Treatment Of Breast Cancer Research Articles

Abstract C063: Using a disparities dashboard to identify racial/ethnic differences in breast cancer treatment: Implications for improving cancer care delivery

Abstract C063: Using a disparities dashboard to identify racial/ethnic differences in breast cancer treatment: Implications for improving cancer care delivery

Abstract C019: Peripheral Absolute Lymphocyte Count and Breast Cancer Mortality among Racially Diverse Women

Abstract Background: Among patients with triple-negative breast cancer (TNBC), higher tumor infiltrating lymphocytes (TILs) are associated with increased overall mortality (OM) and breast cancer-specific mortality (BCSM). We previously found that low peripheral absolute lymphocyte count (ALC) is associated with increased OM and BCSM in a sample of mostly non-Hispanic White (NHW) patients with TNBC. Here, we investigated the association between low ALC and mortality (OM and BCSM) across different breast cancer subtypes and whether the association is potentially modified by race and ethnicity. Methods: We used the Oncoshare database, which links electronic medical records (EMRs) data to the California Cancer Registry (CCR), and assessed women diagnosed with stage I-III breast cancer between 2000-2017, who had at least one ALC measurement and treated at two healthcare systems in California. Patient and tumor characteristics were obtained from the CCR and laboratory testing from EMRs. Patients with metastatic disease and chemotherapy receipt after one year of diagnosis were excluded. Multivariable logistic models assessed factors associated with “low ALC” (<1 K/µL, ever vs. never). We applied Cox models to evaluate the association between “min ALC” (lowest ALC value after diagnosis) and OM and BCSM within each breast cancer subtype (Luminal A, HER2-enriched, and TNBC), and further explored the interaction between min ALC and race and ethnicity. All models adjusted for low absolute neutrophil count, demographics, and tumor features. Results: Among 10,750 women analyzed, the risk of “low ALC” was associated with TNBC vs Luminal A (odds ratio (OR) 1.22, p=0.0098), older age (OR 1.01 per year, p<0.001), higher grade (grade 3 vs. 1, OR 1.15, p=0.042), higher stage (stage III vs. I, OR 1.81, p<0.001), and public vs. private health insurance (OR 1.29, p<0.001). Cox models showed that higher min ALC was associated with lower OM across breast cancer subtypes (Luminal A: HR 0.37, HER2-enriched: HR 0.32, TNBC: HR 0.22; all p<0.001) and BCSM (Luminal A: HR 0.29, HER2-enriched: HR 0.23, TNBC: HR 0.19; all p<0.001). Interaction analysis showed that race and ethnicity modified the association between min ALC and OM (interaction-p <0.001) and BCSM (interaction-p < 0.001) in the overall cohort; compared to NHW women (HR 0.38, 95% confidence interval [0.34-0.43]), the association between min ALC and OM was stronger among Hispanic (HR 0.24, [0.18-0.33]), Asian (HR 0.19, [0.14-0.25]), and Black (HR 0.21, [0.13-0.35]) women. Similar results were observed for BCSM. Conclusions: Low peripheral ALC, a routinely measured clinical lab result, strongly predicts higher BCSM and OM across breast cancer subtypes, beyond TNBC. The association between min ALC and BCSM/OM was stronger among Black and Asian women vs. NHW women, suggesting that maintaining normal ALC during breast cancer treatment may reduce BCSM and OM, especially for women from racial and ethnic minoritized groups. Future research should investigate differences in ALC, immune response, and BCSM in diverse populations. Citation Format: Candice N. Thompson, Ingrid Luo, Mina Satoyoshi, Lidia Schapira, Esther M. John, Summer S. Han, Allison W. Kurian. Peripheral Absolute Lymphocyte Count and Breast Cancer Mortality among Racially Diverse Women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C019.

