Different Molecular Subtypes Of Breast Cancer Research Articles

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

CYB561 promotes HER2+ breast cancer proliferation by inhibiting H2AFY degradation

Breast cancer (BRCA) has a high incidence and mortality rate among women. Different molecular subtypes of breast cancer have different prognoses and require personalized therapies. It is imperative to find novel therapeutic targets for different molecular subtypes of BRCA. Here, we demonstrated for the first time that Cytochromeb561 (CYB561) is highly expressed in BRCA and correlates with poor prognosis, especially in HER2-positive BRCA. Overexpression of CYB561 could upregulate macroH2A (H2AFY) expression in HER2-positive BRCA cells through inhibition of H2AFY ubiquitination, and high expression of CYB561 in HER2-positive BRCA cells could promote the proliferation and migration of cells. Furthermore, we have demonstrated that CYB561 regulates H2AFY expression, thereby influencing the expression of NF-κB, a downstream molecule of H2AFY. These findings have been validated through in vivo experiments. In conclusion, we propose that CYB561 may represent a novel therapeutic target for the treatment of HER2-positive BRCA.Graphical abstract CYB561 promotes the proliferation of HER2+ BRCA cells: CYB561 enhances the expression of H2AFY by inhibiting its ubiquitination, which leads to an increase expression of NF-κB in the nucleus. H2AFY, together with NF-κB, promotes the proliferation of HER2+ BRCA cells.

Immunohistochemical Expression of Autophagy-Related Marker (LC3B) and Stem Cell Marker (CD44) in Molecular Subtypes of Breast Cancer.

Breast cancer (BC) is among the most prevalent aggressive type of malignancy affecting females worldwide. Despite the advance in early detection and management of BC; recurrence, metastasis and mortality remains high. This may be attributed to heterogeneity of BC which explained by the presence of breast cancer stem cells (BCSCs). BCSCs is characterized by their ability of self-renewal, unlimited proliferation and their differentiation potential. BCSCs maintain their activity through process of autophagy. Autophagy is a catabolic pathway important for maintenance of cellular hemostasis in response to different stressful conditions. Autophagy allows BCSCs to adapt to different stressful conditions. So, it protects BCSCs from cytotoxic effects of anti-cancer therapy and anticancer resistance. Formalin-fixed paraffin embedded fifty specimens of Invasive duct carcinoma of no special type(IDC/NST) of breast was selected and immunostained with stem cell marker CD44 and autophagy related marker LC3B antibodies. Correlation with different clinicopathological, histopathological characteristics and molecular subtypes of studied specimens were evaluated. Both CD44 and LC3B expression were significantly associated with lymph nodal metastasis (p =0.001 and 0.010 respectively), advanced pathological stage (p= 0.045 and 0.004 respectively) and with triple negative molecular subtype of BC (p=0.044 and 0.048 respectively). Statistically positive correlation was also found between both tumor markers expression. Results of this study suggests that CD44 and LC3B expression play a role in the clinical behavior and progression of different molecular subtypes of BC.

Contrast-Enhanced Ultrasound and Conventional Ultrasound Characteristics of Breast Cancer With Different Molecular Subtypes

BackgroundIdentifying molecular subtypes of breast cancer (BC) is of great significance in selecting optimal treatment strategy. Different molecular subtypes of BC have various vascular distribution characteristics. Contrast-enhanced ultrasound (CEUS) can dynamically display the microcirculation of tumor. This study intends to explore the conventional ultrasound and CEUS characteristics of different molecular subtypes of BC. MethodsDuring this prospective study, 86 patients with BC who were divided into Luminal A (LA), Luminal B (LB), HER2 over-expression (H2), and triple-negative (TN). The CEUS qualitative and quantitative characteristics of BC with different molecular subtypes was explored, as well as the conventional ultrasound features. In addition, the diagnostic efficiency of CEUS quantitative parameters in differentiating molecular subtypes of BC was analyzed. ResultsOur study found that the Adler grade differed significantly among 4 molecular subtypes (P < .05). The enhancement speed, enhancement degree and size after enhancement of 4 molecular subtypes were statistically different (P < .05). The wash in slope (WIS), peak intensity (PI), and wash-in area under the curve (WiAUC) differed significantly among 4 subtypes (P < .05). The diagnostic efficiency of PI was better for detecting LA and H2 subtype with the areas under the receiver operating characteristic curve was 0.778 and 0.734, respectively. ConclusionDifferent molecular subtypes of BC have different CEUS and conventional ultrasound characteristics. CEUS can provide valuable imaging basis for precise clinical diagnosis and individualized therapy of BC with different molecular subtypes.

