Outcome In Breast Cancer Patients Research Articles

Long-term oncologic outcomes of unselected triple-negative breast cancer patients according to BRCA1/2 mutations

Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10–20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3–152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers (P = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P < 0.0001). Interestingly, among 29 patients with CBC recurrence, 24 patients (82.8%) had recurring TNBC subtype and among the CBC recurrence patients, 19 patients (65.5%) resumed chemotherapy. In the TNBC subtype, appropriate genetic testing and counseling are pivotal for surgical decisions like risk-reducing mastectomy (RRM). Furthermore, long-term surveillance is warranted, especially in BRCA1/2 carriers who did not receive RRM.

Impact of Low BMI and Nutritional Status on Quality of Life and Disease Outcome in Breast Cancer Patients: Insights From a Tertiary Cancer Center in India

This study investigates the impact of Body Mass Index (BMI) on Quality of Life (QoL) and treatment outcomes in breast cancer (BC) patients, particularly focusing on underweight individuals with compromised nutritional status. A nonrandomized prospective study comprising 121 newly diagnosed patients across various BMI categories utilized FACT-B & FACIT-Sp-12 questionnaires. Follow-ups occurred at baseline, during (3rd and 6th), and after (12th month) anthracycline-taxane chemotherapy, either sequentially or concomitantly. Patients with low BMI (<18.5 kg/m2; 53.7%) exhibited significantly poorer QoL, marked by compromised nutritional indicators (low MUAC and SFT). Repeated measures ANOVA identified significant correlations between BMI groups in functional, social, and emotional QoL aspects (p < 0.05), with no notable differences in other domains. A Chi-square (ꭓ2) test underscored a significant link between BMI and treatment response (p < 0.0001), showing higher rates of non-responders among underweight patients (p = 4.259e−14). The study advocates pretreatment consultation with a dietitian as standard care for Indian BC patients, offering complimentary nutritional support for improved QoL outcomes and treatment responses.

The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth.

Triple-negative breast cancer (TNBC) is a sub-classification of breast carcinomas, which leads to poor survival outcomes for patients. TNBCs do not possess the hormone receptors that are frequently targeted as a therapeutic in other cancer subtypes and, therefore, chemotherapy remains the standard treatment for TNBC. Nuclear envelope proteins are frequently dysregulated in cancer cells, supporting their potential as novel cancer therapy targets. The Lem-domain (Lem-D) (LAP2, Emerin, MAN1 domain, and Lem-D) proteins are a family of inner nuclear membrane proteins, which share a ~45-residue Lem-D. The Lem-D proteins, including Ankle2, Lemd2, TMPO, and Emerin, have been shown to be associated with many of the hallmarks of cancer. This study aimed to define the association between the Lem-D proteins and TNBC and determine whether these proteins could be promising therapeutic targets. GENT2, TCGA, and KM plotter were utilized to investigate the expression and prognostic implications of several Lem-D proteins: Ankle2, TMPO, Emerin, and Lemd2 in publicly available breast cancer patient data. Immunoblotting and immunofluorescent analysis of immortalized non-cancerous breast cells and a panel of TNBC cells were utilized to establish whether protein expression of the Lem-D proteins was significantly altered in TNBC. SiRNA was used to decrease individual Lem-D protein expression, and functional assays, including proliferation assays and apoptosis assays, were conducted. The Lem-D proteins were generally overexpressed in TNBC patient samples at the mRNA level and showed variable expression at the protein level in TNBC cell lysates. Similarly, protein levels were generally negatively correlated with patient survival outcomes. siRNA-mediated depletion of the individual Lem-D proteins in TNBC cells induced aberrant nuclear morphology, decreased proliferation, and induced cell death. However, minimal effects on nuclear morphology or cell viability were observed following Lem-D depletion in non-cancerous MCF10A cells. There is evidence to suggest that Ankle2, TMPO, Emerin, and Lemd2 expressions are correlated with breast cancer patient outcomes, but larger patient sample numbers are required to confirm this. siRNA-mediated depletion of these proteins was shown to specifically impair TNBC cell growth, suggesting that the Lem-D proteins may be a specific anti-cancer target.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade.

Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100-100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99-1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50-1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis.

ScRNA-seq characterizing the heterogeneity of fibroblasts in breast cancer reveals a novel subtype SFRP4+ CAF that inhibits migration and predicts prognosis.

Cancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly impact the tumor microenvironment and therapeutic responses in breast cancer (BC). Despite their importance, the comprehensive profile of CAFs in BC remains to be fully elucidated. To address this gap, we utilized single-cell RNA sequencing (scRNA-seq) to delineate the CAF landscape within 14 BC normal-tumor paired samples. We further corroborated our findings by analyzing several public datasets, thereby validating the newly identified CAF subtype. Additionally, we conducted coculture experiments with BC cells to assess the functional implications of this CAF subtype. Our scRNA-seq analysis unveiled eight distinct CAF subtypes across five tumor and six adjacent normal tissue samples. Notably, we discovered a novel subtype, designated as SFRP4+ CAFs, which was predominantly observed in normal tissues. The presence of SFRP4+ CAFs was substantiated by two independent scRNA-seq datasets and a spatial transcriptomics dataset. Functionally, SFRP4+ CAFs were found to impede BC cell migration and the epithelial-mesenchymal transition (EMT) process by secreting SFRP4, thereby modulating the WNT signaling pathway. Furthermore, we established that elevated expression levels of SFRP4+ CAF markers correlate with improved survival outcomes in BC patients, yet paradoxically, they predict a diminished response to neoadjuvant chemotherapy in cases of triple-negative breast cancer. This investigation sheds light on the heterogeneity of CAFs in BC and introduces a novel SFRP4+ CAF subtype that hinders BC cell migration. This discovery holds promise as a potential biomarker for refined prognostic assessment and therapeutic intervention in BC.

Social capital in the management of breast cancer in Lagos, Nigeria.

Breast cancer is the most common cancer in women worldwide, necessitating substantial social support during diagnosis and treatment. This study examines the role of social capital in breast cancer management, focusing on the experiences of patients. The objective of the study was to explore the role of social capital in breast cancer management among women living with breast cancer in Lagos, Nigeria. Using a qualitative design, the study recruited 23 women with breast cancer receiving treatment at a teaching hospital in Lagos, Nigeria. Data were content analyzed to identify themes related to social capital. The study found that social capital, crucial for breast cancer patients' emotional and instrumental support, stems from various sources such as relatives, immediate family, spouses, places of worship, friends, and neighbors. Effective coping and management of the condition were facilitated through this support network. However, assistance from places of worship, friends, and neighbors was only accessible to those who openly acknowledged their health conditions and had established connections with these social groups. Relationships led to support only when there was a disclosure of the health condition. (1) This finding reinforces the importance of integrating social support mechanisms including family, friends, and community networks into breast cancer management programs. (2) The study identifies diverse sources of social capital, including relatives, family, spouses, places of worship, friends, and neighbors, stressing the need for tailored support networks. (3) Research reveals the link between health condition disclosure and support accessibility from groups like places of worship and friends, and it emphasizes creating stigma-free environments for patients to disclose health status comfortably. (4) The study highlights family involvement in breast cancer management as crucial for effective coping. Healthcare professionals should prioritize interventions strengthening family support systems. (5) Findings of stress community support for better breast cancer outcomes, advocating for initiatives like support groups and awareness campaigns to boost social capital and aid affected individuals. The study emphasizes the significance of involving family members in the breast cancer management process and highlights the need for support systems within families and communities to facilitate better outcomes for breast cancer patients.

