Survival Of Breast Cancer Patients Research Articles

Higher relative survival in breast cancer patients treated in certified and high-volume breast cancer centres – A population-based study in Belgium

ObjectivesThe study was undertaken to assess the association between certification and volume of breast centres on the one hand and survival on the other in patients with invasive breast cancer (IBC). MethodsThe study comprises a cohort of 46,035 patients diagnosed with IBC between 2014 and 2018, selected from the nation-wide Belgian Cancer Registry (BCR) database, which was linked with health insurance, hospital discharge and vital status data. Overall and relative survival probabilities were obtained with Kaplan-Meier method and an actuarial approach based on Ederer II, respectively. The associations between centre certification/volume and relative survival were assessed using Poisson models, adjusted for potential confounders. ResultsFive years after the diagnosis of IBC, the observed and relative survival probabilities for the cohort were 83.4 % (95 %CI: [83.1, 83.8]) and 93.3 % (95 %CI: [92.9, 93.7]), respectively. After adjustment for age and combined tumour stage, the risk to die from BC was 44 % higher (EHR: 1.44, 95 %CI: [1.24, 1.66]) for patients treated in a low-volume centre and 30 % higher (EHR: 1.30, 95 %CI: [1.14, 1.48]) for patients treated in a medium-volume centre, compared to high-volume centres. Likewise, the risk to die from BC was 30 % higher (EHR: 1.30, 95 %CI: [1.15, 1.48], p < 0.001) for patients treated in a non-certified centre (representing 23.8 % of the cohort), compared to patients treated in a coordinating breast clinic. ConclusionThis population-based study reveals that BC survival is higher when patients are treated in certified and high-volume breast clinics.

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. A total of 5176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using the xCell algorithm. The high group was defined as more than two-thirds of the CMP scores in each cohort. CMP cells consist of 0.07% to 0.25% of bulk breast tumor cells, more in estrogen receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1% to 0.75%, 0.18% to 0.33% of immune cells, respectively). CMP cells did not correlate with any of the myeloid lineages or 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 a 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.

Eleven inflammation-related genes risk signature model predicts prognosis of patients with breast cancer.

Changes in gene expression are associated with malignancy. Analysis of gene expression data could be used to reveal cancer subtypes, key molecular drivers, and prognostic characteristics and to predict cancer susceptibility, treatment response, and mortality. It has been reported that inflammation plays an important role in the occurrence and development of tumors. Our aim was to establish a risk signature model of breast cancer with inflammation-related genes (IRGs) to evaluate their survival prognosis. We downloaded 200 IRGs from the Molecular Signatures Database (MSigDB). The data of breast cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Differential gene expression analysis, the least absolute shrinkage and selection operator (LASSO), Cox regression analysis, and overall survival (OS) analysis were used to construct a multiple-IRG risk signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out to annotate functions of the differentially expressed IRGs (DEIRGs) The predictive accuracy of the prognostic model was evaluated by time-dependent receiver operating characteristic (ROC) curves. Subsequently, nomograms were constructed to guide clinical application according to the univariate and multivariate Cox proportional hazards regression analyses. Eventually, we applied gene set variation analysis (GSVA), mutation analysis, immune infiltration analysis, and drug response analysis to compare the differences between high- and low-risk patients. Totally, 65 DEIRGs were obtained after comparing 1,092 breast cancer tissues with 113 paracancerous tissues in TCGA. Among them, 11 IRGs (IL18, IL12B, RASGRP1, HPN, CLEC5A, SCARF1, TACR3, VIP, CCL2, CALCRL, ABCA1) were screened with nonzero coefficient by LASSO regression analysis to construct the prognostic model, which was validated in GSE96058.The 11-gene IRGs risk signature model stratified patients into high- or low-risk groups, with those in the low-risk group having longer survival time and less deaths. Multivariate Cox analysis manifested that risk score, age, and stage were the three independent prognostic factors for breast cancer patients. There were 12 pathways with higher activities and 24 pathways with lower activities in the high-risk group compared with the low-risk group, yet no difference of gene mutation load was observed between the two groups. In immune infiltration analysis, we noted that the proportion of T cells showed a decreased trend according to the increase of risk score and most of the immune cells were enriched in the low-risk group. Inversely, macrophages M2 were more highly distributed in the high-risk group. We identified 67 approved drugs that showed a different effect between the high- and low-risk patients and the top 2 gene-drug pairs were IL12B-sunitinib and SCARF1-ruxolitinib. The 11-IRG risk signature model is a promising tool to predict the survival of breast cancer patients and the expressions of IL12B and SCARF1 may serve as potential targets for therapy of breast cancer.