Association of Dietary Factors and Physical Inactivity with Molecular Subtypes of Breast Cancer- Hospital Based Case-Control Study

Improper diet and physical inactivity are environmental risk factors for breast cancer (BC). This study evaluated the association of dietary risk factors and physical activities with different molecular subtypes of BC. We conducted a case-control study among 130 cases of BC and 150 age-matched controls. Demographic data and tissue marker status were obtained. Diet was assessed using Food Frequency Questionnaire and physical activity was determined using Physical Activity Questionnaire. The association between diet and physical activity with the cancer status was evaluated by Pearson’s Correlation. Among the various dietary factors, refined oil displayed a weak albeit significant positive correlation (r = 0.344) to Luminal B subtype of BC. Consumption of all kinds of non-vegetarian food exhibited significant elevation in BC risk with OR > 1.9 (95% CI 0.825–2.707). A higher odds ratio (>1.66) was observed in individuals who had a limited intake of fruits. Furthermore, a strong association was found between low physical activity and breast cancer risk, with around 14.6% of cases being distinctly linked to this risk (OR = 3.33, 95% CI 1.158–9.403, p < 0.01). In essence, while dietary factors exhibited a negative correlation with breast cancer risk, the risk was heightened by physical inactivity.

Abstract P4-03-39: Breast density and Body Mass Index association with breast cancer molecular subtypes in early breast cancer Spanish population

Abstract Obesity is a major health problem and is closely related to the incidence and progression of breast cancer (BC). Likewise, mammogram breast density (MBD) is a risk factor for breast cancer. This study aims to analyze the potential association between BMI (Body Mass Index) and MBD with different molecular subtypes of BC. The interaction with cholesterol, vitamin D, insulin levels, and lifestyle, will also be evaluated. Materials and methods: This is a transversal, descriptive, multicenter study involving women with a recent diagnosis of early BC for one-year duration (November 2019 to October 2020). BMI was classified as obesity (BMI &amp;gt;=30 kg/m2), overweight (&amp;gt;=25 kg/m2), and normal weight (18-25 Kg/m2). American college of radiology was used to classify MBD into 4 categories: A, B, C, and D. Data of weight, height, MBD, molecular subtype (according to 13th St Gallen International Breast Cancer Panel), cholesterol, insulin, vitamin-D, hypertension, diabetes, exercise, and lifestyle were collected at the moment of diagnosis. Results: 162 women with a recent diagnosis of early BC have been successively evaluated in 3 Spanish hospitals. The median age was 52 years, and 49.1% were postmenopausal. Molecular subtypes were: 43% luminal-A, 25% luminal-B, 17% HER2+, and 15% triple-negative. 7% of patients were MBD type A, 17% type B, 55% type C, and 21% type D. 52% were normal weight, 32% overweight, and 16% obese. 48% of women had normal cholesterol levels and 60% normal vitamin D. There was not association between BMI and molecular subtype, however considering menopausal status, BMI was significantly higher in postmenopausal patients with Luminal A subtype (p= 0.011) and HER2+ subtype (p= 0.027). There was no association between MBD and molecular subtype. However, there were significant differences between BMI and MBD (p&amp;lt; 0.001) with lower BMI in patients who had MBD type C or D. Patients with higher BMI had lower HDL-Cholesterol (p&amp;lt; 0.001) and higher levels of insulin (p&amp;lt; 0.001). Conclusion: This study showed a higher BMI in Luminal A and HER2 positive postmenopausal BC patients. Higher BMI was shown in patients with low MBD independently of menopausal status. More studies are needed to understand the role of obesity and molecular subtype of breast cancer. Citation Format: Isabel Calvo, Marta González, Fernando Neria, Isabel Gallegos, Lourdes García-Sánchez, Silvia Pérez, Laura G. Estévez. Breast density and Body Mass Index association with breast cancer molecular subtypes in early breast cancer Spanish population. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-39.

