Prognosis Of Triple-negative Breast Cancer Research Articles

Dual ferroptosis induction in N2-TANs and TNBC cells via FTH1 targeting: A therapeutic strategy for triple-negative breast cancer.

Tumor-associated neutrophils (TANs) play a critical role in the progression and prognosis of triple-negative breast cancer (TNBC), with N2-type TANs known for their pro-tumor characteristics. This study introduces CT-1, a derivative of cryptotanshinone that effectively suppresses TNBC growth while selectively reducing the proportion of N2-type TANs within tumor tissue. Notably, CT-1 induces simultaneous ferroptosis in both N2-type TANs and TNBC cells, a dual mechanism that enhances its therapeutic efficacy. The study identifies ferritin heavy chain 1 (FTH1), a key protein in iron metabolism, as the direct target of CT-1. By targeting FTH1, CT-1 facilitates the interaction between NCOA4 and ferritin, triggering ferritinophagy-mediated ferroptosis. These findings position CT-1 as a promising therapeutic agent, offering a strategy to combat TNBC by inducing ferroptosis in both N2-type TANs and cancer cells. This approach underscores the potential of FTH1 as a therapeutic target for treating TNBC.

A novel lncRNA AC112721.1 promotes the progression of triple-negative breast cancer by directly binding to THBS1 and regulating miR-491-5p/C2CD2L axis

Triple-negative breast cancer (TNBC) seriously threatens women’s health, and long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in TNBC. This study aimed to identify lncRNAs that represent effective targets for the early diagnosis or treatment of TNBC. Here, we utilized the TCGA database to analyze differentially expressed genes, and survival analysis and ROC curve analysis were also performed. Notably, we identified a novel lncRNA, AC112721.1, that is significantly overexpressed in TNBC and is associated with poor overall survival in TNBC patients. Loss- and gain-of-function experiments revealed that AC112721.1 significantly promoted cell proliferation and migration, suppressed cell apoptosis in vitro and inhibited tumorigenesis in vivo. Further study of the mechanisms underlying these effects revealed that AC112721.1 regulates the Ras pathway by directly binding to THBS1 protein and functions as a ceRNA by sponging miR-491-5p to increase the expression of C2CD2L, thereby influencing the progression of TNBC. Our findings indicate that AC112721.1 may represent a new biomarker for evaluating TNBC prognosis and treating TNBC.

Clinicopathological characteristics and long-term prognosis of triple-negative breast cancer patients with HER2-Low expression: a retrospective propensity score-matched cohort study

PurposeThe objective of the current research was to assess the clinicopathological characteristics and long-term prognosis of triple-negative breast cancer (TNBC) patients with human epidermal growth factor receptor 2 (HER2)-low status following breast surgery.MethodsA total of 202 TNBC patients treated at Qingdao Central Hospital from January 2010 to December 2019 were included, comprising 71 HER2-low and 131 HER2-zero patients. Propensity score matching (PSM) was applied to minimize differences between the cohorts.ResultsHER2-low TNBC patients had lower histological grade, lower Ki-67 expression levels, and a higher prevalence of hypertension compared to HER2-zero TNBC patients. Before and after PSM, the HER2-low group consistently exhibited a lower recurrence rate and longer RFS compared to HER2-zero TNBC patients. HER2-low status was validated as an independent low-risk factor for RFS both pre-PSM (HR 0.354, 95% CI 0.178–0.706, p = 0.003) and post-PSM (HR 0.405, 95% CI 0.185–0.886, p = 0.024). No statistically significant differences in mortality rate and OS were observed, both before and after PSM.ConclusionsHER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients.

