines. Using cell culture inserts, cell migration was also examined. The expression of regulatory proteins was evaluated by real-time PCR, Western blot, and ELISA. Results: We have confirmed that nicardipine inhibits the breast cancer cells migration and colony formation. In addition, we also revealed that nicardipine increases the Nrf2 and HO-1 expression. The inhibition of HO-1 abrogates nicardipine-reduced matrix metalloproteinase-9 expression. Moreover, the end products of HO-1, namely, CO, Fe2+, and biliverdin (will converted to bilirubin), also decreases the expression of matrix metalloproteinase-9. Conclusion: These findings suggest that nicardipine-mediated matrix metalloproteinase-9 reduction is regulated by Nrf2/HO-1 axis and its catalytic end products. Therefore, nicardipine may be a potential candidate for repurposing against advanced breast cancers.
... They synthesized and summarized the existing conclusions about androgen receptors along with breast cancer, showing basic knowledge of this field. Four of them are reviews predominantly on triple-negative breast cancer (16,31,39,40). It is probably due to the Luminal androgen receptor (LAR) subtype of triple-negative breast cancers (TNBCs), which is abundant in AR expression. ...
Article
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Recently, the androgen receptor has been found as a potential prognostic index and therapeutic target for breast cancer. To reveal the current research status and hotspots in this area, we analyzed the characteristics of related publications from 2011 to 2020. All related publications from 2011 to 2020 were retrieved from the Web of Science. Biblioshiny, VOSviewer, and CiteSpace V were applied to obtain the information on annual publications and citations, the highest yielding countries and authors, influential journals and articles, as well as hot keywords. In total, 2,118 documents, including 1,584 original articles and 534 reviews, were retrieved. Annual publication output was rich from 2014 to 2018, reaching the top in 2017. A systematic review written by Lehman et al. in 2011 was the most-cited document and reference. The United States was the leading country with the maximum number of publications, citations, and link strengths with other countries. The journal publishing the most was Oncotarget. Lehmann was the author who had the highest link strengths with other authors. The most highlighted keywords were “androgen receptor” (n = 1,209), “breast cancer” (n = 690), “expression” (n = 545), “breast cancer” (n = 410), “prostate cancer” (n = 290), and so on, revealing the trend from molecular mechanism level to therapeutic use level. The androgen receptor plays a significant role in the development of breast cancers, whereas its therapeutic value seems to be controversial and needs further study. With the help of a scientometric analysis in this field, researchers can clarify the current research status and hotspots worth fully exploring.
... The recurrence and mortality rates associated with TNBC are high [5]. Due to the lack of these three receptors, endocrine therapy and targeted therapy are not effective against TNBC [6]. There is often a poor prognosis and drug resistance with chemotherapy [7]. ...
Article
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MicroRNAs (miRNAs), as key negative regulators of gene expression, are closely related to tumor occurrence and progression. miR-194-5p (miR-194-1) has been shown to play a regulatory role in various cancers however, its biological function and mechanism of action in breast cancer have not yet been well explored. In this study, we use the UALCAN and LinkedOmics databases to analyze transcription expression in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA). The epithelial-mesenchymal transition status of breast cancer cells was evaluated by wound-healing assay, trans-well assays, and gelatin zymography, while protein expression was assessed by Western blotting. miR-194-5p expression was found to be up-regulated in breast cancer clinical specimens but down-regulated in the triple-negative breast cancer (TNBC) cell line MDA-MB-231 and breast cancer clinical specimens in The Cancer Genome Atlas (TCGA). miR-194-5p significantly inhibited the expression of the epithelial marker ZO-1 and increased the expression of mesenchymal markers, including ZEB-1 and vimentin, in MDA-MB-231 cells. miR-194-5p significantly reduced the gelatin-degrading activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 in zymography assays. In MDA-MB-231 cells and TCGA patient samples, ZEB-1 expression was significantly inversely correlated with miR-194-5p expression. High levels of miR-194-5p were associated with good overall survival. miR-194-5p regulates epithelial–mesenchymal transition (EMT) in TNBC. Our findings suggest that miR-194-5p functions as a tumor biomarker in breast cancer, providing new insights for the study of breast cancer development and metastasis.
... Systemic toxicity and acquired tumor resistance represent commonly encountered limitations in chemotherapy and molecularly targeted therapy. These limitations suggest a lack of effective conventional therapeutic options for TNBC [49], and thereby emphasize the significance of identification of naturally-occurring nontoxic testable alternatives for secondary prevention/therapy of TNBC. In this context it is notable that sulforaphane, a bioactive agent present in broccoli and isothiocyanate present in cruciferous vegetables have documented inhibitory efficacy against breast cancer stem-like cells in vitro and in vivo [24,50]. ...
Article
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Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor-α progesterone receptor and human epidermal growth factor receptor-2. Treatment for this breast cancer subtype is restricted to multidrug chemotherapy and survival pathway-based molecularly targeted therapy. The long-term treatment options are associated with systemic toxicity, spontaneous and/or acquired tumor resistance and the emergence a of drug-resistant stem cell population. These limitations lead to advanced stage metastatic cancer. Current emphasis is on research directions that identify efficacious, naturally occurring agents representing an unmet need for testable therapeutic alternatives for therapy resistant breast cancer. Chinese herbs are widely used in traditional Chinese medicine in women for estrogen related health issues and also for integrative support for cancer treatment. This review discusses published evidence on a TNBC model for growth inhibitory effects of several mechanistically distinct nontoxic Chinese herbs, most of them nutritional in nature, and identifies susceptible pathways and potential molecular targets for their efficacy. Documented anti-proliferative and pro-apoptotic effects of these herbs are associated with downregulation of RB, RAS, PI3K, and AKT signaling, modulation of Bcl-2/BAX protein expressions and increased caspase activity. This review provides a proof of concept for Chinese herbs as testable alternatives for prevention/therapy of TNBC.
... Once diagnosed the metastatic disease, a rapid progression of the disease has been observed, most of the deaths occurring in the first 5 years after metastasis onset. (8,9) With regard to the treatment possibilities of TNBC, as antihormons and transtuzumab cannot be used, the only possible options remain surgery and chemotherapy given either individually or in combination. In this review, our purpose is to present the current therapeutic possibilities for women diagnosed with TNBC. ...
Article
At present, breast cancer (BC) has the highest incidence among the most common forms of cancer in women, almost one million women being diagnosed annually worldwide. However, in recent years BC has registered a low mortality rate mainly in developed, high-income countries. The triple negative breast cancer (TNBC) is a subtype of BC which is characterized by the absence of protein expression of the two hormone receptors-estrogen (ER) and progesterone (PgR) after immunohistochemistry (IHC) analysis and the lack of overexpression of the human epidermal growth factor receptor 2 (HER2) after IHC or in situ fluorescence hybridization technique. More than 170,000 of women are currently diagnosed with TNBC (ER–/PR–/HER2) representing 12-20% of all BC. TNBCs are recognized to have a poor prognosis which translates into a relative low disease-free survival rate for women who receive either neoadjuvant or adjuvant chemotherapy as well as a low progression-free survival rate for women who develop distant metastases. Furthermore, biologically, they are much more aggressive than the other types of BC and, owing to their triple “negativity”, a targeted therapy with anti-hormon agents or transtuzumab (anti HER2) cannot be utilized. The aim of this paper is to make a review of the current scientific evidence with regard to the new chemotherapeutic agents used in the neoadjuvant setting as well as the role of surgical treatment in women diagnosed with TNBC.
... * Despite advances in diagnosis and treatment in the last several decades, breast cancer remains responsible for more than 5000 deaths per year in the U.K. [1]. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, with poor prognosis and few treatment options [2]. The triple-negative breast cancer subtype has this name because it lacks receptors for the hormones estrogen and progesterone, as well as the growth-factor HER2. ...
