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Triple-Negative Breast Cancer: An Unmet Medical Need
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.
... Two common adjuvant chemotherapy regimens for breast cancer are the combination of doxorubicin plus cyclophosphamide (AC) [4,6,8], as well as single-agent paclitaxel (T) [4,5]. While previous studies have examined the AC [6] and single-agent T [7] regimens individually, a direct comparative analysis of these two regimens is currently lacking. ...
... Two common adjuvant chemotherapy regimens for breast cancer are the combination of doxorubicin plus cyclophosphamide (AC) [4,6,8], as well as single-agent paclitaxel (T) [4,5]. While previous studies have examined the AC [6] and single-agent T [7] regimens individually, a direct comparative analysis of these two regimens is currently lacking. ...
Background: Cyclophosphamide plus doxorubicin (AC) and single-agent paclitaxel (T) have been shown to be major and effective adjuvant chemotherapy regimens for breast cancer. Personalized treatment plans tailored to individual patient factors have demonstrated significant improvements in curative performance. This study investigated the dataset provided by the CALGB 40101 trial, a phase III randomized study that compared the efficacy of AC and T as adjuvant therapy for breast cancer. Methods: The overall survival (OS) and disease-free survival (DFS) distributions grouped by several factors were described by the Kaplan-Meier method. Additionally, the impact of various factors on the OS and DFS was observed by the Cox proportional hazard model. By stratifying data into different subgroups, the model also showed the association between the characteristics and the efficacy of different regimens. Results: A significant impact of the agents on OS was observed and the HR was 1.279, while different treatment durations did not show a significant association with OS. Also, the agent significantly affected DFS, while a significant difference grouped by duration was not observed. Furthermore, factors, such as tumor size and age, significantly increased the hazard of mortality and relapse. Conclusion: The efficacy of AC and T had significant differences when treating breast cancer as adjuvant therapy, while the treatment duration did not show a significant impact. Also, age, tumor size, receptor status, and histologic grade significantly affect overall or disease-free survival.
... Triple-negative breast cancers (TNBC) manifest heightened aggressiveness and dismal prognoses among the diverse subtypes of breast carcinoma [3]. These aggressive tumors relapse frequently, are more prone to metastasize, and have worse outcomes than those observed in other breast cancer types [4,5]. ...
... After 48 h, the cells were harvested and used for western blot analysis. Two different siRNA oligo duplexes for targeting human HSC70 (siHSC70-1; 5 T T-3' and siATG7-2; 5'-C U C U U G A A A A C C C U G U A C U T T-3'), respectively, were purchased from Bioneer (Daejeon, Korea). Transient transfection of siRNA oligo duplex was accomplished using Lipofectamine™ RNAiMAX Transfection Reagent (Invitrogen, Carlsbad, CA, USA) following manufacturer's instruction. ...
Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions.
... Its elevated expression correlates with an increased capacity for tumor invasion and metastasis, indicating a higher malignancy grade and a poor treatment response and prognosis. 24,25 Conversely, low Ki-67 expression suggests relatively slow tumor growth and a decreased likelihood of dystrophic calcification. Consequently, luminal breast cancer tends to present with a smaller tumor volume 26 and a lower incidence of distant metastasis. ...
Objectives
To analyze differences in programmed cell death protein 1/ligand 1 (PD-1/PD-L1) expression, as well as the relationships between ultrasound/contrast-enhanced ultrasound characteristics and PD-1/PD-L1 expression, among invasive breast cancer molecular subtypes.
Methods
The study included 172 invasive breast cancer patients with surgical resection and pathological confirmation at the First Affiliated Hospital of Xinjiang Medical University from June 2016 to April 2022. PD-1/PD-L1 expression was detected by immunohistochemistry. All patients underwent conventional ultrasound and some underwent contrast-enhanced ultrasound examination before resection.
Results
PD-1 and PD-L1 were expressed in 112 and 121 cases, respectively. The luminal B and HER-2 subtypes had the lowest and highest PD-1 expression rates, respectively. The luminal B and triple-negative subtypes had the lowest and highest PD-L1 expression rates, respectively. Among 112 PD-1-positive cases, most luminal B cases exhibited ill-defined margins, while distant metastasis was more common in triple-negative cases. Among 121 PD-L1-positive cases, many HER-2-positive and triple-negative cases presented as large masses (diameter ≥ 2 cm), while luminal B cases were more likely to show calcification. Most luminal B PD-L1-positive cases displayed indistinct margins on contrast-enhanced ultrasound.
Conclusions
PD-1 expression differed among molecular subtypes of invasive breast cancer. Ultrasound/contrast-enhanced ultrasound features correlated with PD-1/PD-L1 expression in different breast cancer subtypes.
... High-risk early-stage triple-negative breast cancer (TNBC) is often associated with early recurrence and high mortality rates (1). In addition to potentially increasing the likelihood of tumor resectability and breast conservation rate, patients who achieve pathologic complete response (pCR) after preoperative chemotherapy have longer event-free and overall survival (2). ...
Recently, the anti-programmed cell death protein 1 antibody pembrolizumab, a type of immune checkpoint inhibitor (ICI), has been used in preoperative systemic chemotherapy for hormone receptor and human epidermal growth factor 2-negative breast cancer, also known as triple-negative breast cancer (TNBC). Chemotherapy with pembrolizumab has demonstrated clinical activity in terms of pathologic complete response and event-free survival. Despite their efficacy, the current understanding of the full spectrum of side effects associated with relatively new ICIs remains incomplete. The present study describes a case of severe pembrolizumab-induced hemophagocytic lymphohistiocytosis in a patient with early-stage TNBC, and the strategies used to manage the patient in light of their pathophysiology.
... Therefore, non-specific treatments, such as surgery, radiation, and chemotherapy, remain the standard of care for these patients, but they often develop adverse side effects, such as hair loss, nausea, vomiting, infertility, and anemia [2,5,6]. Following treatment, many TNBC patients develop chemoresistance and radioresistance, a perfect storm created by the absence of hormonal receptors paired with an enriched CD44 + /CD24 − breast cancer stem cell (BCSC) population [7][8][9][10]. Therefore, there is a crucial need for developing personalized, precise, and targeted therapies for TNBC patients. ...
Background/Objectives: Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the effect of chemotherapy on genes that improve TNBC outcomes and other SLFN family members following SLFN12 knockout or overexpression. Methods: We overexpressed SLFN12 using a lentiviral vector and knocked out SLFN12 (AdvShSLFN12) using a hairpin adenovirus in MDA-MB-231 TNBC cells. Cells were treated with camptothecin, paclitaxel, zoledronic acid, or carboplatin to evaluate the SLFN12 signature cancer genes associated with improved TNBC outcomes using qPCR. Additionally, cells were treated alone and in combination with AdvShSLFN12, IFN-α2 (known SLFN12 stimulator), carboplatin, and paclitaxel. After treatment, the viable cell numbers were analyzed utilizing a colorimetric crystal violet assay for cell viability. Results: The SLFN family and SLFN12 cancer signature gene mRNA expressions were analyzed by RT-qPCR. Treating SLFN12-overexpressing TNBC cells with chemotherapy agents resulted in the differential expressions of eight cancer-related genes. Notably, GJB3 was downregulated following treatment with each chemotherapeutic drug. Inducing SLFN12 with IFN-α2 resulted in decreased cell viability and increased SLFN12 mRNA levels following treatment with paclitaxel or carboplatin. Conclusions: These results suggest that SLFN12 overexpression significantly affects the expressions of genes driving phenotypic changes in response to chemotherapy and influences additional SLFN family members following IFN-α2 treatment. This may contribute to improving the survival of patients with SLFN12 overexpression. Additionally, patient SLFN12 levels can be used as a factor when pursuing personalized chemotherapy treatments.
