CLINICAL DATABASE ANALYSIS USING DMDT BASED PREDICTIVE MODELLING

Background: Recent clinical trials comparing local recurrence rates in young breast cancer (BC) patients after breast-conserving therapy (BCT) versus mastectomy are limited. The local recurrence (LR) rate in young BC patients is notably higher than in other age groups, whether the recurrence rates after the two surgical options are comparable remains unclear. This meta-analysis aimed to assess the safety of BCT and mastectomy for young age BC patients by comparing LR rates between the two procedures. Methods: We conducted a systematic search of four electronic databases (Medline, PubMed, Cochrane Library, and Web of Science) for relevant studies comparing LR rates in BC patients aged 40 years or younger who were treated with BCT or mastectomy. Studies that met the inclusion criteria were synthesized using a random-effects model, with a primary focus on LR rates. Sensitivity analyses and meta-regression were performed to evaluate bias and heterogeneity, ensuring a thorough assessment of the available evidence. Results: Among the 2,936 studies screened, 10 studies encompassing 9,215 patients were included, with 5,236 undergoing BCT and 5,803 undergoing mastectomy. The summary odds ratio (OR) indicated a significantly greater risk of LR for BCT compared to mastectomy among young BC patients (OR = 1.48; 95% CI: 1.12–1.96). In subgroup analysis, the BCT group exhibited a higher 5-year LR rate (OR = 1.67; 95% CI: 1.13–2.46) compared to the mastectomy group. This trend persisted across tumor stages, with the BCT group showing an increased LR risk in both the T1–2 (OR = 1.84; 95% CI: 1.44–2.36) and T1–4 (OR = 1.74, 95% CI: 1.50–2.03) stages. Nodal status analysis indicated a higher LR risk for BCT in the N0–1 (OR = 2.549, 95% CI: 1.79–3.46) stages. Among very young women (aged ≤35), the difference in LR rates between BCT and mastectomy was even more pronounced (OR = 2.04, 95% CI: 1.47–2.82). Conclusion: Our meta-analysis found that young BC patients undergoing BCT had a significantly higher risk of LR, with a 48% increased risk compared to those who underwent mastectomy (OR = 1.48; 95% CI: 1.12–1.96). This difference was even more pronounced in patients aged 35 years or younger. While the elevated LR risk with BCT in young patients is well documented, individualized treatment planning should weigh this against potential survival advantages and quality-of-life preservation.

Breast cancer (BC) is one of the most common female cancers, and its incidence has been increasing in recent years. Although treatments are continuously improving, the prognosis of patients in the advanced stage is still unsatisfactory. Thus, an in-depth understanding of its molecular mechanisms is necessary for curing breast cancer. KIF15 is a tetrameric spindle motor which can regulate mitosis in cellular process and exert the crucial functions in several cancers. The purpose of our research was to investigate the functions of KIF15 in breast cancer. We tested the expression of KIF15 in breast cancer tissues and the survival rate of breast cancer patients with high or low level of KIF15 through TCGA data. What's more, western blot and immunohistochemistry assay were utilized to evaluate the protein level and mRNA level of KIF15 in breast cancer tissues. Then CCK-8, wound healing, transwell and flow cytometry experiments were adopted separately to test cell viability, migration, invasion and cell cycle distribution. We discovered that KIF15 was highly expressed in breast cancer tissues and high level KIF15 was associated with a low survival rate of breast cancer patients. Moreover, silence of KIF15 suppressed cell viability, migration, invasion and cell cycle distribution. Following, we discovered that ZNF367 was the upstream transcription factor of KIF15. In addition, silenced ZNF367 could also repress the growth of breast cancer cells. And rescue experiments indicated that overexpressed KIF15 could counteract the inhibition effect of silencing ZNF367 on the progression of breast cancer. Importantly, we discovered that KIF15 and ZNF367 were associated with the regulation of cell cycle. In short, ZNF367-activated KIF15 accelerated the progression of breast cancer by regulating cell cycle progress.