Brain Radiotherapy Combined with Targeted Therapy for HER2-Positive Breast Cancer Patients with Brain Metastases.

Research on the sequencing of brain radiotherapy and targeted chemotherapy after brain metastasis (BM) in HER2-positive breast cancer patients is limited and inconclusive. This study investigated the efficacy of sequential delivery of radiotherapy and targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with BM. Fifty-seven patients were categorized into two groups: the targeted-radiotherapy group (receiving 2-8 cycles of anti-HER2-targeted therapy followed by radiotherapy after BM) and the radiotherapy-targeted group (undergoing radiotherapy first, followed by regular anti-HER2-targeted therapy). The study endpoints were intracranial progression-free survival (iPFS) and overall survival. Factors associated with intracranial progression and mortality were assessed by univariate and multivariate Cox proportional hazards analysis. Patients in the radiotherapy-targeted group had better iPFS (P < 0.001), while there was no significant difference in overall survival between the two groups (P = 0.145). Multivariate Cox analysis showed that different sequential treatment groups were independent prognostic factors for iPFS. In patients with a modified breast graded prognostic assessment score of 3.5-4.0, the median survival time was 26 months in the radiotherapy-targeted group and 22 months in the targeted-radiotherapy group (P = 0.019). Overall, radiotherapy followed by targeted therapy may improve survival in HER2-positive breast cancer patients with BM, particularly in those with a modified breast graded prognostic assessment score of 3.5-4.0.

PiRNAs and PIWI-like proteins in cancer and their future as biomarkers and therapy targets in breast cancer

Globally, breast cancer (BC) is the most common type of cancer, with 2.296.840 new cases in 2020 with almost 700.000 related deaths. Due to the high burden this represents, it is imperative to expand horizons to be able to find novel biomarkers and therapeutic targets that can be used to improve prognosis, treatment, and survival of breast cancer patients. In recent years, numerous studies have been conducted looking for the association between piRNAs (PIWI – interacting RNAs) and the development, pathogenesis, metastasis, and progression of different types of cancer, including BC. PiRNAs are small molecules (24-31 nucleotides) that interact with the PIWI-protein complex (PIWI-like proteins - HIWI/HILI in humans) performing regulatory functions by inducing transcriptional, post-transcriptional, translational, and post-translational epigenetic changes, which has been observed to contribute to cancer development through modifications in cell proliferation, transposon silencing, genome rearrangement, epigenetic regulation, protein regulation, and stem cell maintenance. In breast cancer, a strong association has been found between the expression of some piRNAs, PIWI-like proteins and tumor development. If a specific piRNA could be associated with a distinct type of cancer, it could then be used as an early biomarker which would allow for a better prognosis. Findings surrounding these molecular mechanisms could also spark interest in studies focusing on the modification of the expression of piRNAs in cancer cells. In this article, we intend to review in a straightforward manner the current information about piRNAs/PIWI-like proteins focusing on their expression in BC.

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp.

Defining the role of surgery for patients with multiple brain metastases

PurposeTo better define the role of surgery, we investigated survival and functional outcomes in patients with multiple brain metastases.MethodsPertinent clinical and radiological data of 131 consecutive patients (156 surgeries) were analyzed retrospectively.ResultsSurgical indications included mass effect (84.6%) and need for tissue acquisition (44.9%, for molecularly informed treatment: 10 patients). Major (i.e. CTCAE grade 3–5) neurological, surgical and medical complication were observed in 6 (3.8%), 12 (7.7%), and 12 (7.7%) surgical cases. Median preoperative and discharge KPS were 80% (IQF: 60–90%). Median overall survival (mOS) was 7.4 months. However, estimated 1 and 2 year overall survival rates were 35.6% and 25.1%, respectively. Survival was dismal (i.e. mOS ≤ 2.5 months) in patients who had no postoperative radio- and systemic therapy, or who incurred major complications. Multivariate analysis with all parameters significantly correlated with survival as univariate parameters revealed female sex, oligometastases, no major new/worsened neurological deficits, and postoperative radio- and systemic therapy as independent positive prognostic parameters. Univariate positive prognostic parameters also included histology (best survival in breast cancer patients) and less than median (0.28 cm3) residual tumor load.ConclusionsSurgery is a reasonable therapeutic option in many patients with multiple brain metastases. Operations should primarily aim at reducing mass effect thereby preserving the patients’ functional health status which will allow for further local (radiation) and systemic therapy. Surgery for the acquisition of metastatic tissue (more recently for molecularly informed treatment) is another important surgical indication. Cytoreductive surgery may also carry a survival benefit by itself.