... The 4T1 tumor-bearing mice are widely used as triple-negative breast cancer (TNBC) models [38,49], and therefore, this study also provides potential new therapeutic options for this disease. TNBC is a clinically aggressive breast cancer subtype that accounts for approximately 15% of breast cancer cases [50,51]. The poor patient outcomes associated with TNBC are mainly from (1) very few target proteins and (2) high levels of immunosuppression [17,37,38]. ...
Background: We have previously reported engineered macrophages (MacTriggers) that can accelerate the release of tumor necrosis factor-α in response to M2 polarization. MacTriggers are characterized by two original characteristics of macrophages: (1) migration to tumors; and (2) polarization to the M2 phenotype in tumors. Intravenously administered MacTriggers efficiently accumulated in the tumors and induced tumor-specific inflammation. This study reports a novel methodology for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Results: In this study, we newly found that the intravenously administered MacTriggers in BALB/c mouse models upregulated the expression levels of immune checkpoint proteins, such as programmed cell death (PD)-1 in CD8⁺ T cells and PD-ligand 1 (PD-L1) in cancer cells and macrophages. Consequently, in two ICI-resistant tumor-inoculated mouse models, the combined administration of MacTrigger and anti-PD-1 antibody (aPD-1) synergistically inhibited tumor growth, whereas monotherapy with aPD-1 did not exhibit anti-tumor effects. This synergistic effect was mainly from aPD-1 enhancing the tumor-attacking ability of CD8⁺ T cells, which could infiltrate into the tumors following MacTrigger treatment. Importantly, no side effects were observed in normal tissues, particularly in the liver and spleen, indicating that the MacTriggers did not enhance the aPD-1 reactivity in normal tissues. This specificity was from the MacTriggers not polarizing to the M2 phenotype in normal tissues, thereby avoiding inflammation and increased PD-1/PD-L1 expression. MacTriggers could enhance aPD-1 reactivity only in tumors following tumor-specific inflammation induction. Conclusions: Our findings suggest that the MacTrigger and aPD-1 combination therapy is a novel approach for potentially overcoming the current low ICI response rates while avoiding side effects.
... Studies have consistently shown that, in addition to a distinct pattern of timing of recurrence, there are unique patterns of relapse site among TNBC patients. It has been demonstrated that luminal A subtype typically causes late bone metastases, whereas TNBC is more likely to cause early visceral metastases [30]. In our study, bone metastasis was more common in non-TNBC subtypes, especially in luminal A (51.2%), and less in TN subtype (25.0%; ...
... HER2 status can also be used to sub-classify hormone receptornegative [ER-/PR-] tumors into distinct subgroups of [ER-/PR-]HER2? and [ER-/PR-]HER2-. One of these groups of hormone receptor-negative breast cancer, the [ER-/PR-]HER2-subtype, is also called triplenegative breast cancer (TNBC) given its negative status in relation to the three receptors, and it forms a clinically challenging group with poor prognosis and difficulties in treatment compared with non-TNBC (Hudis and Gianni 2011;Dai et al. 2014). About 15% of women who develop breast cancer are diagnosed with TNBC (Bianchini et al. 2016). ...
Circadian clocks, biochemical oscillators that are regulated by environmental time cues including the day/night cycle, have a central function in the majority of biological processes. The disruption of the circadian clock can alter breast biology negatively and may promote the development of breast tumors. The expression status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were used to classify breast cancer into different molecular subtypes such as triple-negative breast cancer (TNBC). Receptor status-dependent expression of circadian clock genes have been previously studied in breast cancer using relatively small sample sizes in a particular population. Here, using TCGA-BRCA data (n=1119), we found that the expressions of CRY1, PER1, PER2, PER3, BMAL1, CLOCK, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in ER+ breast cancer cells compared with those of ER− status. Similarly, we showed that transcript levels of CRY2, PER1, PER2, PER3, BMAL1, RORA, RORB, RORC, NR1D1, NR1D2, and FBXL3 were higher in PR+ breast cancer cells than in PR− breast cancer cells. We report that the expressions of CRY2, PER1, BMAL1, and RORA were lower, and the expression of NR1D1 was higher, in HER2+ breast cancer cells compared with HER2− breast cancer cells. Moreover, we studied these receptor status-dependent changes in the expressions of circadian clock genes also based on the race and age of breast cancer patients. Lastly, we found that the expressions of CRY2, PER1, PER2, PER3, and CLOCK were higher in non-TNBC than in TNBC, which has the worst prognosis among subtypes. We note that our findings are not always parallel to the observations reported in previous studies with smaller sample sizes performed in different populations and organisms. Our study suggests that receptor status in breast cancer (thus, subtype of breast cancer) might be more important than previously shown in terms of its influence on the expression of circadian clock genes and on the disruption of the circadian clock, and that ER or PR might be important regulators of breast cancer chronobiology that should be taken into account in personalized chronotherapies.
... While there has been substantial progress in the development of targeted therapeutics for breast cancer, tumor-related mortality has remained high, especially in TNBC, due to limited therapeutic options, drug resistance, and metastasis [2]. While it accounts for around 15% of breast cancer cases, TNBC is considered to be the most aggressive subtype with the worst outcome [3]. Therefore, a better understanding of the biology of TNBC could open a new window for therapeutic intervention that could halt the disease progression and improve survival outcomes. ...
Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascinKD+NORF) and rescue (fascinKD+FORF) in the naturally fascin-positive (fascinpos+NORF) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography–mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascinpos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascinKD+NORF counterparts. Fascin rescue (fascinKD+FORF) revealed 2710 significantly dysregulated cellular metabolites compared to fascinKD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascinKD+FORF and fascinpos+NORF were significantly dysregulated in the fascinKD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression.
... To test whether lowering systemic glucose could affect hypoxic tumors, we applied the combination regimen of a ketogenic diet and metformin to two mouse models of triple-negative breast cancer (TNBC). TNBC often metastasizes, and is ultimately responsible for more than 90% of breast cancer deaths [41]. As TNBC is genetically heterogeneous, effective therapies are lacking [42]. ...
Background
Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.
Methods
To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC).
Results
Here, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms.
Conclusion
This preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.
... The triple-negative breast cancer (TNBC) is a prevalent form of common cancer among women worldwide, making up 15%-20% of all cases (Derakhshan & Reis-Filho, 2022;Hudis & Gianni, 2011). Due to the absence of effective therapeutic targets, chemotherapy remains the primary treatment modality for TNBC. ...
2′,4′‐Dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC) is a typical and abundant chalcone compound from the buds of Cleistocalyx operculatus, which is well‐known for its edible and medicinal qualities. In this study, DMC showed effective cell cycle arrest at G2/M on MDA‐MB‐231 cells, though dual impacts, including the inhibition of microtubule polymerization through binding to β‐tubulin and the stimulation of reactive oxygen species (ROS) production by inhibiting catalase activity. The increased ROS level inhibited PI3K/Akt/mTOR pathway and further suppressed the expression level of Cdc2, Cdc25C, and Cyclin B1, alongside stimulated the expression level of p21 and p27. Above 29.5% MDA‐MB‐231 cells were arrested at G2/M phase, subsequently undergoing apoptosis due to heightened levels of apoptosis‐related proteins Bax and caspase 3. In summary, this study demonstrated that DMC concomitantly plays dual roles in apoptotic inducing by inhibiting the ROS consumption and microtubules formation in triple‐negative breast cancer cells.