Breast cancer is the most common cancer among Malaysian women. Other than hospital-based results, there are no documented population-based survival rates of Malaysian women for breast cancers. This population- based retrospective cohort study was therefore conducted. Data were obtained from Health Informatics Centre, Ministry of Health Malaysia, National Cancer Registry and National Registration Department for the period from 1st Jan 2000 to 31st December 2005. Cases were captured by ICD-10 and linked to death certificates to identify the status. Only complete data were analysed. Survival time was calculated from the estimated date of diagnosis to the date of death or date of loss to follow-up. Observed survival rates were estimated by Kaplan- Meier method using SPSS Statistical Software version 17. A total of 10,230 complete data sets were analysed. The mean age at diagnosis was 50.6 years old. The overall 5-year survival rate was 49% with median survival time of 68.1 months. Indian women had a higher survival rate of 54% compared to Chinese women (49%) and Malays (45%). The overall 5-year survival rate of breast cancer patient among Malaysian women was still low for the cohort of 2000 to 2005 as compared to survival rates in developed nations. Therefore, it is necessary to enhance the strategies for early detection and intervention.

Doxorubicin (Adriamycin) is an anthracycline effective in breast cancer. Despite a worldwide acceptance of Adriamycin in the adjuvant chemotherapy to maximize the survival benefit in the higher risk patients with breast cancer with promising results, oncologists in general do not favorably consider anthracyclines in the adjuvant treatment setting because of concern about the acute and chronic drug-related toxicity. For high-risk patients with breast cancer with more than three positive axillary lymph nodes, this series adopted a modified sequential regimen of ACMF first with Adriamycin (A) as a single agent in 3-weekly administration for three courses, and then a combination of cyclophosphamide, methotrexate, fluorouracil (CMF) every 3 to 4 weeks for six courses given in an outpatient setting concurrent with radiation therapy as an adjuvant treatment. A total of 56 patients underwent modified radical mastectomy and 3 others breast conservation surgery for their invasive breast cancer. Forty-seven (84%) patients completed the intended adjuvant treatment and 1 patient died of infection from treatment-related neutropenia. As a whole, the 3-year overall survival and disease-free survival rates of 56 patients analyzed were 82.3% and 64.4%, respectively. In this high-risk group, patients with four to nine positive nodes showed a slightly better trend of survival than those with 10 or more positive nodes without reaching statistically significant difference (36-month overall survival: 90.9% vs. 72.5%, p = 0.06; disease-free survival: 78.7% vs. 47.8%, p = 0.38). In this entire group of patients, locoregional recurrence was absent. A total of 55 episodes of grade III and IV hematologic toxicity were observed, with only one death from neutropenic sepsis. This modified ACMF regimen offers a good survival rate in breast cancer patients with more than three positive axillary lymph nodes. When these patients are carefully managed, the morbidity and mortality related to the treatment are low.

Background: DNA methylation is a common event in the early development of various tumors, including breast cancer (BRCA), which has been studies as potential tumor biomarkers. Although previous studies have reported a cluster of aberrant promoter methylation changes in BRCA, none of these research groups have proved the specificity of these DNA methylation changes. Here we aimed to identify specific DNA methylation signatures in BRCA which can be used as diagnostic and prognostic markers.Methods: Differentially methylated sites were identified using the Cancer Genome Atlas (TCGA) BRCA data set. We screened for BRCA-differential methylation by comparing methylation profiles of BRCA patients, healthy breast biopsies and blood samples. These differential methylated sites were compared to nine main cancer samples to identify BRCA specific methylated sites. A BayesNet model was built to distinguish BRCA patients from healthy donors. The model was validated using three Gene Expression Omnibus (GEO) independent data sets. In addition, we also carried out the Cox regression analysis to identify DNA methylation markers which are significantly related to the overall survival (OS) rate of BRCA patients and verified them in the validation cohort.Results: We identified seven differentially methylated sites (DMSs) that were highly correlated with cell cycle as potential specific diagnostic biomarkers for BRCA patients. The combination of 7 DMSs achieved ~94% sensitivity in predicting BRCA, ~95% specificity comparing healthy vs. cancer samples, and ~88% specificity in excluding other cancers. The 7 DMSs were highly correlated with cell cycle. We also identified 6 methylation sites that are highly correlated with the OS of BRCA patients and can be used to accurately predict the survival of BRCA patients (training cohort: likelihood ratio = 70.25, p = 3.633 × 10−13, area under the curve (AUC) = 0.784; validation cohort: AUC = 0.734). Stratification analysis by age, clinical stage, Tumor types, and chemotherapy retained statistical significance.Conclusion: In summary, our study demonstrated the role of methylation profiles in the diagnosis and prognosis of BRCA. This signature is superior to currently published methylation markers for diagnosis and prognosis for BRCA patients. It can be used as promising biomarkers for early diagnosis and prognosis of BRCA.

