Good Prognosis In Breast Cancer Research Articles

Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer.

Studies have shown that screen detection by national screening programs is independently associated with better prognosis of breast cancer. The aim of this study is to evaluate the association between tumor biology according to the 70-gene signature (70-GS) and survival of patients with screen-detected and interval breast cancers. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041/BIG3-04) accrued 2007-2011, who participated in the national screening program (biennial screening, ages 50-75) were included (n = 1102). Distant Metastasis-Free Interval (DMFI) was evaluated according to the 70-GS for patients with screen-detected (n = 754) and interval cancers (n = 348). Patients with screen-detected cancers had 8-year DMFI rates of 98.2% for 70-GS ultralow-, 94.6% for low-, and 93.8% for high-risk tumors (p = 0.4). For interval cancers, there was a significantly lower 8-year DMFI rate for patients with 70-GS high-risk tumors (85.2%) compared to low- (92.2%) and ultralow-risk tumors (97.4%, p = 0.0023). Among patients with 70-GS high-risk tumors, a significant difference in 8-year DMFI rate was observed between interval (85.2%, n = 166) versus screen-detected cancers (93.8%, n = 238; p = 0.002) with a HR of 2.3 (95%CI 1.2-4.4, p = 0.010) adjusted for clinical-pathological characteristics and adjuvant systemic treatment. Among patients with 70-GS high-risk tumors, a significant difference in DMFI was observed between screen-detected and interval cancers, suggesting that method of detection is an additional prognostic factor in this subgroup and should be taken into account when deciding on adjuvant treatment strategies.

Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN

Notch receptors (Notch1–4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.

Expression and clinical prognostic value of m6A RNA methylation modification in breast cancer

BackgroundN6-methyladenosine(m6A) methylation modification affects the tumorigenesis, progression, and metastasis of breast cancer (BC). However, the expression characteristics and prognostic value of m6A modification in BC are still unclear. We aimed to evaluate the relationship between m6A modification and clinicopathological characteristics, and to explore the underlying mechanisms.MethodsThree public cohorts and our clinical cohort were included: 1091 BC samples and 113 normal samples from the TCGA database, 1985 BC samples from the METABRIC database, 1764 BC samples from the KM Plotter website, and 134 BC samples of our clinical cohort. We collected date from these cohorts and analyzed the genetic expression, gene-gene interactions, gene mutations, copy number variations (CNVs), and clinicopathological and prognostic features of 28 m6A RNA regulators in BC.ResultsThis study demonstrated that some m6A regulators were significantly differenially expressed in BCs and their adjacent tissues, and also different in various molecular types. All 28 studied m6A regulators exhibited interactions. KIAA1429 had the highest mutation frequency. CNVs of m6A regulators were observed in BC patients. The expression of the m6A regulators was differentially associated with survival of BC. Higher CBLL1 expression was associated with a better prognosis in BC than lower CBLL1 expression. Functional analysis showed that CBLL1 was related to the ESR1-related pathway, apoptosis-related pathway, cell cycle pathway and immune-related pathway in BC.Conclusionsm6A RNA modification modulated gene expression and thereby affected clinicopathological features and survival outcomes in BC. CBLL1 may be a promising prognostic biomarker for BC patients.

Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer.

Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004–2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1–3) and dichotomized as high expression (grade 2–3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0–2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.

Brown adipose tissue (BAT) activation at 18F-FDG PET/CT: correlation with clinicopathological characteristics in breast cancer

