Outcomes In Triple-negative Breast Cancer Research Articles

Comprehensive characterization of fatty acid oxidation in triple-negative breast cancer: Focus on biological roles and drug modulation.

Triple-negative breast cancer (TNBC) presents an unmet medical challenge due to poor outcomes and limited treatment options. Metabolic signals are coupled to oncogenesis. Fatty acid oxidation (FAO) plays a crucial role in cancer initiation, progression, metastasis, and therapy resistance, but its precise functions and underlying molecular mechanisms in TNBC remain unclear. Here, we conducted a comprehensive study to investigate the biological roles and drug modulation of FAO in TNBC using data from The Cancer Genome Atlas (TCGA), Genomics of Drug Sensitivity in Cancer (GDSC), and Connectivity Map (CMap) databases. We found that altered FAO activity was not related to patient age, clinical stage, tumor mutational burden, microsatellite instability, or homologous recombination deficiency. Nevertheless, upregulated FAO activity correlated with poor prognosis, increased stemness, accelerated cell cycle progression, altered mutation rates of several top 20 most frequently mutated genes, as well as higher activity of pathways involving oncogenic signaling, cellular metabolism, protein turnover, and so forth. Elevated FAO activity also appeared to foster an immunosuppressive microenvironment, influence microbial composition, and confer resistance to chemotherapies. What's more, we identified several compounds that may regulate FAO activity, including the HDAC inhibitor chidamide, which induced FAO activation in TNBC cells. Co-treatment with an FAO inhibitor etomoxir enhanced the combined effects of chidamide with established chemotherapy drugs, as well as their efficacy as single agents in TNBC cells. In conclusion, FAO likely exerts pleiotropic biological effects in TNBC and modulating FAO may offer a promising strategy to improve therapeutic outcomes in TNBC.

A preliminary study on the prognostic significance of cysteine-rich EGF ligand domain 2 protein (CRELD2) in patients with triple negative breast cancer.

The cysteine-rich epidermal growth factor ligand domain 2 protein (CRELD2) is associated with pathways that regulate epithelial-to-mesenchymal transition, a critical process driving cancer metastasis. This study aimed to determine the prognostic value of CRELD2 status on survival outcomes in triple-negative breast cancer (TNBC). Seventy patients were included in the study. Thirty-four patients were metastatic, and 36 patients were non-metastatic. CRELD2 protein expression in tumor tissue was determined by immunohistochemical staining (IHC). The patients were divided into two groups: CRELD2 positive and negative groups. Clinicopathological features and survival outcomes were compared between the groups. In the survival analysis of the non-metastatic patient group, five-year overall survival (OS) rate was 91.7% in the CRELD2-positive patient group and 91% in the negative group (P = 0.91). Median progression free survival (PFS) was 9.4 (95% confidence interval [CI]: 6.4-12.4) months in the CRELD2-positive group and 11.9 (95% CI: 8.2-18.6) months in the CRELD2-negative group (P = 0.04). The median OS was 17.2 (95% CI: 13.7-22.3) months in the CRELD2-positive group and 24.7 (95% CI: 21.8-29.6) months in the CRELD2-negative group (P = 0.02). In multivariate analysis, CRELD2 status (negative vs positive) (hazard ratio [HR]: 0.50, 95% CI: 0.38-0.96, P = 0.02) was determined to be a risk factor for OS and CRELD2 status (negative vs positive) (HR: 0.82, 95% CI: 0.33-0.96, P = 0.01) was defined as a risk factor for PFS in patients with metastatic TNBC. This is the first clinical study to determine the effect of CRELD2 on survival and as a prognostic marker in patients with triple metastatic breast cancer. These results need to be validated prospectively with a large sample size.

Exploring the Prognostic Role of Trop-2, CD47, and CD163 Expression Levels on Survival Outcomes in Patients with Triple-Negative Breast Cancer.

