Survival Of Breast Cancer Patients Research Articles

Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Doxorubicin downregulates cell cycle regulatory hub genes in breast cancer cells.

Breast cancer (BC) is the leading commonly diagnosed cancer in the world, with complex mechanisms underlying its development. There is an urgent need to enlighten key genes as potential therapeutic targets crucial to advancing BC treatment. This study sought to investigate the influence of doxorubicin (DOX) on identified key genes consistent across numerous BC datasets obtained through bioinformatic analysis. To date, a meta-analysis of publicly available coding datasets for expression profiling by array from the Gene Expression Omnibus (GEO) has been carried out. Differentially Expressed Genes (DEGs) identified using GEO2R revealed a total of 23 common DEGs, including nine upregulated genes and 14 downregulated genes among the datasets of three platforms (GPL570, GPL6244, and GPL17586), and the commonly upregulated DEGs, showed significant enrichment in the cell cycle in KEGG analysis. The top nine genes, NUSAP1, CENPF, TPX2, PRC1, ANLN, BUB1B, AURKA, CCNB2, and CDK-1, with higher degree values and MCODE scores in the cytoscape program, were regarded as hub genes. The hub genes were activated in disease states commonly across all the subclasses of BC and correlated with the unfavorable overall survival of BC patients, as verified by the GEPIA and UALCAN databases. qRT-PCR confirmed that DOX treatment resulted in reduced expression of these genes in BC cell lines, which reinforces the evidence that DOX remains an effective drug for BC and suggests that developing modified formulations of doxorubicin to reduce toxicity and resistance, could enhance its efficacy as an effective therapeutic option for BC.

Enhanced anti-tumor effects by combination of tucatinib and radiation in HER2-overexpressing human cancer cell lines

BackgroundTucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established.MethodsNine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily.ResultsIn BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes.ConclusionOur data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

Fragmentation of care in breast cancer: greater than the sum of its parts.

Fragmentation of care (FC, the receipt of care at > 1 institution) has been shown to negatively impact cancer outcomes. Given the multimodal nature of breast cancer treatment, we sought to identify factors associated with FC and its effects on survival of breast cancer patients. A retrospective analysis was performed of surgically treated, stage I-III breast cancer patients in the 2004-2020 National Cancer Database, excluding neoadjuvant therapy recipients. Patients were stratified into two groups: FC or non-FC care. Treatment delay was defined as definitive surgery > 60days after diagnosis. Multivariable logistic regression was performed to identify factors predictive of FC, and survival was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. Of the 531,644 patients identified, 340,297 (64.0%) received FC. After adjustment, FC (OR 1.27, 95% CI 1.25-1.29) was independently associated with treatment delay. Factors predictive of FC included Hispanic ethnicity (OR 1.04, 95% CI: 1.01-1.07), treatment at comprehensive community cancer programs (OR 1.06, 95% CI: 1.03-1.08) and integrated network cancer programs (OR 1.55, 95% CI: 1.51-1.59), AJCC stage II (OR 1.06, 95% CI 1.05-1.07) and stage III tumors (OR 1.06, 95% CI: 1.02-1.10), and HR + /HER2 + tumors (OR 1.05, 95% CI: 1.02-1.07). Treatment delay was independently associated with increased risk of mortality (HR 1.23, 95% CI 1.20-1.26), whereas FC (HR 0.87, 95% CI 0.86-0.88) showed survival benefit. While treatment delay negatively impacts survival in breast cancer patients, our findings suggest FC could be a marker for multispecialty care that may mitigate some of these effects.

Influence of tumour grade on disease survival in male breast cancer patients: a systematic review.

Histological grading of tumours is a well-established biomarker used to guide treatment in female breast cancer. However, its significance in male breast cancer remains unclear. This systematic review investigates the prognostic significance of tumour grade in relation to breast cancer-specific survival (BCSS) in male breast cancer patients undergoing surgery. MEDLINE, PUBMED Central and EMBASE databases were searched to identify randomised trials and observational studies related to male breast neoplasms, tumour grading, recurrence, and survival. A total of fifteen observational type studies were included in the review. A significant association between tumour grade and BCSS was reported in a majority of studies. This association was most evident with regard to high-grade (grade III) compared to low grade (grade I) tumours, with a significant relationship in 4 out of 4 studies. For intermediate-grade II tumours an association was demonstrated in a minority of studies. This study confirms an association between high-grade male breast cancers and poorer disease-specific survival, however, the significance of intermediate-grade tumours remains unclear. Further research is required to investigate the biology of male breast cancer in relation to histological grade and optimally define intermediate-grade disease.