... The antioxidant capacity of HUE was assessed using the free-radical-scavenging activity of DPPH (Sigma-Aldrich Co., St. Louis, MO, USA). Different concentrations of HUE (5,10,25,50,100,200, and 400 µg/mL) were added to 0.5 mL of DPPH solution (from a stock of 0.5 mM in methanol) and 3 mL of methanol and incubated in the dark at room temperature for 30 min. The absorbance was then measure at 517 nm using an ELISA microplate reader (Thermo Scientific MULTISKAN GO, Waltham, MA, USA). ...
Natural remedies have been indispensable to traditional medicine practices for generations, offering therapeutic solutions for various ailments. In modern times, these natural products continue to play a pivotal role in the discovery of new drugs, especially for cancer treatment. The marine ecosystem offers a wide range of plants with potential anticancer activities due to their distinct biochemical diversity and adaptation to extreme situations. The seagrass Halodule uninervis is rich in diverse bioactive metabolites that bestow the plant with various pharmacological properties. However, its anticancer activity against invasive triple-negative breast cancer (TNBC) is still poorly investigated. In the present study, the phytochemical composition of an ethanolic extract of H. uninervis (HUE) was screened, and its antioxidant potential was evaluated. Moreover, the anticancer potential of HUE against MDA-MB-231 cells was investigated along with the possible underlying mechanisms of action. Our results showed that HUE is rich in diverse phytochemicals that are known for their antioxidant and anticancer effects. In MDA-MB-231 cells, HUE targeted the hallmarks of cancer, including cell proliferation, adhesion, migration, invasion, and angiogenesis. The HUE-mediated anti-proliferative and anti-metastatic effects were associated with the downregulation of the proto-oncogenic STAT3 signaling pathway. Taken together, H. uninervis could serve as a valuable source for developing novel drugs targeting TNBC.
... Triple-negative breast cancer (TNBC) is an aggressive malignancy associated with poor prognosis and high risk of early relapse (1). TNBCs are heavily infiltrated by immune cells (2), and a high tumor-infiltrating lymphocyte count has been associated with improved survival (3)(4)(5), providing a biological rationale for the use of immune checkpoint blockade in TNBC. ...
As indications for immune checkpoint inhibitors for breast cancer continue to expand, rare toxicities will emerge that require careful consideration and multidisciplinary management. We report the case of a 40-year-old female receiving neoadjuvant pembrolizumab and chemotherapy for locally advanced triple-negative breast cancer who developed cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH). CRS/HLH secondary to pembrolizumab are scarcely documented in the literature and, to our knowledge, have never been reported in the context of neoadjuvant treatment for breast cancer.
... Consequently, conventional chemotherapy persists as the primary treatment for metastatic TNBC. However, significant drawbacks such as treatment-related side effects, drug resistance, and limited progression-free survival are major hindrances to its widespread application (Hudis and Gianni, 2011;Jhan and Andrechek, 2017). ...
Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.
... Although extensively applied in anti-cancer treatments [10], chemotherapy has limitations that significantly decrease its efficacy, including poor bio-availability, rapid blood clearance, non-selective distribution, and drug resistance [11,12]. A retrospective study found that the objective response (OR) rate of platinum-based drugs in CRC patients was less than 45% [13], while the pathological complete response (PCR) rate in breast cancer patients was less than 25% [14]. The non-selective cytotoxic effects of chemotherapeutic drugs can also lead to multiple side effects, including short-and long-term treatmentrelated adverse events (AEs) such as weight loss, marrow suppression, skeletal muscle loss, psychiatric complications, and a variety of gastrointestinal symptoms [15,16]. ...
The involvement of the gut microbiota in anti-cancer treatment has gained increasing attention. Alterations to the structure and function of the gut bacteria are important factors in the development of cancer as well as the efficacy of chemotherapy. Recent studies have confirmed that the gut microbiota and related metabolites influence the pharmacological activity of chemotherapeutic agents through interactions with the immune system. This review aims to summarize the current knowledge of how malignant tumor and chemotherapy affect the gut microbiota, how the gut microbiota regulates host immune response, and how interactions between the gut microbiota and host immune response influence the efficacy of chemotherapy. Recent advances in strategies for increasing the efficiency of chemotherapy based on the gut microbiota are also described. Deciphering the complex homeostasis maintained by the gut microbiota and host immunity provides a solid scientific basis for bacterial intervention in chemotherapy.
... Breast cancers that are HER2-enriched account for 10-15% of all cases. It is distinguished by strong HER2 expression in the absence of ER and PR (54)(55)(56)(57). However, TNBC accounts for~15% of all breast cancers diagnosed worldwide and is the most challenging in comparison to other groups of BC (53, 55,58). ...
Recent advancements in genetic engineering have made it possible to modify Natural Killer (NK) cells to enhance their ability to fight against various cancers, including solid tumors. This comprehensive overview discusses the current status of genetically engineered chimeric antigen receptor NK-cell therapies and their potential for treating solid tumors. We explore the inherent characteristics of NK cells and their role in immune regulation and tumor surveillance. Moreover, we examine the strategies used to genetically engineer NK cells in terms of efficacy, safety profile, and potential clinical applications. Our investigation suggests CAR-NK cells can effectively target and regress non-hematological malignancies, demonstrating enhanced antitumor efficacy. This implies excellent promise for treating tumors using genetically modified NK cells. Notably, NK cells exhibit low graft versus host disease (GvHD) potential and rarely induce significant toxicities, making them an ideal platform for CAR engineering. The adoptive transfer of allogeneic NK cells into patients further emphasizes the versatility of NK cells for various applications. We also address challenges and limitations associated with the clinical translation of genetically engineered NK-cell therapies, such as off-target effects, immune escape mechanisms, and manufacturing scalability. We provide strategies to overcome these obstacles through combination therapies and delivery optimization. Overall, we believe this review contributes to advancing NK-cell-based immunotherapy as a promising approach for cancer treatment by elucidating the underlying mechanisms, evaluating preclinical and clinical evidence, and addressing remaining challenges.
... However, there are notable variations in its subtypes between younger and older women. Specifically, there is an elevated prevalence of basal-like, apocrine, and neuroendocrine TNBC in younger compared to older women (Hudis and Gianni, 2011). Additionally, African American and Hispanic women are at a higher risk of being diagnosed with TNBC, with a poorer prognosis shown by African American women compared to other ethnic groups (Dietze et al., 2015). ...