Background: This study evaluated the prognostic impact of Trop-2, CD47, and CD163 expression on clinical outcomes in triple-negative breast cancer (TNBC) and investigated their interactions with tumor progression. Methods: A retrospective cohort of 92 patients with TNBC was analyzed. The expression scores for Trop-2, CD47, and CD163 were categorized as negative/low (0-3 points) or high (4-6 points). The primary endpoint was overall survival (OS). Results: The median age of the cohort was 50 years old. High Trop-2 expression was observed in 55.4% of the patients and was significantly associated with advanced disease stage (p < 0.001). High CD47 expression (44.6%) was correlated with advanced stage (p = 0.044), whereas high CD163 expression (45.7%) was associated with advanced stage (p = 0.021), absence of comorbidities (p = 0.022), and lower pT stage (p = 0.023). Moderate positive correlations were found between Trop-2 and CD47 (p = 0.022), Trop-2 and CD163 (p = 0.037), and CD47 and CD163 (p < 0.001), respectively. Kaplan-Meier survival analysis revealed that patients with low Trop-2 expression exhibited significantly prolonged OS (p = 0.021) and progression-free survival (PFS) (p = 0.026) compared to those with high Trop-2 expression. Univariate and multivariate analyses revealed significant associations between OS and PFS for Trop-2, lymphovascular invasion, and BRCA status. Conclusions: Trop-2 expression is a significant prognostic factor for TNBC and is correlated with worse outcomes. Although CD47 and CD163 showed trends for poorer prognosis, their significance was not confirmed. These findings offer promising prospects for future studies on combined antibody-drug conjugates (ADCs), as they may present opportunities to address multiple resistance mechanisms in the management of TNBC and enhance clinical outcomes.

A Three-agent Regimen for Triple Negative Breast Cancer Treatment.

Triple-negative breast cancer (TNBC) has a poor prognosis with current treatment options. Novel therapeutic strategies are urgently needed to enhance treatment outcomes for TNBC. This study evaluated the efficacy of a three-agent regimen compared to existing treatment regimens in a TNBC mouse model, and elucidated its potential mechanisms of action. The TNBC xenograft tumor mouse model was established using a 4T1 cell line in female BALB/c mice. Mice were treated with the three-agent regimen and other comparative treatments. Tumor volume was monitored to assess the anti-tumor effects. Biochemical and pathological evaluations were conducted to examine the impact of the regimen on anti-tumor immunity, anti- tumor angiogenesis, and tumor cell apoptosis. The three-agent regimen consisting of SIN+BEV+PAB demonstrated significant anti-tumor efficacy compared to controls, PAB alone, SIN+PAB, and BEV+PAB groups from day 9 of drug administration. The superior anti-tumor effect of SIN+BEV+PAB was primarily attributed to enhanced anti-tumor immunity, evidenced by increased percentages of CD4+ and CD8+ T cells, elevated IFN-γ levels, and decreased percentages of Tregs, reduced levels of TGF-β, IL-6, and IL-10. Additionally, the regimen showed potent anti-angiogenic effects by reducing VEGF expression and micro vessel density (MVD). Furthermore, it promoted tumor cell apoptosis through upregulation of BAX and cleaved caspase3, while downregulating Bcl2. These findings suggest that the novel three-agent combination of SIN+BEV+PAB may prove beneficial in improving treatment outcomes for patients with TNBC. The development of this regimen, which may be eligible for patent protection, could facilitate its introduction as a new therapeutic option for advanced TNBC in clinical practice.

Establishment and clinical application of a prognostic index for inflammatory status in triple-negative breast cancer patients undergoing neoadjuvant therapy using machine learning

ObjectiveThis study aims to establish a new prognostic index using machine learning models to predict the clinical outcomes of triple-negative breast cancer (TNBC) patients receiving neoadjuvant therapy.MethodsIn this study, we collected data from the electronic medical records system of Harbin Medical University Cancer Hospital to establish a training set of 501 breast cancer patients who received neoadjuvant therapy from January 2017 to December 2021. Additionally, we collected data from Harbin Medical University Affiliated Cancer Hospital, Harbin Medical University Affiliated Second Hospital, and Harbin Medical University Affiliated Sixth Hospital to establish a validation set of 1533 patients during the same period. All patients underwent blood tests, and the following inflammatory and immune indices were calculated for each patient: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammatory index (SII), systemic inflammatory response index (SIRI), and advanced lung cancer inflammation index (ALI). The observed outcomes included Disease-free survival (DFS) and overall survival (OS). Survival analysis was performed using Kaplan‒Meier survival curves, Cox survival analysis, propensity score matching analysis (PSM), and a nomogram to comprehensively investigate the impact of inflammatory status on patient survival.ResultsThe training set comprised 501 patients with a mean age of 48.63 (9.41) years, while the validation set comprised 1533 patients with a mean age of 49.01 (9.51) years. The formula for ANLR established through Lasso regression analysis on the training set is: ANLR index = NLR − 0.04 × ALB (g/L). In both the training and validation sets, ANLR was significantly associated with patient DFS and OS (all P < 0.05). Additionally, ANLR was found to be an independent prognostic factor in this study. PSM analysis further confirmed its significant correlation with patient DFS and OS (76 cases vs. 76 cases, χ2 = 2.179, P = 0.001 and χ2 = 2.063, P = 0.002). The nomogram containing ANLR also demonstrated high prognostic value. The C-index for the nomogram in the training set was 0.742 (0.619–0.886) for DFS and 0.758 (0.607–0.821) for OS, while in the validation set, the C-index was 0.733 (0.655–0.791) for DFS and 0.714 (0.634-0.800) for OS.ConclusionANLR was associated with the prognosis of TNBC patients receiving neoadjuvant therapy and could identify high-risk postoperative patients.