: PCNA, an essential protein in the DNA synthesis and repair, was shown to be phosphorylated at Y2111 by a nuclear kinase. A consequence of this post-transitional modification has been highly correlated with a reduced survival rate of breast cancer patients. However, no basic of clinical studies have addressed if these inhibitors down-regulate the nuclear function of the protein. The original observations indicated that the EGFR was a major kinase involved in this phosphorylation. Inhibitors of EGFR have exciting potential in treatment but have failed to show clinical efficacy as a mono-therapy treatment option for breast cancer patients. By screening a panel of protein kinase inhibitors in triple negative breast cells for impact on phosphorylation, a direct correlation with EGFR inhibition is not indicated, rather a broader network connecting PCNA modification on chromatin with DNA damage response is implicated. Novel bioconjugates of getfitinib (Iressa) with nuclear targeting peptide-peptoid hybrid sequences have been shown to retain growth inhibitory activity in this context and open avenues for utility in research and new therapies. A new analytical method for enhanced detection of the phosphorylated PCNA isoforms has been shown to be feasible. In addition, by adopting this assay to screen nuclear proteomes of breast tumor cells indicated a more diverse array of PCNA isoforms bearing post-translational modifications opening the door to select specific markers to stage breast cancer patients for molecular therapies.

Enhancing the invasive traits of breast cancers by CYP1B1 via regulation of p53 to promote uPAR expression

The comparison of survival among patients with breast cancer was analyzed using the Cox proportional hazards model and the Kaplan-Meier estimator to model the survival outcomes. A sample of 563 patients was selected to evaluate the impact of risk factors such as age, tumor stage, type of surgery, chemotherapy, radiotherapy, and hormone therapy. The log-rank test results indicated that radiotherapy (p = 0.8) and age (p = 0.08) did not significantly affect survival distribution. Conversely, tumor stage (p < 0.0001), surgical type (p = 0.0004), chemotherapy (p = 0.04), and hormone therapy (p = 0.0004) showed significant differences in survival outcomes. Cox regression analysis identified tumor stage as the most influential factor, with patients at Stage 2, 3, and 4 exhibiting 1.85 to 3.98 times higher risks of mortality compared to those at Stage 1. Additionally, patients undergoing mastectomy had a 1.32 times higher risk than those receiving breast-conserving surgery (p = 0.0288). The assumptions of proportional hazards were violated for chemotherapy and hormone therapy (p = 0.015 and p = 0.018, respectively), which contributed to the overall significance of the model (p = 0.048). Stratification of these variables confirmed the robustness of the model, with tumor stage and surgical option remaining key factors. These findings underscore the importance of early diagnosis in improving survival outcomes for breast cancer patients.