Single-cell Atlas reveals core function of CPVL/MSR1 expressing macrophages in the prognosis of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis among all subtypes. The impact of distinct cell subpopulations within the tumor microenvironment (TME) on TNBC patient prognosis has yet to be clarified. Utilizing single-cell RNA sequencing (scRNA-seq) integrated with bulk RNA sequencing (bulk RNA-seq), we applied Cox regression models to compute hazard ratios, and cross-validated prognostic scoring using a GLMNET-based Cox model. Cell communication analysis was used to elucidate the potential mechanisms of CPVL and MSR1. Ultimately, RNA interference-mediated gene knockdown was utilized to validate the impact of specific genes on the polarization of tumor-associated macrophages (TAMs). Our findings revealed that the function of immune cells is more pivotal in prognosis, with TAMs showing the strongest correlation with TNBC patient outcomes, compared with other immune cells. Additionally, we identified CPVL and MSR1 as critical prognostic genes within TAMs, with CPVL expression positively correlated with favorable outcomes and MSR1 expression associated with poorer prognosis. Mechanistically, CPVL may contribute to favorable prognosis by inhibiting the SPP1-CD44 ligand-receptor and promoting CXCL9-CXCR3, C3-C3AR1 ligand-receptor, through which TAMs interact with other cells such as monocytes, neutrophils, and T cells. Moreover, cytokines including IL-18, IFNγR1, CCL20, and CCL2, along with complement-related gene like TREM2 and complement component CFD, may participate in the process of CPVL or MSR1 regulating macrophage polarization. Furthermore, RT-PCR experiments confirmed that CPVL is positively associated with M1-like TAM polarization, while MSR1 is linked to M2-like TAM polarization. Finally, the prognostic significance of these two genes is also validated in HER2-positive breast cancer subtypes. CPVL and MSR1 are potential biomarkers for macrophage-mediated TNBC prognosis, suggesting the therapeutic potential of macrophage targeting in TNBC.

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.

CLINCIOPATHOLOGICAL VALUE OF SOX10 EXPERSSION IN TRIPLE NEGATIVE BREAST CARCINOMA. A COMPHEHENSIVE REVIVEW

Background: Triple-negative breast cancer (TNBC) is a biologically heterogeneous subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu amplification. TNBC poses significant therapeutic and prognostic challenges due to its aggressive nature, high recurrence rates, and limited targeted treatment options. SOX10, initially identified as a neural crest marker, has emerged as a potential biomarker with diagnostic and prognostic value in TNBC. Understanding its role could provide insights into tumor biology and therapeutic approaches. Objective: This review aims to evaluate the clinicopathological significance of SOX10 expression in TNBC by synthesizing data from recent studies to understand its diagnostic, prognostic, and therapeutic implications in diverse patient populations. Methods: A systematic review was conducted of studies published up to June 2024 from databases including PubMed, Embase, Google Scholar, Scopus, ScienceDirect, and the Chinese Biomedical Literature Database. Keywords such as "breast carcinoma," "SOX10," and "triple-negative breast cancer" were used. Inclusion criteria were original studies from 2018 to 2024, investigating SOX10 expression using immunohistochemical (IHC) methods and its association with clinical features and prognosis in TNBC. Review articles, expert opinions, case studies, duplicates, letters, and animal studies were excluded. A total of 28 studies involving 3,178 TNBC cases were included in the final analysis. Results: Among the 3,178 TNBC cases, 1,796 (56.51%) were SOX10 positive, while 1,382 (43.48%) were negative. Analysis of 17 studies involving 1,987 Caucasian cases showed 1,226 (61.7%) were SOX10 positive, and 761 (38.3%) were negative. In contrast, 11 studies with 1,191 Asian cases revealed 570 (47.81%) SOX10 positivity and 621 (52.19%) negativity. SOX10 positivity was associated with aggressive tumor behavior, including higher tumor grade and lymph node involvement, suggesting its potential as a prognostic biomarker. Conclusion: SOX10 is a promising biomarker for TNBC, with significant diagnostic and prognostic implications across diverse populations. The observed racial differences in SOX10 expression underscore the importance of incorporating biomarker profiling into clinical practice to guide personalized treatment strategies. Further research is needed to explore its molecular mechanisms and therapeutic potential, particularly in racially diverse cohorts.

Concurrent Versus Sequential Adjuvant Capecitabine-Based Chemoradiation in Residual Triple-Negative Breast Cancer After Neoadjuvant-Chemotherapy: A Multicenter Comparative Study.