Deep learning and genetic algorithm-based ensemble model for feature selection and classification of breast ultrasound images

Feature extraction and selection are important techniques in the classification of medical images. Extraction of key features and selection of relevant features are the preliminary processes that are essential for identifying the shape of an object or diagnosis of a tumor in images. In this study, we conduct a thorough comparison of deep neural networks' performance. The comparison of the networks infers MobileNet as optimal for feature extraction from medical images, where it has minimal parameters and high validation accuracy. For feature selection, we employ the Genetic Algorithm (GA) because of its proficiency in handling high-dimensional and complex feature space. GA's iterative process aligns well with the unique characteristics of breast ultrasound (BUS) images, which enhances its efficacy in selecting salient features of BUS images. An ensemble model, capitalizing on the collective decision-making capabilities of multiple classifiers based on a weighted voting scheme for classification, is proposed. Empirical evaluations are conducted using two publicly available BUS image datasets, BUSI and UDIAT. The proposed model demonstrates a notable improvement of approximately 4% and 9% in accuracy for the BUSI and UDIAT, respectively. The improved diagnostic accuracy in breast abnormality identification allows for early abnormality diagnosis. This improves treatment outcomes for breast cancer patients and highlights the practical value of the proposed method for improving BUS image categorization.

Pathway-based signatures predict patient outcome, chemotherapy benefit and synthetic lethal dependencies in invasive lobular breast cancer.

Invasive Lobular Carcinoma (ILC) is a morphologically distinct breast cancer subtype that represents up to 15% of all breast cancers. Compared to Invasive Breast Carcinoma of No Special Type (IBC-NST), ILCs exhibit poorer long-term outcome and a unique pattern of metastasis. Despite these differences, the systematic discovery of robust prognostic biomarkers and therapeutically actionable molecular pathways in ILC remains limited. Pathway-centric multivariable models using statistical machine learning were developed and tested in seven retrospective clinico-genomic cohorts (n = 996). Further external validation was performed using a new RNA-Seq clinical cohort of aggressive ILCs (n = 48). mRNA dysregulation scores of 25 pathways were strongly prognostic in ILC (FDR-adjusted P < 0.05). Of these, three pathways including Cell-cell communication, Innate immune system and Smooth muscle contraction were also independent predictors of chemotherapy response. To aggregate these findings, a multivariable machine learning predictor called PSILC was developed and successfully validated for predicting overall and metastasis-free survival in ILC. Integration of PSILC with CRISPR-Cas9 screening data from breast cancer cell lines revealed 16 candidate therapeutic targets that were synthetic lethal with high-risk ILCs. This study provides interpretable prognostic and predictive biomarkers of ILC which could serve as the starting points for targeted drug discovery for this disease.

Hyaluronic acid-based injectable formulation developed to mitigate metastasis and radiation-induced skin fibrosis in breast cancer treatment

The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 μg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 μg/mL). In vitro, SCH agents significantly enhance cell–cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.

Abstract LB434: Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine

Abstract We have developed a novel single-cell derived 3D organoid culture platform, Rapid, Reproducible, Rare Cell 3D Expansion (R3CE), capable of generating 3D organoids from solid tumors and normal tissues obtained via surgical tissues and needle biopsies within one week. This method demonstrates over 90% success in banking for at least two passages with over 106 cells across various cancer types, including breast cancer, colorectal cancer, hepatoma cancer, and ovarian cancer. The organoids maintain high fidelity to original tissues, as evidenced by H&amp;E staining, WES, and protein marker analysis across generations. Notably, the R3CE platform can also cultivate circulating tumor cells (CTCs) from peripheral blood. The drug sensitivity profiles of RCE-cultured CTCs closely mirrored clinical outcomes in breast cancer patients. For a patient with stage IV HER2-positive breast cancer, our real-time assay results led to an adjustment in treatment from lapatinib/5-FU to lapatinib/Trastuzumab emtansine (TDM-1), which resulted in substantial clinical improvement. To our knowledge, the R3CE platform is the first 3D organoid system that does not require aggregation or 3D scaffold such as matrigel system. These advancements position the R3CE platform as a promising tool for personalized medicine, offering a rapid and accurate method for drug screening and therapeutic response prediction to guide clinical decision-making in cancer treatment. Citation Format: Wen-Hung Kuo, Yen-Jang Huang, Jia-Yang Chen, Yi-Chun Wu, Chia-Chun Chen, Mark D. Pegram, Ying-Chih Chang. Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB434.