BackgroundThere is conflicting results of few published human 18F-FDG PET/CT studies about BAT activation in breast cancer (BC). The aim of the study is to evaluate the association between the levels of BAT metabolic activity detected by 18F-FDG PET/CT and clinicopathological characteristics of a tumor in patients with primary BC.ResultsBAT was activated in 16 out of 157 (10.2%) consecutive female patients with BC who underwent 18F-FDG PET/CT for initial evaluation. The majority of patients (15/16) had bilateral uptake in the supraclavicular regions. The mean values of the highest SUVmax and total metabolic activity (TMA) of activated BAT were 13.3 ± 9.9 and 79.6 ± 45, respectively. Median outdoor temperature was significantly lower in the activated BAT group (P value=0.035). Patients with BAT activation tended to have a lower median primary tumor size and primary SUVmax, but not statistically significant than those without BAT activation. BAT activation was significantly more frequent among younger age groups (14/16) and patients with lower body mass index (BMI) (10/16), but it was insignificantly more frequent among estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor2 negative (HER2-), invasive ductal carcinoma (IDC), grade II, luminal B subtype, high Ki-67 expression level, patients with positive nodal metastasis, and in patients without distant metastasis. TMA was significantly higher among HER2+ patients (P value=0.019), but insignificantly higher among the younger age groups, stages I and II, invasive lobular carcinoma (ILC), grade I, luminal B subtype, ER+, PR−, higher Ki-67 expression level, patients with positive nodal, and distant metastasis. BMI and patient’s age were the significant independent predictor factors for BAT activation on multivariate regression analysis.ConclusionBAT activation in young age females is sex hormone-dependent, positively associated with less aggressive molecular subtypes of BC, less frequent in patients with distant metastasis. BAT activation may be a prognostic factor that carries a better prognosis in BC.

Novel immune-related genes in the tumor microenvironment with prognostic value in breast cancer

BackgroundBreast cancer is one of the most frequently diagnosed cancers among women worldwide. Alterations in the tumor microenvironment (TME) have been increasingly recognized as key in the development and progression of breast cancer in recent years. To deeply comprehend the gene expression profiling of the TME and identify immunological targets, as well as determine the relationship between gene expression and different prognoses is highly critical.MethodsThe stromal/immune scores of breast cancer patients from The Cancer Genome Atlas (TCGA) were employed to comprehensively evaluate the TME. Then, TME characteristics were assessed, overlapping genes of the top 3 Gene Ontology (GO) terms and upregulated differentially expressed genes (DEGs) were analyzed. Finally, through combined analyses of overall survival, time-dependent receiver operating characteristic (ROC), and protein-protein interaction (PPI) network, novel immune related genes with good prognosis were screened and validated in both TCGA and GEO database.ResultsAlthough the TME did not correlate with the stages of breast cancer, it was closely associated with the subtypes of breast cancer and gene mutations (CDH1, TP53 and PTEN), and had immunological characteristics. Based on GO functional enrichment analysis, the upregulated genes from the high vs low immune score groups were mainly involved in T cell activation, the external side of the plasma membrane, and receptor ligand activity. The top GO terms of the upregulated DEGs from the high vs low immune score groups exhibited better prognosis in breast cancer; 15 of them were related to good prognosis in breast cancer, especially CD226 and KLRC4-KLRK1.ConclusionsHigh CD226 and KLRC4-KLRK1 expression levels were identified and validated to correlate with better overall survival in specific stages or subtypes of breast cancer. CD226, KLRC4-KLRK1 and other new targets seem to be promising avenues for promoting antitumor targeted immunotherapy in breast cancer.

Overexpression of LncRNA BM466146 Predicts Better Prognosis of Breast Cancer.