Article
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Single-cell analysis has revolutionised genomic science in recent years. However, due to cost and other practical considerations, single-cell analyses are impossible for studies based on medium or large patient cohorts. For example, a single-cell analysis usually costs thousands of euros for one tissue sample from one volunteer, meaning that typical studies using single-cell analyses are based on very few individuals. While single-cell genomic data can be used to examine the phenotype of individual cells, cell-type deconvolution methods are required to track the quantities of these cells in bulk-tissue genomic data. Hormone receptor negative breast cancers are highly aggressive, and are thought to originate from a subtype of epithelial cells called the luminal progenitor. In this paper, we show how to quantify the number of luminal progenitor cells as well as other epithelial subtypes in breast tissue samples using DNA and RNA based measurements. We find elevated levels of cells which resemble these hormone receptor negative luminal progenitor cells in breast tumour biopsies of hormone receptor negative cancers, as well as in healthy breast tissue samples from BRCA1 (FANCS) mutation carriers. We also find that breast tumours from carriers of heterozygous mutations in non-BRCA Fanconi Anaemia pathway genes are much more likely to be hormone receptor negative. These findings have implications for understanding hormone receptor negative breast cancers, and for breast cancer screening in carriers of heterozygous mutations of Fanconi Anaemia pathway genes.
... High-risk early-stage breast cancer is frequently associated with a high recurrence rate (2). Neoadjuvant chemotherapy (NACT) is the gold standard treatment in this setting (3)(4)(5). ...
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The addition of platinum compounds to standard neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) is highly controversial. Platinum agents, such as cisplatin and carboplatin, are DNA-damaging agents which exhibit activity in breast cancer, particularly in the TNBC subgroup. In order to assess the efficacy of each most representative platinum agent (cisplatin and carboplatin) in patients with TNBC treated with NACT, the present study performed a systematic review and meta-analysis of all available published studies on TNBC. A search of PubMed was performed to identify studies that investigated platinum-based NACT in patients with TNBC. The primary endpoints were the pooled rate of the pathological complete response (pCR) between cisplatin vs. carboplatin-based NACT. A total of 24 studies were selected (17 studies for carboplatin and 6 studies for cisplatin and 1 study with both carboplatin and cisplatin, with 20 prospective studies) for the analysis of 1,711 patients with TNBC. Overall, the pooled rate of pCR in patients treated with platinum-based NACT was 48%. No significant differences were observed between the rates of pCR obtained under carboplatin vs cisplatin treatment. The carboplatin pCR rate was 0.470 [95% confidence interval (CI), 0.401-0.539], while the cisplatin pCR rate was 0.473 (95% CI, 0.379-0.568). The comparison between these two categories revealed no significant differences (P=0.959). In the whole, the present study demonstrates that neoadjuvant platinum-based chemotherapy improves the pCR rate in patients with TNBC, regardless of the platinum agent used. Carboplatin may thus represent a viable option due to its more favorable toxicity profile.
... Triple-negative breast cancer (TNBC) accounts for 12-20% of all breast cancer subtypes [3]. Compared to other breast cancer subtypes, TNBC has the most aggressive behavior with high recurrence rate and worst outcome [4]. This has been mainly attributed to limited therapeutic options due to lack of biomarkers or valid treatment targets. ...
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Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1KD) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1KD. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1KD, fascin-positive (FSCN1CON) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1high (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1CON vs. FSCN1KD) correlates with worst survival outcome. Taken together, these data confirmed fascin’s role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts.
... TNBC accounts for about 15%-20% of all breast cancers (6). Due to the lack of hormone receptor and HER2 expression, chemotherapy has been the mainstay treatments for TNBC for many years (7). However, suboptimal survival and tolerance of chemotherapy impels the development of novel strategies for treating this difficult-to-treat disease (8). ...
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Breast cancer is a major killer of women’s health worldwide. While breast cancer is thought to have lower immunogenicity compared with other solid tumors, combination therapy is able to improve the immunogenicity of the tumor and sensitize breast cancer cells to immunotherapy. Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been largely explored in the field of breast cancer, including both early and advanced disease. Immunotherapy for triple-negative breast cancer (TNBC) has been the most studied, and the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel has been used in the first-line treatment of TNBC. Immunotherapeutic data for human epidermal growth factor receptor-positive and hormone receptor-positive breast cancer are also accumulating. This review summarizes the clinical trial data of ICIs or ICI-containing therapies in different types and stages of breast cancer.
... Despite substantial progress in treating breast cancer, triple-negative breast cancer remains the most daunting to be treated as it lacks welldefined targets [145,146]. Nanoparticle-induced siRNA therapy can trick lysosomes/endosomes and permeate the tumor vasculature better due to enhanced permeation and retention effect [147]. Also, the manipulation of chemical properties of metallic nanoparticles for extending therapeutic benefits has paved the way for their use in pharmaceuticals. ...
Article
As per the WHO, every year around 2.1 million women are detected with breast cancer. It is one of the most invasive cancer in women and second most among all, contributing around 15% of death worldwide. The available anticancer therapies including chemo, radio, and hormone therapy are associated with a high load of reversible and irreversible adverse effects, limited therapeutic efficacy, and low chances of quality survival. To minimize the side effects, improving therapeutic potency and patient compliance promising targeted therapies are highly desirable. In this sequence, various nanocarriers and target modified systems have been explored by researchers throughout the world. Among these chitosan-based nanocarriers offers one of the most interesting, flexible, and biocompatible systems. The unique characteristics of chitosan like surface flexibility, biocompatibility, hydrophilicity, non-toxic and cost-effective behavior assist to overcome the inadequacy of existing therapy. The present review throws light on the successes, failures, and current status of chitosan modified novel techniques for tumor targeting of bioactives. It also emphasizes the molecular classification of breast cancer and current clinical development of novel therapies. The review compiles most relevant works of the past 10 years focusing on the application of chitosan-based nanocarrier against breast cancer.
... Although breast cancer prognosis has improved during the past two decades, breast cancer-related death remains a major cause of cancer-related mortality in women (1,2). The main reason is that a significant proportion of breast cancer patients develop recurrence and distant metastases (3,4). Once metastases occur, breast cancer is treatable but no longer curable (5). ...
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Background Patients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT). Methods Plasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations. Results A total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery. Conclusions This study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.
... TNBC cases, as the name implies, lack targeted therapy and despite initial good response to chemotherapy, recurrence of tumour due to development of resistance ensues with development of multiple metastases [6]. All the above makes TNBCs a formidable clinical challenge, with a critical need for the discovery of prognostic biomarkers which could reliably stratify patients with triple-negative disease into different treatment modalities [7]. ...
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The quest for discovering novel biomarkers of triple-negative breast cancers (TNBCs) is ongoing. By lacking expression of hormonal receptors, this aggressive subtype of breast cancer presents a clinical dilemma with early recurrence, metastases and poor survival outcome. Filamin-A is a recent novel protein which has proven to play a dual role as an oncogene and a tumour-suppressor in many malignancies. This study analysed the expression of Filamin-A in TNBC cases. Filamin-A was significantly expressed by the majority of the study’s sample, and was correlated with grade, clinical stage and TNM staging. Filamin-A is a versatile protein with numerous interactions with the cytoskeleton components of the tumour cell and with signalling proteins. Its role in modulating chemosensitivity to the chemotherapeutic agent Docetaxel is particularly important, especially in TNBC patients, who have few management options to choose from. This study provides evidence of the clinical significance of Filamin-A in TNBCs, and propose further functional studies to pinpoint the exact function of this protein in this difficult-to-treat subset of breast cancer patients.
... Breast cancer is the most common malignancy found in women throughout the world (Bray et al., 2018). TNBC, which is the most aggressive subtype of breast cancer without an expression of the progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2, accounts for 10-20% of all breast cancers (Venkitaraman, 2010;Hudis and Gianni, 2011). Compared with other breast cancer subtypes, TNBC presents a highly invasive nature with a higher risk of distant metastasis, a higher rate of recurrence, and a shorter overall survival (OS) rate in the metastatic setting (Foulkes et al., 2010;Morante et al., 2018). ...
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Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell–related genes were identified. The drug–herb–active compound–target gene–disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.
... Of them, close to 60% are BC ER-positive and about 20% are negative for ER, PR, and HER2 expression [10]. Despite great progress in the early detection and development of clinical therapy, still is the leading cause of women's death mainly associated with cancer metastases [11,12]. This highlights the need to explore new therapeutic approaches in BC. ...
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Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells.
... Breast cancer (BCa) is the most commonly diagnosed cancer in women in the UK and is the cause of $600,000 cancer death worldwide (Bray et al., 2018). The triple-negative BCa (TNBC) subtype has higher rates of recurrence in the first three years after prognosis and increased mortality rates (Hudis and Gianni, 2011). TNBC is defined by low estrogen (ER), progesterone (PR), and Her2 receptor expression (Perou et al., 2000). ...