Breast edema score at breast MRI: its value in prediction of molecular subtype of breast cancer and its impact on axillary LN metastasis

BackgroundSince many newly diagnosed breast cancer patients have breast MRI, the value of preoperative breast magnetic resonance imaging would improve if molecular subtypes could be consistently identified, and prognostic information provided in addition to diagnostic imaging. Breast edema may improve the ability to predict molecular subtypes and clinical and pathological outcomes in invasive breast cancer patients. The prognosis for breast cancer prognosis based on the findings of breast edema by magnetic resonance imaging will be useful in both pretreatment planning and prognosis. Breast edema on T2-weighted images and STIR was scored on a scale of 1 to 4, as follows: (a) breast edema score (BES) 1, no edema; (b) BES 2, peritumoral edema; (c) BES 3, pre pectoral edema; and (d) BES 4, subcutaneous edema (suspicious for occult inflammatory breast cancer “IBC”). Axillary lymph node status and number were also evaluated in T2 and STIR and after contrast administration. The aim of this work was to assess the role of tumour-related breast edema MRI features in distinguishing molecular subtypes of breast cancer and its effect on pathological axillary lymph nodes in patients with breast cancer.ResultsThere was a highly significant difference between BES with respect to the molecular subtypes of breast cancer, size of the mass, Ki-67 expression, LN status, and LN number (p < 0.0001, 0.045, < 0.0001, < 0.0001, and < 0.0001 respectively). However, there was no significant difference between BES and histopathological grade in studied masses, such as p-value = 0.49.ConclusionsTumour-related breast edema MRI characteristics may be useful in distinguishing molecular subtypes of breast cancer and could be used as a promising feature to improve the predictive performance of pathological axillary lymph nodes in patients with breast cancer, contributing to preoperative treatment planning and prognostic outcome.

Small Non-Coding RNAs and Their Role in Locoregional Metastasis and Outcomes in Early-Stage Breast Cancer Patients.

Deregulation of small non-coding RNAs (sncRNAs) has been associated with the onset of metastasis. We evaluated the expression of sncRNAs in patients with early-stage breast cancer, performing RNA sequencing in 60 patients for whom tumor and sentinel lymph node (SLN) samples were available, and conducting differential expression, gene ontology, enrichment and survival analyses. Sequencing annotation classified most of the sncRNAs into small nucleolar RNA (snoRNAs, 70%) and small nuclear RNA (snRNA, 13%). Our results showed no significant differences in sncRNA expression between tumor or SLNs obtained from the same patient. Differential expression analysis showed down-regulation (n = 21) sncRNAs and up-regulation (n = 2) sncRNAs in patients with locoregional metastasis. The expression of SNHG5, SNORD90, SCARNA2 and SNORD78 differentiated luminal A from luminal B tumors, whereas SNORD124 up-regulation was associated with luminal B HER2+ tumors. Discriminating analysis and receiver-operating curve analysis revealed a signature of six snoRNAs (SNORD93, SNORA16A, SNORD113-6, SNORA7A, SNORA57 and SNORA18A) that distinguished patients with locoregional metastasis and predicted patient outcome. Gene ontology and Reactome pathway analysis showed an enrichment of biological processes associated with translation initiation, protein targeting to specific cell locations, and positive regulation of Wnt and NOTCH signaling pathways, commonly involved in the promotion of metastases. Our results point to the potential of several sncRNAs as surrogate markers of lymph node metastases and patient outcome in early-stage breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant sncRNAs and to validate our results in a larger cohort of patients.

Outcome of Breast Cancer Patients with Involved Axillary Lymph Nodes at Presentation Treated with Internal Mammary Irradiation

Outcome of Breast Cancer Patients with Involved Axillary Lymph Nodes at Presentation Treated with Internal Mammary Irradiation

Comprehensive analysis of risk factors for postoperative wound infection following radical mastectomy in breast cancer patients.