SCAMP3 promotes breast cancer progression through the c-MYC-β-Catenin-SQSTM1 growth and stemness axis

The cellular trafficking protein secretory-carrier-membrane-protein 3 (SCAMP3) has been previously shown to promote hepatocellular carcinoma, melanoma, glioma and pancreatic adenocarcinoma. Moreover, previous work has shown that SCAMP3 regulates the epidermal growth factor receptor (EGFR) in triple negative breast cancer (TNBC). However, the oncogenic role of SCAMP3 in different molecular subtypes of breast cancer (BRCA) remains largely unknown. In this study, the role of SCAMP3 in different molecular subtypes of BRCA was investigated using in silico, in vitro and in vivo approaches. In silico analysis of BRCA patient samples showed that SCAMP3 is highly overexpressed in different BRCA molecular subtypes, advanced disease grades and lymph node metastatic stages. Depletion of SCAMP3 inhibited BRCA cell growth, stemness, clonogenic potential and migration and promoted autophagy and cellular senescence. The expression of stemness markers CD44 and OCT4A was reduced in SCAMP3-silenced MDA-MB-231 cells. SCAMP3 overexpression promoted cell proliferation, clonogenicity, tumor spheroid formation and migration in vitro and tumor growth in vivo. SCAMP3 promoted epithelial-mesenchymal-transition (EMT) by regulating E-cadherin expression. SCAMP3 enhanced in vivo tumor growth in MDA-MB-231 tumor xenograft mouse model. Mechanistically, SCAMP3 depletion inhibited β-Catenin, c-MYC and SQSTM1 expression, while its overexpression increased the expression of the same oncogenic proteins. Increased SCAMP3 expression associated with increased chemoresistance in BRCA cells while its depletion associated with increased sensitivity to chemotherapy. BRCA patients with high SCAMP3 expression showed poor prognosis, decreased overall survival and relapse free survival relative to counterparts with reduced SCAMP3 expression. These findings suggest that SCAMP3 exerts a wide range of oncogenic effects in different molecular subtypes of BRCA by modulating the c-MYC-β-Catenin-SQSTM1 axis that targets tumor growth, metastasis, stemness and chemoresistance.

The Value of Semiquantitative Parameters Derived from 18F-FDG PET/CT for Predicting Response to Neoadjuvant Chemotherapy in a Cohort of Patients with Different Molecular Subtypes of Breast Cancer

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is a strong prognostic factor in breast cancer (BC). The aim of this study was to investigate whether semiquantitative parameters derived from baseline [18F]Fluorodeoxyglucose ([18F]FDG) positron emission computed tomography/computed tomography (PET/CT) could predict pCR after NAC and survival outcomes in patients affected by different molecular subtypes of BC. We retrospectively retrieved patients from the databases of two Italian hospitals (Centre A: University Hospital of Ferrara; Centre B: University of Padua) meeting the following inclusion criteria: (1) diagnosis of BC; (2) history of NAC; (3) baseline [18F]FDG PET/CT performed before the first cycle of NAC; (4) available follow-up data (response after NAC and survival information). For each [18F]FDG PET/CT scan, semiquantitative parameters (SUVmax, SUVmean, MTV and TLG) related to the primary tumor (B), to the reference lesion for both axillary (N) and distant lymph node (DN), and to the whole-body burden of disease (WB) were evaluated. Patients enrolled were 133: 34 from centre A and 99 from centre B. Patients' molecular subtypes were: 9 luminal A, 49 luminal B, 33 luminal B + HER-2, 10 HER-2 enriched, and 32 triple negative (TNBC). Luminal A and HER-2 enriched BC patients were excluded from the analysis due to the small sample size. pCR after NAC was achieved in 47 patients (41.2%). [18F]FDG PET/CT detected the primary tumor in 98.3% of patients and lymph node metastases were more frequently detected in Luminal B subgroup. Among Luminal B patients, median SUVmean_B values were significantly higher (p = 0.027) in responders (7.06 ± 5.9) vs. non-responders (4.4 ± 2.1) to NAC. Luminal B + HER-2 non-responders showed a statistically significantly higher median MTV_B (7.3 ± 4.2 cm3 vs. 3.5 ± 2.5 cm3; p = 0.003) and TLG_B (36.5 ± 24.9 vs. 18.9 ± 17.7; p = 0.025) than responders at baseline [18F]FDG PET/CT. None of the semiquantitative parameters predicted pCR after NAC in TNBC patients. However, among TNBC patients who achieved pCR after NAC, 4 volumetric parameters (MTV_B, TLG_B, MTV_WB and TLG_WB) were significantly higher in patients dead at follow-up. If confirmed in further studies, these results could open up a widespread use of [18F]FDG PET/CT as a baseline predictor of response to NAC in luminal B and luminal B + HER-2 patients and as a prognostic tool in TNBC.