Objectives: Triple-negative breast cancer (TNBC) poses a significant challenge due to the lack of reliable prognostic gene signatures and an understanding of its immune behavior. Methods: We analyzed clinical information and mRNA expression data from 162 TNBC patients in TCGA-BRCA and 320 patients in METABRIC-BRCA. Utilizing weighted gene coexpression network analysis, we pinpointed 34 TNBC immune genes linked to survival. The least absolute shrinkage and selection operator Cox regression method identified key TNBC immune candidates for prognosis prediction. We calculated chemotherapy sensitivity scores using the “pRRophetic” package in R software and assessed immunotherapy response using the Tumor Immune Dysfunction and Exclusion algorithm. Results: In this study, 34 survival-related TNBC immune gene expression profiles were identified. A least absolute shrinkage and selection operator-Cox regression model was used and 15 candidates were prioritized, with a concomitant establishment of a robust risk immune classifier. The high-risk TNBC immune groups showed increased sensitivity to therapeutic agents like RO-3306, Tamoxifen, Sunitinib, JNK Inhibitor VIII, XMD11-85h, BX-912, and Tivozanib. An analysis of the Search Tool for Interaction of Chemicals database revealed the associations between the high-risk group and signaling pathways, such as those involving Rap1, Ras, and PI3K-Akt. The low-risk group showed a higher immunotherapy response rate, as observed through the tumor immune dysfunction and exclusion analysis in the TCGA-TNBC and METABRIC-TNBC cohorts. Conclusion: This study provides insights into the immune complexities of TNBC, paving the way for novel diagnostic approaches and precision treatment methods that exploit its immunological intricacies, thus offering hope for improved management and outcomes of this challenging disease.
... Tailoring treatment to an individual patient's specific cancer characteristics contributes to the effectiveness and safety of therapy. 31 Initiating treatment promptly after diagnosis helps prevent the progression of the disease. Delayed treatment may lead to the advancement of the cancer, which can decrease treatment effectiveness and pose greater risks to the patient. ...
Purpose
The complex nature of breast cancer demands flexible and adaptable principles that can account for the diverse characteristics and evolving conditions of each patient. However, there are no common breast cancer treatment agility principles that can influence policies and direct breast cancer professionals and healthcare providers into enhancing the delivery of health outcomes to patients under these conditions along with continuous rapid improvements in breast cancer treatment plan design. The incorporation of agile principles from software engineering offers a promising avenue for enhancing patient care. This research is conducted to identify breast cancer treatment agility principles adopted from the software engineering field and to validate their conformance to agility through work reported from literature in breast cancer treatment context.
Material and Methods
The authors applied a structured research methodology that involved interviews for eliciting and validating twelve agility principles from oncologists. Discussion of each principle is reflected using work reported from literature as a form of validation. Finally, a domain expert reviewed the literature-driven validation for each of the twelve identified breast cancer treatment agile principle to finally validate their conformance to agility and provide results.
Results
This work resulted twelve validated agility principles for breast cancer treatment and classified whether they are meeting, partially-(hybrid), or not meeting agility. Seven out of the twelve agile principles resulted as meeting agility, where the remaining five principles resulted as partially meeting agility. None of them is recorded as not meeting agility.
Conclusion
The work contributes to forming an agile mindset that can empower breast cancer professionals to optimize treatment plans, enhance patient experiences, and continuously improve the quality of care. The twelve identified agile principles are anticipated to contribute to driving more efficient oncology practices, policies, and protocols. It is concluded that the breast cancer treatment agility principles are not limited to twelve.
... About 15% of breast cancers do not express estrogen (ER) or progesterone receptor (PgR) expression (≤ 1%) or show human epidermal growth factor receptor 2 (HER 2) overexpression or amplification [1,2]. These triple negative breast cancers (TNBCs) usually have an aggressive tumor biology associated with a young age at diagnosis of less than 40 years [3]. Most TNBCs not only metastasize early in the course of the disease, but tend to develop prognostically unfavorable visceral and central nervous system metastases [4]. ...
Purpose
The optimal time to initiation of adjuvant chemotherapy (TTAC) for triple negative breast cancer (TNBC) patients is unclear. This study evaluates the association between TTAC and survival in TNBC patients.
Methods
We conducted a retrospective study using data from a cohort of TNBC patients diagnosed between January 1, 2010 to December 31, 2018, registered in the Tumor Centre Regensburg was conducted. Data included demographics, pathology, treatment, recurrence and survival. TTAC was defined as days from primary surgery to first dose of adjuvant chemotherapy. The Kaplan–Meier method was used to evaluate impact of TTAC on overall survival (OS) and 5-year OS.
Results
A total of 245 TNBC patients treated with adjuvant chemotherapy and valid TTAC data were included. Median TTAC was 29 days. The group receiving systemic therapy within 22 to 28 days after surgery had the most favorable outcome, with median OS of 10.2 years. Groups receiving systemic therapy between 29–35 days, 36–42 days, and more than 6 weeks after surgery had significantly decreased median survival, with median OS of 8.3 years, 7.8 years, and 6.9 years, respectively. Patients receiving therapy between 22–28 days had significantly better survival compared to those receiving therapy between 29–35 days (p = 0.043), and patients receiving therapy after 22–28 days also demonstrated significantly better survival compared to those receiving therapy after more than 43 days (p = 0.033).
Conclusion
Timing of adjuvant systemic therapy can influence OS in TNBC patients. Efforts should be made to avoid unnecessary delays in administering chemotherapy to ensure timely initiation of systemic therapy and optimize patient outcomes.
... In our patient, the breast tumor was predominantly sarcomatous (>80% tumor mass), and in hindsight we wondered if early initiation of sarcoma-specific therapy would have provided benefits beyond mastectomy with confirmation of cancer-free lymph nodes. Retrospective studies suggest that breast sarcoma behaves comparably to other soft tissue sarcomas, therefore proposed treatment regimens have been extrapolated from meta-analyses which detect a moderate survival advantage (11% increase in 10-year overall survival compared to resection alone) of short-course intra-arterial or intravenous infusion of doxorubicin +/-iphosphamide; however, marginal efficacy and significant morbidity highlights the need for development of better pharmacologic options [13][14][15][16]. Due to the paucity of reports and lack of prospective clinical trials, there is currently no consensus on the optimal treatment protocol. ...
A 69-year-old female with a history of breast carcinoma presented with a large non-obstructive soft tissue mass in the small bowel radiologically suggestive of sarcoma. She also had multiple hepatic cystic lesions, bilateral adrenal masses, a blastic iliac bone lesion, and a left lung mass consistent with metastases. The lung mass was biopsied and revealed a spindle cell tumor positive for vimentin, smooth muscle actin (SMA), and BCL-2. History of prior breast carcinoma was investigated and it was found to have been reported as metaplastic carcinoma with a prominent spindle cell sarcomatous component. Pathological analysis of the small bowel tumor was consistent with multiple metastases. Metaplastic breast carcinoma is more aggressive than ductal carcinoma, with larger tumor size, higher grade, more distant metastases, and poor prognosis. These tumors are usually negative for mucin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), complicating diagnosis and management. It is important to distinguish metaplastic breast carcinoma and initiate an individualized treatment protocol to avoid a devastating outcome.
... A lot of patients benefit from these treatments, the cure rate, disease-free survival, and overall survival have been improved significantly through standardized systemic treatment, but there are still some exceptions. Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancers, which is characterized by a lack of over-expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) (Hudis and Gianni 2011). TNBC tends to be more aggressive and highly heterogeneous, which makes it the subtype with the worst prognosis among all breast cancers (Garrido-Castro et al. 2019;Gazinska et al. 2013). ...
Background
Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for ⁸⁹Zr and ¹⁷⁷Lu radiolabelling, respectively. The theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model.
Results
The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (P < 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [¹⁷⁷Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [¹⁷⁷Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (P < 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies.
Conclusion
As a drug platform for radiotheranostics, ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003.
... TNBC poses a significant medical challenge due to its unfavorable prognosis and limited therapeutic options (124). Mesothelin, a membrane protein with limited normal tissue expression but frequently elevated levels in a substantial portion of TNBC cases, has garnered attention as a promising target for therapy (125). ...
Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa.