Abstract B096: Patient, Provider, and Advocate Perspectives on Factors that Impact Participation of Black Women in Breast Cancer Clinical Trials

Abstract Background: Black women are more likely to present with advanced stage disease and to die following a breast cancer (BC) diagnosis compared with women from other racial and ethnic groups. This persistent health inequity is in part driven by underrepresentation in clinical trials (CTs), as well as structural and social drivers of health. Multi-level factors impact patients’ decision to enroll on a cancer CT. Objective: The goal of the FOR ME (Fostering Opportunities in Research through Messaging and Education) study is to develop, optimize, and test a narrative web-based video intervention for Black women diagnosed with BC to promote shared decision making and CT participation. Here, we report findings from the development phase, wherein we engaged Black women with BC, oncologists and CT office staff, and cancer advocates. Our objective was to identify cross-cutting and unique themes concerning barriers and motivating factors to CT participation, intervention priorities, and to understand lived experiences to enhance authenticity and to inform video content. Methods: Guided by community engaged research approaches, we used multiple qualitative methods, including story circles and 1:1 interviews. We used thematic analysis and inductive and deductive coding approaches. Data analysis for each group followed the same approach: we annotated a subset of transcripts, compiled the annotations into a preliminary codebook, and conducted inter-coder reliability to improve quality and refine the codebook. Finally, we used Dedoose to analyze quotations and code co-occurrences, application frequencies, and relationships. We examined cross-cutting and unique themes during data collection and analysis. Results: In total, 38 Black women with BC participated in interviews and story circles, ranging in age from 27-75 years (M=59, SD =12); about 27% were currently receiving BC treatment and 27% had prior CT participation. Oncologists (n=16) and CT office staff (n=4) reported having on average 11.6 and 9.5 years of CT experience, respectively). Finally, 15 cancer advocates completed interviews, of whom 73% identified as Black women; 87% reported that the organization they were involved with connected patients to or provided education about CTs. Several cross-cutting themes were identified, including: 1) Acknowledgement of time, financial, and logistical burdens of CT participation; 2) The impact that current and historical racism, discrimination and mistreatment has had on CT enrollment for Black BC patients; 3) A lack of accessible CT information poses significant challenges for health literacy; and 4) Positive provider relationships and communication are important facilitators to CT participation. Conclusion: To promote health equity and participation in CTs among Black women with BC, interventions should consider multiple perspectives and prioritize addressing culturally sensitive patient-provider communication, shared decision-making, and patient empowerment. The information we learned will inform the development of a culturally tailored decision aid video. Citation Format: Leslie R. Carnahan, Eliza B. Cohn, Tigist Mersha, Neha Hippalgaonkar, Ryan Nguyen, Kauthar Salum, Ana Williams Waite, Christen Sandoval, Lolita Coleman, Beulah Brent, Paris Thomas, Paramjeet Khosla, Kent F. Hoskins, Vida Henderson. Patient, Provider, and Advocate Perspectives on Factors that Impact Participation of Black Women in Breast Cancer Clinical Trials [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B096.

Abstract B087: Inflammation and breast cancer: Understanding the interplay and implications for prevention and treatment

Abstract Breast cancer continues to be a major global health issue, affecting millions and posing challenges for researchers and healthcare workers. Recent research has revealed the importance of inflammation in the development and progression of a variety of malignancies, including breast cancer. The aim of this study is to investigate the complex association between inflammation and breast cancer in order to improve treatment and preventative techniques. A mixed-methods approach was used, with both quantitative and qualitative studies. The study included 580 breast cancer patients and 2,573 control participants. Patient records, hospital databases, and publicly available datasets were all used as data sources. Statistical methods, including univariate and multivariate logistic regression models, were employed to discover breast cancer predictors associated with inflammation. Breast cancer growth is strongly linked to chronic inflammation and specific inflammatory markers (CRP, IL-6, and TNF-α). Breast cancer incidence is correlated with geographical, demographic, and lifestyle characteristics such as region, age, gender, race, education level, and overall health condition. Comorbidities like hypertension, diabetes, and arthritis, as well as BMI, smoking, and physical activity levels, all have a role in risk. Anti-inflammatory drugs and lifestyle changes show promise for lowering the risk of breast cancer and improving patient outcomes. The study reveals significant relationships between breast cancer incidence and a variety of demographic, lifestyle, and health-related variables. Chronic inflammation is important in the development of breast cancer; therefore, inflammatory indicators could be used as diagnostic or therapeutic tools. The study suggests that tailored anti-inflammatory medications and lifestyle changes could have a significant impact on breast cancer prevention and therapy. This study emphasizes the necessity of knowing the relationship between inflammation and breast cancer. The insights revealed can lead to novel methods for breast cancer management, stressing the importance of ongoing research to fully understand the connection between inflammation and breast cancer and to implement these discoveries in clinical practice. Citation Format: Opeyemi O. Ogungbola, Samuel O. Ejeh, Jane Odeh, Olajumoke R. Omoniyi, Abayomi A. Akomolafe, Emmanuel K. Abudu. Inflammation and breast cancer: Understanding the interplay and implications for prevention and treatment [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B087.

