Enhance Breast Cancer Research Articles

Combinatorial Therapy of Letrozole- and Quercetin-Loaded Spanlastics for Enhanced Cytotoxicity against MCF-7 Breast Cancer Cells.

Breast cancer is the most widespread cancer in women with rising incidence, prevalence, and mortality in developed regions. Most breast cancers (80%) are estrogen receptor–positive, indicating that disease progression could be controlled by estrogen inhibition in the breast tissue. However, drug resistance limits the benefits of this approach. Combinatorial treatment could overcome the resistance and improve the outcome of breast cancer treatment. In the current study, we prepared letrozole-(LTZSPs) and quercetin-loaded spanlastics (QuSPs) using different edge activators—Tween 80, Brij 35, and Cremophor RH40—with different concentrations. The spanlastics were evaluated for their average particles size, surface charge, and percent encapsulation efficiency. The optimized formulations were further examined using transmission electron microscopy, Fourier transform infrared spectroscopy, in vitro drug release and ex vivo skin permeation studies. The prepared spherical LTZSPs and QuSPs had average particle sizes ranged between 129–310 nm and 240–560 nm, respectively, with negative surface charge and high LTZ and Qu encapsulation (94.3–97.2% and 97.9–99.6%, respectively). The in vitro release study of LTZ and Qu from the selected formulations showed a sustained drug release for 24 h with reasonable flux and permeation through the rat skin. Further, we evaluated the in vitro cytotoxicity, cell cycle analysis, and intracellular reactive oxygen species (ROS) of the combination therapy of letrozole and quercetin either in soluble form or loaded in spanlastics against MCF-7 breast cancer cells. The LTZSPs and QuSPs combination was superior to the individual treatments and the soluble free drugs in terms of in vitro cytotoxicity, cell cycle analysis, and ROS studies. These results confirm the potential of LTZSPs and QuSPs combination for transdermal delivery of drugs for enhanced breast cancer management.

Deep learning of longitudinal mammogram examinations for breast cancer risk prediction

Information in digital mammogram images has been shown to be associated with the risk of developing breast cancer. Longitudinal breast cancer screening mammogram examinations may carry spatiotemporal information that can enhance breast cancer risk prediction. No deep learning models have been designed to capture such spatiotemporal information over multiple examinations to predict the risk. In this study, we propose a novel deep learning structure, LRP-NET, to capture the spatiotemporal changes of breast tissue over multiple negative/benign screening mammogram examinations to predict near-term breast cancer risk in a case-control setting. Specifically, LRP-NET is designed based on clinical knowledge to capture the imaging changes of bilateral breast tissue over four sequential mammogram examinations. We evaluate our proposed model with two ablation studies and compare it to three models/settings, including 1) a “loose” model without explicitly capturing the spatiotemporal changes over longitudinal examinations, 2) LRP-NET but using a varying number (i.e., 1 and 3) of sequential examinations, and 3) a previous model that uses only a single mammogram examination. On a case-control cohort of 200 patients, each with four examinations, our experiments on a total of 3200 images show that the LRP-NET model outperforms the compared models/settings.

Abstract 99: Interplay between CDK5 and IRF2BP1 enhances breast cancer brain metastasis