This study analyzes the expression and clinical significance of long non-coding RNA (lncRNA) BM466146 in breast cancer, and explores the role of BM466146 in immune regulation. The expression of BM466146 in 89 cases of breast cancer and their corresponding non-cancerous breast tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis was applied to evaluate patient survival. EDU and CCK-8 experiments on breast cancer cells were performed to verify the function of BM466146 in vitro. The target genes of BM466146 were screened by informatics analysis to predict associated miRNAs and their corresponding mRNAs, immune genes associated with lncRNAs and chemokines associated with CD8. Immunohistochemistry was used to detect the expression of CD8, Ki-67, and CXCL-13 in the 89 breast cancer tissues. It was found that the expression of lncRNA BM466146 in breast cancer tissues was significantly lower than that in normal breast tissues (P < 0.001). In breast cancer, tissues that overexpressed BM466146 exhibited a lower Ki-67 index compared with that of low BM466146 expression (P = 0.048). Kaplan-Meier survival analysis showed that breast cancer patients with overexpression of BM466146 had longer overall survival. EDU and CCK8 experiments showed that overexpression of BM466146 inhibited the proliferation of breast cancer cells. The hsa-miR-224-3p is associated with BM466146, and its target gene might be CXCL-13. The positive CD8 cells in the BM466146 overexpression group was higher than that in the low BM466146 expression group (P=0.027), and the positive CD8 cells in the CXCL-13 positive group was higher (P=0.023) than that of the negative group. Our results indicate that the lncRNA BM466146 has the function of tumor suppressor gene. Overexpression of BM466146 is associated with better prognosis. BM466146 could regulate CXCL-13 by adsorbing hsa-miR-224-3p and inducing CD8+ T cells to accumulate in the tumor area which regulate immune response. Therefore, BM466146 could be a prognostic biomarker and a molecular immune target of breast cancer.

Nuclear ING3 Expression Is Correlated With a Good Prognosis of Breast Cancer.

The inhibitor of growth (ING) family was discovered as the type II tumor suppressors, which regulated the proliferation, apoptosis, differentiation, angiogenesis, metastasis, and invasion of tumor cells through multiple pathways. ING3, a new member of ING family, has been reported to be downregulated in several types of tumors. However, few studies on ING3 in breast cancer have been reported. In this study, we investigated the expression of ING3 and determined its prognostic value in breast cancer. The immunohistochemistry was performed to evaluate the expression of ING3 in tissue microarrays (TMA) including breast cancer tissues (n=211) and normal breast tissues (n=50). In normal breast tissues, ING3 protein was detected in both the cytoplasm and nucleus. In breast cancer tissues, ING3 protein was principally detected in the cytoplasm. Compared with normal breast tissues, the expression of ING3 in nucleus was remarkably reduced in breast cancer tissues. The downregulated ING3 in nucleus was significantly correlated with clinicopathological characteristics including histological grade, lymph node metastasis, and the status of ER and PR. In HER2 positive-type and triple-negative breast cancer (TNBC) patients, it had the lower rate of nuclear ING3 with high expression than that in luminal-type. Moreover, Kaplan-Meier curves demonstrated that the reduced expression of ING3 in nucleus was correlated with a poorer 5-DFS and 5-OS of breast cancer patients. Importantly, multivariate Cox regression analysis suggested that the reduced expression of ING3 in nucleus was an independent prognostic factor in breast cancer. Our study comprehensively described the expression of ING3 in breast cancer for the first time and proved that it was an independent prognostic predictor of breast cancer, as well as a new idea for study of breast cancer.

Integrated analysis of Solute carrier family-2 members reveals SLC2A4 as an independent favorable prognostic biomarker for breast cancer

ABSTRACT Most of Solute carrier family-2 (SLC2) members play a key role of facilitative transporters, and glucose transporter (GLUT) proteins encoded by SLC2s can transport hexoses or polyols. However, the function and mechanism of SLC2s remain unclear in human cancers. Here, we explored the dysregulated expression, prognostic values, epigenetic, genetic alterations, and biomolecular network of SLC2s in human cancers. According to the data from public-omicsrepository, SLC2A4 (GLUT4) was found to be significantly downregulated in most cancers, and higher messenger RNA (mRNA) expression of SLC2A4 significantly associated with better prognosis of breast cancer (BRCA) patients. Moreover, DNA hypermethylation in the promoter of SLC2A4 may affect the regulation of its mRNA expression, and SLC2A4 was strongly correlated with pathways, including the translocation of SLC2A4 to the plasma membrane and PID INSULIN PATHWAY. In conclusion, these results provide insight into SLC2s in human cancers and suggest that SLC2A4 could be an unfavorable prognostic biomarker for the survival of BRCA patients.

Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

Deciphering the structural and chemical composition of breast cancer using FTIR spectroscopy

A critical factor to favor a good prognosis in breast cancer (BC) patients is early detection. Offering prompt diagnosis, treatment, and delaying or stopping the progression of the disease are the key aspects of breast cancer management. The use of FTIR spectroscopy on ex vivo breast samples can elucidate important biochemical information associated with the presence and progression of breast cancer. In this study, tissue microarrays of breast cancer biopsy samples (n = 378), and normal breast (n = 134) were analyzed using FTIR spectroscopy, principal component analysis (PCA) for feature extraction, and validation employing linear discriminant analysis (LDA). The differentiation between normal breast and breast cancer was successfully achieved with a sensitivity of 92% and specificity of 86%. Lipids and proteins spectral bands were identified as the main differentiators between normal and breast cancer. FTIR results also highlighted that chemical structural changes formed an important part of breast cancer evolution. Regardless of the heterogeneity of breast cancer, the use of multivariate analysis and FTIR spectroscopy offers a suitable and reliable tool for BC monitoring and diagnosis. The integration of spectroscopic techniques such as FTIR in cancer diagnosis and monitoring could add useful information enabling the diagnosis and management of breast cancer patients

Patterns of Delaying Surgery for Breast Cancer During the COVID-19 Outbreak in Daegu, South Korea.

Background: The coronavirus disease 2019 (COVID-19) outbreak in South Korea has affected the diagnosis, treatment, and follow-up protocols of various cancers. This study investigated the patterns of delaying surgery for breast cancer during the COVID-19 outbreak in South Korea and evaluated factors that may have affected the decision to delay surgery.Methods: From February 18 to April 18, 2020, which was the critical period for COVID-19 in South Korea, patients with breast cancer who were scheduled for surgery were evaluated in terms of their decision in delaying the procedure. The patients were divided into two groups: delaying and non-delaying surgery groups. The association between personal and clinicopathological factors and delaying surgery was evaluated.Results: In patients belonging to the delaying surgery group, the mean delay period was 15.9 (standard deviation [SD], ±10.9) days. Patients in the non-delaying surgery group were relatively younger (p = 0.003), single (p = 0.038), had planned mastectomy (p = 0.041), received needle biopsy for diagnosis (p = 0.021), and had a higher clinical N stage (p = 0.049) and multifocal lesions of breast cancer (p = 0.020). However, there were no significant differences in terms of the pathological T and N stages between the two groups.Conclusion: During the COVID-19 outbreak, there was no occurrence of nosocomial infection in the non-delaying surgery group and no statistical difference in pathological stage between the delaying and non-delaying surgery groups. Although patients in the delaying surgery group tended to be relatively older and married and had planned small-scale surgery with a good prognosis of breast cancer, the prognosis did not appear to have changed whether delaying or proceeding with surgery for breast cancer during the COVID-19 outbreak.

The Relationship of GATA3 and Ki-67 With Histopathological Prognostic Parameters, Locoregional Recurrence and Disease-free Survival in Invasive Ductal Carcinoma of the Breast.

In recent years, GATA-binding protein 3 (GATA3) has been indicated as a marker showing good prognosis in breast cancer. In luminal breast cancer, which has good a prognosis, it shows more significant elevation in small-sized and low-grade tumors. In contrast, Ki-67 is defined as a poor prognostic factor. The aim of this study was to emphasise the prognostic importance of GATA3 and the inverse relationship with Ki-67. In our study, 90 patients with invasive ductal breast cancer were immunohistochemically evaluated for Ki-67 and GATA3 expression. The relationship between GATA3 and Ki-67 expression was examined. In addition, the relationship between these two factors with estrogen, progesterone, human epidermal growth factor 2 receptor antibodies and other prognostic parameters such as disease-free survival and local recurrence was investigated. We accepted the level of ≥5% nüclear reaction as positive for GATA 3. A Ki-67 cut-off value of 20% was accepted as positive. In GATA3 positive breast cancers, good prognostic parameters were seen including high estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, small tumor size and low histological grade as well as low Ki-67 expression. In breast cancers showing high Ki-67 expression, ER, PR, and GATA3 positivity were lower and there was higher human epidermal growth factor receptor 2 (HER2) positivity and high histological grade while the tumor size was larger. Our study has revealed that GATA3 has an inverse relationship with Ki-67, whereas it has a positive releationship with good prognostic factors.