... The overlap ratio can be as high as 60-90% between basal-like breast cancer (BLBC) and triple negative breast cancer (without expression of hormonal receptors) (TNBC), compared to only 11.5% between non-TNBC and BLBC [2,4]. High risk early triple-negative breast cancer is frequently associated with early recurrence and high mortality [5]. In this subgroup of aggressive breast cancer, neoadjuvant chemotherapy is the preferred treatment approach [6]. ...
(1) Background: Triple negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting high level of recurrence and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis related R-packages were developed for integrative transcriptome to analyze transcriptome datasets: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), breast tumors with clinical data (TCGA and METABRIC cohorts). Protein level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers up-regulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated to overall survival. Breast tumors presenting high expression of CD274 up-regulated some ferroptosis drivers associated to prognosis: IDO1, IFNG and TNFAIP3. CD274-ferroptosis-driver score computed on breast tumor transcriptome stratified patients on their prognosis: low score was observed in basal subgroup with higher level of recurrent risk scores: oncotypeDx, ggi and gene70 scores. In METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found overexpressed in TNBC subgroup. CD274-ferroptosis-driver score was found associated to overall survival independently of TNM classification and age diagnosis. Tumor expression of CD274, TNFAIP3, IFNG and IDO1 in biopsy of breast ductal carcinoma was confirmed at protein level (4) Conclusion: Ferroptosis inducers up-regulate PD-L1 in TNBC cells, known as effective target of immunotherapy in high risk early TNBC which received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. CD274-ferroptosis driver score is associated to prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested in recurrent TNBC.
... [37][38][39] Unfortunately, TNBC is a heterogeneous disease itself, consisting of multiple entities with distinct histopathological, transcriptomic, and genomic features, 40 leading to challenges in finding appropriate drugs or drug combinations for individuals with TNBC. [41][42][43] In addition to the diseaselevel complexity with the highly heterogeneous cancer cell populations, the desmoplastic stroma components in tumor microenvironment (TME) are multifaceted and can influence the growth, invasion, and drug sensitivity of tumor cells. The stromal tissue, which is a complex environment that stores numerous growth factors and cytokines, can greatly impact tumor growth and drug response. ...
Microphysiological systems (MPSs), also known as organ-on-chip or disease-on-chip, have recently emerged to reconstitute the in vivo cellular microenvironment of various organs and diseases on in vitro platforms. These microfluidics-based platforms are developed to provide reliable drug discovery and regulatory evaluation testbeds. Despite recent emergences and advances of various MPS platforms, their adoption of drug discovery and evaluation processes still lags. This delay is mainly due to a lack of rigorous standards with reproducibility and reliability, and practical difficulties to be adopted in pharmaceutical research and industry settings. This review discusses the current and potential use of MPS platforms in drug discovery processes while considering the context of several key steps during drug discovery processes, including target identification and validation, preclinical evaluation, and clinical trials. Opportunities and challenges are also discussed for the broader dissemination and adoption of MPSs in various drug discovery and regulatory evaluation steps. Addressing these challenges will transform long and expensive drug discovery and evaluation processes into more efficient discovery, screening, and approval of innovative drugs.
... The overlap ratio can be as high as 60-90% between basal-like breast cancer (BLBC) and triple-negative breast cancer (without expression of hormonal receptors) (TNBC), compared to only 11.5% between non-TNBC and BLBC [2,4]. High-risk early triple-negative breast cancer is frequently associated with early recurrence and high mortality [5]. In this subgroup of aggressive breast cancer, neo-adjuvant chemotherapy is the preferred treatment approach [6]. ...
Simple Summary
Triple-negative breast cancer (TNBC) is characterized by a quick and high rate of recurrence. The benefits from neo-adjuvant chemotherapy associated with anti-PDL1 have been shown to be efficient in this aggressive form of breast cancer. Ferroptosis inducers (erastin/RSL3) induced the upregulation of CD274 in TNBC cells. Basal and TNBC subtypes of breast cancers overexpressed CD274 conjointly with three ferroptosis drivers: TNFAIP3, IFNG and IDO1 (IDO1: inhibitory immune checkpoint). These tumors present higher levels of recurrence. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested in recurrent TNBC.
Abstract
(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.
... TNBC often metastasize which is ultimately responsible for more than 90% of breast cancer deaths (41). ...
BACKGROUND
Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.
METHODS
To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a controlled reduction in systemic glucose by combining dietary carbohydrate restriction, using a ketogenic diet, with gluconeogenesis inhibition, using metformin, on two mouse models of triple-negative breast cancer (TNBC).
RESULTS
We confirmed that MET − 1 breast cancer cells require abnormally high glucose concentrations to survive in a hypoxic environment in vitro. Then, we showed that, compared to a ketogenic diet or metformin alone, animals treated with the combination regimen showed significantly lower tumor burden, higher tumor latency and slower tumor growth. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse model by 31 days, which is approximately equivalent to 3 human years.
CONCLUSION
This is the first preclinical study to demonstrate that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types, one that can also augment existing treatment options to improve patient outcomes.
... Only non-specific treatments, such as surgery, radiation, and chemotherapy, can be offered, even though they are less specific and may have harsh side effects [2,4]. The absence of hormonal receptors paired with an enriched CD44 + CD24 − breast cancer stem cell (BCSC) population drives the chemoresistant, radioresistant, and aggressive nature of TNBC [2,3,5]. Therefore, the search for alternative treatment regimens for TNBC patients is critical. ...
Simple Summary
TNBC is an aggressive subtype of breast cancer that responds differently to treatment. SLFN12 expression correlates with better survival in TNBC patients, but there is no known treatment to upregulate SLFN12. This study indicates that IFN-α2 treatment induces SLFN5, SLFN11, SLFN12, SLFN12-Like, SLFN13, and SLFN14 expression in TNBC while simultaneously reducing cell viability. However, IFN-α2 does not work through SLFN12 exclusively but rather through the SLFN family as a whole. Following simultaneous SLFN knockdown, IFN-α2 signaling initiates a complex signaling cascade among Schlafen family members in TNBC.
Abstract
Triple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival, yet no treatment is known to upregulate SLFN12 in TNBC. We hypothesized that Interferon-α (IFN-α2) upregulates SLFN12 in TNBC, subsequently reducing cell viability. We utilized short hairpin adenovirus to knockout SLFN12 (AdvShSLFN12) in MDA-MB-231, Hs-578T, and BT-549 TNBC cells. Cells were treated with AdvShSLFN12 and IFN-α2. After treatment, TNBC cell viability, SLFN family mRNA, and protein expression were analyzed. Treating TNBC cells with IFN-α2 increased SLFN12 expression and reduced cell viability. However, when AdvShSLFN12 knocked down SLFN12 during IFN-α2 treatment, TNBC cell viability was still reduced. We, therefore, investigated the potential involvement of other SLFN members IFN-α2 effects on cell viability. IFN-α2 increased SLFN5, SLFN12-Like, and SLFN14 but not SLFN11 or SLFN13. During AdvShSLFN12 + IFN-α2 treatment, the expressions of SLFN5, SLFN12-Like, and SLFN14 further increased. However, when siRNA knocked down SLFN5, SLFN12-Like, and SLFN14, the IFN-α2 reduction in viability was blunted. Although the interpretation of these results may be limited by the potential interactions between different siRNAs, these data suggest a complex regulatory signaling cascade among SLFN family members. Targeting this cascade to manipulate SLFN levels may, in the future, offer the potential to manipulate the chemosensitivity of TNBC tumors.