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Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple negative breast cancer relative to other breast cancer subtypes driving drug resistance and metastatic gene signatures. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRα splice variants were associated with poor prognosis, consistent with a role as an oncogenic driver of triple negative tumour pathophysiology. Contrary to this was the observation that high expression of truncated LXRα splice variants or any LXRβ splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology.
... Cyclin E overexpression is associated with aggressive breast cancer. SU9516 (CDK2 inhibitor) obstructs CDK2/Cyclin E oncogenic signaling in CD44⁺/CD24⁻ CSCs subpopulation of Triple-Negative Breast Cancer Cells (TNBC) resulting in improved sensitivity to cancer chemotherapy [23]. A study highlighted the role of celastrol, a phytocompound in inhibiting cancer stem cells in ovarian cancer by downregulating expression of CDK2, CDK4 and Cyclin D1 through Pin1 signaling network. ...
Article
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Within a tumor, Cancer Stem Cells (CSCs) exists and own similar characteristics of a normal stem cell thus contributing towards aggressiveness of cancer by playing crucial role in tumor recurrence and metastasis capability. Various studies have been conducted to therapeutically target CSCs. One of the approaches include is to inhibit cell cycle progression in CSCs. Within last two decades cell cycle and role of various components in its regulation is firmly established. Cell cycle is regulated by Cyclin Dependent Kinases (CDK) bound to cyclin. CDK activity can be blocked by Cyclin-Dependent Kinase Inhibitors (CKIs) which can either bind cyclin/CDK complex or CDK alone and thus stops cell cycle. In this review various studies are discussed that have investigated the therapeutic role of CKIs in eradicating CSCs by inhibiting cell cycle. Overall, the analysis suggests that CKIs could be a potential therapeutic option in controlling CSCs populating in a tumor.
... Treatment for triple negative breast cancer (TNBC) remains a big challenge in clinical practice. Because TNBC cells express neither estrogen receptor (ER) nor progesterone receptor (PR) and nor overexpress human epidermal growth factor receptor 2 (HER2), they respond poorly to either hormone or HER2 targeted therapy [1]. Chemotherapy is the backbone of systemic treatment for TNBC, among which anthracyclines are important agents and represent the current standard treatment option [2,3]. ...
Article
Resistance to doxorubicin (DOX) remains a big challenge to breast cancer treatment especially for triple negative breast cancer (TNBC). Our previous study revealed that the antioxidant system plays an important role in conferring metastasis derived DOX resistance. In this study, we used two-dimensional difference gel electrophoresis (2D-DIGE) proteomics to compare the expression profiles of two generations of TNBC cell lines which have increased metastatic ability in nude mice and exhibited resistance to DOX. Through careful analyses, one antioxidant protein: glucose-6-phosphate dehydrogenase (G6PD) was identified with 3.2-fold higher level in metastatic/DOX-resistant 231-M1 than its parental 231-C3 cells. Analyses of clinical data showed that TNBC patients with higher G6PD levels exhibited lower overall survival than patients with lower G6PD level. Reducing G6PD expression by siRNA or inhibiting its activity with dehydroepiandrosterone (DHEA) significantly increased DOX's cytotoxicity in both cell lines. Importantly, inhibiting G6PD's activity with DHEA dramatically increased the apoptotic rate of 1.25 µM DOX from 2% to 54%. Our results suggest that high level of G6PD can help TNBC to resist DOX-induced oxidative stress. Thus, inhibiting G6PD shall be a good strategy to treat DOX-resistant TNBC.
... GLOBOCAN 2020 recently reported that female breast cancer is the most common diagnosis (2.3 million new cases) and the fifth leading cause of cancer mortality (0.68 million cases) worldwide [1,2]. Triple negative breast cancer (TNBC) accounts for 15-20% of total breast cancer cases worldwide [3][4][5][6][7]. The absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) expression in TNBC makes it difficult to treat with chemotherapy [5]. ...
Article
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Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7–9 expression and downregulation of Bcl-2 and full-length caspase-7–9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.
... About 15-20% of all breast cancers (BCa) are triple-negative (TNBC) [7][8][9] , a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN/AKT signaling pathway are common in TNBC 10 . ...
Article
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About 15–20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.
... The reason for the lack of success of current treatments is due to a poor understanding of the molecular mechanisms underlying TNBC. TNBC is devoid of the three major receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [13]. These three receptors are the main targets for several breast cancer therapeutics [14] and absence of the aforementioned receptors leads to development of drug resistance [15,16]. ...
Article
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Background Triple-negative breast cancer (TNBC) constitutes 10–20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801. Methods RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies. Results Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1 and TAGLN (validated by RT-qPCR) and upregulation of GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4 and RNASEK-C17orf49 when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation. Conclusion JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.
... Triple-negative breast cancer (TNBC), which represents 15-20% of breast cancers (BC), is classified based on the exclusion criteria of lack of estrogen and progesterone receptor expression and absence of human epidermal growth factor receptor 2 (HER2) overexpression. TNBC is particularly aggressive, with a higher probability of metastatic progression and a lack of effective targeted therapies [1]. Given its classification method of BC, TNBC is a heterogeneous malignancy that encloses tumors with different histopathological and molecular features [2]. ...
Article
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Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.
... In BC, close to 60% are BC ER-positive, and about 20% are negative for ER, PR, and HER2 expression (Cleator et al., 2007). Unfortunately, the remarkable progress in the development of clinical therapy fail to treat cancer metastases, which are still the leading cause of cancer patients' death (Hudis and Gianni, 2011;Marmé and Schneeweiss, 2015). This fact highlights the need to explore new therapeutic approaches in BC. ...
Article
Ethnopharmacological relevance In Paraguay, healers from the Mbya culture treat cancer with a recipe prepared with the native toad Rhinella schneideri. However, the chemical composition and biological effects of the recipe remain unknown. Aim of the study: The aim is to determine the composition of the traditional preparation made using the toad R. schneideri and to evaluate its effect on human breast cancer (BC) cells. Materials and methods The metabolites contained in the preparation were concentrated using XAD-7 resin, and the concentrate was analyzed by HPLC-MS/MS. The effect of the preparation was assessed in normal (MCF10F) and BC cells (MDA-MB-231 and MCF7). The mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) levels, and cell cycle progression were determined by flow cytometry. The oxygen consumption rate (OCR) was measured by Clark electrode, and fibronectin-dependent migration in normoxia and hypoxia-like conditions were evaluated by transwell assay. Results From the Amberlite-retained extract from the preparation, 24 compounds were identified, including alkaloids, amino acids, bufadienolides, and flavonoids, among others. The crude extract (CE) did not affect cell cycle progression and viability of BC cell lines. Moreover, it did not make cancer cells more sensitive to the cytotoxic effect of the chemotherapeutics doxorubicin and teniposide. On the other hand, the CE reduced the menadione-induced ROS production and increased NADH, Δψm, and the OCR. Respiratory complexes I and III as well as ATP synthase levels were increased in an AMPK-dependent manner. Moreover, the CE inhibited the migration of BC cells in normoxia and a hypoxia-like condition using CoCl2 as a HIF1α-stabilizing agent. This latter effect involved an AMPK-dependent reduction of HIF1α and β1-integrin levels. Conclusions The Paraguayan toad recipe contains metabolites from the toad ingredient, including alkaloids and bufadienolide derivatives. The CE lacks cytotoxic effects alone or in combination with chemotherapeutics. However, it increases mitochondrial bioenergetics and inhibits the cancer cell migration in an AMPK-dependent manner in BC cells. This is the first report of the in vitro anticancer effect of a traditional Rhinella sp. toad preparation based on Mbya tradition.
... However, novel therapies for patients diagnosed with TNBC remain a clinical challenge. Thus, the identification and development of new drugs effective against TNBC cells remain an unmet need (Hudis and Gianni, 2011). Given that the conventional cell-surface receptors that allow for therapeutic targeting in other breast cancers are absent in TNBCs, interfering with their metabolic process may represent an effective paradigm to eliminate these cancer cells (Pelicano et al., 2014). ...