MSFN: a multi-omics stacked fusion network for breast cancer survival prediction

Introduction: Developing effective breast cancer survival prediction models is critical to breast cancer prognosis. With the widespread use of next-generation sequencing technologies, numerous studies have focused on survival prediction. However, previous methods predominantly relied on single-omics data, and survival prediction using multi-omics data remains a significant challenge.Methods: In this study, considering the similarity of patients and the relevance of multi-omics data, we propose a novel multi-omics stacked fusion network (MSFN) based on a stacking strategy to predict the survival of breast cancer patients. MSFN first constructs a patient similarity network (PSN) and employs a residual graph neural network (ResGCN) to obtain correlative prognostic information from PSN. Simultaneously, it employs convolutional neural networks (CNNs) to obtain specificity prognostic information from multi-omics data. Finally, MSFN stacks the prognostic information from these networks and feeds into AdaboostRF for survival prediction.Results: Experiments results demonstrated that our method outperformed several state-of-the-art methods, and biologically validated by Kaplan-Meier and t-SNE.

Pan-immune-inflammation value and survival in patients with breast cancer from a Peruvian reference hospital

The pan-immune-inflammation value (PIV), calculated as (neutrophil × platelet × monocyte)/lymphocyte count, may be useful for estimating survival in breast cancer patients. To determine the prognostic value of PIV for overall survival in breast cancer patients in Lima, Peru. A retrospective cohort study was conducted. 97 breast cancer patients diagnosed between January 2010 and December 2016 had their medical records analyzed. The primary dependent variable was overall survival, and the key independent variable was the PIV, divided into high (≥ 310) and low (< 310) groups. Patient data included demographics, treatment protocols and other clinical variables. Statistical analysis involved Kaplan–Meier survival curves and Cox proportional hazards modeling. Patients with a PIV ≥ 310 had significantly lower 5-year survival functions (p = 0.004). Similar significant differences in survival were observed for clinical stage III-IV (p = 0.015), hemoglobin levels < 12 mg/Dl (p = 0.007), histological grade (p = 0.019), and nuclear grade (p < 0.001); however, molecular classification did not show a significant survival difference (p = 0.371). The adjusted Hazard Ratios showed that PIV ≥ 310 was significantly associated with poor outcome (5.08, IC95%: 1.52–16.92). While clinical stage and hemoglobin levels were associated with survival in the unadjusted model. These factors did not maintain significance after adjustment. PIV is an independent predictor of reduced survival in Peruvian breast cancer patients.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

TME-analyzer: a new interactive and dynamic image analysis tool that identified immune cell distances as predictors for survival of triple negative breast cancer patients

Spatial distribution of intra-tumoral immune cell populations is considered a critical determinant of tumor evolution and response to therapy. The accurate and systemic search for contexture-based predictors would be accelerated by methods that allow interactive visualization and interrogation of tumor micro-environments (TME), independent of image acquisition platforms. To this end, we have developed the TME-Analyzer, a new image analysis tool, which we have benchmarked against 2 software tools regarding densities and networks of immune effector cells using multiplexed immune-fluorescent images of triple negative breast cancer (TNBC). With the TME-Analyzer we have identified a 10-parameter classifier, predominantly featuring cellular distances, that significantly predicted overall survival, and which was validated using multiplexed ion beam time of flight images from an independent cohort. In conclusion, the TME-Analyzer enabled accurate interactive analysis of the spatial immune phenotype from different imaging platforms as well as enhanced utility and aided the discovery of contextual predictors towards the survival of TNBC patients.