... Due to a lack of effective targeting therapies (Tang et al., 2016), treatment of TNBC heavily relies on conventional chemotherapy, such as Taxanes (paclitaxel, docetaxel, cabazitaxel, and abraxane) as the standard of care (Hudis and Gianni, 2011;Park et al., 2018). Taxanes, such as paclitaxel, produce their efficacy by targeting and stabilizing microtubules during the G2-M phase of the cell cycle, thereby inhibiting the depolymerization of microtubules into soluble tubulin (Malla et al., 2022b). ...
Introduction: This study presents a microfluidic tumor microenvironment (TME) model for evaluating the anti-metastatic efficacy of a novel thienopyrimidines analog with anti-cancer properties utilizing an existing commercial platform. The microfluidic device consists of a tissue compartment flanked by vascular channels, allowing for the co-culture of multiple cell types and providing a wide range of culturing conditions in one device.
Methods: Human metastatic, drug-resistant triple-negative breast cancer (TNBC) cells (SUM159PTX) and primary human umbilical vein endothelial cells (HUVEC) were used to model the TME. A dynamic perfusion scheme was employed to facilitate EC physiological function and lumen formation.
Results: The measured permeability of the EC barrier was comparable to observed microvessels permeability in vivo. The TNBC cells formed a 3D tumor, and co-culture with HUVEC negatively impacted EC barrier integrity. The microfluidic TME was then used to model the intravenous route of drug delivery. Paclitaxel (PTX) and a novel non-apoptotic agent TPH104c were introduced via the vascular channels and successfully reached the TNBC tumor, resulting in both time and concentration-dependent tumor growth inhibition. PTX treatment significantly reduced EC barrier integrity, highlighting the adverse effects of PTX on vascular ECs. TPH104c preserved EC barrier integrity and prevented TNBC intravasation.
Discussion: In conclusion, this study demonstrates the potential of microfluidics for studying complex biological processes in a controlled environment and evaluating the efficacy and toxicity of chemotherapeutic agents in more physiologically relevant conditions. This model can be a valuable tool for screening potential anticancer drugs and developing personalized cancer treatment strategies.
... Due to a lack of effective targeting therapies (Tang et al., 2016), treatment of TNBC heavily relies on conventional chemotherapy, such as Taxanes (paclitaxel, docetaxel, cabazitaxel, and abraxane) as the standard of care (Hudis and Gianni, 2011;Park et al., 2018). Taxanes, such as paclitaxel, produce their efficacy by targeting and stabilizing microtubules during the G2-M phase of the cell cycle, thereby inhibiting the depolymerization of microtubules into soluble tubulin (Malla et al., 2022b). ...
Introduction: This study presents a microfluidic tumor microenvironment (TME) model for evaluating the anti-metastatic efficacy of a novel thienopyrimidines analog with anti-cancer properties utilizing an existing commercial platform. The microfluidic device consists of a tissue compartment flanked by vascular channels, allowing for the co-culture of multiple cell types and providing a wide range of culturing conditions in one device. Methods: Human metastatic, drug-resistant triple-negative breast cancer (TNBC) cells (SUM159PTX) and primary human umbilical vein endothelial cells (HUVEC) were used to model the TME. A dynamic perfusion scheme was employed to facilitate EC physiological function and lumen formation. Results: The measured permeability of the EC barrier was comparable to observed microvessels permeability in vivo. The TNBC cells formed a 3D tumor, and co-culture with HUVEC negatively impacted EC barrier integrity. The microfluidic TME was then used to model the intravenous route of drug delivery. Paclitaxel (PTX) and a novel non-apoptotic agent TPH104c were introduced via the vascular channels and successfully reached the TNBC tumor, resulting in both time and concentration-dependent tumor growth inhibition. PTX treatment significantly reduced EC barrier integrity, highlighting the adverse effects of PTX on vascular ECs. TPH104c preserved EC barrier integrity and prevented TNBC intravasation. CITATION Sigdel I, Ofori-Kwafo A, Heizelman RJ III, Nestor-Kalinoski A, Prabhakarpandian B, Tiwari AK and Tang Y (2023), Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines.
... 64 Dysregulation of lncRNAs is associated with critical functions in regulating chemoresistance in TNBC. 65,66 Though they are implicated in both inhibition and promotion of chemoresistance, by acting as ceRNA most of them stimulate chemoresistance in TNBC, thereby sponging miRNAs functionality in TNBC (Table 2). LncRNAs target drug efflux pump of ATP-binding cassette (ABC) transporter superfamily or and mediate MDR (multidrug resistance) in various cancers, including TNBC ( Figure 2). ...
Introduction
Long noncoding RNAs (lncRNAs) play crucial roles in regulating various hallmarks in cancers. Triple‐negative (Estrogen receptor, ER; Human epidermal growth factor receptor 2, HER2; Progesterone receptor, PR) breast cancer (TNBC) is the most aggressive form of breast cancers with a poor prognosis and no available molecular targeted therapy.
Methods
We reviewed the current literature on the roles of lncRNAs in the pathogenesis, therapy resistance, and prognosis of patients with TBNC.
Results
LncRNAs are associated with TNBC pathogenesis, therapy resistance, and prognosis. For example, lncRNAs such as small nucleolar RNA host gene 12 (SNHG12), highly upregulated in liver cancer (HULC) HOX transcript antisense intergenic RNA (HOTAIR), lincRNA‐regulator of reprogramming (LincRNA‐ROR), etc., are aberrantly expressed in TNBC and are involved in the pathogenesis of the disease. LncRNAs act as a decoy, scaffold, or sponge to regulate the expression of genes, miRNAs, and transcription factors associated with pathogenesis and progression of TNBC. Moreover, lncRNAs such as ferritin heavy chain 1 pseudogene 3 (FTH1P3), BMP/OP‐responsive gene (BORG) contributes to the therapy resistance property of TNBC through activating ABCB1 (ATP‐binding cassette subfamily B member 1) drug efflux pumps by increasing DNA repair capacity or by inducing signaling pathway involved in therapeutic resistance.
Conclusion
In this review, we outline the functions of various lncRNAs along with their molecular mechanisms involved in the pathogenesis, therapeutic resistance of TBNC. Also, the prognostic implications of lncRNAs in patients with TNBC is illustrated. Moreover, potential strategies targeting lncRNAs against highly aggressive TNBC is discussed in this review.
... In patients with secondary metastatic disease, the tumor histologically tends to be triple-negative for hormone receptors [13]. In our study, the rate of triple negativity was significantly higher in Group 2 (p=0.007). ...
... However, the reason behind is still not fully understood. In this study, we used the most commonly studied TNBC cell line, MDA-MB-231, which was established in the 1970s and has been extensively studied as one of the best triplenegative breast cancer cells (51)(52)(53). Initially, we evaluated the cytotoxicity of the newly prepared citrate-conjugated gold FIGURE 10 Schematic representation illustrating the therapeutic potential of AuNPs investigated in this study. IFN-g activated NF-kB mediated signaling in TNBC cells through SOCS1is inhibited by AuNP via negative regulation of has-miR155-5p. ...
Objective
Triple-negative breast cancer (TNBC) is a very aggressive form of cancer that grows and spreads very fast and generally relapses. Therapeutic options of TNBC are limited and still need to be explored completely. Gold nanoparticles conjugated with citrate (citrate-AuNPs) are reported to have anticancer potential; however, their role in regulating microRNAs (miRNAs) in TNBC has never been investigated. This study investigated the potential of citrate-AuNPs against tumorigenic inflammation via modulation of miRNAs in TNBC cells.