Sentinel Lymph Node Assessment in Endometrial Cancer: A Review

As the number of patients diagnosed with endometrial cancer rises, so does the number of patients who undergo surgical treatment, consisting of radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy or lymph node sampling. The latter entail intra- and post-surgical complications, such as lymphedema and increased intra-operative bleeding, which often outweigh their benefits. Sentinel Lymph Node (SLN) sampling is now common practice in surgical management of breast cancer, as it provides important information about the disease without jeopardizing surgical radicality and patient outcomes. While this technique has also been shown to be feasible in patients with endometrial cancer, there is little consensus on several aspects, such as tracer injection volume and site, pathological ultrastaging, and result interpretation. The aim of this review is to analyze the current literature on SLN assessment in order to help standardize the procedure.

A Complete Appraisal of Polymeric Micelle-Based Nanocarrier for Targeting Breast Cancer: Recent Strategies and Advancements

Aim/Objective: Polymeric micelle-based drug delivery systems have emerged as a beacon of hope in the challenging landscape of breast cancer therapy. This review aimed to explore the recent advancements and promising developments in the field, offering an in-depth analysis of their potential and challenges. The significance of this study lies in providing a comprehensive examination of the current advances in polymeric micelles technology, which have the potential to improve the efficiency and specificity of breast cancer therapy while minimizing adverse events. Methods: Polymeric micelles offer a revolutionary therapy by encapsulating therapeutic agents, allowing for controlled drug release and the precise targeting of malignant cells, while lowering systemic toxicity. Recent advances have focused on enhancing targeting strategies, including active and passive targeting, to increase the specificity of polymeric micelle-based therapies. A systematic review of literature was carried out using databases, like PubMed, Scopus, and Web of Science, which included papers published between 2010 and 2023. The selection criteria of the literature focused on the drug-loading capabilities and targeting strategies of the polymeric micelles, which could be advantageous for breast cancer treatment. Results: Clinical drug approaches leverage the versatility of micelles to co-deliver multiple agents, addressing the multifaceted nature of breast tumors and combating drug resistance. Additionally, polymeric micelles are finding applications in breast cancer diagnostics and imaging, enabling early detection and precise monitoring. The journey of polymeric micelle-based breast cancer therapy extends to formulation and engineering, preclinical and clinical studies, and confronts regulatory and commercialization challenges. However, the horizon is illuminated by emerging technologies, like personalized medicine, biomarker-driven targeting, and integration with novel therapies, promising a future where breast cancer treatment is tailored to individual patients and marked by improved efficacy and reduced side effects. Conclusion: In conclusion, this review underscores the transformative potential of polymeric micelle- based delivery systems in breast cancer therapy.

Adherence to cardiovascular medications and risk of cardiovascular disease in breast cancer patients: A causal inference approach in the Pathways Heart Study