Tumor suppressive function of Matrin 3 in the basal-like breast cancer

BackgroundBasal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized.MethodsWe analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets.ResultsMATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients.ConclusionsOur data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Overexpressed Pseudogene HLA-DPB2 Promotes Tumor Immune Infiltrates by Regulating HLA-DPB1 and Indicates a Better Prognosis in Breast Cancer.

Immune checkpoint inhibitors (ICIs) have been successfully used for treating melanoma and non-small cell lung cancer. However, many patients with breast cancer (BC) show low response to ICIs due to the paucity of infiltrating immune cells. Pseudogenes, as a particular kind of long-chain noncoding RNA, play vital roles in tumorigenesis, but their potential roles in tumor immunology remain unclear. In this study that used data from online databases, the novel pseudogene HLA-DPB2 and its parental gene HLA-DPB1 were overexpressed and correlated with better prognosis in BC. Mechanistically, our results revealed that HLA-DPB2 might serve as an endogenous RNA to increase HLA-DPB1 expression by competitively binding with has-miR-370-3p. Functionally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the HLA-DPB2/HLA-DPB1 axis was strongly relevant to immune-related biological functions. Further analysis demonstrated that high expression levels of the HLA-DPB2 and HLA-DPB1 were significantly associated with high immune infiltration abundance of CD8+ T cells, CD4+ T cells, Tfh, Th1, and NK cells and with high expression of majority biomarkers of monocytes, NK cell, T cell, CD8+ T cell, and Th1 in BC and its subtype, indicating that HLA-DPB2 can increase the abundance of tumor-infiltrating lymphocytes in the BC microenvironment. Also, the HLA-DPB2 and HLA-DPB1 expression levels positively correlated with the expression levels of programmed cell death protein 1, programmed cell death ligand 1, and cytotoxic T-lymphocyte-associated antigen-4. Our findings suggest that pseudogene HLA-DPB2 can upregulate HLA-DPB1 through sponging has-miR-370-3p, thus exerting its antitumor effect by recruiting tumor-infiltrating immune cells into the breast tumor microenvironment, and that targeting the HLA-DPB2/HLA-DPB1 axis with ICIs may optimize the current immunotherapy for BC.

Expression pattern, regulation, and clinical significance of TOX in breast cancer.

Thymocyte selection-associated high mobility group box protein (TOX) is a transcription factor implicated in the regulation of T cell exhaustion during chronic infection and cancer. While TOX is being targeted for cancer immunotherapy, limited information is available about its significance in breast cancer and other solid tumors. We performed a comprehensive analysis of TOX gene expression, its epigenetic regulation, protein localization, relation to tumor infiltrating immune cell composition, and prognostic significance in breast cancer using publicly available datasets. Our results suggest an inverse correlation between TOX expression and DNA methylation in tumor cells. However, its expression is elevated in tumor infiltrating immune cells (TIICs), which may compensates for the total TOX levels in the tumor as a whole. Furthermore, higher TOX levels in tumors are associated with T cell exhaustion signatures along with presence of active inflammatory response, including elevated levels of T cell effector cytokines. Survival analysis also confirmed that higher expression of TOX is associated with better prognosis in breast cancer. Therefore, expression of TOX may serve as a novel prognostic marker for this malignancy.