FAM64A is a mitotic regulator which promotes cell metaphase-anaphase transition and is highly expressed in a cell-cycle-dependent manner. In this study, we examined the clinicopathological and prognostic significance of FAM64A mRNA expression in gynecological cancers. We conducted a bioinformatics analysis of FAM64A mRNA expression using Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), xiantao, The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and Kaplan-Meier (KM) plotter databases. FAM64A expression was elevated in breast, cervical, endometrial, and ovarian cancers when compared with normal tissue. Expression was positively correlated with white race, low T stages, infiltrating ductal carcinoma, or favourable PAM50 classification in breast cancer patients, and with clinical stage, histological grade and TP53 mutation, and endometrial cancer serous subtype. FAM64A expression was negatively associated with overall and/or recurrence-free survival rates in breast and endometrial cancer patients, while the opposite was observed in cervical and ovarian cancer patients. FAM64A functioned as an independent predictor of overall and disease-specific survival in breast cancer patients. FAM64A-correlated genes were involved in ligand-receptor interactions, and chromosomal, cell cycle, and DNA replication processes in breast, cervical, endometrial and ovarian cancers. Top hub genes primarily included cell cycle-related proteins in breast cancer, mucins and acetylgalactosaminyl transferases in cervical cancer, kinesin family members in endometrial cancer, and synovial sarcoma X and the cancer/testis antigen in ovarian cancer. FAM64A mRNA expression was positively related to Th2 cell infiltration, but negatively associated with neutrophil and Th17 cell infiltration in breast, cervical, endometrial, and ovarian cancers. FAM64A expression may be considered a potential biomarker reflecting carcinogenesis, histogenesis, aggressive behaviour, and prognosis in gynecological cancers. Impact statement What is already known on this subject? FAM64A is located in cell nucleolar and nucleoplasmic regions, and during mitosis it putatively controls metaphase-to-anaphase transition. FAM64A appears to regulate different physiological processes, including apoptosis, tumorigenesis, neural differentiation, stress responses, and the cell cycle. What the results of this study add? FAM64A expression was up-regulated in breast, cervical, endometrial, and ovarian cancers, and positively correlated with white race, low T stages, infiltrating ductal carcinoma, or favourable PAM50 classification in breast cancer patients, and with clinical stage, histological grade, and TP53 mutation, and a serous subtype in endometrial cancer. FAM64A expression was negatively associated with overall and/or recurrence-free survival rates in breast and endometrial cancer patients, while the opposite was observed in cervical and ovarian cancer patients. FAM64A functioned as an independent predictor of overall and disease-specific survival in breast cancer. FAM64A-correlated genes were involved in ligand-receptor interactions, chromosomal, cell cycle, and DNA replication processes, while FAM64A mRNA expression was positively related to Th2 cell infiltration but negatively correlated with neutrophil and Th17 cell infiltration in four gynecological cancers. What the implications of these findings for clinical practice and/or further research? In the future, abnormal FAM64A mRNA expression may serve as a biomarker of carcinogenesis, histogenesis, aggressiveness, and prognosis in gynecological malignancies.

Expression of miR-129-5p and miR-433 was detected in breast cancer to explore the relationship with clinicopathological features of breast cancer. Seventy-eight patients with breast cancer diagnosed in Zhengzhou Central Hospital Affiliated to Zhengzhou University (Zhengzhou, China) from February 2016 to September 2017 were collected and enrolled into the research group. Additionally, 72 healthy people who underwent physical examination during the same period were selected as the control group. The expression levels of miR-129-5p and miR-433 in peripheral blood of the two groups were detected by fluorescence quantitative PCR (RT-PCR). The relationship between the expression of miR-129-5p, miR-433 and clinicopathological features, clinical stages of breast cancer, and the degree of differentiation were analyzed. Expression of miR-129-5p and miR-433 in the research group was significantly lower than that in the control group (P<0.05). Expression of miR-129-5p in the blood of breast cancer patients was correlated with tumor size, differentiation degree, lymph node metastasis, depth of invasion and clinical stages (P<0.05). Expression level of miR-433 was correlated with the degree of differentiation, lymph node metastasis, depth of invasion and clinical stages (P<0.05). miR-129-5p and miR-433 were positively correlated with differentiation degree (r=0.8507, r=0.7522; P<0.05), and negatively correlated with clinical stages (r=−0.6595, −0.8947; P<0.05). The sensitivity and area under curve (AUC) were higher in joint detection (87.5 and 0.95% respectively), compared with those in single detection. Patients were separated into high and low expression groups according to the median values of miR-129-5p and miR-433. The one-year survival rate of breast cancer patients was analyzed. Patients in the low expression groups had lower survival rates than patients in the high expression groups (P<0.05). In conclusion, the expression of miR-129-5p and miR-433 in peripheral blood of breast cancer patients is lower than that of healthy people, and the expression level is closely related to clinical stages and differentiation degree, which is expected to provide reference value for judging the state of breast cancer patients. The combined detection of miR-129-5p and miR-433 is of great significance in the diagnosis and treatment of breast cancer.