Surgical site infections (SSIs) following radical mastectomy in breast cancer patients can significantly affect patient recovery and healthcare resources. Identifying and understanding the risk factors for postoperative wound infections (PWIs) are crucial for improving surgical outcomes. This retrospective study was conducted from June 2020 to June 2023, including 23 breast cancer patients who developed PWIs post-radical mastectomy and a control group of 46 patients without such infections. Comprehensive patient data, including variables such as intraoperative blood loss, hospital stay duration, body mass index (BMI), operation time, anaemia, drainage time, diabetes mellitus, cancer stage, white blood cell (WBC) count, serum albumin levels and preoperative neoadjuvant chemotherapy, were meticulously gathered. Statistical analyses, including univariate and multivariate logistic regression, were performed using SPSS software (Version 27.0). The univariate analysis identified several factors significantly associated with an increased risk of PWIs, including preoperative neoadjuvant chemotherapy, low serum albumin levels, advanced cancer stage, diabetes mellitus and reduced WBC count. Multivariate logistic regression highlighted anaemia, prolonged drainage time, diabetes mellitus, advanced cancer stage, reduced WBC count, hypoalbuminemia and preoperative neoadjuvant chemotherapy as significant contributors to the increased risk of PWIs. Anaemia, extended drainage time, diabetes mellitus, advanced cancer stage, low WBC count, hypoalbuminemia and preoperative neoadjuvant chemotherapy are key risk factors for SSIs post-radical mastectomy. Early identification and proactive management of these factors are imperative to reduce the incidence of postoperative infections and enhance recovery outcomes in breast cancer patients.

The Prognostic Value of Low HER2 Expression on Treatment Outcomes in Metastatic Hormone Receptor-positive Breast Cancer Patients Treated with CDK4/6 Inhibitors and Endocrine Therapy

The Prognostic Value of Low HER2 Expression on Treatment Outcomes in Metastatic Hormone Receptor-positive Breast Cancer Patients Treated with CDK4/6 Inhibitors and Endocrine Therapy

Abstract 5797: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing

Abstract Introduction: ADCs have had tremendous impact on patient outcomes in breast cancer and are now second line therapy for stage IV HER2 positive metastatic breast cancer. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. We are developing next generation ADCs that deliver targeted combination chemotherapies with a single molecule. Method: CatenaBio has developed a novel system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of highly stable single-molecule targeted combination therapies, Multi-Payload-Conjugates (MPCs), with a well-defined drug-antibody ratio (DAR). Results: We screened combinations of different payloads targeting several different mechanisms of cell division attached to trastuzumab at different DARs to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Additionally, these novel MPCs show potent inhibition of tumor growth in a HER2+ xenograft model of cancer. Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. Multi-payload Conjugates® offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines and HER2 expression levels. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses. Citation Format: Richard L. Kendall, Marco Lobba, Saurabh Johri, Chanez Symister, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Andrew Lau, Matthew B. Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing [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 5797.

Abstract 5892: SCUBE3 promotes therapy resistance in triple negative breast cancer