Prognostic impact of tumor‑associated stroma in triple-negative breast cancer.

To establish the histological categorization of tumor‑associated stroma (TAS) that reflects the biological behavior of triple-negative breast cancer (TNBC). One-hundred-and-twenty surgically resected cases of TNBC were examined. We histologically categorized the TAS in the invasive frontal region into two groups: mature stroma (MS) and immature stroma (IS). The designation of IS was applied for tumors in which the largest myxoid stroma filled a high-power magnification field. When there were no myxoid stroma that meet the criteria for IS, TAS was categorized as MS. The tumors with type MS were observed in 103 (85.8%) of patients, whereas 17 (14.2%) of patients had tumors with IS. In total, 72 out of 120 patients with TNBC exhibited high tumor-infiltrating lymphocytes (TILs) representing 60% of the cohort. The incidences of high TILs were 66% (68 out of 103) in the MS group but only 23.5% (4 of 17) in the IS group (p = 0.001). Progression-free survival (PFS) and overall survival (OS) curves were different between IS and MS groups (p < 0.001 each), and Cox multivariate regression analysis revealed that IS was an independent indicator for lower PFS and OS rates (p < 0.001; p = 0.008). Our findings suggest that TAS characteristics, particularly the distinction between IS and MS, play a significant role in the prognosis of TNBC. The presence of IS, associated with poor prognosis and low TILs, contrasts with the favorable outcomes observed in cases with MS. Understanding these TAS dynamics could aid in identifying patients with varying prognostic outcomes in TNBC, necessitating further research into the mechanisms behind these observations.

A TROP2/Claudin Program Mediates Immune Exclusion to Impede Checkpoint Blockade in Breast Cancer.

Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. Here, we demonstrate that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of emerging anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in Triple-Negative Breast Cancer (TNBC) through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and strongly associated with outcomes in TNBC. Loss-of-function and reconstitution experiments demonstrate TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of Sacituzumab govitecan (SG), enhances the anti-PD1 response associated with improved T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Thus, TROP2 controls an immune exclusion program that can be targeted to enhance immunotherapy response.

Combining ultrasound technology with targeted fucoidan/arginine-gelatin nanoparticles loaded with doxorubicin to enhance therapeutic efficacy and modulate bioeffects in drug-resistant triple-negative breast cancer.

Triple-negative breast cancer (TNBC) presents formidable challenges due to its aggressive nature and high recurrence rates, compounded by the involvement of epithelial-mesenchymal transition (EMT) in its progression and metastasis. Standard chemotherapy, which typically employs doxorubicin (DOX), remains a primary treatment approach. However, multidrug resistance (MDR) mechanisms, which include ATP-binding cassette transporters and EMT, contribute to treatment failures. Ultrasound has emerged as a promising modality among the various strategies explored to address MDR in TNBC. It serves as a diagnostic tool and holds therapeutic potential by inducing various biological effects depending on the exposure level. Targeted nanoparticles offer a means to enhance drug delivery efficiency. Our study aims to advance ultrasound technology combined with biocompatible nanoparticles using simplified preparation methods to improve treatment outcomes for drug-resistant TNBC. In particular, employing DOX-loaded fucoidan/arginine-gelatin nanoparticles facilitated the targeted delivery of chemotherapy drugs to tumors by effectively interacting with P-selectin, resulting in tumor growth inhibition. Furthermore, these nanoparticles mitigated MDR and EMT, particularly when combined with ultrasound treatment. This integrated approach of nanoparticle delivery with ultrasonography opens up a promising and innovative avenue for clinical cancer research.