Purpose Women with breast cancer (BC) are at high risk of developing cardiovascular disease (CVD). We examined adherence to CVD medications and their association with major CVD events over 14 years of follow-up in the Pathways Heart Study, a prospective study of 4,776 stage I-III BC patients diagnosed from 2005–2013. Methods Eligibility included being alive 6 months post-BC diagnosis, with dyslipidemia, hypertension, or diabetes at diagnosis along with ≥1 prior outpatient order or dispensing for a statin, anti-hypertensive, or diabetes medication, respectively, in the 30 months prior. Medication adherence was measured from pharmacy data to calculate cumulative average adherence (CAA). Incident heart failure (HF), ischemic heart disease (IHD), and stroke were determined via validated diagnosis and procedure codes. Working marginal structural models (MSM) fitted with inverse probability weighting evaluated the effect of adherence regimens on the hazards for each CVD event, while controlling for baseline and time-varying confounders. MSM parameterizations included: 1) CAA<100% versus CAA = 100% (ref), 2) CAA<80% versus CAA≥80% (ref) and 3) CAA<80% versus 80%≤CAA<100% versus CAA = 100%. Results Poor statin adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.54; 95% CI: 1.09, 5.94) versus CAA≥80%. Poor statin adherence was also associated with a higher risk of stroke (HR = 8.13; 95% CI: 2.03, 32.51) but not risk of IHD and HF. Further, compared with perfect adherence (CAA = 100%), good adherence (80%≤CAA<100%) was associated with lower risk (HR = 0.35; 95% CI: 0.13, 0.92) while poor adherence (CAA<80%) was associated with higher risk of composite CVD (HR = 2.45; 95% CI: 1.05, 5.70). Levels of adherence to anti-hypertensives and diabetes medications had mixed or null associations with risk of CVD. Conclusions Maintaining good adherence (≥80%) to statins after BC treatment is beneficial for cardiovascular health in patients with dyslipidemia. Future studies should determine factors associated with lower adherence to statins and ways to improve adherence.

Investigating the Salience of Clinical Meaningfulness and Clinically Meaningful Outcomes in Metastatic Breast Cancer Care Delivery

PURPOSE As metastatic breast cancer (mBC) treatment evolves, there is a need to understand how clinical meaningfulness, or a meaningful change in a patient's daily life, and clinically meaningful outcomes inform patient-centered care. Partnering with key stakeholders ensures patient-centered research incorporates the knowledge and expertise of advisors with lived experience. We describe a multistakeholder engagement approach to examine how people living with mBC (PLWmBC), caregivers, and health care providers interpret clinical meaningfulness and clinically meaningful outcomes and their influence on mBC treatment decision making and care. METHODS Qualitative focus groups with PLWmBC, caregivers, and health care providers were conducted and analyzed along three overarching themes: interpretations of clinical meaningfulness and clinically meaningful outcomes; treatment recommendations, preferences, and decisions; and implications for clinical practice. Patient-led and professional organizations served as research partners in study design, implementation, and interpretation of findings. RESULTS Partnerships were established with four patient-led and three professional organizations representing diverse constituencies throughout the United States. Twenty-two focus groups were conducted with 50 PLWmBC, 24 caregivers, and 41 health care providers (oncologists, n = 11; advanced practice providers, n = 13; oncology nurses, n = 17) between March and June 2023. PLWmBC and caregivers were unfamiliar with the concepts of clinical meaningfulness and clinically meaningful outcomes. Although health care providers were familiar, they did not use the terms when discussing treatment with PLWmBC. Across groups, participants emphasized the importance of meaningful outcomes beyond overall survival, including quality of life and improvement in symptoms and functioning. Participants noted that outcomes considered meaningful are individualized and dynamic. CONCLUSION This study offers insight into how partnering with patient advocacy and professional organizations can enhance research quality and aid translation of findings to clinical practice, thereby supporting patient-centered care.

Effectiveness of combined targeted and hormonal therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer: A systematic review and meta-analysis of RCTs.

we aim to synthesize available evidence on the effectiveness of hormonal plus targeted therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer. We searched the following databases: Medline, PubMed, Cochrane Library, CINAHL, Web of Science, Scopus, and African Journal. Only studies that investigated the effectiveness of hormonal therapy combined with targeted therapy for HR+/HER2- advanced breast cancer treatment were included. The outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). A random-effect meta-analysis model was employed. Statistical analysis was performed using Comprehensive Meta-analysis version 3. 24 studies were included in the meta-analysis with an overall sample size of 7635. Median PFS, OS and ORR were found to be significantly increased in the combination group compared to hormonal monotherapy [SMD = 6.072 (95% CI = 3.785-8.360), p < 0.001], [SMD = 1.614 (95% CI = 0.139-3.089), p = 0.032] and [OR = 1.584 (CI 1.134-2.213), p = 0.007] respectively. Subgroup analysis showed a significant difference in PFS and ORR between patients who received "hormonal therapy + CDK4/6 inhibitors" vs hormonal therapy only [SMD = 6.015 (CI 3.069-8.960), p < 0.001], (OR = 1.828 (CI 1.030-3.243), p = 0.039] respectively. Compared with hormonal monotherapy, targeted plus hormonal therapy significantly improves PFS, OS and ORR in postmenopausal women with HR+/HER2- advanced breast cancer.