A quantitative characterization of the spatial distribution of brain metastases from breast cancer and respective molecular subtypes.

Brain metastases (BM) remain a significant cause of morbidity and mortality in breast cancer (BC) patients. Specific factors promoting the process of BM and predilection for selected neuro-anatomical regions remain unknown, yet may have major implications for prevention or treatment. Anatomical spatial distributions of BM from BC suggest a predominance of metastases in the hindbrain and cerebellum. Systematic approaches to quantifying BM location or location-based analyses based on molecular subtypes, however, remain largely unavailable. We analyzed stereotactic Cartesian coordinates derived from 134 patients undergoing gamma- knife radiosurgery (GKRS) for treatment of 407 breast cancer BMs to quantitatively study BM spatial distribution along principal component axes and by intrinsic molecular subtype (ER, PR, Herceptin). We used kernel density estimators (KDE) to highlight clustering and distribution regions in the brain, and we used the metric of mutual information (MI) to tease out subtle differences in the BM distributions associated with different molecular subtypes of BC. BM location maps according to vascular and anatomical distributions using Cartesian coordinates to aid in systematic classification of tumor locations were additionally developed. We corroborated that BC BMs show a consistent propensity to arise posteriorly and caudally, and that Her2+ tumors are relatively more likely to arise medially rather than laterally. To compare the distributions among varying BC molecular subtypes, the mutual information metric reveal that the ER-PR-Her2+ and ER-PR-Her2- subtypes show the smallest amount of mutual information and are most molecularly distinct. The kernel density contour plots show a propensity for triple negative BC to arise in more superiorly or cranially situated BMs. We present a novel and shareable workflow for characterizing and comparing spatial distributions of BM which may aid in identifying therapeutic or diagnostic targets and interactions with the tumor microenvironment. Further characterization of these patterns with larger multi-institutional data-sets may have major impacts on treatment or management of cancer patients.

Machine Learning-Devised Immune-Related lncRNA Signature Panel Predicts the Prognosis and Immune Landscape in Breast Cancer Novel IRLP Signature in BRCA.

Long noncoding RNAs (lncRNAs) actively participate in breast cancer (BRCA) tumorigenesis via epigenetic mechanisms. Our study identified immune-related lncRNA (irlncRNA) pairs and compiled them into a set of noncoding gene signatures able to stratify subtypes of BRCA associated with variable degrees of survival and immune cell infiltration. A 40 immune-related lncRNA pair (IRLP) signature including 43 irlncRNAs was built, with high sensitivity and specificity for the prediction of survival in different molecular subtypes of BRCA. Results demonstrated that the low-risk group showed a significantly longer survival rate, and this novel IRLP signature was highly associated with survival status, T stage, metastatic disease, and overall stage in BRCA. Immune infiltrating analyses found that the low-risk group has a lower expression level of macrophage M2 and a higher expression level of immunosuppressed biomarkers than the high-risk group. DEirlncRNAs were further proven to be significantly related to the MAPK signaling, Jak-STAT signaling, and ErbB signaling pathways in BRCA. In conclusion, the 40 IRLP signature showed a promising clinical prediction value in the prognosis of different molecular subtypes and immunotherapy response in BRCA, and the underlying mechanism for these IRLPs warrants further investigations.

