Subtypes Of Breast Cancer Patients Research Articles

Abstract PO3-06-03: Overall Survival and Disease Interval Among Breast Cancer Subtypes in Patients with Brain Metastasis

Abstract Background: Breast cancer brain metastasis (bcbm) is associated with limited survival. There is a paucity of clinical trials and real-world data on the survival and disease interval [primary breast cancer (pbc) to metastatic breast cancer (mbc) or bcbm] of bcbm patients. We performed a retrospective study comparing the overall survival (OS) and disease intervals (INT) between the date of pbc surgery, diagnoses of mbc, and bcbm among 3 subtypes of bc in patients with bcbm. Methods: The informatics team generated a preliminary list of patients with a history of breast cancer and brain metastasis who were treated at the Wilmot Cancer Institute (WCI) of the University of Rochester. Key inclusion criteria were evidence of bcbm, bcbm diagnosed between Jan 1st, 2010 and June 1st, 2021, and adequate medical records available. Patients with de novo mbc were excluded. Final eligible patients were registered for the study. Median OS in bc subtypes was assessed with the Kaplan-Meier method and compared using the log-rank test. Median INTs among bc subtypes were compared using the Kruskal-Wallis test. Registered patients were divided into triple-negative (TNBC), estrogen receptor-positive/HER2 negative (ER+/HER2-), and HER2+ subtypes. Results: Out of 191 patients screened, 83 patients were eligible for the study. The total number of patients enrolled by subtype was 26 (TNBC), 35 (ER+/HER2-), and 22 (HER2+). Disease and patient characteristics are shown in Table 1. Median OS from pbc, mbc, and bcbm among 3 subtypes are shown in Table 2. The differences in the median OS from these 3 different time points were not statistically significant among 3 subtypes. After adjusting for important variables (age, race, tumor grade, stage, and presence of perioperative therapy) in a Cox regression model, there was still no statistical evidence that these 3 subtypes differed in OS. Three different INTs (pbc-mbc, pbc-bcbm, mbc-bcbm) among 3 subtypes are shown in Table 3. INTpbc-mbc and INTpbc-bcbm were significantly different among 3 subtypes of bc. After adjusting for the factors in the model, the subtypes didn’t differ significantly with respect to INTpbc-mbc and INTpbc-bcbm. Stage 3 at pbc was significantly associated with shorter INTpbc-mbc and INTpbc-bcbm. The distribution of INTmbc-bcbm was highly non-normal due to the high % of patients with concurrent diagnoses of mbc and bcbm. Thus an exploratory logistic regression model assessed the association of subtypes and important variables with the odds of having mbc and bcbm concurrently (INTmbc-bcbm< 1 month). It showed that the ER+/HER2- subtype had 4 times lower odds of concurrent mbc and bcbm diagnosis than the HER2+ subtype (p=0.03). In an unadjusted pairwise comparison between the subtypes (Table 3), the ER+/HER2- group had statistically longer INTpbc-mbc and INTpbc-bcbm than TNBC. However, when the subtypes were adjusted for Stage 3 vs 1 or 2, these subtypes were not significantly different for these INT. In our study, a higher proportion of Stage 3 tumors in TNBC subtype is likely associated with the shorter INTs seen with TNBC in unadjusted analysis. Conclusion: Adjusted comparison of OS and disease intervals from pbc between TNBC, ER+/HER2-, and HER2+ subtypes were not statistically different in this cohort of bcbm patients. Interestingly, median OS from mbc were numerically very similar (3.6-3.7 years) among these subtypes. Median OS from pbc and bcbm were numerically longer in HER2+ bc than the other 2 subtypes. Intervals between pbc to mbc and to bcbm and between mbc to bcbm were numerically longer in ER+/HER2- subtypes than the other 2 subtypes. ER+/HER2- subtype was 4 times less likely to have concurrent bcbm at the time of mbc diagnosis than the HER2+ subtype. These results are exploratory and hypotheses generating. Table 1: Disease and Patients Characteristics Table 2: Overall Survival Unadjusted Table 3: Disease Intervals Unadjusted Citation Format: Asis Shrestha, Sugam Gouli, Sujan Niraula, Ramandeep Babbra, Niraj Neupane, Sarah Stanford, Myla Strawderman, Zeni Kharel, Huina Zhang, Sara Hardy, Nimish Mohile, Carey Anders, David Hicks, Ruth O'Regan, Ajay Dhakal. Overall Survival and Disease Interval Among Breast Cancer Subtypes in Patients with Brain Metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-03.