Amplitude do rastreio e diagnóstico do câncer de mama no estado do Piauí e o impacto da pandemia da COVID-19

Introduction: The COVID-19 pandemic has brought about a new epidemiological reality worldwide that is responsible for altering the entire dynamics of addressing health issues globally. Cancer management policies were directly impacted, potentially leading to a decline in early case detection and a consequent increase in morbidity and mortality among patients with cancer. Objective: To analyze the impacts of the pandemic on breast cancer screening measures in the state of Piauí. Method: This epidemiological study used secondary data provided by the Department of Health Information of the Brazilian Unified Health System regarding the performance of mammograms and breast cancer diagnoses in the state of Piauí between 2017 and 2021. Results: Between 2017 and 2019, an average of 39,165 mammograms were performed annually, compared with an average of 22,367 exams in each year between 2020 and 2021. The data presented in this study indicate a significant decrease in the number of exams performed, associated with a decline in the absolute number of diagnoses, as well as delayed diagnoses. Conclusions: The scenario described in this study suggests the possibility of developing an epidemiological emergency related to breast cancer, both due to the structural incapacity of the state of Piauí to provide adequate assistance to patients and the increasing observation of more advanced cases. Therefore, we highlight the need for intensified efforts to strengthen breast cancer management and early diagnosis strategies in the state of Piauí.

Utilizing Indigenous Flora in East Africa for Breast Cancer Treatment: An Overview

Background: Breast cancer is a significant global health challenge, contributing substantially to cancer- related deaths. Conventional treatment methods, including hormone therapy, chemotherapy, surgical interventions, and radiation, have long been utilized. However, these traditional treatments are often associated with serious side effects and drug resistance, limiting their efficacy. Aim: This review aims to explore the potential of medicinal plants used in breast cancer management in East Africa, focusing on their bioactive compounds and anticancer properties. Methods: A comprehensive literature search was conducted to examine the effectiveness of medicinal plants in treating breast cancer across Kenya, Ethiopia, Uganda, Tanzania, and Rwanda. Relevant studies published between 2003 and 2023 were identified using keywords related to breast cancer and medicinal plants. The search was performed across multiple databases, including Google Scholar, PubMed, Scopus, Web of Science Core Collection, and Science Direct. Results: Numerous natural compounds found in East African medicinal plants including Cymbopogon citratus (Lemongrass,) Tabebuia avellanedae, Prunus africana (African Cherry), Euclea divinorum, Berberis holstii, Withania somnifera (Ashwagandha, Curcuma longa (Turmeric), Garcinia mangostana (Mangosteen, Vitis vinifera (Grapevine), Eugenia jambolana (Java Plum), Moringa oleifera (Drumstick Tree), Camellia sinensis (Tea), Glycine max (Soybean), Catharanthus roseus, Madagascar Periwinkle), Rhus vulgaris (Wild Currant) exhibit significant anticancer properties. These compounds have demonstrated the ability to reduce breast cancer aggressiveness, inhibit cancer cell proliferation, and modulate cancer-related pathways. Current research focuses on these natural and dietary compounds to develop more effective strategies for treating breast cancer. Conclusion: The findings suggested that East African medicinal plants hold promise as complementary treatments for breast cancer, offering potential benefits such as affordability, cultural appropriateness, and sustainability. Further research into these plants and their bioactive compounds could revolutionize breast cancer treatment, improving survival rates and addressing the rising incidence of breast cancer-related fatalities. Other: The review underscores the importance of continued research, conservation, and the integration of ancient healing methods to fully harness the potential of East African flora in breast cancer management.