Methods
Gold nanoparticles were chemically synthesized using the trisodium-citrate method and were characterized by UV-Vis spectrophotometry and dynamic light scattering studies. Targetscan bioinformatics was used to analyze miRNA target genes. Levels of miRNA and mRNA were quantified using TaqMan assays. The pairing of miRNA in 3'untranslated region (3'UTR) of mRNA was validated by luciferase reporter clone, containing the entire 3'UTR of mRNA, and findings were further re-validated via transfection with miRNA inhibitors.
Results
Newly synthesized citrate-AuNPs were highly stable, with a mean size was 28.3 nm. The data determined that hsa-miR155-5p is a direct regulator of SOCS1 (suppressor-of-cytokine-signaling) expression and citrate-AuNPs inhibits SOCS1 mRNA/protein expression via modulating hsa-miR155-5p expression. Transfection of TNBC MDA-MB-231 cells with anti-miR155-5p markedly increased SOCS1 expression (p<0.001), while citrate-AuNPs treatment significantly inhibited anti-miR155-5p transfection-induced SOCS1 expression (p<0.05). These findings were validated by IFN-γ-stimulated MDA-MB-231 cells. Moreover, the data also determined that citrate-AuNPs also inhibit IFN-γ-induced NF-κB p65/p50 activation in MDA-MB-231 cells transfected with anti-hsa-miR155-5p.
Conclusion
Newly generated citrate-AuNPs were stable and non-toxic to TNBC cells. Citrate-AuNPs inhibit IFN-γ-induced SOCS1 mRNA/protein expression and deactivate NF-κB p65/50 activity via negative regulation of hsa-miR155-5p. These novel pharmacological actions of citrate-AuNPs on IFN-γ-stimulated TNBC cells provide insights that AuNPs inhibit IFN-γ induced inflammation in TNBC cells by modulating the expression of microRNAs.
Neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab have been established as the optimal systemic therapies for patients with early stage triple-negative breast cancer (TNBC); however, their efficacy and feasibility in the Japanese population remain unexplored.
This study included patients with early stage TNBC or low estrogen receptor (ER) positivity (1–9%) with human epidermal growth factor receptor type 2- (HER2-) negative breast cancer who received neoadjuvant pembrolizumab plus chemotherapy from October 2022 at Cancer Institute Hospital of Japanese Foundation for Cancer Research. Information regarding clinicopathological features, systemic therapy, treatment outcomes, and adverse events of patients who underwent surgery by February 2024 was retrospectively collected.
Overall, 69 patients received neoadjuvant pembrolizumab plus carboplatin and paclitaxel therapy, and 46 underwent surgery by February 2024. The median age of the patients was 53.5 years, and 80.4% and 19.6% had stage II and III disease, respectively. TNBC and ER-low HER2-negative breast cancer accounted for 82.6% and 17.4% cases, respectively. Overall pathological complete response rate was 56.5%, with 87.5% in patients with ER-low HER2-negative tumors. The completion rates for neoadjuvant pembrolizumab, chemotherapy, and pembrolizumab plus chemotherapy were 65.2%, 56.5%, and 52.2%, respectively. Furthermore, 80.4% and 15.2% of patients experienced grade 3 or higher treatment-related adverse events and immune-related adverse events, respectively, and 34% experienced unexpected hospitalization during neoadjuvant treatment.
The efficacy and safety profiles of neoadjuvant pembrolizumab plus chemotherapy in the Japanese population are consistent with previous reports. This regimen may have therapeutic potential against ER-low HER2-negative tumors and TNBC.
Cancer remains a major global health challenge, prompting the search for effective and less toxic treatments. Anethole, a bioactive compound found in essential oils of anise and fennel, commonly used as a food preservative, has recently garnered attention for its potential anti-cancer properties. This comprehensive review aims to systematically assess the anti-cancer effects of anethole, elucidating its mechanisms of action, pharmacokinetics, bioavailability, and synergistic potential with conventional cancer therapies. A detailed literature search was conducted across databases including PubMed, Embase, Scopus, Science Direct, Web of Science, and Google Scholar. Criteria for inclusion were experimental studies in peer-reviewed journals focusing on the anti-cancer properties of anethole. Extracted data included study design, intervention specifics, measured outcomes, and mechanistic insights. Anethole demonstrates multiple anti-cancer mechanisms, such as inducing apoptosis, causing cell cycle arrest, exhibiting anti-proliferative and anti-angiogenic effects, and modulating critical signaling pathways including NF-κB, PI3K/Akt/mTOR, and caspases. It enhances the efficacy of chemotherapeutic agents like cisplatin and doxorubicin while reducing their toxicity. In vitro and in vivo studies have shown its effectiveness against various cancers, including breast, prostate, lung, and colorectal cancers. Anethole shows significant potential as an anti-cancer agent, with its multi-faceted mechanisms of action and ability to synergize with existing chemotherapy. Further clinical research is essential to fully understand its therapeutic potential and application in oncology.
Background
Pegylated liposomal doxorubicin (PLD), epirubicin and pirarubicin are the main anthracyclines widely used in China. PLD demonstrates therapeutic response comparable to epirubicin and pirarubicin in neoadjuvant chemotherapy (NAC) of breast cancer.
Objectives
The objectives of our study were to retrospectively assess the real-world effectiveness and prognostic characteristics of PLD as NAC for HR ⩽ 10%/human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
Design
This was a retrospective study.
Methods
Our study enrolled patients with HR ⩽ 10%/HER2-negative breast cancer who received PLD-, epirubicin- or pirarubicin-based NAC from three centres in Hunan Province, China, between 2015 and 2022. We employed inverse probability of treatment weighting to balance the differences in patients’ characteristics among the PLD, epirubicin, and pirarubicin groups. The endpoints were pathological complete response (pCR), event-free survival (EFS), and overall survival (OS).
Results
A total of 267 patients were included. After NAC, the pCR rates in PLD group were superior to epirubicin group (PLD, 34.1%; epirubicin, 20.8%, p = 0.038). The differences in EFS (log-rank p = 0.99) and OS (log-rank p = 0.33) among the three groups were not statistically significant. Among the three groups, non-pCR patients had worse EFS than pCR patients (log-rank p = 0.014). For patients with pCR, the differences in EFS (log-rank p = 0.47) and OS (log-rank p = 0.38) were not statistically significant among the three groups, and the EFS (log-rank p = 0.59) and OS (log-rank p = 0.14) of non-pCR patients in the PLD group were similar to those in the epirubicin and pirarubicin groups.
Conclusion
PLD had a similar therapeutic response and prognosis compared to epirubicin or pirarubicin in NAC for patients with HR ⩽ 10%/HER2 negative breast cancer, which means that PLD represents a potential NAC option.
Background:
In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival.
Methods:
We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point.
Results:
Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab-chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group (P = 0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy.
Conclusions:
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
Background Information
The control of epithelial cell polarity is key to their function. Its dysregulation is a major cause of tissue transformation. In polarized epithelial cells,the centrosome is off‐centred toward the apical pole. This asymmetry determines the main orientation of the microtubule network and intra‐cellular traffic. However, the mechanism regulating centrosome positioning at the apical pole of polarized epithelial cells is still poorly undertood.