Given the aggressive nature and poor prognosis of triple-negative breast cancer (TNBC), adjuvant capecitabine has been the standard therapy for residual disease after preoperative systemic therapy (PST). However, the optimal sequence of postoperative radiation therapy (RT) and capecitabine remains unclear. This study evaluated the efficacy and safety of concurrent RT and capecitabine (RT+CAP) versus sequential RT followed by capecitabine (RT→CAP) in patients with residual TNBC after PST. In this multicenter retrospective study, data from 491 patients treated at 14 tertiary hospitals were analyzed. The patients received either postoperative RT→CAP (n = 255) or RT+CAP (n = 236). Survival outcomes were analyzed using the Kaplan-Meier method, and multivariable Cox regression was used to adjust for potential confounders. There were no significant differences in the baseline characteristics between the 2 groups. With a median follow-up of 41.8 months, the 4-year rates of disease-free survival (DFS) and overall survival (OS) were 68.8% and 82.4%, respectively. The RT+CAP group demonstrated improvements in DFS (74.6% vs 63.7%, P = .045) and OS (86.8% vs 78.3%, P = .006) compared with the RT→CAP group. Specifically, RT+CAP showed superior DFS and OS outcomes in patients with a low disease burden (ypT0-1, ypN0/axillar level I only, or Ki67 <15%). Additionally, the incidence of ≥grade 2 toxicities and discontinuation of capecitabine because of toxicity did not differ, indicating that RT+CAP was well tolerated. RT+CAP offers improvements in oncologic outcomes without an increase in adverse events compared with RT→CAP, suggesting it is a promising treatment option for patients with residual TNBC after PST.

SPP1 mRNA Expression Is Associated with M2 Macrophage Infiltration and Poor Prognosis in Triple-Negative Breast Cancer.

(1): Triple-negative breast cancer (TNBC) is an especially aggressive form of breast cancer defined by a poor prognosis and a lack of effective treatment options. There is a pressing need for validated predictive and prognostic biomarkers to assist in making treatment decisions and improve the prognostic accuracy for patients with this challenging disease. (2): We analyzed the RNA-seq data from three TNBC tissue samples alongside their corresponding normal tissues. Gene set enrichment analysis (GSEA) identified potential pathways. Additionally, we examined SPP1 mRNA expression datasets available in the Kaplan-Meier plotter and investigated the SPP1 protein expression patterns in our own tissue microarray cohort via immunohistochemistry. (3): The results revealed that genes associated with the Toll-like receptor signaling pathway showed a significant increase in activity in TNBC tissues when compared to normal breast tissues. Furthermore, SPP1 expression was found to be elevated in the TCGA TNBC dataset and correlated with a poor prognosis. This pattern was corroborated at the protein level in our TNBC tissue cohort; however, SPP1 protein expression did not demonstrate a significant impact on survival. Notably, SPP1 mRNA expression was strongly linked to tumor-associated macrophages (TAMs), particularly the M2 macrophage subtype, indicating a substantial association in the context of TNBC. (4): Our research highlights the significance of SPP1 mRNA as a key prognostic indicator and a potential molecular responder for TNBC treatment utilizing targeted therapies that focus on Toll-like receptor signaling pathways.

Antitumor effect of bromo-naphthoquinone associated with tannic acid in triple negative breast cancer cells

Triple-negative breast cancer (TNBC) is an aggressive type of tumor that tends to recur in women. It is characterized by the absence of hormonal receptors, making it challenging to diagnosis and treatment. In this study, we investigated the anti-tumor effects of a pro-oxidant naphthoquinone derivative called bromo-naphthoquinone (BrNQ) isolated and combined with the antioxidant tannic acid (TA) in order to improve treatment. We used tumor cell lines MDA-MB-231 and HCC-70, as well as normal breast cells, HB4a, as control. Initially, viability assays conducted within 72 hours showed that the combination of compounds had a synergistic and notable cytotoxic effect on the tumor cells. The increased cytotoxicity appeared to be linked to changes in the cellular redox status, as indicated by a significant rise in reactive oxygen species (ROS) and though alterations in the level of thiol. The treatment also induced apoptosis, inhibited proliferation, and reduced migration, particularly in the MDA-MB-231 cell line. Furthermore, relevant changes were detected in the expression of Bcl-2, BAX, FAS, and BIRC-5, while no significant alteration in the expression of NOXs was observed. In conclusion, our findings suggested that the combination of BrNQ and TA though the ability to change redox status in tumor cells could act as a potential adjuvant treatment modality for improve prognosis in TNBC.