Breast cancer is one of the leading diseases that affect women’s lives. It affects their lives in so many ways by denying them the required standard of health needed to carry out all of their daily activities for some days, weeks, months or years before eventually causing death. This research estimates the survival rate of breast cancer patients and investigates the effects of stage of tumor, gender, age, ethnic group, occupation, marital status and type of cancer upon the survival of patients. Data used for the study were extracted from the case file of patients in the Radiation Oncology Department, University College Hospital, Ibadan using a well-structured pro forma in which 74 observations were censored and 30 events occurred. The Kaplan-Meier estimator was used to estimate the overall survival probability of breast cancer patients following their recruitment into the study and determine the mean and median survival times of breast cancer patients following their time of recruitment into the study. Since there are different groups with respect to the stages of tumor at the time of diagnosis, the log-rank test was used to compare the survival curve of the stages of tumor with considering p-values below 0.05 as statistically significant. Multivariate Cox regression was used to investigate the effects of some variables on the survival of patients. The overall cumulative survival probability obtained is 0.175 (17.5%). The overall estimated mean time until death is 28.751 weeks while the median time between admission and death is 23 weeks. As the p-value (0.000032) of the log-rank test for comparing stages of tumor is less than 0.05, it is concluded that there is significant evidence of a difference in survival times for the stages of tumor. The survival function plot for the stages of tumor shows that patients with stage III tumor are less likely to survive. From the estimated mean time until death for the stages of tumor, it was deduced that stage I tumor patients have an increased chance of survival. Types of cancer, gender, marital status, ethnic group, occupation and patient’s age at entry into the study are not important predictors of chances of survival.

The development of brain metastasis is associated with a significant reduction in the survival rate of breast cancer patients. Improving the prognosis of women with brain metastasis from breast cancer relies on the elucidation of the mechanisms underlying this process. Our group and others have shown that the formation of brain metastases occurs along the abluminal side of brain vessels, a process called “vessel co-option”. These observations prompted our hypothesis that the cellular and extracellular matrix (ECM) components of the blood-brain-barrier (BBB) can serve as a pre-metastatic niche for breast cancer brain metastases. The role of tumor-derived exosomes (TEx) in the preparation of a pre-metastatic niche in distant organs has been shown in a number of cancers. To investigate the mechanisms driving the vessel co-option of breast cancer brain metastases, we studied the role of breast cancer-derived exosomes in preparation of the BBB for metastasis formation. Exosomes were isolated from the MDA-MB-231 breast cancer cell line, a brain-seeking variant of these cells, and a bone-seeking variant as a non-brain metastatic control. Brain endothelial cells, astrocytes, and brain vascular pericytes, the three components of the BBB, were treated with exosomes for 3 days to recapitulate the continuous exposure of cells to the circulating TEx in vivo. The treated cells were analyzed for cellular activities relevant to pre-metastatic niche preparation in the brain such as the integrity of the BBB, expression of cytokines, and modulation of the ECM. An initial screen was performed using cytokine antibody arrays and PCR arrays for ECM and adhesion molecules and results were validated in three separate experiments using western blots, ELISA, and Multiplex assays. Exosomes derived from brain-seeking cells significantly increased astrocyte migration and decreased the expression of Integrin β1 in brain endothelial cells, both of which can lead to the disruption of the BBB integrity. Moreover, the expression of Interleukin 8 was increased by TEx in astrocytes. TEx also increased the expression of MMP-3 and -9 (Matrix Metalloproteinases) from an undetectable baseline level and decreased the expression of TIMP-1 and -2 (Tissue Inhibitors of MMPs) in astrocytes. While the importance of these two MMPs for brain metastasis from breast cancer has been previously reported, our study is the first to demonstrate that secretion of these MMPs is triggered by TEx. Surprisingly, we did not observe any significant TEx-derived modulations in the expression of cytokines, ECM, and adhesion molecules in brain pericytes. These findings indicate that within the BBB, astrocytes and endothelial cells, but not pericytes, can be affected by breast cancer-derived exosomes in such a way that can potentially lead to preparation of a suitable niche for future metastasis formation along the brain vasculature. (This work is supported by the Breast Cancer Research Foundation.) Citation Format: Golnaz Morad, Jiang Yang, Marsha A. Moses. The role of breast cancer-derived exosomes in brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5808. doi:10.1158/1538-7445.AM2017-5808