Abstract 1389: Understanding the differential role of an IL-6 family cytokine in varying subtypes of breast cancer patients for novel therapeutic intervention

Abstract In the United States, it is estimated that over 295,000 women will be diagnosed with breast cancer, and over 43,000 breast cancer deaths in 2023. Mortality in breast cancer is due in large part due to distant metastasis to organs such as the bone, lung, liver, and brain. Our laboratory has identified that the IL-6-family cytokine oncostatin M (OSM) plays a crucial role in initiating metastasis by secreting pro-metastatic molecules such as VEGF, LOXL2 and IL-6, and increasing circulating tumor cell numbers and metastases to bone and lung in vivo. More recent work within our lab has identified unique roles for OSM in varying subtypes of breast cancer patients, particularly between estrogen receptor positive (ER+) and ER- patients. It is well known that patients with ER- breast cancer, specifically triple negative breast cancer (TNBC; ER- PR- HER2-), have limited therapeutic options. However, the divergent role OSM plays in ER+ and ER- breast cancer and the mechanism by which this occurs has yet to be fully understood. Thus, we aimed to fully elucidate the difference between OSM in ER+ versus ER- breast cancer. RNA sequencing analysis on OSM-treated human ER+ cells and ER- TNBC cells discovered significant differences in gene expression between both cell lines upon treatment with OSM, including alteration in DNA-replication and cell cycle pathway genes. Afterwards to evaluate the correlation between OSM and DNA synthesis and this role on metastasis, we evaluated the role of a novel anti-OSM therapeutic and its correlation with decreased metastasis. This research aims to elucidate the unique role OSM plays in ER+ and ER- breast cancer and will provide a molecular understanding of how this occurs and will provide detailed information on which patients will benefit most from anti-OSM therapeutics. Citation Format: Cody L. Wolf, Ken Tawara, Cheryl L. Jorcyk. Understanding the differential role of an IL-6 family cytokine in varying subtypes of breast cancer patients for novel therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1389.

Cuproptosis-associated ncRNAs predict breast cancer subtypes.

Cuproptosis is a novel copper-dependent mode of cell death that has recently been discovered. The relationship between Cuproptosis-related ncRNAs and breast cancer subtypes, however, remains to be studied. The aim of this study was to construct a breast cancer subtype prediction model associated with Cuproptosis. This model could be used to determine the subtype of breast cancer patients. To achieve this aim, 21 Cuproptosis-related genes were obtained from published articles and correlation analysis was performed with ncRNAs differentially expressed in breast cancer. Random forest algorithms were subsequently utilized to select important ncRNAs and build breast cancer subtype prediction models. A total of 94 ncRNAs significantly associated with Cuproptosis were obtained and the top five essential features were chosen to build a predictive model. These five biomarkers were differentially expressed in the five breast cancer subtypes and were closely associated with immune infiltration, RNA modification, and angiogenesis. The random forest model constructed based on Cuproptosis-related ncRNAs was able to accurately predict breast cancer subtypes, providing a new direction for the study of clinical therapeutic targets.

Prognostic implications of response to neoadjuvant chemotherapy in breast cancer subtypes

The current study was designed to assess the response to treatment, as well as clinical and survival outcomes, across different breast cancer subtypes in patients who underwent neoadjuvant chemotherapy (NAC). From 2014 to 2019, a total of 139 patients who were histologically confirmed to have breast cancer, underwent NAC, and subsequently received breast and axillary surgery, were retrospectively included in this study. The rates of pathological complete response (pCR) to NAC were significantly higher for HER2-positive and triple-negative subtypes than for luminal A and HER2-negative subtypes (p = 0.013). Multivariate analysis for disease-free survival (DFS) revealed that tumour grade and the presence of pCR were independent prognostic factors. The presence or absence of a pCR with NAC was an independent prognostic indicator in the multivariate analysis for overall survival (OS). Lastly, achieving a pCR was independently predicted by 18F-FDG PET/CT findings, the HER2-positive subtype, and the triple-negative subtype. Despite the inherent methodological limitations, our findings underscore the significance of identifying predictive markers to tailor NAC plans, with the aim of improving survival outcomes.