Abstract P5-06-08: Triple-negative breast cancer CAFs induce a metastatic phenotype in MCF-7 cells via the SDF-1/CXCR4 axis

Abstract Background: Metastatic disease is the foremost cause of breast cancer (BC) related mortality in women. One of the crucial challenges in reducing metastasis-related mortality is in identifying and understanding why certain BCs metastasize and recur. Although cancer cell-intrinsic factors are a key determinant in BC metastasis, host-intrinsic factors like the cells of the tumor microenvironment (TME), such as cancer-associated fibroblasts (CAFs) are what might be driving certain BCs to metastasize and recur. We recently showed that CAFs from the primary (TME) enter into circulation as cCAFs, form heterotypic clusters with tumor cells, and arrive at metastatic sites. This interaction between CAFs and tumor cells is crucial in furthering the metastatic cascade. However, the functional heterogeneity of the different CAF phenotypes and how that impacts BC metastasis is unknown. Stromal derived factor-1 (SDF-1/CXCL12) is an important chemokine that is known to be involved in promoting tumor cell invasion and metastasis. In this study, we examine the functional differences between CAF isolated from different molecular subtypes of BC. Furthermore, we elucidate the role of CAF secreted SDF-1 as being one of the mechanisms by which a subset of CAF cells permanently reprograms poorly-metastatic MCF-7 cells to augment EMT-driven genes and become metastatic in vivo. Methods: We used primary CAF cell lines derived from BCs of different molecular subtypes and examined their global gene expression profiles using RNAseq. We used NSG mice xenografted with MCF-7 BC cells and primary CAF cells to evaluate the contribution of two different CAF phenotypes in promoting BC progression and metastasis. We developed dissociated tumor cell lines from CAF co-injected MCF-7 xenografts to determine the molecular changes that CAFs impart to MCF-7 cells in vivo. Using limiting dilution tumor xenograft assays and gene expression profiles we examined the molecular pathways, BC stemness markers, and tumor-initiating capacity of the dissociated tumor cell lines. By long-term SDF-1 treatment of MCF-7 cells in vitro and using these cells in various RNASeq, in vitro, and in vivo assays we determined the role of SDF-1 in altering the phenotype of MCF-7 cells. Results: We found that CAFs from different molecular subtypes have a differential effect on tumor initiation, progression, and metastasis in xenograft assays. We also found that a subset of CAFs has the ability to make the poorly-metastatic MCF-7 cells metastatic in vivo. We also found that this subset of CAF cells has a higher expression of SDF-1 and the tumors formed with the co-injection of MCF-7 cells with this subset of CAF cells are enriched in cancer stem cell-like metastasis initiating cells. We also found that upon serial transplant, the tumors formed by CAF-reprogramed MCF-7 cells have a gene expression profile that shows enrichment for EMT-driven genes and these tumors are robustly metastatic. Furthermore, we found that the SDF-1/CXCR4 axis is one of the critical mechanisms by which this subset of CAF cells permanently reprograms the phenotype of the MCF-7 cells. Conclusions: CAFs are a highly heterogeneous population of cells in the breast TME. This study examines the contribution of the functional heterogeneity of the CAF cells in BC metastasis. We have found that a unique subset of CAF cells has the ability to reprogram a poorly metastatic BC cell to not only become metastatic but induce a permanent EMT-driven phenotypic shift in the BC cells. SDF-1 may be one of the mechanisms that drive this CAF-induced change and understanding the CAF functional landscape and its role in BC metastasis might be crucial to developing new therapeutic modalities to abrogate BC metastasis. Citation Format: Utsav Sharma, Jun Sun, Kelsie Medina-Saenz, Susan Bare, Philip Miller, Manuel Picon-Ruiz, Joyce Slingerland, Dorraya El-Ashry, Marc Lippman. Triple-negative breast cancer CAFs induce a metastatic phenotype in MCF-7 cells via the SDF-1/CXCR4 axis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-08.