Mechanisms of stress-attributed breast cancer incidence and progression.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women, with psychosocial stress commonly cited by patients as one of its causes. While there is conflicting epidemiological evidence investigating the association between psychosocial stress and breast cancer incidence and progression, there is reason to believe that interventions aimed at reducing stress pharmacologically or psychologically may improve breast cancer outcomes. The aim of this review is to discuss the molecular and biological mechanisms of stress-attributed breast cancer incidence and progression, including the induction of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as well as decreased immune function and stress hormone-induced resistance to chemotherapy. Moreover, these mechanisms have been cited as potential therapeutic targets of pharmacologic and psychological interventions that may improve the care, well-being and survival of breast cancer patients. Further research is recommended to investigate whether interventions in the primary care setting for women with risk factors for breast cancer development may lead to a decreased incidence of invasive breast tumors.

The effect of BMI on survival outcome of breast cancer patients: a systematic review and meta-analysis.

The main goal of the present research is to explore the potential link of body mass index (BMI) with different survival metrics in breast cancer patients. Our aim is to offer the latest and most thorough meta-analysis, assessing the strength and reliability of the connection that BMI has with prognostic indicators in this disease. As of January 2024, we conducted a systematic literature search across PubMed, Embase, Web of Science, and the Cochrane Library databases. Our search aimed to identify studies examining BMI as an exposure factor, with breast cancer patients constituting the study population, and utilizing adjusted hazard ratio (HR) as the data type of interest. The evidence synthesis incorporated a total of 61 eligible articles involving 201,006 patients. Being underweight posed a risk factor for overall survival (OS) in breast cancer patients compared to normal weight (HR 1.15, 95% CI 0.98-1.35; P = 0.08). Overweight or obesity, in comparison to normal weight, was a risk factor for OS (HR 1.18, 95% CI 1.14-1.23; P < 0.00001), disease-free survival (DFS) (HR 1.11, 95% CI 1.08-1.13; P < 0.00001), relapse-free survival (RFS) (HR 1.14, 95% CI 1.06-1.22; P = 0.03), and breast cancer-specific survival (BCSS) (HR 1.18, 95% CI 1.11-1.26; P < 0.00001), but not for progression-free survival (PFS) (HR 0.91, 95% CI 0.76-1.10; P = 0.33). Notably, in subgroup analyses, overweight patients achieved prolonged PFS (HR 0.80, 95% CI 0.64-0.99; P = 0.04), and compared to the obese population, the overweight cohort exhibited a significant difference in OS (HR 1.11, 95% CI 1.05-1.16; P < 0.00001) and DFS (HR 1.06, 95% CI 1.03-1.10; P = 0.0004), with a considerably stronger association. Furthermore, compared to HER- patients, HER + patients exhibited a greater predictive value for OS (HR 1.23, 95% CI 1.10-1.37; P = 0.0004), RFS (HR 1.30, 95% CI 1.03-1.64; P < 0.00001), and DFS (HR 1.10, 95% CI 1.03-1.17; P = 0.003). The results of our meta-analysis reveal a notable association between BMI and various survival measures in breast cancer prognosis. These findings provide a solid basis for predicting breast cancer outcomes and implementing more effective therapeutic approaches.

The association of breast cancer patients survival and prior menopausal hormone therapy in women with type 2 diabetes

We investigated the association of prediagnostic use of menopausal hormone therapy (MHT) with breast cancer survival among women with type 2 diabetes (T2D). The study cohort was identified from a Finnish nationwide diabetes database, and consisted of women with T2D, who were diagnosed with breast cancer between 2000 and 2011 (n = 3189). The patients were classified according to their previous MHT use: systemic MHT, local MHT, and no history of any MHT. The cumulative mortality from breast cancer, cardiovascular diseases, and other causes in three MHT groups was described by the Aalen-Johansen estimator. The cause-specific mortality rates were analyzed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of MHT. The breast cancer mortality appeared to be lower among systemic MHT users (HR 0.49, 95% Cl 0.36–0.67) compared with non-users of MHT. The mortality from cardiovascular diseases and from other causes of death was found to be lower among systemic MHT users, (HR 0.49, 95% Cl 0.32–0.74), and (HR 0.51, 95% Cl 0.35–0.76), respectively. In conclusion, prediagnostic systemic MHT use is associated with reduced breast cancer, cardiovascular, and other causes of mortality in women with T2D.

Prognostic and Therapeutic Implications of Cell Division Cycle 20 Homolog in Breast Cancer.