FOXM1 Transcriptionally Co-Upregulates Centrosome Amplification and Clustering Genes and Is a Biomarker for Poor Prognosis in Androgen Receptor-Low Triple-Negative Breast Cancer

There are currently no approved targeted treatments for quadruple-negative breast cancer [QNBC; ER−/PR−/HER2−/androgen receptor (AR)−], a subtype of triple-negative breast cancer (TNBC). AR-low TNBC is more proliferative and clinically aggressive than AR-high TNBC. Centrosome amplification (CA), a cancer hallmark, is rampant in TNBC, where it induces spindle multipolarity-mediated cell death unless centrosome clustering pathways are co-upregulated to avert these sequelae. We recently showed that genes that confer CA and centrosome clustering are strongly overexpressed in AR-low TNBCs relative to AR-high TNBCs. However, the molecular mechanisms that index centrosome clustering to the levels of CA are undefined. We argue that FOXM1, a cell cycle-regulated oncogene, links the expression of genes that drive CA to the expression of genes that act at kinetochores and along microtubules to facilitate centrosome clustering. We provide compelling evidence that upregulation of the FOXM1-E2F1-ATAD2 oncogene triad in AR-low TNBC is accompanied by CA and the co-upregulation of centrosome clustering proteins such as KIFC1, AURKB, BIRC5, and CDCA8, conferring profound dysregulation of cell cycle controls. Targeting FOXM1 in AR-low TNBC may render cancer cells incapable of clustering their centrosomes and impair their ability to generate excess centrosomes. Hence, our review illuminates FOXM1 as a potential actionable target for AR-low TNBC.

Safety profile of trastuzumab originator vs biosimilars: a systematic review and meta-analysis of randomized clinical trials.

In the last decade trastuzumab biosimilars became more and more frequent. Among their uses, from several years, they have been available in Europe for the treatment of HER2-positive metastatic breast cancer, as an alternative to Herceptin®. This meta-analysis aimed to analyze the available literature with particular focus on phase 3 randomized clinical trials (RCTs) comparing adverse events between trastuzumab biosimilar and originator. A systematic review was conducted in Pubmed and Scopus to include all phase 3 RCTs related to trastuzumab in patients with HER2-positive breast cancer and published up to July 31, 2023. Of the 508 records identified, 14 articles were meta-analyzed for safety information, including serious treatment emergent adverse events, death-related adverse events, neutropenia, leukopenia, infections, increased ALT, increased AST, anti-drug antibody, and neutralizing antibody. Included patients had an early breast cancer (N=2,877) or a metastatic breast cancer (N=2,603). No significant difference in death-related adverse events was found for trastuzumab biosimilar and originator when evaluated for an early breast cancer in the neoadjuvant phase (Risk Ratio [RR], 1.30; 95% confidence interval [CI], 0.47-3.59; I2 = 0%; p = 0.57) and overall (RR, 0.43; 95%CI, 0.11-1.66; I2 = 20%; p = 0.26), and for metastatic breast cancer (RR, 0.61; 95%CI, 0.30-1.26; I2 = 0%; p = 0.85). No difference was also observed for all other safety outcomes as in accordance with clinical studies necessary for the registration and approval of a biosimilar at a European level.

TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naïve repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.

Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis in breast cancer

CoQ10 (Coenzyme Q10) is an essential fat-soluble metabolite that plays a key role in cellular metabolism. A less-known function of CoQ10 is whether it may act as a plasma membrane-stabilizing agent and whether this property can affect cancer development and progression. Here, we show that CoQ10 and its biosynthetic enzyme UBIAD1 play a critical role in plasmamembrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. CoQ10 and UBIAD1 increase membrane fluidity leading to increased cell stiffness in BC. Furthermore, CoQ10 and UBIAD1 states impair ECM (extracellular matrix)-mediated oncogenic signaling and reduce ferroptosis resistance in BC settings. Analyses on human patients and mouse models reveal that UBIAD1 loss is associated with BC development and progression and UBIAD1 expression in BC limits CTCs (circulating tumor cells) survival and lung metastasis formation. Overall, this study reveals that CoQ10 and UBIAD1 can be further investigated to develop therapeutic interventions to treat BC patients with poor prognosis.