Association Between Contrast-Enhanced Ultrasound Characteristics and Molecular Subtypes of Breast Cancer.

This study aimed to investigate the correlation between contrast-enhanced ultrasound (CEUS) features and molecular subtypes of breast cancer (BC). A total of 116 patients (116 lesions) with pathologically diagnosed BC who received conventional ultrasound and CEUS before surgery were enrolled in this study. BC molecular subtypes were identified by postoperative pathological and immunohistochemical analysis as Luminal A (LA), Luminal B (LB), HER2 (H2) over-expression, and triple-negative (TN). Qualitative and quantitative CEUS characteristics were analyzed by one-way analysis of variance (continuous variables) or Pearson's χ2 test or Fisher's exact probability method (categorical variables). There were significant differences in enhancement speed and enhancement degree among the four subtypes (P < .05). The area under the curve (AUC), time to peak (TTP), and peak intensity (PI) differed among the four subtypes (P < .05). The AUC of the LA subtype (305.1 ± 188.4) was significantly smaller compared with the H2 (535.7 ± 222.0, P=.007) and TN subtypes (496.6 ± 254.7, P=.019). In addition, TTP was shorter in the H2 subtype (19.8± 4.9) compared with the other subtypes, and was significantly shorter than in the LA subtype (26.3 ± 7.2, P=.008) and LB subtype (23.1 ± 6.7, P=.036). The PI of the LA subtype (4.7 ± 2.3) was significantly lower than that of the LB (6.6 ± 2.3, P=.027), H2 (7.4 ± 2.2, P=.005), and TN subtypes (6.9 ± 2.6, P=.014). CEUS features differed significantly among different molecular subtypes of BC. The enhancement patterns and parameters may be important predictive features of different subtypes of BC.

Genomic profiling of DVL-1 and its nuclear role as a transcriptional regulator in triple negative breast cancer.

Dishevelled-1 (DVL-1) mediates Wnt signals critical for development and cellular homeostasis. DVL-1 is also linked with tumorigenesis, however its association with specific breast cancer (BC) subtypes and how it contributes to tumorigenicity remains poorly studied. Herein, using bioinformatics and genomics analyses, we investigate the role of DVL-1 in different molecular subtypes of BC. Our results demonstrate that DVL-1 is highly expressed in triple-negative BC compared to non-cancer tissues and associated with various clinical factors that may contribute to poor prognosis and survival rate.Another critical knowledge gap which remains poorly investigated involves the role of DVL-1 in the nucleus. While the cytoplasmic role of DVL-1 as a signaling hub has been extensively studied, the nuclear role of DVL-1 remains virtually unexplored. Herein for the first time, we have performed ChIP-Seq analyses to identify genomic regions targeted and regulated by DVL-1, thus highlighting its potential role as a regulator of transcription. Furthermore, we observed that DVL-1 peaks co-localize with H3K27me3 and EZH2, a repressive epigenetic mark and a histone methyltransferase respectively. Overall, our findings emphasize the importance of DVL-1 with TNBC-related pathology and identified unexpected gene targets of DVL-1, that may help explain the complexity of aberrant Wnt signaling in cancer.

214P Landscape of homologous recombination repair gene mutations in different molecular subtypes of breast cancer

Breast cancer (BC) is one of the most prevalent malignancies throughout the world. Important therapeutic progress has been achieved over the past decade, and the identification of genomic alterations in the homologous recombination repair (HRR) pathway sensitizes tumors to therapeutics such as PARP inhibitors and platinum-based chemotherapy. Here we evaluated the characteristics of HRR related gene mutations in patients with different molecular subtypes of BC.