Clinical Outcomes and Intrinsic Subtypes of Breast Cancer Patients with Single Hormone Receptor-positive Receiving Neoadjuvant Chemotherapy

BackgroundExtensive studies have highlighted the significance of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer (BRCA). However, our understanding of patients with single hormone receptor (HR)-positive (sHR+) BRCA remains limited. This lack of understanding poses challenges in predicting prognosis and selecting appropriate treatments. Patients and MethodsWe collected data from a total of 825 human epidermal growth factor receptor 2 negative (HER2-) BRCA patients who underwent neoadjuvant chemotherapy (NAC) in two distinct cohorts. Four subgroups were created within each cohort based on their HR expression: ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR-. We conducted comparative analyses to assess clinicopathological characteristics, chemotherapy responsiveness, clinical outcomes, and intrinsic subtyping among these subgroups. ResultsER+/PR- constituted 11.1% and 14.9% of samples in two cohorts, respectively, whereas ER-/PR+ comprised 8.3% and 3.7%. Higher histologic grades were more common in the ER-/PR+ group as compared to the ER+/PR+ subgroup (P = .0075 in cohort 1; P = .026 in cohort 2). Additionally, after multivariable analysis, ER-/PR+ were more likely to achieve pathological complete response (pCR) (cohort 1: OR =6.67; 95%CI, 2.63-16.94; P < .001; cohort 2: OR =3.70; 95%CI, 1.08-11.84; P = .030;). Between ER+/PR- and ER+/PR+, the distant recurrence-free survival (DRFS) was comparable. The survival outcomes in the ER-/PR+ subgroup present a partial inconsistency between the 2 cohorts. Furthermore, the ER-/PR+ subgroup exhibited a higher incidence of the basal-like subtype, while the ER+/PR- subgroup had a higher proportion of luminal-like subtypes. ConclusionThis study highlighted the distinct clinical and genetic characteristics of sHR+ BRCA, emphasizing the potential need for optimized treatment strategies.

Molecular and clinical characterization of ICOS expression in breast cancer through large-scale transcriptome data.

ICOS (Inducible T Cell Costimulator), one of the co-stimulatory B7 superfamily members, was characterized as a co-stimulatory receptor for T-cell enhancement. However, the role of ICOS in breast cancer remains largely unknown. The present study systematically investigated the expression pattern and its relation to clinical characteristics and immunotherapy by integrating multiple clinical cohorts and large-scale gene expression data. This study included 2994 breast tumor samples with transcriptome data and matched clinical data. To make our findings more reliable, we set the TCGA cohort as the discovery set and the METABRIC cohort as the validation set. The expression of ICOS in breast cancer is strongly associated with major clinical and molecular characteristics. There is an association between higher ICOS expression and malignant subtypes and grades of tumors. In addition, gene ontology analysis based on genes significantly correlated with ICOS expression indicated that the expression of ICOS is mainly associated with immune responses and inflammation. We also observed strong correlations between ICOS and other promising immune-checkpoint molecules, including PD1, PDL1, CTLA4, and IDO1. Furthermore, we found that ICOS expression is associated with the response to anti-PDL1 immunotherapy and may serve as a biomarker for immunotherapy prediction. Our results indicated higher ICOS expression is significantly associated with favorable survival in triple-negative breast cancer (TNBC) patients, but not for all subtypes of breast cancer patients. In summary, ICOS correlates with higher malignant breast cancers, and it contributes to the regulation of the immune microenvironment of breast tumors, making it a potential biomarker and immunotherapy target.

TNF-α induced NF-κB mediated LYRM7 expression modulates the tumor growth and metastatic ability in breast cancer

Tumor microenvironment (TME) of solid tumors including breast cancer is complex and contains a distinct cytokine pattern including TNF-α, which determines the progression and metastasis of breast tumors. The metastatic potential of triple negative breast cancer subtypes is high as compared to other subtypes of breast cancer. NF-κB is key a transcription factor regulating inflammation and mitochondrial bioenergetics including oxidative phosphorylation (OXPHOS) genes which determine its oxidative capacity and generating reducing equivalents for synthesis of key metabolites for proliferating breast cancer cells. The differential metabolic adaptation and OXPHOS function of breast cancer subtypes in inflammatory conditions and its contribution to metastasis is not well understood. Here we demonstrated that different subunits of NF-κB are differentially expressed in subtypes of breast cancer patients. RELA, one of the major subunits in regulation of the NF-κB pathway is positively correlated with high level of TNF-α in breast cancer patients. TNF-α induced NF-κB regulates the expression of LYRM7, an assembly factor for mitochondrial complex III. Downregulation of LYRM7 in MDA-MB-231 cells decreases mitochondrial super complex assembly and enhances ROS levels, which increases the invasion and migration potential of these cells. Further, in vivo studies using Infliximab, a monoclonal antibody against TNF-α showed decreased expression of LYRM7 in tumor tissue. Large scale breast cancer databases and human patient samples revealed that LYRM7 levels decreased in triple negative breast cancer patients compared to other subtypes and is determinant of survival outcome in patients. Our results indicate that TNF-α induced NF-κB is a critical regulator of LYRM7, a major factor for modulating mitochondrial functions under inflammatory conditions, which determines growth and survival of breast cancer cells.

Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer.

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER + ) subtype of breast cancer patients, which accounts for 70-80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular sensitivity to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment.

Identification of glycogene-based prognostic signature and validation of B3GNT7 as a potential biomarker and therapeutic target in breast cancer.

Breast cancer is the most common cancer worldwide, with the fifth highest mortality rate among all cancers and high risk of metastasis. However, potential biomarkers and molecular mechanisms underlying the stratification of breast cancer in terms of clinical outcomes remain to be investigated. Therefore, we aimed to find a novel prognostic biomarker and therapeutic target for breast cancer patients. Unsupervised hierarchical clustering was used to perform comprehensive transcriptomic study of total 185 glycogenes in public datasets of breast cancer with clinicopathological and survival information. A glycogene-based signature for subtype classification was discovered using Limma packages, and relevance to four known molecular features was identified by GSVA. Experimental verification was performed and biological functions of B3GNT7 were characterized by quantitative RT-PCR, western blot, transwell assays, and lectin immunofluorescence staining in breast cancer cells. A 23-glycogene signature was identified for the classification of breast cancer. Among the 23 glycogenes, B3GNTs showed significantly positive associations with ER-/Her2- subtype in breast cancer patients (n = 2655). Overexpressed B3GNT7 were correlated with poor prognosis in breast cancer patients based on public datasets. B3GNT7 depletion inhibited cell proliferation, migration, and invasion, and decreased global fucosylation in MDA-MB-231 and HCC1937 breast cancer cells. Herein, we discovered a unique 23-gene signature for breast cancer patient glycogene-type classification. Among these genes, B3GNT7 was shown to be a potential biomarker for unfavorable outcomes and therapeutic target of breast cancer.

Use of Drugs in Clinical Practice and the Associated Cost of Cancer Treatment in Adult Patients with Solid Tumors: A 10-Year Retrospective Cohort Study.

Cancer is one of the leading causes of morbidity and mortality in the world. Its growing incidence and prevalence, as well as the advances in diagnostic and treatment tools, motivate an open debate about the economic burden it may place on health systems and have raised concerns about access to this technological innovation. There is a lack of information on the detailed costs of pharmacological treatment of cancer in our health setting. In this context, it is necessary to know the use of drugs in cancer treatment in conditions of real clinical practice. A real-word, evidence-based retrospective cohort study was conducted at Vall d'Hebron University Hospital (VHUH), the largest hospital complex in Catalonia, Spain, in order to determine the use of drugs and the associated cost in real clinical practice for the treatment of solid tumors in adult patients attended at this institution over 10 years (2010-2019). This was a single-center retrospective cohort study of adult cancer patients attended in clinical practice at the Medical Oncology Department of VHUH between 1 January 2010 and 31 December 2019. Data of prescription, preparation, and cost of antineoplastic treatments were analyzed by pharmacological class (cytotoxic drugs, immunotherapy, targeted therapy, radiopharmaceuticals, and others), by antineoplastic agent, and by type of tumor. The number of patients and the pharmaceutical expenditure corresponding to all these subgroups were recorded. The cost per patient in each tumor location was also calculated. The study population included 13,209 patients with an overall pharmaceutical antineoplastic expenditure of EUR 120,396,097, increasing from 7.67% in relation to the total HUVH pharmaceutical expenditure in 2010 to 12.82% in 2019. By pharmacological class, the specific weight of the cost of targeted therapy is relevant (75.22% of pharmaceutical antineoplastic expenditure, 21.3% of patients) compared to the group of conventional cytotoxics (17.25% of pharmaceutical antineoplastic expenditure, 76.37% of patients), while immunotherapy has represented the largest relative increase, from 5% in 2014 to 12% in 2019. Eight targeted therapy drugs represented 50% of the costs of the targeted therapy drug class (palbociclib, trastuzumab, pertuzumab, bevacizumab, nivolumab, cetuximab, pembrolizumab, and trastuzumab emtansine). Eleven tumor sites accounted for 90% of the expenditure in 71% of all patients. Breast cancer had the highest expenditure during the study period (EUR 34,332,210) and at each individual year. Melanoma showed the highest increase, with 9.7% of total pharmaceutical antineoplastic expenditure in 2019 (2% of patients), representing a paradigm of the rising costs of cancer treatment due to the incorporation of new high-cost therapies. The average annual cost per patient was highly variable depending on the pathology. There was a growing increase in costs per patient in most tumor locations, particularly in patients with melanoma (from EUR 1922 in 2010 to EUR 37,020 in 2019), prostate cancer (from EUR 2992 in 2010 to EUR 14,118 in 2019), and non-small cell lung cancer (from EUR 3545 in 2010 to EUR 8371 in 2019). The relevance of the difference in monthly cost per patient that has been identified for the different intrinsic subtypes in breast cancer patients during 2019 (HER2+ EUR 2661/month, Luminal EUR 881/month, Triple negative EUR 386/month) makes us consider suggesting differentiated reimbursement rates for certain clinical conditions. Finally, support treatment with antiemetic drugs, erythropoietin stimulating agents, granulocyte-colony stimulating factor (G-CSF), and bone resorption inhibitors has involved a cost of EUR 5,751,910, which represents 4.6% of the overall pharmacological cost of cancer treatment. This study provides detailed insights on the oncological pharmaceutical expenditure for the treatment for solid tumors in the VHUH, based on real cost information from our hospital practice and for all antineoplastic therapies and types of solid tumors. This type of information on all the different types of cancer can be useful to better understand the economic burden of the disease and can be decisive for allocating public resources and funds for research, especially in those areas where information is scarce and therefore where further studies are needed. The contribution to knowledge of the cost of oncology therapy is of great value due to its realism and scope.