DHDH-mediated D-xylose metabolism induces immune evasion in triple-negative breast cancer.

Although the prognosis of triple-negative breast cancer (TNBC) has significantly improved in the era of immunotherapy, many TNBC patients are resistant to therapies, and their disease progresses rapidly. Deciphering the metabolic mechanisms regulating anticancer immunity will provide new insights into therapeutic strategies for TNBC. In this study, we performed bioinformatics analysis in our multi-omics TNBC database and identified that a metabolic enzyme, dihydrodiol dehydrogenase (DHDH), might promote the phenotype of "cold tumor" in TNBC. The biological function of DHDH was verified by invitro and invivo functional experiments, and the potential molecular mechanism of DHDH promoting TNBC immune escape was further explored. Mechanistically, DHDH mediated the synthesis and depletion of the substrate D-xylose and inhibited the activation of the proteasome subunit beta type 9 (PSMB9) and further induction of the immune response. We demonstrated that D-xylose supplementation could enhance the proliferation of CD8+ Tcells and the expression of cytotoxic markers against cocultured DHDH-wild type (WT) cells. Consistently, D-xylose supplementation invivo promoted CD8+ Tcell infiltration and the expression of cytotoxic markers and increased the sensitivity of DHDH-overexpressing tumors to immune checkpoint blockade (ICB). Our findings reveal that a D-xylose-regulated PSMB9-dependent pathway governs tumor-intrinsic immunogenicity and, hence, the sensitivity to ICB, which may provide approaches to promote the "cold-to-hot" transition in TNBC. This study was funded by the National Key Research and Development Plan of China, Shanghai Science and Technology Commission, National Natural Science Foundation of China, and China Postdoctoral Science Foundation.

Continental differences in the association between excess body weight and prognosis in triple-negative breast cancer: a meta-analysis.

The association between obesity and triple-negative breast cancer (TNBC) prognosis has been equivocal, with considerable heterogeneity between and within studies. Recent meta-analyses report adverse associations with overall survival (OS) and disease-free survival (DFS) in TNBC. We update this evidence and examine study- and disease-specific sources of heterogeneity. A systematic search of four databases was conducted until February 22, 2023. Random-effects meta-analyses were used to pool hazard ratios (HR) for OS, DFS, and breast cancer-specific mortality (BCSM). Subgroup analyses examined sources of study heterogeneity. In meta-analyses of included studies (n = 33), significant associations were observed between excess body weight and worse OS (n = 24; HR = 1.20; 95%CI 1.20-1.34), DFS (n = 26; HR = 1.15; 1.05-1.27), and BCSM (n = 9; HR = 1.13; 1.00-1.27). In subgroup meta-analyses, significant inter-study survival differences were observed for study location (OS, DFS), time period of diagnoses (DFS), menopausal status (OS), and body mass index cut points examined (OS). Asian and European studies reported significant associations with OS (HR = 1.31; 1.11-1.54 and HR = 1.38; 1.00-1.89, respectively) and DFS (HR = 1.28; 1.07-1.54 and HR = 1.44; 1.13-1.84, respectively); however, no association was observed between obesity and TNBC prognosis in North American studies (OS: HR = 1.03; 0.89-1.19; DFS: HR = 1.05; 0.95-1.15). Location subgroup differences remained robust after excluding poor-quality studies. Post hoc analysis in the subset of studies reporting predominantly (≥ 70%) White sample showed no statistically significant associations for OS (HR = 1.13; 95%CI 0.96, 1.34), DFS (HR = 1.03; 95%CI 0.86, 1.23), or BCSM (HR = 1.08; 95%CI 0.91, 1.27). This study further confirms that obesity is associated with poor prognosis in TNBC and identified subgroups at higher risk. Ethnic differences in the association between excess body weight and TNBC are reported. Further exploration of study and patient characteristics is needed to properly understand the populations most at risk.