Article
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Chemical agents that specifically exploit metabolic vulnerabilities of cancer cells will be beneficial but are rare. The role of oxidative phosphorylation (OXPHOS) in promoting and maintaining triple negative breast cancer (TNBC) growth provides new treatment opportunity. In this work, we describe AuPhos-19, a small-molecule gold(III)-based agent bearing chiral phosphine ligands that selectively disrupts mitochondrial metabolism in murine and human TNBC cells but not normal epithelial cells. AuPhos-19 induces potent cytotoxic effect with half maximal inhibitory concentration (IC50) in the nanomolar range (220 – 650 nM) across different TNBC cell lines. The lipophilic cationic character of AuPhos-19 facilitates interaction with mitochondrial OXPHOS. AuPhos-19 inhibits mitochondria respiration and induce significant AMPK activation. Depolarization of the mitochondria membrane, mitochondria ROS accumulation and mitochondria DNA depletion provided further indication that AuPhos-19 perturbs mitochondria function. AuPhos-19 inhibits tumor growth in tumor-bearing mice. This study highlights the development of gold-based compounds targeting mitochondrial pathways for efficacious cancer treatment.
... Because of its high heterogeneity, the diagnosis and treatment of BC remain a challenging task. These distinct subtypes of breast tumor would respond differently to treatment, making breast cancer extremely intractable [41]. Therefore, we further correlated the level of arginine and IFN-γ in plasma or tissue with the clinicopathological characteristics of patients with BC. ...
... ER + ve breast cancers can be treated with tamoxifen, aromatase inhibitors, competitive estrogen antagonists, and phytoestrogens like quercetin [4,5]. Current treatment strategies against TNBCs include chemotherapy agents, such as anthracyclines, taxanes, ixabepilone, and platinum agents, as well as selected biological agents [6]. Targeted therapy trials with anti-epidermal growth factor receptor (anti-EGFR) and EGFR tyrosine kinase inhibitors are going on [7]. ...
Article
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Breast cancer treatment strategy depends mainly on the receptor status. Our aim was to identify a herbal preparation, effective against breast cancer, irrespective of hormone sensitivity, and to understand its molecular mechanism. The rich antioxidant composition of hawthorn (Crataegus oxyacantha) makes it a promising anti-cancer drug candidate. Polyphenol-rich methanolic extract of C. oxyacantha berry (M.Co) was found to be cytotoxic on hormone receptor positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines, at a dose (75 μg/ml) safe on normal cells. It could effectively inhibit tumor cell proliferation and arrest cell cycle at G1/S transition in both cell lines. Molecular targets were selected from different levels of canonical Wnt signaling pathway (such as autocrine and antagonistic ligands, receptor, effector, cytoplasmic components, downstream targets, and pathway antagonist), since they are frequently found dysregulated in all breast cancers and their aberrant activation is associated with cancer stem cell expansion. M.Co could significantly downregulate the expression of Wnt pathway agonists and upregulate that of Wnt antagonists at transcriptional and translational levels, in both cell lines. To conclude, C. oxyacantha berry extract is effective against breast cancer irrespective of its hormone dependency, and cancer growth inhibition at stem cell level can be expected.
... Wide variations in response kinetics have been observed in immunotherapy treatment compared to traditional cytotoxic therapy (chemotherapies and radiation) [21]. This variation makes assessment monitoring or predictive imaging on a personalized basis difficult [22]. Traditional anatomical imaging techniques and Response Evaluation Criteria in Solid Tumours (RECIST; v.1.1) ...
Article
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Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.
... BACKGROUND Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers and is associated with a high risk of early recurrence and poor survival once metastasised [1,2]. Trials evaluating escalation of adjuvant treatment are emerging [3,4]. ...
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Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1 -like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial. Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1 -like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm. Results For 129/202 (63.9%) patients the BRCA1 -like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non- BRCA1 -like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1 -like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17). Conclusion Based on our data, patients with non- BRCA1 -like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1 -like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1 -like TNBC patients who may not benefit from adjuvant capecitabine.
... Triple negative (TNBC) breast cancer accounts for 10-20% of all breast cancer cases. TNBC patients have poor prognosis due to the aggressive nature of the tumors, the lack of therapeutic targets, and the high rate of tumor recurrence (metastasis) [1,2]. Identifying novel factors that promote TNBC growth, recurrence, and survival is critical for development of new therapies to combat TNBC [3][4][5]. ...
Article
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TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment.
... Moreover, the majority of TN cancers are of BL phenotype and the majority of tumors expressing 'basal' markers are triple negative [2]. TN breast cancers are characterized by an aggressive clinical history, poor clinical outcome, and show a trend toward a poorer outcome [3]. TN breast cancers occur most frequently in young women, especially African Americans, and tend to exhibit an aggressive and metastatic behavior. ...
Article
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Background: Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor prognosis. Inhibitor of DNA binding 4 (ID4) has been shown to be overexpressed in these tumors acting as an oncogene responsible for many of its aggressive features. CDC42, a plasma membrane-associated small GTPase, can downregulate ID4 gene expression through hypermethylation of its promoter in colorectal adenocarcinomas. Since ID4 acts as an oncogene and is hypomethylated in TN breast tumors, here we asked whether CDC42 could also epigenetically silence ID4 and in doing so revert aggressive features of this tumor type. Methods: Gene expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and gene expression was assessed using Kaplan-Meier plotter. In vitro experiments involved ectopic expression of CDC42 in MDA-MB231and in MDA-MB468 breast cancer cell lines. Gene expression was analyzed by qPCR, western blot and inmunofluorescence assays and methylation by MSP, MS-MLPA, or ddMSP. Results: Data mining analysis revealed that CDC42 expression varies among breast cancer subtypes that in the basal-like subtype there is an inverse correlation between CDC42 and ID4 expression and a positive correlation between CDC42 expression and ID4 methylation. In vitro experiments revealed that CDC42 overexpression induced ID4 methylation through the activation of the EZH2 pathway. ID4 silencing produced an increase in BRCA1 expression and a less aggressive phenotype in the tested cell line. Conclusion: We show that CDC42 silences ID4 through methylation in TN breast cancer. Given that ID4 acts as an oncogene in these tumors, we think that finding an epigenetic regulator of ID4 contributes to the research and clinical management of TN breast tumors.
... TNBC accounts for 15-25% of all breast cancers (Yin et al., 2020). The TNBC proportion in all age groups followed a similar trend (Hudis and Gianni, 2011;Khan et al., 2017). However, younger and older women have increased rates of BRCA and basal TNBC and apocrine and neuroendocrine TNBC. ...
Article
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Triple-negative breast cancer (TNBC) is a kind of breast cancer that lacks estrogen, progesterone, and human epidermal growth factor receptor 2. This cancer is responsible for more than 15–20% of all breast cancers and is of particular research interest as it is therapeutically challenging mainly because of its low response to therapeutics and highly invasive nature. The non-availability of specific treatment options for TNBC is usually managed by conventional therapy, which often leads to relapse. The focus of this review is to provide up-to-date information related to TNBC epidemiology, risk factors, metastasis, different signaling pathways, and the pathways that can be blocked, immune suppressive cells of the TNBC microenvironment, current and investigation therapies, prognosis, and the role of artificial intelligence in TNBC diagnosis. The data presented in this paper may be helpful for researchers working in the field to obtain general and particular information to advance the understanding of TNBC and provide suitable disease management in the future.
... TNBC is characteristically aggressive, rapidly proliferative, and has a higher propensity for metastasis when compared with other breast tumor subtypes [1][2][3][4]. Current treatment strategies are nonspecific, resulting in the poorest morbidity and mortality when compared to all the breast cancer subtypes [5][6][7]. One of the promising therapies in TNBC currently undergoing clinical trials is based on Polo-like Kinase 1 (PLK1) inhibitors. ...