Cell division cycle 20 homolog (CDC20) is a well-known regulator of cell cycle progression. Abnormal expression of CDC20 leads to mitotic defects, which play a significant role in cancer development. In breast cancer (BC), CDC20 has been identified as a biomarker that has been linked to poor patient outcomes. In this study, we investigated the association of CDC20 with BC prognosis and immune cell infiltration by using multiple online databases, including UALCAN, KM plotter, TIMER2.0, HPA, TNM-plot, bc-GenExMiner, LinkedOmics, STRING, and GEPIA. The results demonstrate that BC patients have an elevated CDC20 expression in tumor tissues compared with the adjacent normal tissue. In addition, BC patients with overexpressed CDC20 had a median survival of 63.6 months compared to 169.2 months in patients with low CDC20 expression. Prognostic analysis of the examined data indicated that elevated expression of CDC20 was associated with poor prognosis and a reduction of overall survival in BC patients. These findings were even more prevalent in chemoresistance triple-negative breast cancer (TNBC) patients. Furthermore, the Gene Set Enrichment Analysis tool indicated that CDC20 regulates BC cells' cell cycle and apoptosis. CDC20 also significantly correlates with increased infiltrating B cells, CD4+ T cells, neutrophils, and dendritic cells in BC. In conclusion, the findings of this study suggest that CDC20 may be involved in immunomodulating the tumor microenvironment and provide evidence that CDC20 inhibition may serve as a potential therapeutic approach for the treatment of BC patients. In addition, the data indicates that CDC20 can be a reliable prognostic biomarker for BC.

Establishing nomograms for predicting disease-free survival and overall survival in patients with breast cancer

Background Prognostic factors-based nomograms have been utilised to detect the likelihood of the specific cancer events. We have focused on the roles of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the prognosis of BC patients. This study was designed to establish nomograms based on the integration of aldehyde dehydrogenase 1 (ALDH1) and p-AKT in predicting the disease-free survival (DFS) and overall survival (OS) of breast cancer (BC) patients. Methods Demographic and clinical data were obtained from BC patients admitted to our hospital between September 2015 and August 2016. Univariate and multivariate Cox regression analyses were utilised to analyse the risk factors of recurrence and mortality. The nomograms for predicting the DFS and OS were established using the screened risk factors. Stratified analysis was performed with the cut-off value of exp (pi) of 4.0-fold in DFS and OS, respectively. Results Multivariate Cox regression analysis indicated that ALDH, p-AKT and pathological stage III were independent risk factors for the recurrence among BC patients. ALDH1, p-AKT, pathological stage III and ER-/PR-/HER2- were independent risk factors for the mortality among BC patients. The established nomograms based on these factors were effective for predicting the DFS and OS with good agreement to the calibration curve and acceptable area under the receiver operating characteristic (ROC) curve. Finally, stratified analyses showed patients with a low pi showed significant decrease in the DFS and OS compared with those of high risk. Conclusion We established nomograms for predicting the DFS and OS of BC patients based on ALDH1, p-AKT and pathological stages. The ER-/PR-/HER2- may be utilised to predict the OS rather than DFS in the BC patients.

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway.

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-κB cascade and an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

The deubiquitinating enzymes-related signature predicts the prognosis and immunotherapy response in breast cancer.

Breast cancer is a prevalent disease that has a dismal prognosis for patients and a bad outlook for treatments. Ubiquitination is a reversible biological process that regulates protein production and degradation, as well as plays a vital role in protein transport, localization, and biological activity. We obtained the breast cancer patient sample data and used a machine learning technique to create a novel index called Deubiquitinating enzyme related index (DUBRI) by gathering genes associated to deubiquitinating enzymes. Based on DUBRI, we systematically analyze patients' prognosis, clinical characteristics, tumor immune microenvironment, chemotherapy response and immunotherapy response. Finally, the function of OTUB2 was explored in breast cancer cells. DUBRI, which consists of five deubiquitinating enzyme genes (OTUB2, USP41, MINDY2, YOD1, and PSMD7), is a reliable predictor of survival in breast cancer patients. We found that the high DUBRI group presented higher levels of immune cell infiltration. We performed molecular docking prediction of core target proteins in deubiquitinating enzymes. In vitro experiments verified that knockdown of OTUB2 could inhibit the proliferation and migration of breast cancer. The DUBRI discovered in this research may effectively evaluate the outlook of breast cancer patients and identify groups of patients who would gain advantages from immunotherapy, offering vital knowledge for the future targeted treatment of breast cancer patients.