Abstract Prognosis of patients with breast cancer brain metastasis is poor due to unavailability of effective treatments. Hence, more fundamental research is needed to broaden our understanding of mechanisms underlying the origin and development of brain metastasis. We have identified that expression of cyclin-dependent kinase 5 (CDK5) in cancer cells promotes brain metastasis growth in experimental mouse models through suppressing the antitumor immunity. Here, we interrogated the underlying mechanism that connects CDK5 with defective antitumor immunity. To understand the repertoire of CDK5 phosphorylation targets, we performed a quantitative stable isotope labeling by amino acids in cell culture (SILAC) phopshoproteomics analysis of cultured brain-seeking cell lines that have been genetically engineered to express shRNA targeting the CDK5 gene. The knockdown of CDK5 resulted in a dramatic dephosphorylation of multiple proteins, among which Interferon Regulatory Factor 2 Binding Protein 1 (Irf2bp1) is well recognized to function in mediating the immune response. Knockdown of CDK5 reduced the phosphorylation of Irf2bp1 at Ser66 in both 4T1 and T11 cells (Log10 fold change: -0.51 and -0.39, respectively, P less than 0.0001). These findings were further validated by co-immunoprecipitation of Irf2bp1 in cell lysates from shCtl and shCDK5 brain-seeking cancer cell lines, followed by immunoblotting for phosphoserine. Furthermore, analysis of Irf2bp1 protein band shifts and intensities using Phos-tag™ gels also demonstrated that CDK5 knockdown reduces the Irf2bp1 phosphorylation. In order to investigate the function of Irf2bp1, we established a stable knockdown of the Irf2bp1 gene in brain metastasis-derived cell lines 4T1.Br3 and T11.Br1. We observed that Irf2bp1-knockdown cells displayed a reduced expression of genes encoding the class I major histocompatibility complex (MHC-I) as well as Nlrc5, a key transcriptional regulator of MHC I. Thus, these findings indicate that CDK5 may regulate the expression of surface MHC-I in breast cancer brain metastasis cells through Irf2bp1 phosphorylation at Ser66, in the absence of Interferon gamma or other classically recognized MHC-I agonists. These findings reveal a previously unknown mechanism of MHC-I regulation in cancer cells, that might improve our knowledge about cancer cell immune evasion through MHC-I loss. Citation Format: Arseniy E. Yuzhalin, Frank Lowery, Yohei Saito, Patrick Zhang, Dihua Yu. Interplay between CDK5 and IRF2BP1 enhances breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 99.

Ethanol Exposure Up-Regulates PD-L1/PD-1 Immune Checkpoint Pathway and Promotes Mammary Tumor Development.

Alcohol consumption in women enhances breast cancer incidence and ethanol is the main causal factor. Compromised host immunity through immunosuppression facilitates the development of many types of cancer, including breast cancer. Immune cells in breast tissues, particularly tumor-infiltrating CD8 cytotoxic T cells, play a critical role in the host anti-tumor immunity against breast tumorigenesis. These cytotoxic T cells are the major immune cells to carry out anti-tumor immunity through their cytotoxic effector function, which can be regulated by immune checkpoint pathways. The PD-1/PD-L1 pathway (the interaction between programmed death-1, PD-1, and its ligand, programmed death-ligand 1, PD-L1) is the best characterized one. However, the effects of ethanol exposure on T cell anti-tumor immunity and how that may contribute to ethanol-enhanced mammary tumorigenicity remain unknown. FVB.Cg-Tg(Wnt1)1Hev/J transgenic mice develop spontaneous mammary tumors starting around the age of 2-3 months and have been a widely-used mouse model for breast cancer research. Using this mouse model, the current study determined the effects of ethanol on the PD-L1/PD-1 pathway and how that may contribute to mammary tumorigenesis. The results indicated that ethanol exposure enhanced mammary tumor formation accompanied with an up-regulation of PD-1/PD-L1 pathway (increased PD-L1 levels in tumor tissue cells and the amount of PD-1-expressing tumor-infiltrating CD8 T cells) and inhibited T cell anti-tumor function, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated ethanol-enhanced tumorigenesis.

MAPK/ERK-CBP-RFPL-3 Mediates Adipose-Derived Stem Cell-Induced Tumor Growth in Breast Cancer Cells by Activating Telomerase Reverse Transcriptase Expression.

Adipose-derived stem cells (ASCs) improve the self-renewal and survival of fat grafts in breast reconstruction after oncology surgery. However, ASCs have also been found to enhance breast cancer growth, and its role in tumor proliferation remains largely elusive. Here, we explored a novel mechanism that mediates hTERT reactivation during ASC-induced tumor growth in breast cancer cells. In this study, we found the proliferative ability of breast cancer cells markedly increased with ASC coculture. To explore the molecular mechanism, we treated cells with anibody/inhibitor and found that the activation of MEK-ERK pathway was triggered in breast cancer cells by SCF secreted from ASCs, leading to the nuclear recruitment of CBP. As a coactivator of hTERT, CBP subsequently coordinated with RFPL-3 upregulated hTERT transcription and telomerase activity. The inhibition of CBP and RFPL-3 abrogated the activation of hTERT transcription and the promotion of proliferation in breast cancer cells with cocultured ASCs in vitro and in vivo. Collectively, our study findings indicated that CBP coordination with RFPL-3 promotes ASC-induced breast cancer cell proliferation by anchoring to the hTERT promoter and upregulating telomerase activity, which is activated by the MAPK/ERK pathway.