Article
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MicroRNAs (miRNAs) are small noncoding RNAs that act as endogenous regulatory molecules targeting specific mRNAs for translational repression. Studies of breast cancer genomics indicate that breast cancer subtypes are distinguished and regulated by specific sets of miRNAs which affect activities such as tumor initiation, progression, and even drug response. Polo-like Kinase 1 (PLK1) is widely considered to be a proto-oncogene due to its increased expression in multiple tumor types, as well as its crucial role in regulating mitosis. Pharmacological inhibition of PLK1 can reduce tumor volume and induce tumor cell death in solid and hematologic malignancies. This prompted us to investigate how PLK1 inhibition with the target-specific inhibitor NMS-P937 would impact breast cancer cells, and how miRNAs may influence the overall response of these cells to this inhibition. We found that miR-183-5p targets PLK1 gene, effectively reducing its protein expression. Such miRNA-driven regulation of PLK1 expression sensitizes breast cancer cells to NMS-P937, resulting in synergistically increased apoptosis. We also show that the miRNA-regulated reduction of PLK1 influences the expression of apoptosis-related key proteins and possibly inducing further indirect PLK1 downmodulation through a DNMT1-p53 axis. These results suggest a potential biologically significant link between the expression of miR-183-5p and the efficacy of PLK1-specific inhibitors in breast cancer cells. Our work further elucidates how miR-183-5p regulates PLK1 gene while also enhancing NMS-P937 effect in breast cancer. Future studies assessing the role of miR-183-5p as a novel biomarker for anti-PLK1 chemotherapy agents are warranted.
... To date, unlike other breast cancer subtypes, no specific targeted approaches exist for TNBC, and toxic chemotherapeutic agents are the primary treatment regimen, highlighting the need to develop new targeted therapies. TNBC contains a high degree of cellular heterogeneity and plasticity that has emerged as a hallmark of the malignant state and accounts for the observed persistent tumor growth, therapeutic resistance, and metastasis [6][7][8][9] . TNBC also contains self-renewing, therapeutically resistant cancer stem cells (CSCs) that are responsible for tumor progression and metastasis [10][11][12][13] . ...
Preprint
Purpose Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype and has limited treatment options. We previously identified a protein complex unique to TNBC cancer stem cells composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK). We sought to determine whether a peptide mimetic of Cx26 designed to target the complex could attenuate tumor growth in pre-clinical models. Experimental Design Histological assessment was employed to verify expression of complex members. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Peptides with high affinity were engineered with a cell-penetrating sequence and assessed in functional assays including cell proliferation, self-renewal, and in vivo tumor growth, and downstream signaling changes were measured. Results Binding studies revealed that the Cx26 cytoplasmic C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar to micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. An antennapedia cell penetrating peptide sequence was engineered to the Cx26 C-terminal tail and confirmed intracellular localization. The cell-penetrating Cx26 C-terminal tail peptide (aCx26-pep) disrupted self-renewal as assessed by the tumorsphere formation assay and inhibited NANOG target gene expression in TNBC cells but not in luminal mammary epithelial cells. In a pre-clinical setting, aCx26-pep reduced tumor growth and proliferation and induced cell death. Conclusions We provide proof-of-concept that a Cx26 peptide-based strategy can inhibit TNBC growth. Translational Relevance Triple-negative breast cancer (TNBC) is the most treatment-refractory breast cancer subtype and has limited targeted therapy options. TNBC contains a cancer stem cell (CSC) population that underlies growth and therapeutic resistance. We leveraged an aberrant intracellular protein complex in TNBC CSCs containing the gap junction subunit connexin 26 (Cx26), focal adhesion kinase (FAK), and NANOG to develop a peptide-based therapeutic strategy. We show that TNBC can be selectively targeted using this approach. Our findings provide a new strategy for treatment of this patient population by disrupting intracellular Cx26 signaling, which is linked to the CSC and epithelial-to-mesenchymal programs. Our results support the development of therapeutics targeting the Cx26/NANOG/FAK complex via peptide- and small molecule-based approaches, and future efforts will also focus on the development of a combinatorial treatment strategy with FDA-approved chemotherapeutics. One Sentence Summary A peptide-based targeting strategy for triple-negative breast cancer was developed by targeting connexin 26-associated signaling partners.
Chapter
Type 2 diabetes and obesity are factors that may cause elevation in the insulin level in the body, possibly leading to insulin resistance. Recent studies have shown the association between insulin resistance and obesity leading to various cancer types including breast, colon, liver, kidney, pancreatic, gastric, and leukemia. The increase in bioavailable insulin-like growth factor 1 (IGF-1) and hyperinsulinemia are instrumental in the formation of tumors in insulin-resistant patients. Overproduction of reactive oxygen species is another cause of developing cancer in insulin-resistant patients as it damages the DNA that contributes to mutagenesis and carcinogenesis. The adipose tissue in diabetic and obese individuals produces high levels of inflammation in cells which promotes tumorigenesis. Hence, weight loss and preventive diabetic therapies offer protective interventions in the development of cancers. In this chapter, we examined the interrelationship between obesity, diabetes, and the mechanism linking to cancer development and also the potential treatment recommendations that may help in controlling cancer.
Chapter
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Obesity is characterized by excessive accumulation of fats in the adipose tissues. Accumulation of excess fat releases a large number of adipokines that can cause obesity and diabetes mellitus due to irregularity between demand and the production of insulin. Obesity affects many organs and influences the heart, liver, intestines, respiratory organs, endocrine, and reproductive functions. Polydipsia, polyuria, weight reduction, coronary illness, kidney injury, diabetic foot, and diabetic ketoacidosis are pathophysiological manifestations and complications of diabetes. Obesity and overweight also contribute to the immune system dysfunction due to increased secretion of pro-inflammatory cytokines which are also risk factors for many types of cancer.
Chapter
Fisetin, 2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one, is a plant flavonoid initially isolated from Rhus cotinus L. This bioactive molecule often occurs in herbal teas and strawberry and has been extracted using aqueous methanol, water, and supercritical fluids. Besides keeping in view its pharmacological importance, microorganism such as yeast (Saccharomyces cerevisiae) and certain bacteria such as Escherichia coli have been successfully engineered for the enhanced production of fisetin from 4-coumaric acid and amino acids. The evaluation of available clinical records indicated that the oral administration of fisetin especially late in life (old age) can restore tissue homeostasis, inflammations, and certain type of cancers such as lung, bladder, breast, and blood cancer. Moreover, the administration of fisetin to wild-type mice late in life restored tissue homeostasis and control senescence-associated secretory phenotypes to extend the median and maximum lifespans.
Chapter
Obesity and cancer are two of the major highly prevailing health disorders of public health concern. Obesity is a documented strong risk factor for many cancers particularly breast and pancreatic cancers. With a progressively increasing prevalence over the past few decades, obesity and cancer continues to leave a footprint of significant morbidity and mortality across different age groups and populations around the world. The global burden of obesity and cancer on health systems has reached alarming proportions necessitating ongoing research into novel approaches and innovative solutions for prevention and control. Such innovative research endeavors have yielded an evolution of efficacious drug treatments for obesity and cancers over time, some of which are used separately or in combination. This chapter highlights the meeting point between obesity and cancer with focus on their management.
Article
Triple-negative breast cancer (TNBC) is the most aggressive subtype among breast cancers with high recurrence and this condition is partly due to chemoresistance. Therefore, fully understanding the mechanism of TNBC-resistance is the key to overcoming chemoresistance, which will be an effective strategy for TNBC therapy. Various potential mechanisms involved in the chemoresistance of TNBC have been investigated and indicated that noncoding RNAs (ncRNAs) especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) take part in most TNBC resistance. The ncRNA-induced chemoresistance process is involved in the alteration of many activities. here, we mainly summarize the mechanisms of ncRNAs in the chemoresistance of TNBC and discuss the potential clinical application of ncRNAs in the treatment of TNBC, indicating that targeting ncRNAs might be a promising strategy for resensitization to chemotherapies.
Preprint
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Triple-negative breast cancer (TNBC) is characterized by poor prognosis and aggressive growth, with limited therapeutic options for many patients. Here, we use two syngeneic mouse TNBC models, 4T1 and E0771, to investigate the chemo-immunogenic potential of cyclophosphamide and the mechanistic contributions of cyclophosphamide-activated type-I interferon (IFN) signaling to therapeutic activity. Chemically-activated cyclophosphamide induced robust IFNα/β receptor-1-dependent signaling linked to hundreds of IFN-stimulated gene responses in both TNBC lines. Further, in 4T1 tumors, cyclophosphamide given on a medium-dose, 6-day intermittent metronomic schedule induced strong IFN signaling but comparatively weak immune cell infiltration associated with long-term tumor growth stasis. Induction of IFN signaling was somewhat weaker in E0771 tumors but was followed by extensive downstream gene responses, robust immune cell infiltration and prolonged tumor regression. The immune dependence of these effective anti-tumor responses was established by CD8 T-cell immunodepletion, which blocked cyclophosphamide-induced E0771 tumor regression and led to tumor stasis followed by regrowth. Strikingly, IFNα/β receptor-1 antibody blockade was even more effective in preventing E0771 immune cell infiltration and blocked the major tumor regression induced by cyclophosphamide treatment. Type-I IFN signaling is thus essential for the robust chemo-immunogenic response of these TNBC tumors to cyclophosphamide administered on a metronomic schedule. Significance TNBC has poor prognosis and few therapeutic options. We show that cyclophosphamide treatment can induces extensive tumor regression in syngeneic mouse models of TNBC via a chemo-immunogenic mechanism linked to type-I IFN production. Our findings establish that IFN signaling is essential for the robust anti-tumor actions of cyclophosphamide and suggest that treatment resistance may stem from silencing the IFN pathway. This suggests a new avenue for improving TNBC treatment efficacy.