Endoxifen Concentration is Associated with Recurrence-Free Survival in Hormone-Sensitive Breast Cancer Patients.

The metabolism of tamoxifen is influenced by various cytochrome p450 enzymes, including CYP2D6 and CYP2C19, leading to variations in the levels of endoxifen, even with the same tamoxifen dosage. However, the clinical significance of endoxifen on the prognosis of breast cancer patients remains controversial. This study aimed to elucidate the relevance of endoxifen level to recurrence-free survival censored with tamoxifen discontinuation (RFSt), representing the RFS for tamoxifen itself, of breast cancer patients and determine a suitable cutoff for prognostication. The study included 478 breast cancer patients, and tamoxifen and its metabolites, including endoxifen, were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). An optimal cutoff was determined with maximally selected rank statistics. Survival analysis and Cox regression were conducted based on this cutoff. An endoxifen level of 21.00 ng/mL was the optimal cutoff for prognostication. Survival analysis revealed a statistically significant difference in RFSt between the low endoxifen group (≤ 21.00 ng/mL) and high endoxifen group (> 21.00 ng/mL) (log-rank test, p=0.032). The 10-year probability of RFSt was 83.2% (95% CI, 77.0-89.9%) and 88.3% (95% CI, 83.3-93.5%) in the low and high endoxifen groups, respectively. Multivariable Cox proportional hazards regression indicated endoxifen concentration as a significant factor affecting prognosis, which was adjusted with other clinical characteristics. Endoxifen could serve as a marker for appropriate tamoxifen treatment, and an endoxifen cutoff of 21.00 ng/mL could be advantageous in prognostication. Based on this cutoff, therapeutic drug monitoring would benefit patients displaying a suboptimal concentration.

MicroRNA-1205 promotes breast cancer cell metastasis by regulating epithelial-to-mesenchymal transition via targeting of CDK3

Metastasis poses a huge obstacle to the survival of breast cancer patients. The microRNA miR-1205 acts as a tumor suppressor in various cancers, but its roles in breast cancer and metastasis remain unclear. To elucidate its function in breast cancer progression, we analyzed miR-1205 expression in human tumor samples and carried out a series of functional studies in in vitro and in vivo. miR-1205 was expressed more highly in metastatic breast tumor samples than in non-metastatic samples and was associated with lymph node metastasis, clinical stage, and poor prognosis. Moreover, miR-1205 promoted breast cancer cell invasiveness in vitro and metastasis in mice by directly targeting CDK3 and reducing CDK3 protein levels. We also showed that CDK3 interacts with Snail protein, inducing Snail degradation via the ubiquitin-proteasome system and potentially affecting epithelial-to-mesenchymal transition. Furthermore, analysis of clinical tissue samples indicated that CDK3 and miR-1205 levels were inversely correlated in lymph node metastasis-positive primary tumors. This study demonstrated the pro-metastatic role of miR-1205 in breast cancer, mediated via a novel miR-1205/CDK3/Snail axis. Moreover, we identified miR-1205 and CDK3 as potential markers of invasion and progression in breast cancer.

Disruption of P2Y2 signaling promotes breast tumor cell dissemination by reducing ATP-dependent calcium elevation and actin localization to cell junctions.

The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neurological cell signaling. Here we report its role and importance in breast epithelial cell signaling and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular Ca 2+ in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca 2+ responses. The non-tumorigenic cells respond to increased Ca 2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca 2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca 2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca 2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.