Distinct Prognosis of Minimal Residual Disease According to Breast Cancer Subtype in Patients with Breast or Nodal Pathologic Complete Response After Neoadjuvant Chemotherapy.

Few studies have reported on patient prognosis according to residual cancer burden after neoadjuvant chemotherapy (NAC). Herein, we evaluated the survival of patients based on residual disease after NAC to identify subpopulations with distinct prognoses. We retrospectively reviewed 728 patients treated with NAC from 2010 to 2017. Patients were divided into four subgroups depending on post-surgical residual disease according to the staging system: pathological complete response (pCR) (ypT0/TisN0), minimal residual disease (MRD) (ypT1mi/T1aN0 or ypT0/Tis ypN0i+/N1mic), node-only pCR (≥ ypT1b ypN0), and breast-only pCR (ypT0/Tis ≥ ypN1a). Clinicopathological characteristics and survival outcomes were analyzed by adjusting for factors affecting survival. Overall, 50.4% (n = 367) of patients achieved pCR, with the MRD group accounting for 16.5% (n = 120). Although age and clinical stage were not different among the study groups, histologic grade, subtypes, chemotherapy response, and local treatment showed differences. Event-free survival (EFS) and overall survival (OS) demonstrated no significant difference between the pCR and MRD groups. In the multivariate analysis, pCR status was the only significant factor in EFS, and no statistical difference was noted between the pCR and MRD groups. However, clinical stage, pCR status, and subtype significantly affected the OS. MRD showed favorable outcomes in terms of both EFS and OS in all subtypes, except for those with triple-negative breast cancer (TNBC). Patients with MRD showed outcomes comparable to those of patients who achieved pCR and may be candidates for de-escalation of post-NAC treatment, except for those with a TNBC subtype.

Prediction of prognosis and immunotherapy response in breast cancer based on neutrophil extracellular traps-related classification.

Neutrophil extracellular traps (NETs), a network of DNA histone complexes and proteins released by activated neutrophils, have been demonstrated to be associated with inflammation, infection related immune response and tumorigenesis in previous reports. However, the relationship between NETs related genes and breast cancer remains controversial. In the study, we retrieved transcriptome data and clinical information of BRCA patients from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. The expression matrix of neutrophil extracellular traps (NETs) related genes was generated and consensus clustering was performed by Partitioning Around Medoid (PAM) to classify BRCA patients into two subgroups (NETs high group and NETs low group). Subsequently, we focus on the differentially expressed genes (DEGs) between the two NETs-related subgroups and further explored NETs enrichment related signaling pathways by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, we constructed a risk signature model by LASSO Cox regression analysis to evaluate the association between riskscore and prognosis. Even more, we explored the landscape of the tumor immune microenvironment and the expression of immune checkpoints related genes as well as HLA genes between two NETs subtypes in breast cancer patients. Moreover, we found and validated the correlation of different immune cells with risk score, as well as the response to immunotherapy in different subgroups of patients was detected by Tumor Immune Dysfunction and Exclusion (TIDE) database. Ultimately, a nomogram prognostic prediction model was established to speculate on the prognosis of breast cancer patients. The results suggest that high riskscore is associated with poor immunotherapy response and adverse clinical outcomes in breast cancer patients. In conclusion, we established a NETs-related stratification system that is beneficial for guiding the clinical treatment and predicting prognosis of BRCA.