Facile and One-step Direct Synthesis of Poly(valine) as a Robust Drug Nanocarrier for Enhanced Breast Cancer Therapy

Facile and One-step Direct Synthesis of Poly(valine) as a Robust Drug Nanocarrier for Enhanced Breast Cancer Therapy

NDR1 increases NOTCH1 signaling activity by impairing Fbw7 mediated NICD degradation to enhance breast cancer stem cell properties

BackgroundThe existence of breast cancer stem cells (BCSCs) causes tumor relapses, metastasis and resistance to conventional therapy in breast cancer. NDR1 kinase, a component of the Hippo pathway, plays important roles in multiple biological processes. However, its role in cancer stem cells has not been explored. The purpose of this study was to investigate the roles of NDR1 in modulating BCSCs.MethodsThe apoptosis was detected by Annexin V/Propidium Iodide staining and analyzed by flow cytometry. BCSCs were detected by CD24/44 or ALDEFLUOR staining and analyzed by flow cytometry. The proliferation ability of BCSCs was evaluated by sphere formation assay. The expression of interested proteins was detected by western blot analysis. The expression of HES-1 and c-MYC was detected by real-time PCR. Notch1 signaling activation was detected by luciferase reporter assay. Protein interaction was evaluated by immunoprecipitation. Protein degradation was evaluated by ubiquitination analysis. The clinical relevance of NDR1 was analyzed by Kaplan–Meier Plotter.ResultsNDR1 regulates apoptosis and drug resistance in breast cancer cells. The upregulation of NDR1 increases CD24low/CD44high or ALDEFLUORhigh population and sphere-forming ability in SUM149 and MCF-7 cells, while downregulation of NDR1 induces opposite effects. NDR1 increased the expression of the Notch1 intracellular domain (NICD) and activated the transcription of its downstream target (HES-1 and c-MYC). Critically, both suppression of Notch pathway activation by DAPT treatment or downregulation of Notch1 expression by shRNA reverses NDR1 enhanced BCSC properties. Mechanically, NDR1 interactes with both NICD or Fbw7 in a kinase activity-independent manner. NDR1 reduces the proteolytic turnover of NICD by competing with Fbw7 for NICD binding, thereby leading to Notch pathway activation. Furthermore, NDR1 might function as a hub to modulate IL-6, TNF-α or Wnt3a induced activation of Notch1 signaling pathway and enrichment of breast cancer stem cells. Moreover, we find that the elevation of NDR1 expression predictes poor survival (OS, RFS, DMFS and PPS) in breast cancer.ConclusionOur study revealed a novel function of NDR1 in regulating BCSC properties by activating the Notch pathway. These data might provide a potential strategy for eradicating BCSC to overcome tumor relapses, metastasis and drug resistance.

Data imputation in deep neural network to enhance breast cancer detection

AbstractBreast cancer is one of the most precarious cancers that claims many women's' lives every year. The existing automated systems for mammography datasets are designed to detect the abnormalities and classify them as benign or malignant. However, these systems ignore the incompleteness of data due to missing or irrelevant values in the dataset, which severely impede the automated system's reliability. To enhance the reliability of the decision outcomes, this study proposes a composite imputed multilayer fully connected deep networks (MFCN) that can replace the incomplete values in the dataset to augment the efficient feature learning for breast cancer classification. The data imputation techniques and one‐hot encoding transformation applied to the dataset are proved to improve the feature representation. The imputed features extracted from the instances are fed into the MFCN to classify malignant and benign by utilizing mammographic mass (MM) and INbreast datasets. The performance of the proposed missing data imputation treated MFCN (MdI‐MFCN) is compared with competitive machine learning (ML) classifiers by incorporating stratified 6‐fold cross‐validation. The experimental results of the models are evaluated with and without imputed data using the five performance metrics, namely, accuracy, precision, recall, F1‐score, and specificity. The performance of the proposed MdI‐MFCN has outperformed the competitive classifiers with the highest accuracy of 93% and 98% of the area under the receiver operating characteristic (ROC) curve on MM and INbreast datasets, respectively. The simplicity and reliability of this proposed approach its potential in characterizing mammography datasets during breast cancer diagnosis.