Abstract Introduction: The development of novel targeted therapies is urgently required for improving the outcome of triple negative breast cancer (TNBC) patients. Chemotherapy is the common treatment option for TNBC. However, resistance and tumor relapse remain the major obstacles hindering the effectiveness of chemotherapeutic agents in cancer patients. Therefore, identifying genes/factors that sensitize breast cancer cells to chemotherapeutic agents could improve treatment outcome in patients. Here we report Signal peptide CUB domain EGF-like 3 (SCUBE3) genes as a novel therapeutic adjuvant that can improve the efficacy of doxorubicin, a chemotherapeutic agent commonly used in treating breast cancer patients. Methods: Unbiased high-throughput loss of function genomic screen was performed on breast cancer cells in the presence or absence of doxorubicin. Breast cancer cells lines (MDA-MB-231 and MDA-MB-468) were purchased from the American Type Culture Collection and cultured in standard medium. Breast cancer cells were transfected either with SCUBE3 overexpression plasmid or shRNA specific to SCUBE3. These overexpression/knockdown breast cancer cells were analyzed for cell viability, migration, invasion, colony formation, cell cycle, apoptosis assays, western blotting, and in vivo tumor xenograft study. Results: Our finding demonstrated that SCUBE3 promotes breast cancer cell progression as knockdown of SCUBE3 inhibited the ability of breast cancer cells to form colony, migrate, and invade, while overexpression of SCUBE3 promoted tumor growth in preclinical mouse models. Our results revealed that SCUBE3 mediates its protumor effects by regulating genes involved in growth and survival in the MAPK pathway, DNA damage surveillance pathway including RAD51 and FOXM1, and apoptotic pathway including Mcl-1. We demonstrated that SCUBE3 promotes tumor growth and progression by interacting with and activating several oncoproteins. Conclusions: Overall, our data suggests that SCUBE3 can be a potent therapeutic target for treating TNBC patients. Citation Format: Deepika Singh, Daisy Medina, Benjamin Onyeagucha, Rahul Mojidra, Panneerdoss Subbarayallu, Alex Taylor, Dongwen Lyu, Santosh Timilsina, Prabhakar Pitta Venkata, Saif S R Nirzhor, Shahad M. Abdulsahib, Trong Phat Do, Yidong Chen, Ratna Vadlamudi, Manjeet K. Rao. SCUBE3 promotes therapy resistance in triple negative breast cancer [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 5892.

Comprehensive evaluation of the relationship between biomarker profiles and neoadjuvant chemotherapy outcomes for breast cancer patients

BackgroundAccurately predicting the response to neoadjuvant chemotherapy (NAC) in breast cancer patients is crucial for guiding treatment strategies and enhancing clinical outcomes. Current studies have primarily focused on a limited set of biomarkers. More importantly, the results of many studies are in conflict. To address this, we conducted a comprehensive evaluation of the predictive value of a diverse range of clinically available molecular biomarkers in breast cancer, including HER2, ER, PR, TOPO II, EGFR, Ki67, CK5/6, AR, and p53. Additionally, we assessed changes in these biomarkers after NAC administration.MethodsOur study involved 189 patients with invasive breast cancer who underwent NAC at our institute. We examined biomarker profiles in core-needle biopsies taken before NAC and in surgical specimens obtained after NAC. We examined the association between these biomarkers and NAC outcomes, focusing on two main aspects: the rate of pathological complete response (pCR) and the reduction in tumor size. We used Chi-square and Mann-Whitney U tests to compare biomarker status changes between pCR and non-pCR patients. Linear regression analysis was employed to evaluate the relationship between biomarker status and tumor shrinkage rate. Additionally, we compared the expression status of these biomarkers before and after NAC using Chi-square and Wilcoxon signed-rank tests.Results and conclusionsOur results demonstrated significant differences in the expression levels of HER2, ER, PR, TOPO II, EGFR, and Ki67 between pCR and non-pCR patients, underscoring their potential as predictive markers for NAC outcomes. Importantly, our results have shed light on the contentious issue surrounding TOPO II in NAC outcome prediction. We have provided evidence that establishes a significantly positive association between TOPO II expression level and the pCR rate. Notably, tumor size was identified as a relevant predictive factor for achieving pCR. Regarding biomarker profiles, only Ki67 levels and TOPO II status exhibited changes following NAC, resolving previous controversies. While the ER and PR status remained unchanged, their expression values exhibited a slight but significant decrease post-NAC. Our results provide clarity and insights into the value and potential of using these biomarkers to predict NAC responses and prognosis in breast cancer patients.

A Genome-Wide Association Study of Endoxifen Serum Concentrations and Adjuvant Tamoxifen Efficacy in Early-Stage Breast Cancer Patients.

Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30-100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome-wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early-stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse-free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome-wide significance (P value: ≤5 × 10-8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.