Survival analysis of breast cancer patients luminal subtype B on lymphovascular invasion (LVI), tumor-infiltrating lymphocyte (TIL), and expression of mammaglobin A

Background: With 1 in 10 women receiving a new cancer diagnosis each year, breast cancer is the most frequent cancer among women. Luminal B breast cancer incidence rates are rising in non-Hispanic white women aged 55 to 69 in Asia/Pacific and Indonesia subtype across all age groups. In Bali, Luminal B is the most prevalent subtype with the greatest fatality rate. This study aims to prove the survival analysis of Luminal B subtype breast cancer patients based on lymphovascular invasion (LVI), tumor-infiltrating lymphocyte (TIL), and mammaglobin A expression. Methods: This study is a survival analysis using nested and prospective cohort methods. Retrospective data were taken from the Cancer Registry and Medical Records (MR) of patients in Sanglah General Hospital, mammaglobin results (Paraffin block test) on anatomical pathology analysis. Statistical Kaplan Meier and Cox Proportional hazard calculations performed with the SPSS program were significant (p&lt;0.05). Results: The number of research subjects was 60, with 32 subjects dying and 28 still alive until the data collection was completed. There was no difference in age between the two groups. The mean of all ages is 50.12 ± 9.93 years. Positive LVI has 9 months median survival (95% CI 8-10) with p= 0.013 risk 2,797 times. TIL high (positive 2- positive 3) median survival 8 months (95% CI 6.3-9.7) with p=0.003 and risk 3,151 times. Strong expression of mammaglobin A (3-4) had a median survival of 12 months (95% CI 4.4-19.5 months; p=0.015) and risk 3.34 times. Conclusion: LVI, TIL, and mammaglobin A expression significantly affected poor survival in the breast cancer Luminal B subtype.

Plasma Levels of Metalloproteinase 3 (MMP-3) and Metalloproteinase 7 (MMP-7) as New Candidates for Tumor Biomarkers in Diagnostic of Breast Cancer Patients

Matrix metalloproteinases (MMPs) are a group of enzymes that mediate both physiological and pathological processes such as carcinogenesis. The role of matrix metalloproteinase-3 (MMP-3) and (MMP-7) in the pathogenesis of breast cancer (BC) has been demonstrated, suggesting that they may be considered as potential markers of this condition. The aim of this study was to assess plasma concentrations and diagnostic utility of MMP-3 and MMP-7 in 100 patients with early-stage breast cancer with Luminal A subtype or Luminal B HER-negative subtype, before and after surgical treatment, and in the following control groups: patients with a benign tumor (fibroadenoma) and healthy subjects. The concentrations of MMP-3 and MMP-7 were referenced to the levels of the widely recognized marker for BC diagnosis CA 15-3. MMP-3 and MMP-7 was measured by ELISA method and CA 15-3 by CMIA. Plasma levels of MMP-7 were significantly higher in Luminal A and Luminal B HER2-negative subtype breast cancer patients as compared to the healthy group. MMP-7 demonstrated comparable but mostly higher to CA 15-3 or MMP-3 values of diagnostic sensitivity, specificity, positive and negative predictive values and AUC (0.6888 for Luminal A subtype; 0.7612 for Luminal B HER2-negative; 0.7250 for BC total group, respectively) in the groups tested. The combined use of the tested parameters resulted in a further increase in diagnostic criteria and AUC. These results suggest the usefulness of combining MMP-7 with CA 15-3 in the diagnostics of breast cancer, especially in Luminal B HER2-negative subtypes patients, as a new candidate for tumor markers.