Identification of a PANoptosis-related prognostic model in triple-negative breast cancer, from risk assessment, immunotherapy, to personalized treatment

BackgroundTriple-negative breast cancer is a breast cancer subtype characterized by its challenging prognosis, and establishing prognostic models aids its clinical treatment. PANoptosis, a recently identified type of programmed cell death, influences tumor growth and patient outcomes. Nonetheless, the precise impact of PANoptosis-related genes on the prognosis of triple-negative breast cancer has yet to be determined. MethodsClinical information for the triple-negative breast cancer samples was collected from the Gene Expression Omnibus and The Cancer Genome Atlas databases, while 19 PANoptosis-related genes were sourced from previous studies. We first categorized PANoptosis-related subtypes and determined the differentially expressed genes between them. Subsequently, we developed and validated a PANoptosis-associated predictive model using LASSO and Cox multivariate regression analyses. Statistical evaluations were conducted using R software, and the mRNA expression levels of the genes were quantified using real-time PCR. ResultsUsing consensus clustering analysis, we divided triple-negative breast cancer patients into two clusters based on PANoptosis-related genes and identified 1054 differentially expressed genes between these clusters. Prognostic-related genes were subsequently selected to re-cluster patients, validating their predictive ability. A prognostic model was then constructed based on four genes: BTN2A2, CACNA1H, PIGR, and S100B. The expression and enriched cell types of these genes were examined and the expression levels were validated in vitro. Furthermore, the model was validated, and a nomogram was created to enhance personalized risk assessment. The risk score, proven to be an independent prognostic indicator for triple-negative breast cancer, showed a positive correlation with both age and disease stage. Immune infiltration and drug sensitivity analyses suggested appropriate therapies for different risk groups. Mutation profiles and pathway enrichment were analyzed, providing insights into potential therapeutic targets. ConclusionA PANoptosis-related prognostic model was successfully developed for triple-negative breast cancer, offering a novel approach for predicting patient prognosis and guiding treatment strategies.

Abstract C105: Novel cancer-specific hypoxia signature predicts poor prognosis and highlights racial disparities in breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC displays exceptional transcriptional heterogeneity, both between patients and intratumorally, and disproportionately affects underserved women. Hypoxia, a state of low oxygen levels, is often present in the solid tumor microenvironment. In TNBC, hypoxia is a key driver of aggressiveness and therapeutic resistance. Past bulk RNA sequencing (RNAseq) studies in cancer research have lacked spatial resolution, failing to uncover precise transcriptional differences within tumor regions. This spatial limitation has been especially problematic for studying transcriptional heterogeneity of the cellular hypoxia response within tumors. By integrating single-cell RNA sequencing and spatial transcriptomic analyses in a TNBC xenograft tumor model, our research has uncovered a novel hypoxia gene signature, specific to cancer cells. Elevated expression of this hypoxia signature predicts poorer prognosis in breast cancer patients, especially within TNBC patients and those of African ancestry. This suggests that hypoxia may play a role in the racial disparities observed in TNBC prognosis, potentially informing treatment strategies. This workflow introduces a novel framework for translating general spatial transcriptomics data into clinically relevant and accurate gene signatures. Citation Format: Kent Schechter, Long C. Nguyen, Geetha P. Yerradoddi, Rania Bassiouni, John D. Carpten, Marsha R. Rosner. Novel cancer-specific hypoxia signature predicts poor prognosis and highlights racial disparities in breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C105.

Abstract C147: Impact of genetic ancestry in triple-negative breast cancer subtypes