Results
In this study we used transcriptomic data from breast cancer cells to identify molecular changes associated with the different stages of tumour transformation. We correlated these changes with variations in centrosome position or with cell progression along the epithelial‐to‐mesenchymal transition (EMT), a process that involves centrosome repositioning. We found that low levels of epiplakin, desmoplakin and periplakin correlated with centrosome mispositioning in cells that had progressed through EMT or tissue transformation. We further tested the causal role of these plakins in the regulation of centrosome position by knocking down their expression in a non‐tumorigenic breast epithelial cell line (MCF10A). The downregulation of periplakin reduced the length of intercellular junction, which was not affected by the downregulation of epiplakin or desmoplakin. However, down‐regulating any of them disrupted centrosome polarisation towards the junction without affecting microtubule stability.
Conclusions
Altogether, these results demonstrated that epiplakin, desmoplakin and periplakin are involved in the maintenance of the peripheral position of the centrosome close to inter‐cellular junctions. They also revealed that these plakins are downregulated during EMT and breast cancer progression, which are both associated with centrosome mispositioning.
Significance
These results revealed that the down‐regulation of plakins and the consequential centrosome mispositioning are key signatures of disorganised cytoskeleton networks, inter‐cellular junction weakening, shape deregulation and the loss of polarity in breast cancer cells. These metrics could further be used as a new readouts for early phases of tumoral development.
EH domain‐containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear‐cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N‐terminal of EHD2 is attached to the cell membrane, while its C‐terminal binds to the actin‐binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.
Recently, immunotherapy has emerged as a promising and effective method for treating triple-negative breast cancer (TNBC). However, challenges still persist. Immunogenic cell death (ICD) is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells. Nevertheless, the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood. In this study, we observed dysregulation of the ICD process and verified the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To investigate the potential role of the ICD process in TNBC progression, we determined the ICD-dependent subtypes, and two were identified. Analysis of their distinct tumor immune microenvironment (TIME) and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune “cold” and “hot” phenotypes, respectively. In addition, we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability. The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identification of targeted effective agents for individualized clinical strategies.
Background
Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC.
Methods
Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper.
Findings
IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70–0.85], I² = 18%) and OS (pooled HR = 0.79, [0.73–0.85], I² = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10–1.50]) and BrighTNess (OR 1.57 [1.25–1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75–2.55], I² = 0%) and death (pooled HR = 1.99, 95% [0.84–4.73], I² = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis.
Interpretation
IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments.
Funding
This study received funding from: Associació Beca Marta Santamaria, European Union’s Horizon 2020 research and innovation and Marie Skłodowska–Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, 10.13039/501100004587Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, 10.13039/100001006Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM.
Despite advances in treatment and early detection, breast cancer remains one of the most common types of cancer and is the second leading cause of cancer death after lung cancer in women. Therefore, there is an urgent need to develop new biomarkers and therapeutic targets for the treatment of breast cancer. Based on gene expression profiles and subsequent screening performed in a preliminary study, kinesin family member 20B (KIF20B) was selected as a candidate target molecule, because it was highly and frequently expressed in all subtypes of breast cancer and barely detected in normal tissues. Reverse transcription‑quantitative PCR and western blotting revealed that KIF20B mRNA and protein expression levels were upregulated in most breast cancer cell lines but were scarcely expressed in normal mammary epithelial cells. Immunohistochemical staining of a tissue microarray showed that KIF20B was detected in 145 out of 251 (57.8%) breast cancer tissues. Strong KIF20B expression was significantly related to advanced pathological N stage. Moreover, patients with breast cancer and strong KIF20B expression exhibited a significantly worse prognosis than those with weak or negative KIF20B expression (P<0.0001, log‑rank test). In multivariate analysis, strong expression was an independent prognostic factor for patients with breast cancer. Furthermore, knockdown of KIF20B expression by small interfering RNA inhibited breast cancer cell proliferation and induced apoptosis. In addition, Matrigel cell invasion assays revealed that the invasiveness of breast cancer cells was significantly decreased by KIF20B silencing. Since KIF20B is an oncoprotein that is strongly expressed in highly malignant clinical breast cancer and serves a pivotal role in breast cancer cell proliferation, survival and invasion, KIF20B could be considered a candidate biomarker for prognostic prediction and a potential molecular target for developing new therapeutics, such as small molecule inhibitors, for a wide variety of breast cancers.
The treatment of early breast cancer is individualized based on the tumor biology, tumor stage, and individual factors. Medication-based treatment can be conducted as primary systemic treatment before or as adjuvant therapy after completing local treatment. Primary systemic treatment follows a two-step concept: based on the result of the postoperative histopathological assessment, the subsequent postneoadjuvant treatment can be adjusted and the risk of recurrence can be reduced. The selection and combination of substances in the postneoadjuvant setting are carried out on an individual risk-adapted basis, whereby achieving pathological complete remission (pCR) is of significant importance in addition to the tumor biology, initial tumor stage and genetic risk. As the treatment options are complex, these decisions should be made individually in the interdisciplinary tumor board both preoperatively and postoperatively, also in coordination with local treatment.
Triple-negative breast cancer (TNBC) represents the most lethal and treatment-resistant breast cancer subtype with limited treatment options. We previously identified a protein complex unique to TNBC 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 the interaction region of Cx26 attenuated tumor growth in pre-clinical models. We designed peptides based on Cx26 juxtamembrane domains and performed binding experiments with NANOG and FAK using surface plasmon resonance. Binding studies revealed that the Cx26 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. Peptides with high affinity were engineered with a cell-penetrating antennapedia sequence and assessed in functional assays including cell proliferation, tumorsphere formation, and in vivo tumor growth, and downstream signaling changes were measured. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumor growth and proliferation and induced cell death. Here, we provide proof-of-concept that a Cx26 peptide-based strategy inhibits growth and alters NANOG activity specifically in TNBC, indicating the therapeutic potential of this targeting approach.
Breast cancer is one of the most frequent causes of cancer death among women worldwide. In particular, triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype because it is characterized by the absence of molecular targets, thus making it an orphan type of malignancy. The discovery of new molecular druggable targets is mandatory to improve treatment success. In that context, non-coding RNAs represent an opportunity for modulation of cancer. They are RNA molecules with apparently no protein coding potential, which have been already demonstrated to play pivotal roles within cells, being involved in different processes, such as proliferation, cell cycle regulation, apoptosis, migration, and diseases, including cancer. Accordingly, they could be used as targets for future TNBC personalized therapy. Moreover, the peculiar characteristics of non-coding RNAs make them reliable biomarkers to monitor cancer treatment, thus, to monitor recurrence or chemoresistance, which are the most challenging aspects in TNBC. In the present review, we focused on the oncogenic or oncosuppressor role of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) mostly involved in TNBC, highlighting their mode of action and depicting their potential role as a biomarker and/or as targets of new non-coding RNA-based therapeutics.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6093.
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
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.
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.
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.
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.
Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.
Triple-negative breast cancer (TNBC) is a clinically relevant term referring to breast carcinomas that do not express the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 and became operational after human epidermal growth factor receptor type 2 testing was introduced. This is a challenging disease to treat because of the absence of a specific target, but these tumors are sensitive to chemotherapy. An improved understanding of the biology of TNBC has led to evaluation of DNA-damaging chemotherapy drugs, specifically, platinum compounds, and several targeted agents, including poly(ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors, angiogenesis inhibitors, microtubule inhibitors, Src inhibitors, checkpoint kinase I inhibitors, mammalian target of rapamycin inhibitors, androgen receptor blocker, tumor necrosis factor-related apoptosis-inducing ligand receptor agonists, and transforming growth fa