e22029 Background: Although many effective therapies improve the survival rate in breast cancer patients, a significant number of patients could not avoid recurrence and metastasis. Liquid biopsy u...

SummaryIntroductionBreast cancer is the common cancer among females and a leading cause of mortality among them globally, its rates are three times higher in developing countries. Breast self-examination (BSE) had an important role in early detection, increasing the survival rate of breast cancer patients, despite these benefits, the rates of practicing BSE are low, especially in developing countries.ObjectiveTo assess the levels of awareness about breast cancer, and BSE among the detainees of Dar-Altaebat facility, a female’s detention facility in Khartoum, Sudan.MethodsA cross-sectional study conducted at Dar-Altaebat a female imprisonment facility in Khartoum, Sudan. 354 participants were randomly selected from the total population of the facility. Data was collected using a self-administered structured questionnaire, which was composed of socio-demographic section, knowledge section, attitude section, and breast self-examination section. Data was analyzed using statistical package for social sciences(SPSS) software.Results330 participants responded to the questionnaire, their mean age was (31, SD: 11.2) years, 126 (38.2%) of them were illiterate, 196 (59.4%) were married, and the majority of them 177 (76.3%) were housewives. their overall knowledge score revealed that 185(56.2%) of them had poor knowledge about breast cancer. 218 (66.3%) of them had poor knowledge about breast self-examination, however 314 (95.3%) thought that it was important. 315 (95.5%) of the participants had poor practice towards breast self-examination.ConclusionPoor levels of knowledge about breast cancer were reported among the detainees. Additionally, their level of knowledge and practice of breast self-examination was also low, thus more health education campaigns are recommended in such facilities.

HER2 is a crucial therapeutic target in breast cancer, and the survival rate of breast cancer patients has increased because of this receptor's inhibition. However, tumors have shown resistance to this therapeutic strategy due to oncogenic mutations that decrease the binding of several HER2-targeted drugs, including lapatinib, and confer resistance to this drug. Neratinib can overcome this drug resistance and effectively inhibit HER2 signaling and tumor growth. In the present study, we examined the efficacy of lapatinib and neratinib using breast cancer cells by Raman microscopy combined with a deep wavelet scattering-based multivariate analysis framework. This approach discriminated between control cells and drug-treated cells with high accuracy, compared to classical principal component analysis. Both lapatinib and neratinib induced changes in the cellular biochemical composition. Furthermore, the Raman results were compared with the results of several in vitro assays. For instance, drug-treated cells exhibited (i) inhibition of ERK and AKT phosphorylation, (ii) inhibition of cellular proliferation, (iii) cell-cycle arrest, and (iv) apoptosis as indicated by western blotting, real-time cell analysis (RTCA), cell-cycle analysis, and apoptosis assays. Thus, the observed Raman spectral changes are attributed to cell-cycle arrest and apoptosis. The results also indicated that neratinib is more potent than lapatinib. Moreover, the uptake and distribution of lapatinib in cells were visualized through its label-free marker bands in the fingerprint region using Raman spectral imaging. These results show the prospects of Raman microscopy in drug evaluation and presumably in drug discovery.