Clinico-pathological Profile of Triple-negative Breast Cancer (TNBC) And Comparative Analysis Of Oncological Outcomes Of TNBC Vs. Non-TNBC: A Tertiary Care Centre Experience From Eastern India

Clinico-pathological Profile of Triple-negative Breast Cancer (TNBC) And Comparative Analysis Of Oncological Outcomes Of TNBC Vs. Non-TNBC: A Tertiary Care Centre Experience From Eastern India

Plant-derived extracellular vesicles release combined with systemic DOX exhibits synergistic effects in 3D bioprinted triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, lacking targeted therapeutic options. Hydrogels, particularly gelatin methacrylate (GelMA), have emerged as promising materials for localized drug delivery due to their biocompatibility and tunable properties. This study investigates a dual-delivery system for enhancing the treatment efficacy of triple-negative breast cancer (TNBC) using a combination of extracellular vesicles (EVs) derived from Citrus limon L. and the chemotherapeutic drug doxorubicin (DOX). We fabricated 3D bioprinted GelMA scaffolds to achieve localized and controlled release of EVs and evaluated their synergistic effects with systemic DOX delivery on both primary and metastatic 3D TNBC models.The GelMA scaffolds, especially those with 95 % methacrylation, exhibited higher stiffness, which enhanced their sustained release. Following 48-h incubation, the combination of EVs and DOX significantly increased cytotoxicity in the primary 3D TNBC model, reducing cell viability to approximately 30 % compared to controls. This was notably more effective than treatments with DOX or EVs alone. During the extended 7-day incubation period, the combination treatment continued to show superior efficacy, with persistently high levels of ROS generation and further reduction in cell viability. In a metastatic 3D TNBC model, a significant sensitivity to the combined treatment was observed, which notably inhibited aggregate formation and migration. Importantly, EVs-embedded scaffolds promoted the proliferation of human fibroblasts, highlighting their non-toxic nature, while concurrently inhibiting TNBC cell growth. This approach provides a promising strategy to improve the treatment outcomes of TNBC by exploiting the synergistic effects of local EVs release and systemic chemotherapy.

The TRIM37 variant rs57141087 contributes to triple-negative breast cancer outcomes in Black women

Triple-negative breast cancer (TNBC) disproportionately affects younger Black women, who show more aggressive phenotypes and poorer outcomes than women of other racial identities. While the impact of socioenvironmental inequities within and beyond health systems is well documented, the genetic influence in TNBC-associated racial disparities remains elusive. Here, we report that cancer-free breast tissue from Black women expresses TRIM37 at a significantly higher level relative to White women. A reporter-based screen for regulatory variants identifies a non-coding risk variant rs57141087 in the 5’ gene upstream region of the TRIM37 locus with enhancer activity. Mechanistically, rs57141087 increases enhancer–promoter interactions through NRF1, resulting in stronger TRIM37 promoter activity. Phenotypically, high TRIM37 levels drive neoplastic transformations in immortalized breast epithelial cells. Finally, context-dependent TRIM37 expression reveals that early-stage TRIM37 levels affect the initiation and trajectory of breast cancer progression. Together, our results indicate a genotype-informed association of oncogenic TRIM37 with TNBC risk in Black women and implicate TRIM37 as a predictive biomarker to better identify patients at risk of aggressive TNBC.

High tumor glucocorticoid receptor expression in early-stage, triple-negative breast cancer is associated with increased T-regulatory cell infiltration

PurposeIn early-stage, triple-negative breast cancer (TNBC), immune cell infiltration contributes to cancer cell survival, tumor invasion, and metastasis. High TNBC glucocorticoid receptor (GR) expression in early-stage TNBC is associated with poor long-term outcomes; it is unknown if high GR expression is associated with an immunosuppressed tumor microenvironment. We hypothesized that high tumor GR expression would be associated with an immune-suppressed tumor microenvironment, which could thus account for the poor prognosis observed in GR-positive TNBC.MethodsFormalin fixed-paraffin embedded tissue (n = 47) from patients diagnosed with early-stage TNBC from The University of Chicago (2002–2014) were evaluated for both tumor cell anti-GR immunohistochemistry and for infiltrating immune cells by immunofluorescence. Multiplexed antibodies were used to enumerate CD8+, FOXP3+, and BATF3+ immune cells infiltrating within pan-cytokeratin positive tumor cell regions of interest, and nonparametric tests compared absolute counts of each of these tumor-infiltrating immune cell types.ResultsThe average age of patients represented in this study was 52 years, and 63% self-identified as Black. There was no significant association between tumor GR expression and age, race, or clinical stage at diagnosis. Compared to GR-low tumors, high GR expression in early-stage, treatment-naïve TNBC was associated with relatively increased numbers of immunosuppressive FOXP3 + regulatory T cells (p = 0.046) and BATF3+immune cells (p = 0.021). While there was a positive correlation with high GR expression and CD8+ cell infiltration, it was not significant (p = 0.068). The ratio of CD8+/FOXP3+cells was also not significant (p = 0.24).ConclusionsThese data support the hypothesis that in early-stage TNBC, high GR expression is significantly associated with infiltration of immunosuppressive regulatory T cells, suggesting a tumor-intrinsic role in shaping the immunosuppressive immune cell milieu. Furthermore, suppression of GR activity may regulate the tumor immune microenvironment and improve long-term outcomes in GR-high TNBC.