Abstract P3-07-07: Functional hotness score of cytotoxic T-lymphocytes infiltration to predicts outcome of triple-negative breast cancer patients

Abstract Introduction: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor has been shown to predict better prognosis in breast cancer. Triple-negative breast cancer (TNBC) has been shown to have higher immunogenicity and enhanced CTL attraction. CD8A is a surface marker of CTLs and Granzyme B (GZMB) is a serine protease, secreted by CTLs to mediate apoptosis of the target cells. CXCL10 is a chemokine, which is known to attract CTLs into tumors in some types of cancers. However, the impact of CXLC10 expression and its role in the CTL attraction to TNBC remain unknown. Therefore, we hypothesized that Functional Hotness Score (FHS) that incorporate expressions of CXLC10 and CTL markers associates with anti-cancer immune cell infiltration and better survival of TNBC independent of mutation burden. Methods: Based on CD8A, GZMB and CXCL10 expression levels of the tumor, we established Functional Hotness Score (FHS) utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort. As a validation cohort, METABRIC cohort was utilized. As neoadjuvant chemotherapy cohort, GSE20271, GSE20194, GSE22093, GSE23988, GSE25066 and GSE28844 from Gene Expression Omnibus (GEO) were utilized. As metastatic breast cancer dataset, GSE110590 from GEO was utilized. Gene Set Enrichment Analysis (GSEA) was conducted utilizing hallmark gene sets. Infiltrated immune cell fraction was estimated by CIBERSROT algorithm. Results: Out of 6 neoadjuvant cohorts, 5 cohorts showed higher CXCL10 expression levels in pathological completely response (pCR) tumors compared to residual tumors (RD). On the other hand, 1 and 3 cohorts showed higher expression levels of CD8A and GZMB in pCR tumors, respectively. Utilizing these 3 gene expression levels and hazard ratio of overall survival (OS) of the patients, prognostic Functional Hotness Score (FHS) was developed. As we expected, patients with High FHS tumors showed significantly better OS in TCGA cohort (p=0.006). This finding was validated in METABRIC cohort. In the metastatic breast cancer cohort, metastatic tumors showed lower FHS compared to primary tumors, such as liver (p=0.003) and lung metastases (p=0.031). Whereas, most of the brain metastases tissues showed similar level of FHS compared to primary tumors (p=0.068). Subgroup analysis based on subtype revealed that TNBC showed highest FHS among each subtype with wide variation. TNBC was the only subtype that high FHS showed better OS (p=0.001). High FHS TNBC significantly enriched immune response related gene sets, such as allograft rejection (p&amp;lt;0.001), complement (p&amp;lt;0.001), IFN-γ response (p&amp;lt;0.001), IL2/STAT5 signaling (p&amp;lt;0.001), inflammatory response (p=0.002), IL6/JAK/STAT3 signaling (p&amp;lt;0.001) and IFN-α response (p&amp;lt;0.001). High FHS TNBC showed higher anti-cancer immune cell infiltration, such as CD8+ T lymphocytes, activated memory CD4+ T lymphocytes, γδ T lymphocytes, memory B lymphocytes and M1 macrophage, and lower resting or pro-cancer immune cells such as resting CD4+ T lymphocytes, regulatory T lymphocytes, naïve B lymphocytes and M2 macrophages. There was no correlation between FSH and mutation count (r=0.443). To investigate if the prognostications of FHS are associated with mutation burden, we stratified TNBC into high and low mutation burden group. Interestingly, higher FHS showed better OS regardless mutation burden (high mutation; p=0.019, low mutation; p=0.049) in TNBC. Conclusion: In conclusion, TNBC with higher FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher immune cell infiltration and immune reaction regardless mutation burden. Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Functional hotness score of cytotoxic T-lymphocytes infiltration to predicts outcome of triple-negative breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-07.

Advances in Oral Oncolytic Agents for Breast Cancer and Recommendations for Promoting Adherence.