Disparities in stage at diagnosis among breast cancer molecular subtypes in China

Disease stage at diagnosis and molecular subtypes are the main determinants of breast cancer treatment strategies and prognosis. We aimed at examining the disparities and factors associated with the stage at diagnosis among the molecular subtypes in breast cancer patients in China. We identified patients with first primary breast cancer diagnosed between January 1, 2016, and December 31, 2017, from 23 hospitals in 12 provinces in China. We analyzed the proportion of non-early-stage (stages II-IV) breast cancer cases based on the family history of breast cancer, body mass index (BMI), insurance status, and molecular subtypes. Multivariable analyses were used to estimate the factors associated with non-early-stage diagnosis among the molecular subtypes. We further compared these estimates with that in the United States using the Surveillance, Epidemiology, and End Results database. A total of 9398 Chinese were identified with first primary invasive breast cancer. Of the 8767 patients with known stages, the human epidermal growth factor receptor 2 (HER2)-enriched subtype had the highest proportion of stages II-IV (76.6%) patients, followed by triple-negative breast cancer (73.2%), luminal B (69.9%), and luminal A (62.3%). The percentage of non-early-stage patients was higher in women with overweight or obesity than in those with a body mass index (BMI) <25 kg/m2 (adjusted odds ratio [OR] 1.3, 95% confidence interval (CI) 1.1-1.4). Patients with a family history of breast cancer had a higher likelihood of early-stage (adjusted OR 0.7, 0.5-0.8) breast cancer. Patients with rural insurance had a substantially higher risk of non-early-stage disease than those with urban insurance (adjusted OR 1.8, 1.4-2.2). Regarding the subtype, being overweight/obese only increased the risk of non-early-stage in luminal A breast cancer. Compared with the United States, China had a higher proportion of non-early-stage breast cancer for all subtypes, with the largest gap in luminal A (adjusted OR 2.2, 95% CI 2.0-2.4). The wide disparities in stage at breast cancer diagnosis imply that China urgently needs to improve early breast cancer diagnosis and health equity.

Abstract P1-04-17: Clinical and pathological differences between HER2 Low and other cancer subtypes in breast cancer patients

Abstract Background: HER2 is a tyrosine kinase receptor belonging to the human epidermal receptor family and is considered an important proto-oncogene in the biology of breast carcinoma. HER2 overexpression is determined by a +3 score on the immunohistochemistry (IHC) assay. In addition, tumors with IHC results of +1 or +2 with ISH negative were defined as HER2-low. Recent studies have shown that the clinicopathological characteristics of HER2-low tumors, pointing out potential differences regarding hormone receptor status and new treatment possibilities in this patients. Objective: To assess the frequency and clinicopathological differences between cancer subtypes, as well as the survival of these patients. Methods: All patients with breast cancer diagnosed between 1987 and 2021 included in the Pérola Byington Hospital database were eligible. Patients were excluded if they had bilateral disease, had participated in clinical studies, or had incomplete data. The primary endpoint was overall survival stratified by cancer subtype, secondary endpoints were clinicopathological differences between cancer subtypes and death probability. Both the t-test and the chi-square test were used to analyze the association of each variable between the groups. Multivariate analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the death outcome. Cox regression was used for survival analysis, with the Log-rank method and the results were presented in a survival graph using the Kaplan-Meier method. The R software version 4.1.1 was used to perform all analyzes, with a p-value &amp;lt; 0.05 being considered statistically significant. Results: 11,234 patients were included: 4,541 (40.42%) had Luminal cancer subtype, 2,955 (26.30%) HER2 Low, 2,242 (19.96%) triple negative, and 1,496 (13.32%) HER2 overexpression. Age, self-reported ethnicity, BMI, presence of comorbidities, clinical stage, nuclear grade, histological grade, family history, radiotherapy, chemotherapy, surgery, local, and systemic recurrence, and death showed statistically significant differences between cancer subtypes (table 1). In the multivariate regression (adjusted for the other evaluated characteristics), patients with HER2 overexpression cancer subtype showed a 44.8% greater probability of death than patients with HER2 Low (OR 1.448, 95%CI 1.046-2.004, p=0.026), while the patient with triple-negative cancer had a 26.1% lower probability of evolving to death when compared to the HER2 Low patient (OR 0.739, 95%CI 0.562-0.969, p=0.0229). The luminal subtype showed no statistically significant difference when compared to the patient with HER2 Low. Overall survival showed a statistically significant difference between cancer subtypes, with a median of 12 years for Luminal HR 0.816 (0.73-0.913), 15 years for HER2 overexpression HR 1.154 (1.003-, 327), and no statistical difference for triple negative HR 0.978 (0.859-1.114) compared to 12 years for HER2 Low. Conclusion: This study in breast cancer patients demonstrates significant differences between cancer subtypes, with a higher probability of progression to death for patients with HER2 overexpression, while patients with Luminal subtype had a lower probability, when compared with HER2 Low. More studies are needed to clarify the impact of these differences between cancer subtypes on response to therapy. Association between cancer subtype and other variables (n=11,234). Citation Format: ANDRE MATTAR, Andressa Amorim, Marina Diogenes, Jorge Shida, Luiz Henrique Gebrim. Clinical and pathological differences between HER2 Low and other cancer subtypes in breast cancer patients [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 P1-04-17.