Conference Paper
We conducted a case-control study of breast cancer (306 cases and 612 controls) in the Chechen population to determine the effect on carcinogenesis of the genetic variant CHST9 rs1436904, identified in GWAS as a potential marker of breast cancer risk, by real-time PCR using TaqMan probes. It has been established that the genetic variant CHST9 rs1436904, in addition to the usual risk factors, can be included in the prognostic panel for breast cancer in Chechen women. Odds ratio for triple negative breast cancer (THBC) was 1,26 (CI 0.90 - 1.76) (P <0.001).
Article
In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.
Article
In response to the long-term potential toxicity concerns of tubulin destabilizer, an enzyme-responsive prodrug therapy for triple-negative breast cancer was developed based on the different β-glucuronidase levels between tumor and normal tissues in this study. All the prodrugs synthesized herein showed remarkable stability in phosphate buffer and bovine serum solution, among which 17a was found to be more susceptible to enzymatic cleavage. 17a exhibited excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase-pretreated and -untreated cancer cells (IC50 (+Enz) = 8.9–15.7 nM, IC50 (-Enz) > 50 μM), along with favorable liver microsomal metabolic stability and improved aqueous solubility. Furthermore, as a candidate prodrug 17a showed potent antitumor efficacy in MDA-MB-231 xenograft mouse model without causing perceptible injury to organs. Importantly, 17a exhibited superior safety profiles with higher LD50 value and no perceivable cardiotoxicity, which was a major dose-limiting adverse effect for the parent compound 1. These salient toxicity-reduced effects of 17a would merit further in-depth assessment of this compound for preclinical therapeutic usages.
Article
Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.
Article
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Yiqi Fan, Shuai He Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People’s Republic of ChinaCorrespondence: Shuai HeDepartment of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People’s Republic of ChinaEmail hs43555@163.comAbstract: Triple-negative breast cancer (TNBC) is a special subtype of breast cancer, accounting for 10– 20% of breast cancers with high intrinsic heterogeneity. Its unique immune microenvironment, including high expression of vascular endothelial growth factors, tumor infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and other molecules that promote the growth and migration of tumor cells, has been shown to play a dual role in the occurrence, growth, and metastasis of TNBC. Understanding the TNBC microenvironment is of great significance for the prognosis and treatment of TNBC. In this article, we describe the composition and function of immune cells in the TNBC microenvironment and summarize the major cytokine growth factors and chemokines in the TNBC microenvironment. Finally, we discuss the progress of TNBC, cytokine-induced killer cell therapy, and immune checkpoint therapy.Keywords: triple negative breast cancer, microenvironment, immune cells, immunotherapy
Article
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Purpose Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. Patients and Methods Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m ² every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). Conclusion Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
Article
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To investigate the prognostic and predictive significance of subtyping node-positive early breast cancer by immunohistochemistry in a clinical trial of a docetaxel-containing regimen. Pathologic data from a central laboratory were available for 1,350 patients (91%) from the BCIRG 001 trial of docetaxel, doxorubicin, and cyclophosphamide (TAC) versus fluorouracil, doxorubicin, and cyclophosphamide (FAC) for operable node-positive breast cancer. Patients were classified by tumor characteristics as (1) triple negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, HER2/neu [HER2]-negative), (2) HER2 (HER2-positive, ER-negative, PR-negative), (3) luminal B (ER-positive and/or PR-positive and either HER2-positive and/or Ki67(high)), and (4) luminal A (ER-positive and/or PR-positive and not HER2-positive or Ki67(high)), and assessed for prognostic significance and response to adjuvant chemotherapy. Patients were subdivided into triple negative (14.5%), HER2 (8.5%), luminal B (61.1%), and luminal A (15.9%). Three-year disease-free survival (DFS) rates (P values with luminal B as referent) were 67% (P < .0001), 68% (P = .0008), 82% (referent luminal B), and 91% (P = .0027), respectively, with hazard ratios of 2.22, 2.12, and 0.46. Improved 3-year DFS with TAC was found in the luminal B group (P = .025) and a combined ER-positive/HER2-negative group treated with tamoxifen (P = .041), with a marginal trend in the triple negatives (P = .051) and HER2 (P = .068) subtypes. No DFS advantage was seen in the luminal A population. A simple immunopanel can divide breast cancers into biologic subtypes with strong prognostic effects. TAC significantly complements endocrine therapy in patients with luminal B subtype and, in the absence of targeted therapy, is effective in the triple-negative population.
Article
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This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. Patients with invasive breast cancer >or= 3 cm were eligible. Ixabepilone 40 mg/m(2) was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) -negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes predictive of ixabepilone sensitivity in preclinical experiments included ER and tau and had higher PPV (45%) and comparable NPV (89%) to ER1. Grade 3 to 4 adverse events (AEs) were reported for 32% of patients. Except for neutropenia and leukopenia, all grade 3 to 4 AEs occurred in <or= 3% of patients. Reversible peripheral neuropathy was experienced by 3% of patients. CONCLUSION ER, microtubule-associated protein tau, and a 10-gene PLR model that included ER were identified as predictors of ixabepilone-induced pCR. indicate an inverse relation between ER expression levels and ixabepilone sensitivity. Neoadjuvant ixabepilone demonstrated promising activity and a manageable safety profile in patients with invasive breast tumors.
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BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, cytokeratin 5/6, cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal cytokeratin 8/18 (15/18), EGFR (13/18), and cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER- and HER2-. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P<0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, cytokeratin 8/18, and cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype.
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Little is known of the underlying biology of estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer (BC), and few targeted therapies are available. Clinical heterogeneity of ER(-)/PR(-) tumors suggests that molecular subsets exist. We performed genome-wide expression analysis of 99 primary BC samples and eight BC cell lines in an effort to reveal distinct subsets, provide insight into their biology and potentially identify new therapeutic targets. We identified a subset of ER(-)/PR(-) tumors with paradoxical expression of genes known to be either direct targets of ER, responsive to estrogen, or typically expressed in ER(+) BC. Differentially expressed genes included SPDEF, FOXA1, XBP1, CYB5, TFF3, NAT1, APOD, ALCAM and AR (P<0.001). A classification model based on the expression signature of this tumor class identified molecularly similar BCs in an independent human BC data set and among BC cell lines (MDA-MB-453). This cell line demonstrated a proliferative response to androgen in an androgen receptor-dependent and ER-independent manner. In addition, the androgen-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of the unique ER(-)/PR(-) subclass of human tumors. This subset of BCs, characterized by a hormonally regulated transcriptional program and response to androgen, suggests the potential for therapeutic strategies targeting the androgen signaling pathway.