SLFN12 Expression Significantly Effects the Response to Chemotherapy Drugs in Triple-Negative Breast Cancer.

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. 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. 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. 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.

Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer

BackgroundHigher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR...

Spatial Architecture of Single-Cell and Vasculature in Tumor Microenvironment Predicts Clinical Outcomes in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between antitumor immunity and clinical outcomes; however, such connections remain underexplored. Here, we employed a data set derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multiscale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified 10 recurrent cellular neighborhoods—a collection of local TME characteristics with unique cell components. The prevalence of cellular neighborhoods enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich long-term survivors. Furthermore, relative spatial colocalization of SMAhi fibroblasts and tumor cells compared with B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean AUC of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles and suggest novel imaging-based biomarkers for the treatment development in the context of TNBC.

Obesity and lack of breastfeeding: a perfect storm to augment risk of breast cancer?

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with higher rates of recurrence and distant metastasis, as well as decreased 5-year survival rates. Racial disparities are evident in the incidence and mortality rates of triple negative breast cancer particularly increased in young African American women. Concurrently, young African American women have multiple risk factors for TNBC including higher rates of premenopausal abdominal obesity (higher waist-hip ratio) and lower rates of breastfeeding with higher parity, implicating these factors as potentially contributors to poor outcomes. By understanding the mechanisms of how premenopausal obesity and lack of breastfeeding may be associated with increased risk of triple negative breast cancer, we can determine the best strategies for intervention and awareness to improve outcomes in TNBC.

Immune modulation and epigenetic therapies for enhanced outcome of treatment in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor expression. While traditional TNBC treatment primarily relies on systemic chemotherapy, epigenetic modification has an important role in immune evasion and tumor progression. Recent classifications of TNBC into &amp;ldquo;hot&amp;rdquo; and &amp;ldquo;cold&amp;rdquo; tumors, based on immune activity and mutation burden, have revealed that poor response to immune checkpoint inhibitors (ICIs) in these tumors is due to low tumor-infiltrating lymphocytes and the presence of immunosuppressive cells. Emerging treatments such as ICIs and poly(ADP-ribose) polymerase inhibitors offer promising alternatives. The tumor microenvironment (TME) shapes immune responses in TNBC, and a limited subset of patients has shown encouraging responses to ICIs in treating TNBC at both early and advanced stages. However, combination therapies face challenges, including medication interactions and side effects. Epigenetic modulators, such as histone deacetylase and DNA methyltransferase inhibitors, also show promise in reversing epigenetic changes by enhancing anti-tumor immunity in TNBC. The frequent expression of indoleamine 2,3-dioxygenase 1 (IDO1) in TNBC, which catalyzes the conversion of tryptophan to kynurenine, contributes to immune suppression in TNBC patients. High IDO1 levels impair the tumoricidal activity of natural killer cells and correlate with poor responses to anti-PD-L1 therapy, which can be improved using IDO1 inhibitors. Targeting myeloid-derived suppressor cells, regulatory T-cells, and tumor-associated macrophage, along with utilizing epigenetic mechanisms, show promise in modulating the immunosuppressive TME in TNBC. Combining these approaches with standard therapies, along with biomarker-guided patient selection, can enhance treatment efficacy. Clinical trials and preclinical models are essential for optimizing these strategies. This study emphasizes the importance of understanding the mechanisms of modulation, tumor-immune interactions, and the potential of epigenetic therapies in improving treatment outcomes in TNBC.