Hormone receptor positivity and early stage diagnosis are generally considered signs of good prognosis in breast cancer. However, breast cancer all too frequently can become resistant to hormone-based therapies, and women can experience recurrence of their breast cancer decades after the diagnosis of early stage disease. To address the therapeutic needs for advanced and metastatic hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer, a number of new drugs have been tested and approved for this indication, including the class of drugs that works as cyclin-dependent kinase (CDK) 4/6 inhibitors. These drugs, often combined with other hormone-based therapy, have demonstrated considerable success in clinical trials and are now being used widely in oncology practices. Because all of the currently approved CDK4/6 inhibitor agents (palbociclib, ribociclib, and abemaciclib) are given orally, issues of patient comprehension of and adherence to prescribed regimens should be at the forefront of practitioners’ concerns about these drugs. In addition, ways to support and facilitate decision-making by patients related to this class of agents and other therapies recently approved for the same indication require focused attention by health-care providers. Oncology has continued to move toward a more patient-specific, precision medicine approach. Likewise, advanced practitioners have the opportunity to identify patient characteristics, preferences, and needs that are unique to individual patients to enhance precision treatment.

Determinants of breast self-examination practice among women in Surabaya, Indonesia: an application of the health belief model

BackgroundBreast cancer has become one of the most common causes of mortality among Indonesian women. Many women in Indonesia present with late-stage breast cancer, negatively affecting prognosis and treatment outcomes. Better prognosis of breast cancer will be achieved if it is diagnosed in an earlier stage, thus efforts to detect breast cancer earlier are important. Breast Self-Examination (BSE) is considered as an important first step to encourage women to actively be responsible for their own health, especially for women in low-and middle-income countries with limited resources and access to other forms of preventive healthcare (e.g., screening programs). The present study aimed to predict BSE practice among women in Surabaya, Indonesia using the Health Belief Model (HBM).MethodsThis investigation was a cross-sectional survey which was distributed among 1967 women aged 20–60 years. The Indonesian version of Champion’s Health Belief Model Scale (I-CHBMS) was used to explain self-reported BSE practice. Logistic regression analysis was used to examine the association of HBM variables with BSE practice.Results44.4% of the respondents indicated they had performed BSE. Further, the results indicated that the HBM variables were significantly associated with BSE practice. Specifically, higher perceived benefits and self-efficacy, lower perceived barriers and less cues to action were unique correlates of BSE practice. The result also showed that perceived severity and susceptibility were not associated with BSE practice.ConclusionThis study indicated that several HBM constructs significantly associated with BSE practice among Indonesian women, suggesting that BSE health education programs should emphasize the perceived benefits of BSE, focus on increasing women’s self-efficacy to address and overcome perceived barriers in performing BSE, and help them in identifying personally relevant cues to action.

Local extraction and detection of early stage breast cancers through a microneedle and nano-Ag/MBL film based painless and blood-free strategy.

Early diagnosis is the key to the good prognosis of breast cancer. At present, clinical tumor diagnosis is mainly through serum analysis, which is painful and can only detect relatively advanced tumors that have already metastasized from the glands into the blood circulation. Here, we developed an earlier diagnostic method (before tumor cells entering the blood) of breast cancers through a convenient and painless process with blood-free samples. The microneedles were utilized to insert into the animals' testing areas, while the tissue fluid was collected through our synthesized breathable thin film. The obtained tissue fluid sample was then incubated to form blue products. In the area where tumors occurred, the blue changes were more obvious than the healthy area, a semi-localization and semi-quantitative detection of the tumorous area thus could be realized. The results of corresponding animal experiments showed that, after the injection of tumor cells, the proposed nano-Ag based colorimetric method can detect the occurrence of breast cancers in 7 days. What is more, these early tumors could be effectively suppressed through classical DOX treatment. For comparison, the classical blood test needed 14 days to validate the occurrence of breast cancers. The subsequent human tests further demonstrated the feasibility of the present method. The development of this work could provide a more convenient, accurate and comfortable technology to support for the early screening and diagnosis of cancer patients, so as to fundamentally reduce the mortality of the breast cancers.