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Gene expression analysis has identified several breast cancer subtypes, including basal-like, human epidermal growth factor receptor-2 positive/estrogen receptor negative (HER2+/ER-), luminal A, and luminal B. To determine population-based distributions and clinical associations for breast cancer subtypes. Immunohistochemical surrogates for each subtype were applied to 496 incident cases of invasive breast cancer from the Carolina Breast Cancer Study (ascertained between May 1993 and December 1996), a population-based, case-control study that oversampled premenopausal and African American women. Subtype definitions were as follows: luminal A (ER+ and/or progesterone receptor positive [PR+], HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, cytokeratin 5/6 positive, and/or HER1+), HER2+/ER- (ER-, PR-, and HER2+), and unclassified (negative for all 5 markers). We examined the prevalence of breast cancer subtypes within racial and menopausal subsets and determined their associations with tumor size, axillary nodal status, mitotic index, nuclear pleomorphism, combined grade, p53 mutation status, and breast cancer-specific survival. The basal-like breast cancer subtype was more prevalent among premenopausal African American women (39%) compared with postmenopausal African American women (14%) and non-African American women (16%) of any age (P<.001), whereas the luminal A subtype was less prevalent (36% vs 59% and 54%, respectively). The HER2+/ER- subtype did not vary with race or menopausal status (6%-9%). Compared with luminal A, basal-like tumors had more TP53 mutations (44% vs 15%, P<.001), higher mitotic index (odds ratio [OR], 11.0; 95% confidence interval [CI], 5.6-21.7), more marked nuclear pleomorphism (OR, 9.7; 95% CI, 5.3-18.0), and higher combined grade (OR, 8.3; 95% CI, 4.4-15.6). Breast cancer-specific survival differed by subtype (P<.001), with shortest survival among HER2+/ER- and basal-like subtypes. Basal-like breast tumors occurred at a higher prevalence among premenopausal African American patients compared with postmenopausal African American and non-African American patients in this population-based study. A higher prevalence of basal-like breast tumors and a lower prevalence of luminal A tumors could contribute to the poor prognosis of young African American women with breast cancer.
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Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-to-mesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 μM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40–59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (χ 2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with “triple-negative” breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).
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To compare the clinical features, natural history, and outcomes for women with "triple-negative" breast cancer with women with other types of breast cancer. We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P < 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P < 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at approximately 3 years and declined rapidly thereafter. Among the "other" group, the recurrence risk seemed to be constant over the period of follow-up. Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
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The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both. We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed. No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor-positive cancers. The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor-positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide.
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This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E(90)C(600) followed by three cycles of C(600)M(40)F(600) every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E(90)C(600) every 2 weeks followed by two cycles of E(90)C(3000)Thiotepa(400) every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43-0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39-0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.
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Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.
Article
625 Background: Triple-negative breast cancer (TNBC), defined by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, accounts for 15–20% of all breast cancers and is associated with poor prognosis. There is no consensus regarding optimal CT for treatment of such patients. Preclinical data suggests TNBC may be sensitive to platinums because of deficiencies in BRCA-associated DNA repair. The aim of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based CT. Methods: We identified 674 patients with LABC who received neoadjuvant CT between January 1999 and June 2008 at University of Miami. Of these, 125 (18.5%) had histopathologic confirmation of TNBC. All patients received neoadjuvant platinum salts + docetaxel. 76 (61%) also received neoadjuvant AC, while 42 (34%) received adjuvant AC. pCR was defined as no residual invasive disease in breast and axilla. OS was calculated according to Kaplan-Meier. Results: Demographics: median age 50 (28–86 years). 60% premenopausal. TNM stage distribution: T1 0.9%, T2 5.2%, T3 53.4%, T4 40.5%, N0 25.0%, N1 36.2%, N2 35.4%, N3 3.4%, M0 100%, inflammatory 11%, median tumor size = 9.5 cm. Follow up duration ranged from 0.3 to 8.9 years. pCR was observed in 42 of 125 patients (34%; 95% CI 26–43%). Among patients receiving neoadjuvant AC, 30 of 76 (40%; 95% CI 28–51%) had pCR, while amongst those receiving adjuvant AC, 12 of 42 (29%, 95% CI 16–45%) had pCR at the time of definitive surgery. Patients achieving pCR had significantly higher OS (5-yr rate = 73% in pCR, vs. 49% in non-pCR; p < 0.001). OS in TNBC patients receiving cisplatin/docetaxel was significantly superior to those receiving carboplatin/docetaxel (11 mortality events out of 78 patients receiving cisplatin based CT vs 24 out of 47 receiving carboplatin based CT logrank p = 0.001). Conclusions: To date, this is the largest single institution cohort of locally advanced TNBC uniformly treated with platinum+docetaxel-based CT regimens. Platinum/docetaxel-based neoadjuvant CT provided high rates of pCR and excellent OS for women with locally advanced TNBC. No significant financial relationships to disclose.
Article
517 Background: This study compared the disease-free survival (DFS) obtained with 2 regimens of adjuvant therapy for patients (pts) with high-risk breast cancer Methods: Women PS 0–1 with local, operable, confirmed stage I-III adenocarcinoma were eligible. Pts may have had primary surgery, with no residual tumor. Therapy was as follows:Arm 1 (AC→T) - doxorubicin 60 mg/m ² plus cyclophosphamide 600 mg/m ² repeated every 3 weeks for 4 cycles → paclitaxel 175 mg/m ² repeated every 3 weeks for 4 cycles; Arm 2 (AT→T) - doxorubicin 50 mg/m ² plus paclitaxel 200 mg/m ² repeated every 3 weeks for 4 cycles → paclitaxel 80 mg/m ² weekly ×12. Results: 1,830 pts were enrolled and treated; n=915 Arm 1 (AC→T) and n=915 Arm 2 (AT→T). Pts were: PS=0 (70%/Arm), ER+/PR+ (54% and 50%, Arms 1 and 2 respectively), ER-/PR- (35% and 34%) with 0 positive nodes (N+) (28% and 27%), 1–3 (N+) (44% and 46%), 4–9 (N+) (21% and 18%) and 10+ (N+) (7% and 8.5%). Most were postmenopausal (57%/Arm); median age was 52 years/Arm. To date 1,655 pts (90%) are alive. 5-year DFS was 80% vs 81% for Arms 1 and 2 Overall 5-year survival was 86% vs 89%, in Arms 1 and 2. Cause of death was recurrence for 76 pts in Arm 1 and 56 pts in Arm 2. The main reasons for pts being taken off study treatment were toxicity (85 pts Arm 1 vs 128 pts Arm 2), recurrence (79 pts Arm 1 vs 52 pts Arm 2), and consent withdrawal (18 pts Arm 1 vs 30 pts Arm 2). The most frequent toxicities were neutropenia, leukopenia, neuropathy, febrile neutropenia, nausea, vomiting, arthralgia, and myalgia. GI toxicities were more frequent in Arm 1. Alopecia occurred in both Arms (77%). Conclusions: At 5-years, the AT→T produced significantly better OS (p=0.054) and improved DFS (p=0.19). Clinically important toxicities were more frequent with AC→T. Given this, AT→T in the adjuvant treatment of breast cancer is well tolerated and warranted in place of AC→T in these pts. Research support provided by Bristol-Myers Squibb (Princeton, NJ). No significant financial relationships to disclose.
Article
PURPOSE: To compare the efficacy of neoadjuvant (NA) docetaxel (DOC) with anthracycline-based therapy and determine the efficacy of NA DOC in patients with breast cancer initially failing to respond to anthracycline-based NA chemotherapy (CT). PATIENTS AND METHODS: Patients with large or locally advanced breast cancer received four pulses of cyclophosphamide 1,000 mg/m², doxorubicin 50 mg/m², vincristine 1.5 mg/m², and prednisolone 40 mg (4 × CVAP) for 5 days. Clinical tumor response was assessed. Those who responded (complete response [CR] or partial response [PR]) were randomized to receive further 4 × CVAP or 4 × DOC (100 mg/m²). All nonresponders received 4 × DOC. RESULTS: One hundred sixty-two patients were enrolled; 145 patients completed eight cycles of NA CT. One hundred two patients (66%) achieved a clinical response (PR or CR) after 4 × CVAP. After randomization, 50 patients received 4 × CVAP and 47 patients received 4 × DOC. In patients who received eight cycles of CT, the clinical CR (cCR) and clinical PR (cPR) (94% v 66%) and pathologic CR (pCR) (34% v 16%) response rates were higher (P = .001 and P = .04) in those who received further DOC. Intention-to-treat analysis demonstrated cCR and cPR (85% v 64%; P = .03) and pCR (31% v 15%; P = .06). Axillary lymph node examination revealed residual tumor in 33% of patients who received 8 × CVAP and 38% of patients who received further DOC. In patients who failed to respond to the initial CVAP, 4 × DOC resulted in a cCR and cPR rate of 55% and a pCR rate of 2%. Forty-four percent of these patients had residual tumor within axillary lymph nodes. CONCLUSION: NA DOC resulted in substantial improvement in responses to DOC.