REPERTOIRE OF CIRCULATING ANTIBODIES CORRESPONDING TO MOLECULAR SUBTYPES OF BREAST CANCER

Abstract Changes in the repertoire of circulating antibodies is a promising biomarker for various diseases. We have developed microarrays containing more than thousands of peptides with random amino acid sequences that can be used to analyze the entire repertoire of circulating antibodies. Using these peptide microarrays, we have shown that in the blood of patients diagnosed with breast cancer (BC) antibodies interacting with certain peptides are found. Moreover, circulating antibodies of patients with different molecular subtypes of BC (luminal A, luminal B and Basal-like) interact with different, but overlapping, panels of peptides. We have selected 634 peptides from 120K peptides presented on microarrays that specifically interact with circulating antibodies of blood plasma from patients with various subtypes of BC. This panel of peptides that specifically interact with the blood plasma immunoglobulins of patients with various molecular BC subtypes can be used for the development of non-invasive diagnostic test systems. Microchips containing thousands of peptides can be used as a tool for molecular screening populations at risk for various diseases. Thus, peptide microarrays can be used to create a new tool for studying the repertoire of circulating antibodies for different diseases evaluation, as well as for studying and evaluating protein-protein interactions.

Coexpression of PBX1 and EMP2 as Prognostic Biomarkers in Estrogen Receptor-Negative Breast Cancer via Data Mining.

Previous studies revealed that PBX1 ranked the third in the differentially expressed genes about development and progression of breast cancer (BC). Nevertheless, the role of PBX1 contributing to progression of BC has been unevaluated. Here, on the basis of ONCOMINE and GOBO databases, we compared BC samples with normal controls about the expression of PBX1 in various types of cancers, as well as their related expression levels in cancer cell lines by Cancer Cell Line Encyclopedia (CCLE) analysis. It was also found that, when compared with normal controls, PBX1 was markedly higher expressed not only in BC samples but also in BC cell lines, and coexpressed with EMP2 by ONCOMINE and CCLE coexpression analysis, which was also expressed higher in BC samples and BC cell lines similarly. According to Kaplan-Meier plotter, we further explored the prognostic functions of PBX1 and EMP2 in different molecular subtypes of BC, respectively. We demonstrated that overexpression of PBX1 mRNA was correlated with worse survival in luminal B subtype BC, whereas increased EMP2 expression was associated with shorter relapse-free survival in estrogen receptor (ER)-negative patients. Combining with previous studies, we could make a conclusion that coexpression of PBX1 and EMP2 predicts poor prognosis in ER-negative BC, which could be effective biomarkers for BC.

Clinical prognostic evaluation of immunocytes in different molecular subtypes of breast cancer.

To retrospectively analyze the relationship between preoperative blood parameters and postoperative clinical outcomes in patients with different molecular subtypes of breast cancer (BC), a cohort of 601 patients with BC in the Third Affiliated Hospital, Sun Yat-sen University, was retrospectively reviewed. They were categorized into four subtypes according to the expression of ER, PR, HER-2, and KI-67%. White blood cell, neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet counts, the neutrophil-to-lymphocyte ratio (NLR), the neutrophil-to-monocyte ratio (NMR), the lymphocyte-to-monocyte ratio (LMR), and the platelet-to-lymphocyte ratio (PLR) were recorded. Univariate and multivariate analyses were performed to identify the relationship between parameters and ratios and disease-free survival (DFS) and overall survival (OS). Luminal subtypes of BC had smaller tumor volume, better differentiation degree of invasive ductal carcinoma, less lymph node metastasis, and better clinical outcome than the HER-2 overexpression and triple-negative BC (TNBC) subtypes. In multivariate analysis, age and LMR were the independent prognostic factors of DFS in patients with luminal A (age, p = 0.005; LMR, P = 0.026); PLR in patients with luminal B (DFS; p = 0.032; OS, p= 0.012); LMR in patients with HER-2 overexpression (DFS; p = 0.008; OS, p = 0.017); and NLR for DFS (p = 0.014); and WBC for OS (p = 0.008) in patients with TNBC. LMR was the benign predictor of luminal A and HER-2 overexpression. PLR was the adverse predictor of luminal B. WBC and NLR were the adverse predictors of TNBC. Therefore, these peripheral blood parameters can play an important role in the diagnosis and treatment of patients with different molecular subtypes of BC.

Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.