Combining Data-Driven and Structure-Based Approaches in Designing Dual PARP1-BRD4 Inhibitors for Breast Cancer Treatment.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have revolutionized the treatment of many cancers with DNA-repairing deficiencies via synthetic lethality. Advocated by the polypharmacology concept, recent evidence discovered that a significantly synergistic effect in increasing the death of cancer cells was observed by simultaneously perturbating the enzymatic activities of bromodomain-containing protein 4 (BRD4) and PARP1. Here, we developed a novel cheminformatics approach combined with a structure-based method aiming to facilitate the design of dual PARP1-BRD4 inhibitors. Instead of linking pharmacophores, the developed approach first identified merged pharmacophores (a pool of amide-containing ring systems), from which phenanthridin-6(5H)-one was further prioritized. Based on this starting point, several small molecules were rationally designed, among which HF4 exhibited low micromolar inhibitory activity against BRD4 and PARP1, particularly exhibiting strong inhibition of BRD4 BD1 with an IC50 value of 204 nM. Furthermore, it demonstrated potent antiproliferative effects against breast cancer gene-deficient and proficient breast cancer cell lines by arresting cell cycle progression and impeding DNA damage repair. Collectively, our systematic efforts to design lead-like molecules have the potential to open doors for the exploration of dual PARP1-BRD4 inhibitors as a promising avenue for breast cancer treatment. Furthermore, the developed approach can be extended to systematically design inhibitors targeting PARP1 and other related targets.

Deep learning-based prediction of the dose-volume histograms for volumetric modulated arc therapy of left-sided breast cancer.

The advancements in artificial intelligence and computational power have made deep learning an attractive tool for radiotherapy treatment planning. Deep learning has the potential to significantly simplify the trial-and-error process involved in inverse planning required by modern treatment techniques such as volumetric modulated arc therapy (VMAT). In this study, we explore the ability of deep learning to predict organ-at-risk (OAR) dose-volume histograms (DVHs) of left-sided breast cancer patients undergoing VMAT treatment based solely on their anatomical characteristics. The predicted DVHs could be used to derive patient-specific dose constraints and dose objectives, streamlining the treatment planning process, standardizing the quality of the plans, and personalizing the treatment planning. This study aimed to develop a deep learning-based framework for the prediction of organ-specific dose-volume histograms (DVH) based on structures delineated for left-sided breast cancer treatment. We used a dataset of 249 left-sided breast cancer patients treated with tangential VMAT fields. We extracted delineated structures and dose distributions for each patient and derived slice-by-slice DVHs for planning target volume (PTV) and organs-at-risk. The patients were divided into training (70%, n=174), validation (10%, n=24), and test (20%, n=51) sets. Collected data were used to train a deep learning model for the prediction of the DVHs based on the delineated structures. The developed deep learning model comprised a modified DenseNet architecture followed by a recurrent neural network. In the independent test set (n=51), the point-wise differences in the slice-by-slice DVHs between the clinical and predicted DVHs were small; the mean squared errors were 3.53, 1.58, 2.28, 3.37, and 1.44 [×10-4] for PTV, heart, ipsilateral lung, contralateral lung, and contralateral breast, respectively. With the derived cumulative DVHs, the mean absolute difference±standard deviation of mean doses between the clinical and the predicted DVH were 0.08± 0.04Gy, 0.24± 0.22Gy, 0.73± 0.46Gy, 0.07± 0.06Gy, and 0.14± 0.14Gy for PTV, heart, ipsilateral lung, contralateral lung, and contralateral breast, respectively. The deep learning-based approach enabled automatic and reliable prediction of the DVH based on delineated structures. The predicted DVHs could potentially serve as patient-specific clinical goals used to aid treatment planning and avoid suboptimal plans or to derive optimization objectives and constraints for automated treatment planning.

In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis

In addition to residual tumor cells, surgery-induced inflammation significantly contributes to tumor recurrence and metastasis by recruiting polymorphonuclear neutrophils (PMNs) and promoting their involvement in tumor cell proliferation, invasion and immune evasion. Efficiently eliminating residual tumor cells while concurrently intervening in PMN function represents a promising approach for enhanced postoperative cancer treatment. Here, a chitosan/polyethylene oxide electrospun fibrous scaffold co-delivering celecoxib (CEL) and doxorubicin-loaded tumor cell-derived microparticles (DOX-MPs) is developed for postoperative in-situ treatment in breast cancer. This implant (CEL/DOX-MPs@CP) ensures prolonged drug retention and sustained release within the surgical tumor cavity. The released DOX-MPs effectively eliminate residual tumor cells, while the released CEL inhibits the function of inflammatory PMNs, suppressing their promotion of residual tumor cell proliferation, migration and invasion, as well as remodeling the tumor immune microenvironment. Importantly, the strategy is closely associated with interference in neutrophil extracellular trap (NET) released from inflammatory PMNs, leading to a substantial reduction in postoperative tumor recurrence and metastasis. Our results demonstrate that CEL/DOX-MPs@CP holds great promise as an implant to enhance the prognosis of breast cancer patients following surgery.