Article
Background: The combination of Bev with taxane-based therapy, anthracycline-based combination therapy, or capecitabine significantly improves progression-free survival versus chemotherapy alone in LR/MBC, as shown in three randomized, phase III trials (E2100, AVADO, RIBBON-1). Pts with TN LR/MBC appeared to derive similar benefit from Bev compared with non-TN pts in subanalyses of the E2100 and AVADO trials. We conducted a subpopulation analysis of TN pts treated with Bev combination therapy in the MO19391 observational study, which included a broader pt population reflecting general oncology practice.Methods: Pts with HER2-negative (or trastuzumab-pretreated HER2-positive) LR/MBC received first-line Bev 10 mg/kg q2w or 15 mg/kg q3w in combination with taxane-based therapy or other non-anthracycline-containing regimen, according to physician preference. Bev was continued until disease progression. The primary endpoint of MO19391 was safety. Secondary endpoints included time to progression (TTP) and overall survival.Results: 484 of the 2041 pts in MO19391 had TN LR/MBC and 1346 had non-TN disease. The remaining 211 had missing or unknown ER, PgR, or HER2 status and were excluded from this analysis. The proportion of pts with disease-free interval (DFI) ≤24 months was considerably higher in the TN population than in non-TN pts. As expected, the safety profile of Bev combination therapy showed no differences between the two subpopulations. The only pre-defined Bev adverse events of special interest reported at grade ≥3 in >1% of TN pts were hypertension (4.5%) and pulmonary embolism (1.4%). Baseline characteristics, treatment exposure, and efficacy are summarized below. Overall survival data are immature.Conclusions: In this ongoing study, Bev combination therapy demonstrated a 48% response rate and median TTP of 7.1 months in pts with TN LR/MBC. Findings from this observational study are consistent with retrospective analyses of randomized phase III trials. Prospective trials evaluating Bev combination regimens in TN breast cancer (adjuvant and metastatic settings) are ongoing. View this table: • In this window • In a new window Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6093.
Article
CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #705 Background: Retrospective studies have suggested that HER2 and topoisomerase II α (TOP2A) might predict sensitivity to anthracyclines (A) Methods: Four phase III trials comparing A with CMF in early breast cancer (EBC) patients (pts), and with available primary tumor samples, were identified. HER2 and TOP2A genes were evaluated locally by FISH (amplification if ratio ≥ 2). Data were centralized at the statistical office (IDDI, Belgium). On-site visits were performed to check data quality and laboratory procedures. HER2 and TOP2A local scores were validated by submitting randomly selected samples to a central lab (CL) (University of Tampere – Finland), for a 3 color FISH test (HER2, TOP2A, centromere 17, Abbott Labs, IL, USA). Estrogen (ER), progesterone (PgR) receptors, and grade (G) were evaluated locally (no score validation at the CL). Results: We present the results of the planned interim analysis on 1944 pts. Final results (± 3500 pts) will be presented when tumor sample collection for the UK trial is complete. HER2 local scores were validated at the CL in 137 cases (discordance: 8/137, 5.8%). TOP2A local scores were validated in 123 cases (discordance 38/123, 30.8%). Half of the TOP2A discordant cases were locally deleted-centrally normal or vice versa. ![][1] A planned exploratory analysis evaluated the TOP2A predictivity in 4 biologically homogeneous groups: highly or moderately hormone sensitive, HER2+ and ER/PgR negative, triple negative (TN). This analysis did not enhance the TOP2A predictivity in any of the 4 groups. In the TN group (294 pts), the DFS HR was 0.77 (0.54-1.09), suggesting that benefit from A might not be confined to HER2+ pts. Conclusions: The interim analysis shows that HER2 and TOP2A have a clinically modest and a statistically borderline predictive value. In triple negative disease A may be superior to CMF. Acknowledgments: Abbott Laboratories, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Pfizer, Scottish BC trials group. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 705. [1]: /embed/graphic-1.gif
Article
Background Three multicenter, randomized, placebo-controlled Phase III trials of taxane (T), or capecitabine (Cape), or anthracycline (Anth) chemotherapy plus or minus bevacizumab (B) established that the addition of B improves progression-free survival (PFS). Outcomes in clinically important subsets are important to demonstrate the consistency of treatment effect and may guide physicians when considering treatment options for patients. Here we compare various clinically relevant subgroups across three studies to assess the activity of B in patients for these subgroups.Methods Results for PFS based upon investigator assessments were used from all trials. Kaplan-Meier methodology was used to estimate median PFS for chemo+placebo and chemo+B for patient subgroups from the E2100, AVADO, and RIBBON-1 studies. For the overall study results, stratified hazard ratios (HRs) are presented with the same stratification factors as the variables that were used for the randomization, while unstratified HRs are presented here for the subgroups.ResultsIn all 3 studies we observed an improvement in PFS upon addition of B to chemotherapy. For patients with triple-negative (ER-, PR-, HER2-) tumors, the addition of B led to an increase in median PFS (mPFS) from 4.7 mo to 10.2 mo (HR=0.45; 95% confidence interval [CI], 0.33-0.61) in E2100, from 6.0 to 8.1 mo in the AVADO 15 mg/kg B arm (HR=0.60, 95% CI, 0.39-0.92); from 4.2 to 6.1 mo in the RIBBON-1 Cape cohort (HR=0.72, 95% CI, 0.49-1.06); and from 8.2 to 14.5 mo in the RIBBON-1 T/Anth cohort (HR=0.78, 95% CI, 0.53-1.15).For patients ≥65 yr, the addition of B led to an increase in mPFS from 7.4 to 10.4 mo (HR=0.69, 95% CI, 0.46-1.03) in E2100, from 7.6 to 8.4 mo in the AVADO 15 mg/kg B arm (HR=0.62, 95% CI, 0.36-1.08); from 6.2 to 9.1 mo in the RIBBON-1 Cape cohort (HR=0.69, 95% CI, 0.47-1.02); and from 8.5 to 10.1 mo in the RIBBON-1 T/Anth cohort (HR=0.83, 95% CI, 0.52-1.34).For patients who had received prior adjuvant T, the addition of B led to an increase in mPFS from 4.4 to 13.3. mo in E2100 (HR=0.29; 95% CI, 0.19-0.46), 6.6 to 8.5 mo in the AVADO 15 mg/kg B arm (HR=0.42; 95% CI, 0.23-0.77), 4.2 to 8.7 mo in the RIBBON-1 Cape cohort (HR=0.62; 95% CI, 0.45-0.84); and from 6.7 to 9.1 mo in the RIBBON-1 T/Anth cohort (HR=0.65; 95% CI, 0.39-1.09).Conclusions Although the addition of bevacizumab consistently improved mPFS across a number of clinically relevant subsets, regardless of the chemotherapy backbone used, absolute improvements in HRs and median PFS varied within subsets and across the three trials. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 207.
Article
Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. AstraZeneca.
Article
This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 175 mg/m(2) every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m(2) plus paclitaxel 200 mg/m(2) every 3 weeks for four cycles followed by paclitaxel 80 mg/m(2) weekly for 12 weeks. Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC-->P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor-positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.
Article
To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel +/- weekly trastuzumab in resectable and locally advanced breast cancer. Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2) weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) -positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes. Postoperative therapies were at the discretion of the treating physicians. Fifty-five patients were enrolled, and of these 43 had resectable disease. The median age was 54 years (range, 31 to 74 years). Treatment was well tolerated; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia, and there were only two instances of grade 3 peripheral neuropathy. Overall, the pCR rate was 45%. The pCR rate was 43% (95% CI, 28% to 58%) in patients with resectable disease. Higher pCR rates occurred in patients with HER2-positive tumors (76% v 31% for HER2-negative tumors; P = .003), with estrogen receptor (ER) -negative tumors (75% v 27% for ER-positive tumors; P = .001), or with triple-negative tumors (67% v 12% ER-positive and HER2-negative tumors; P = .002). At a median of 28 months postoperation, recurrence-free survival (RFS) was 88.7%. If patients with ER-positive and HER2-negative tumors are excluded from analysis, patients who achieved a pCR were less likely to experience disease recurrence (RFS, 86%) than those who did not achieve a pCR (RFS, 75%). Neoadjuvant carboplatin and weekly paclitaxel +/- trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline. Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received. Additional study of this regimen in high-risk patients is warranted.