TNBC-DX genomic test in early-stage triple-negative breast cancer treated with neoadjuvant taxane-based therapy

Identification of biomarkers to optimize treatment strategies for early-stage triple-negative breast cancer (TNBC) is crucial. This study presents the development and validation of TNBC-DX, a novel test aimed at predicting both short- and long-term outcomes in early-stage TNBC. The objective of this study was to evaluate the association between TNBC-DX and efficacy outcomes [pathologic complete response (pCR), distant disease-free survival (DDFS) or event-free survival (EFS), and overall survival (OS)] in the validation cohorts. Information from 1259 patients with early-stage TNBC (SCAN-B, CALGB-40603, and BrighTNess) was used to establish the TNBC-DX scores. Independent validation of TNBC-DX was carried out in three studies: (i) WSG-ADAPT-TN; (ii) MMJ-CAR-2014-01; and (iii) NeoPACT, including 527 patients with stage I-III TNBC undergoing neoadjuvant chemotherapy. In WSG-ADAPT-TN, patients were randomized to receive nab-paclitaxel plus gemcitabine or carboplatin. In MMJ-CAR-2014-01, patients received carboplatin plus docetaxel. In NeoPACT, patients received carboplatin plus docetaxel and pembrolizumab. TNBC-DX test was created incorporating the 10-gene Core Immune Gene module, the 4-gene tumor cell proliferation signature, tumor size, and nodal staging. In the two independent validation cohorts without pembrolizumab, the TNBC-DX pCR score was significantly associated with pCR after adjustment for clinicopathological variables and treatment regimen [odds ratio per 10-unit increment 1.34, 95% confidence interval (CI) 1.20-1.52, P < 0.001]. pCR rates for the TNBC-DX pCR-high, pCR-medium, and pCR-low categories were 56.3%, 53.6%, and 22.5% respectively (odds ratio for pCR-high versus pCR-low 3.48, 95% CI 1.72-7.15, P < 0.001). Inaddition, the TNBC-DX risk score was significantly associated with DDFS [hazard ratio (HR) high-risk versus low-risk 0.24, 95% CI 0.15-0.41, P < 0.001] and OS (HR 0.19, 95% CI 0.11-0.35, P < 0.001). In the validation cohort with pembrolizumab, the TNBC-DX scores were significantly associated with pCR, EFS, and OS. TNBC-DX predicts pCR to neoadjuvant taxane-carboplatin in stage I-III TNBC and helps to forecast the patient's long-term survival in the absence of neoadjuvant anthracycline-cyclophosphamide, and independent of pembrolizumab use.

179P Multimodal deep learning integrating MRI and molecular profiles for predicting outcomes in triple-negative breast cancer

179P Multimodal deep learning integrating MRI and molecular profiles for predicting outcomes in triple-negative breast cancer

A Prognostic Risk Signature of Two Autophagy-Related Genes for Predicting Triple-Negative Breast Cancer Outcomes.

Triple-negative breast cancer (TNBC) is recognized as the most aggressive molecular subtype of breast cancer. Recent studies have highlighted the complex role of autophagy in the pathogenesis of TNBC. In this study, we evaluated 18,330 genes, including 1111 autophagy-related genes, (ARGs), across 579 TNBC samples from online databases. Differentially expressed ARGs in TNBC were identified using high-throughput RNA-seq data from the Cancer Genome Atlas (TCGA). Prognostic factors were examined through Cox regression and multivariate Cox analyses, with predictive efficacy assessed using receiver operating characteristic (ROC) curves. A nomogram integrating the risk signature with clinicopathological factors, such as TNM stage, was developed. Immunohistochemical analysis of clinical samples was also conducted. EIF4EBP1 and NPAS3 were significantly correlated with prognostic outcomes in patients with TNBC. Multivariate Cox regression analysis demonstrated that the expression levels of these two genes were accurate predictors of disease progression in TNBC samples from TCGA and the GSE31519 dataset. The efficacy of this predictive model was validated using ROC curve analysis and calibration plots, confirming its ability to accurately estimate the 1-, 2-, and 3-year survival rates for individuals with TNBC. Additionally, EIF4EBP1 and NPAS3 expression influenced drug sensitivity in TNBC cell lines, with notably lower NPAS3 expression in TNBC tissues, particularly in Stage III cases. This study is the first to report NPAS3 expression in patients with TNBC. The autophagy-related genes EIF4EBP1 and NPAS3 may serve as independent prognostic factors for individuals with TNBC.