Early Assessment of Neoadjuvant Chemotherapy Response Using Multiparametric Magnetic Resonance Imaging in Luminal B-like Subtype of Breast Cancer Patients: A Single-Center Prospective Study

This study aimed to evaluate the performance of multiparametric breast magnetic resonance imaging (mpMRI) for predicting response to neoadjuvant chemotherapy (NAC) in patients with luminal B subtype breast cancer. The prospective study included thirty-five patients treated with NAC for both early and locally advanced breast cancer of the luminal B subtype at the University Hospital Centre Zagreb between January 2015 and December 2018. All patients underwent breast mpMRI before and after two cycles of NAC. Evaluation of mpMRI examinations included analysis of both morphological (shape, margins, and pattern of enhancement) and kinetic characteristics (initial signal increase and post-initial behavior of the time-signal intensity curve), which were additionally interpreted with a Göttingen score (GS). Histopathological analysis of surgical specimens included grading the tumor response based on the residual cancer burden (RCB) grading system and revealed 29 NAC responders (RCB-0 (pCR), I, II) and 6 NAC non-responders (RCB-III). Changes in GS were compared with RCB classes. A lack of GS decrease after the second cycle of NAC is associated with RCB class and non-responders to NAC.

The Prognostic Role of HuR Varies Between Different Subtypes of Breast Cancer Patients: Data Mining and Retrospective Analysis.

Human-antigen R (HuR) is an RNA-binding protein, which regulates the expression of several oncogenes and tumor suppressor genes through post-transcriptional mechanisms. But the role of HuR in breast cancer remains controversial. The aim of this study was to verify the association between cytoplasmic HuR level and prognosis of breast cancer patients. Data mining from the Human Protein Atlas (HPA) and Kaplan-Meier Plotter (KMP) databases was performed. Then, 394 patients with stage I-III primary breast cancer were enrolled between January 2005 and December 2016. We investigated the association between cytoplasmic HuR level and clinicopathological characteristics or survival of these patients. Immunohistochemical analysis was performed to determine HuR expression level. SPSS 21.0 statistical software was used for analysis. In the HPA and KMP datasets, HuR protein and mRNA expression level were not significantly associated with overall survival of all breast cancer patients enrolled. Results from our 394 patients indicated that higher expression level of cytoplasmic HuR was associated with larger tumor size, lymph node positive, ER negative and triple-negative subtype. For all patients enrolled, the results indicated that compared with HuR negative patients, the DFS (disease-free survival) of HuR 1+ was longer (60.5% vs 78.8, P=0.053, HR=0.616, 95% CI: 0.378-1.005), the P value was borderline. In the triple-negative breast cancer (TNBC) subgroup, HuR positive patients had significantly longer DFS than HuR negative patients (65.5% vs 30.8%, P=0.001, HR=0.345, 95% CI: 0.180-0.658). In the HR+HER2- subgroup, HuR low (0~1+) patients had significantly longer OS than HuR high (2+~3+) patients (97.0% vs 89.5%, P=0.033, HR=2.482, 95% CI: 1.074-5.736). In conclusion, our results revealed that higher expression level of HuR was related to aggressive biological characteristics which supported the findings from previous researches. In the HR+HER2- subgroup, lower HuR expression level patients had better survival time, while in the TNBC subgroup we got the opposite results. Our work indicated that HuR might play different roles in different breast cancer subtypes.

Modulating the Activity of Androgen Receptor for Treating Breast Cancer

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis

BackgroundTriple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to find new therapeutic targets for TNBC. Recent genomic studies implicated the Hippo / Yap signal is over activated in TNBC, manifesting it plays a key role in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha.MethodsRBCK1 and YAP protein expression levels were measured by western blotting, while the mRNA levels of YAP target genes were measured by RT–PCR. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of Hippo signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect YAP protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the YAP protein.ResultsIn our current study, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1 depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies confirmed that RBCK1 could bind to YAP protein and enhance the stability of YAP protein by promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321).ConclusionOur study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment.C9ENSf2mfVdiRkeiVCEbafVideo abstract