Immunotherapy in Breast Cancer.

Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically "cold" tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)-negative type, to less frequent HER2- positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer.

Oscillatory Hypoxia Induced Unfolded Protein Folding Response Gene Expression Predicts Low Survival in Human Breast Cancer Patients.

Hypoxia is one of the key factors in the tumor microenvironment regulating nearly all steps in the metastatic cascade in many cancers, including in breast cancer. The hypoxic regions can however be dynamic with the availability of oxygen fluctuating or oscillating. The canonical response to hypoxia is relayed by transcription factor HIF-1, which is stabilized in hypoxia and acts as the master regulator of a large number of downstream genes. However, HIF-1 transcriptional activity can also fluctuate either due to unstable hypoxia, or by lactate mediated non-canonical degradation of HIF-1. Our understanding of how oscillatory hypoxia or HIF-1 activity specifically influence cancer malignancy is very limited. Here, using MDA-MB-231 cells as a model of triple negative breast cancer characterized by severe hypoxia, we measured the gene expression changes induced specifically by oscillatory hypoxia. We found that oscillatory hypoxia can specifically regulate gene expression differently, and at times opposite to stable hypoxia. Using The Cancer Genome Atlas (TCGA) RNAseq data of human cancer samples, we show that the oscillatory specific gene expression signature in MDA-MB-231 is enriched in most human cancers, and prognosticate low survival in breast cancer patients. In particular, we found that oscillatory hypoxia, unlike stable hypoxia, induces unfolded protein folding response (UPR) in cells resulting in gene expression predicting reduced survival.

The Association of pri-miR34 b/c Gene Polymorphism and Clinicopathologic Data in Breast Cancer Patients.

MiR-34b/c takes an important role in various aspects of carcinogenesis. Notably, pri miR34b/c (rs4938723) T>C polymorphism has been identified as a significant biomarker in various kinds of cancer. The objective of this study was to explore whether pri-miR34b/c rs4938723) T>C was associated with breast cancer susceptibility. Moreover, the association of pri-miR34b/c (rs4938723) T>C and clinicopathologic data, including survival outcomes, were studied in Thai breast cancer patients. DNA extracted from the blood of 100 Thai female breast cancer patients and 100 Thai healthy women were investigated for pri-miR34b/c (rs4938723) T>C polymorphism using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). There was no statistically significant difference between the frequency of pri miR34b/c (rs4938723) T>C genotype between Thai breast cancer patients and normal subjects. This study showed that there is no association between pri-miR34b/c (rs4938723) genotypes and breast cancer susceptibility, clinicopathologic parameters, and survival time. However, age greater than 50 and histologic grade III were the prognostic factors affecting survival in breast cancer patients (p=0.017, p=0.010, respectively). The pri-miR34b/c (rs4938723) genotypes had no association with cancer susceptibility and clinicopathologic parameters in Thai breast cancer patients. Patients with older age and patients with higher histologic grade, but not the pri miR34b/c (rs4938723) genotype, affected survival time among breast cancer patients.

Infiltration of Common Myeloid Progenitor (CMP) Cells is Associated With Less Aggressive Tumor Biology, Lower Risk of Brain Metastasis, Better Response to Immunotherapy and Higher Patient Survival in Breast Cancer.

To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME). The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells. Total of 5,176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using xCell algorithm. High group was defined as more than two thirds of CMP score in each cohort. CMP cells consist of 0.07-0.25% of bulk breast tumor cells, more in Estrogen Receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1-0.75%, 0.18-0.33% of immune cells, respectively). CMP cells did not correlate with any of myeloid lineage nor stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with lower risk of brain metastasis and with better survival, particularly in ER+/HER2- . High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration, and cytolytic activity (P<0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively). CMP in BC is inversely associated with cell-proliferation and brain metastasis, better response to immunotherapy and survival. This is the first to report the clinical relevance of CMP infiltration in BC.