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive BC subtype characterized by significant molecular and clinical heterogeneity, influenced by genetic, phenotypic, and environmental factors, as well as interactions of the tumor with its surrounding milieu. A significant racial disparity has been observed between African American (AA) and European American (EA) women regarding the incidence and clinical progression of TNBC. TNBC frequently occurs in young parous women who self-identify as AA and in women who harbor a germline BRCA1 mutation. Notably, AA women are diagnosed with TNBC at a younger age and exhibit a higher risk of developing stage IV disease. Studies examining gene expression signatures that distinguish AA and EA TNBC have reported distinct tumor-associated immunologic profiles in AA patients. We have developed a novel cell type-driven subtyping system based on a racially diverse TNBC sample set that identified three TNBC subtypes, each with distinct biology and prognosis: CC1- immune signaling/T-cell response; CC2- pro- migratory/inflammatory; CC3- fatty acid and hormone and nuclear receptor signaling. In this study, we propose to examine ancestry-inferred differences within each TNBC subtype between patients with African and European ancestry. Methods: RNA-Sequencing data for the Louisiana Tumor Registry, a TNBC cohort of 250 diverse women [EA: 123 and AA: 127], was obtained from our collaborators at Louisiana State University Health Sciences Center. Genetic admixture was performed on 227/250 patients using the method described by Pakstis, A. J. et al. Differentially expressed genes (DEGs) were identified in pairwise comparisons at p-adj ≤ 0.05. Survival was assessed using log-rank tests. Results: We investigated DEGs within each subtype between patients with &amp;gt;60% African (Aa, n=102) or &amp;gt;60% European ancestry (Ea, n=99) (identified via admixture analysis). In all three subtypes, upregulated genes, and their associated enrichment in Aa were related to immune pathways, while DEGs in Ea patients were related to epithelial cell regulation. In CC1, Aa was associated with the upregulation of immunoglobulin genes involved in immunoglobulin production and antigen recognition, while Ea was associated with the upregulation of embryonic development genes. In CC2, Aa showed enriched complement activation and immunoglobulin genes, while Ea exhibited upregulation of basal cytokeratin and growth factor EGFR. In CC3, Aa was associated with the upregulation of inflammatory genes, whereas Ea showed upregulation of cellular senescence genes. Survival analysis demonstrated favorable outcomes for Aa in CC1 and less favorable outcomes for Aa in CC2. Conclusion: Our study highlights significant ancestry-inferred differences in gene expression within TNBC subtypes, with Aa patients showing immune pathways enrichment and Ea patients exhibiting differential epithelial cell regulation. These findings underscore the importance of considering genetic ancestry in TNBC prognosis and treatment strategies. Citation Format: Zahra Mesrizadeh, Kavitha Mukund, Fokrul Hossain, Jovanny Zabaleta, Denise Danos, Luis De Valle, Xiao-Cheng Wu, Chindo Hicks, Augusto Ochoa, Lucio Miele, Victoria L. Seewaldt, Shankar Subramaniam. Impact of genetic ancestry in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C147.

CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer.

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB-binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Expression of CD28, FAS, PD1, and CTLA4 molecules in the blood of women with triple-negative breast cancer.

Locally advanced triple-negative breast cancer (TNBC) represents a public health problem in Brazil. Its standard treatment consists of neoadjuvant chemotherapy (NAC). This was a longitudinal study with follow-up performed between the years 2015 and 2017. Thirty women with locally advanced TNBC submitted to NAC, and 30 healthy were included. Peripheral blood samples were collected before NAC (Pre-NAC) and after NAC (Post-NAC). Patients with TNBC had elevated levels of CD28+ T, FAS+ T, CTLA4+ T, PD1+ T, CD28+CD4+ T, PD1+CD4+ T and CD8+ T and PD1+ CD8+ T cells compared to controls (p < 0.05). Patients with pathological complete response (pCR) had low FAS+ T cells, FAS+CD4+ T cells, and PD1+CD8+ T cells compared to the non-pCR (p < 0.05). Significant differences were observed in the levels of CD28+ T cells, FAS+ T and PD1+ T, CD4+ T, CD28+CD4+ T, FAS+CD4+ T, PD1+CD4+ T, CD8+ T, and PD1+CD8+ T cells between Pre-NAC and Post-NAC groups (p < 0.05). Alterations in the circulating FAS+CD4+ T and PD1+CD8+ T cell levels Pre-NAC are associated with pCR, suggesting potential predictive biomarkers of NAC response in TNBC. The largest changes in the cellular immune response profile Post-NAC showed that chemotherapy treatment can modulate the immune response and that it is associated with prognosis in TNBC.