TGF-β1 and FOXM1 siRNA co-loaded nanoparticles by Disulfide crosslinked PEG-PDMAEMA for the treatment of triple negative breast cancer and its bone metastases in vitro

Introduction Triple negative breast cancer (TNBC) is characterized with higher malignancy and mortality and is prone to distant metastasis, among which bone is the most common site. It’s urgent to explore new strategies for treatment of TNBC and its bone metastases. Methods A tumor environment responsive vector, poly-(dimethylaminoethyl methacrylate)-SS-poly(ethylene glycol)-SS-poly-(dimethylaminoethyl methacrylate) (PDMAEMA-SS-PEG-SS-PDMAEMA), was constructed to co-delivery transforming growth factor-β1 (TGF-β1) siRNA and forkhead box M1 (FOXM1) siRNA in MDA-MB-231 cells. The preparation, characterization, in vitro release, stability, and transfection efficiency of nanoparticles were measured. Cell viability, migration and invasion of MDA-MB-231 cells were determined. Cell chemotactic migration and cell heterogeneity adhesion of MDA-MB-231 cells to the human osteoblast-like cell line MG-63 were determined. Results PDMAEMA-SS-PEG-SS-PDMAEMA self assembled with siRNA at N/P of 15:1 into nanoparticles with particle size of 122 nm. In vitro release exhibited redox and pH sensitivity, and the nanoparticles protected siRNA from degradation by RNase and serum protein, remaining stable at 4 °C with similar transfection efficiency with lipo2000. Nanoparticles co-loaded with TGF-β1 siRNA and FOXM1 siRNA inhibited the cell viability, migration and invasion of MDA-MB-231 cells, as well as chemotactic migration and heterogeneous adhesion of MDA-MB-231 cells to MG-63 cells, showing a synergetic effect. After gene silencing on TGF-β1 and FOXM1, the epithelial to mesenchymal transition (EMT) related molecules vimentin mRNA expression decreased while E-cadherin increased. Conclusion PDMAEMA-SS-PEG-SS-PDMAEMA was suitable for TGF-β1 siRNA and FOXM1 siRNA delivery, exhibiting synergetic inhibition effect on TNBC and its bone metastases, which might be related to its synergetic inhibition on EMT.

Targeting TRIM26: Unveiling an Oncogene and Identification of Plant Metabolites as a Potential Therapeutics for Breast Cancer.

Breast cancer is the major cause of cancer-related mortality and frequent malignancies among women worldwide. The TRIM (Tripartite Motif) protein family is a broad and diverse set of proteins that contain a conserved structural motif known as the tripartite motif, which comprises of three different domains, B-box domain, Coiled-coil domain and RBR (Ring-finger, B-box, and coiled-coil) domain. TRIM proteins are involved in regulating cancer growth and metastasis. However, TRIM proteins are still unexplored in cancer cell regulation. In this study, by using a cancer database expression of all TRIM proteins was determined in breast cancer. Out of 77 TRIM genes, 16 genes were upregulated in breast cancer. Here, the upregulated TRIM26 gene's role is not yet explored in breast cancer. Indeed, TRIM26 is upregulated in 21 cancer types out of 33 cancer types. To investigate the role of TRIM26 in breast cancer, siRNA-mediated gene silencing was carried out in MCF-7 and MDA-MB 231 breast cancer cells. Reduced expression of TRIM 26 decreased cancer cell proliferation, migration and invasion with simultaneous reduction of various proliferative, cell cycle and mesenchymal markers and upregulation of epithelial markers. Further, docking studies found potential novel plant metabolites. Thus, targeting TRIM26 may provide a novel therapeutic approach for breast cancer treatment.