The Conflicting Prognostic Role of the Stroma–Tumor Ratio in Breast Cancer Molecular Subtypes

The tumor microenvironment plays a key role in tumor progression. The proportion of the stroma-to-tumor cells (stroma-tumor ratio [STR]) has a variable prognostic significance in breast cancer (BC) molecular classes. In this study, we evaluated the mechanisms of stroma formation and composition in different molecular subtypes, which could explain the different prognostic values. This study interrogated 2 large well-characterized BC cohorts. Firstly, an in-house BC cohort (n = 822) encompassing all BC molecular subtypes from the Nottingham series was used. In each subtype, stromal assessment was carried out, and tumors were assigned to 2 groups: high and low STR, and further correlation with tumor characteristics and patient outcomes was investigated. The contribution of tumor-infiltrating lymphocytes (TILs) to the stroma has also been studied. Secondly, the public domain data set (The Cancer Genome Atlas data [TCGA], n = 978) was used as a validation cohort and for differential gene expression (DGE) analysis. DGE was performed to identify a set of genes associated with high STR in the 3 main molecular subtypes. High STR was associated with favorable patient outcomes in the whole cohort and in the luminal subtype, whereas high STR showed an association with poor outcomes in triple-negative BC (TNBC). No association with outcome was found in the HER2 enriched BC. DGE analysis identified various pathways in luminal and TNBC subtypes, with immune upregulation and hypoxia pathways enriched in TNBC, and pathways related to fibrosis and stromal remodeling enriched in the luminal group instead. Low STR accompanied by high TILs was shown to carry the most favorable prognosis in TNBC. In line with the DGE results, TILs played a major prognostic role in the stroma of TNBC but not in the luminal or HER2-enriched subtypes. The underlying molecular mechanisms and composition of the stroma in BC are variable in the molecular subtypes and explain the difference in its prognostic significance.

Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and limited treatment options. This study evaluates the prognostic value of stromal markers in TNBC, focusing on the tumor-stroma ratio (TSR) and overall stroma ratio (OSR) in whole slide images (WSI), as well as the expression of type-I collagen, type-III collagen, and fibrillin-1 on tissue microarrays (TMAs), using both visual assessment and digital image analysis (DIA). A total of 101 female TNBC patients, primarily treated with surgery between 2005 and 2016, were included. We found that high visual OSR correlates with worse overall survival (OS), advanced pN categories, lower stromal tumor-infiltrating lymphocyte count (sTIL), lower mitotic index, and patient age (p < 0.05). TSR showed significant connections to the pN category and mitotic index (p < 0.01). High expression levels of type-I collagen (>45%), type-III collagen (>30%), and fibrillin-1 (>20%) were linked to significantly worse OS (p = 0.004, p = 0.013, and p = 0.005, respectively) and progression-free survival (PFS) (p = 0.028, p = 0.025, and p = 0.002, respectively), validated at the mRNA level. Our results highlight the importance of stromal characteristics in promoting tumor progression and metastasis and that targeting extracellular matrix (ECM) components may offer novel therapeutic strategies. Furthermore, DIA can be more accurate and objective in evaluating TSR, OSR, and immunodetected stromal markers than traditional visual examination.

Preliminary Research of Radiolabeled Atezolizumab for the Noninvasive Evaluation of TNBC PD-L1 Expression InVivo.

Programmed death-ligand 1 (PD-L1) expression is related to the efficacy and prognosis in triple-negative breast cancer. This study employed an indirect labeling method to synthesize [125I]PI-Atezolizumab. The invitro stability of [125I]PI-Atezolizumab was assessed through incubation in phosphate buffered saline and fetal bovine serum, revealing sustained stability. Specific binding of [125I]PI-Atezolizumab to MDA-MB-231 cells expressing humanized PD-L1 was assessed through invitro incubation, yielding a Kd value comparable to that of Atezolizumab. This suggests that the labeling process did not compromise the affinity of the Atezolizumab to PD-L1. Subsequently, pharmacokinetic studies were conducted in normal mice and biodistribution experiments in tumor-bearing mice. A comparison of the biodistribution results between [125I]PI-Atezolizumab and 125I-labeled Atezolizumab indicated better invivo stability for the former. Single photon emission computed tomography (SPECT)/CT imaging further confirmed the targeted specificity of [125I]PI-Atezolizumab for PD-L1 in MDA-MB-231 xenografts, which were validated by immunohistochemistry staining. This research underscores the utility of [125I]PI-Atezolizumab, prepared via indirect labeling, for monitoring PD-L1 in triple-negative breast cancer models.