Olaparib and Doxorubicin Co-Loaded Polypeptide Nanogel for Enhanced Breast Cancer Therapy.

Although great progress has been made in improving the efficacy of cancer treatment through combination treatment using drug agents, there are still challenges in improving the efficiency of drug delivery. In this study, olaparib and doxorubicin were co-loaded on disulfide bond cross-linked polypeptide nanogels for the treatment of breast cancer in mouse models. Under stimulation of a high glutathione environment in cancer cells, the drug is quickly released from the nanogel to target cancer cells. In addition, compared with free drugs and single-drug-loaded nanogels, dual-drug- co-loaded nanogels exhibit the best anti-cancer effect and demonstrated excellent biological safety. Therefore, the co-delivery of olaparib and doxorubicin through polypeptide nanogels presents good prospects for application as anti-cancer treatment.

A high level of the long non-coding RNA MCF2L-AS1 is associated with poor prognosis in breast cancer and MCF2L-AS1 activates YAP transcriptional activity to enhance breast cancer proliferation and metastasis

ABSTRACT Breast cancer (BC) is one of the most prevalent gynecologic malignant tumors with a poor prognosis and the second leading cause of cancer-related deaths in women worldwide. In recent years, it has been shown that long non-coding RNA (lncRNA) plays an important role in the development of breast cancer (BC). An antisense lncRNA from the MCF2 cell line (MCF2L-AS1) has been discovered recently and has been shown to function in a variety of malignancies. However, its function as a regulator of BC development has yet to be determined. Herein, the bioinformatics study analysis showed that MCF2L-AS1 was frequently highly expressed in BC tumors, and this overexpression was associated with worse patient outcomes. BC cells’ proliferation, migration, and invasion are inhibited when MCF2L-AS1 is silenced, whereas the inverse is evident when MCF2L-AS1 is overexpressed. It was also observed that MCF2L-AS1 knockdown decreased carcinogenesis in xenograft tumor models. Furthermore, we discovered that MCF2L-AS1 could bind to and improve the transcription activity of the yes-associated protein (YAP). However, following YAP knockdown, this lncRNA’s ability to drive BC malignancy was considerably reduced. In conclusion, MCF2L-AS1 may represent a potential predictive biomarker in BC patients, as well as a key regulator of BC cell proliferation. It works through positive feedback processes involving direct YAP binding and subsequent modulation of intracellular gene expression. Our findings add to our understanding of MCF2L-AS1 regulation and its potential as a therapeutic target in patients with this fatal cancer type.

Reactive myelopoiesis and FX-expressing monocyte-derived macrophages triggered by chemotherapy promotes cancer lung metastasis

Abstract Lung metastasis-associated macrophages (MAMs) play a very important role in tumor metastasis. In mouse models of lung metastasis, interstitial macrophages (IMs) markedly accumulate and differentiate into MAMs. Several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis. In this study, we hypothesize that host responses to chemotherapy treatment enhance breast cancer metastasis by modulation of lung macrophage toward a pro-metastatic phenotype. Here, we show that multi-dose chemo treatment promotes breast cancer lung metastasis in the spontaneous breast cancer animal model. Pretreatment with Gemcitabine and Paclitaxel induces a significantly higher number of pulmonary metastases in the experimental metastasis model. Mechanistically, multi-dose of chemotherapy induces reactive myelopoiesis characterized by increase of BM LSK cells and multipotent progenitors in tumor-free mice, which is associated with the increase of mitochondrial ROS. Further, chemokine CCL2 expression is significantly increased in the plasma and lung tissues of chemo-treated tumor-free mice. Consequently, the percentage of BM Ly6C+ monocytes are significantly increased because of increased progenitor monocyte differentiation potential and monocyte proliferation, which results in an increase of lung monocytes and IMs with enhanced expression of coagulation factor X (FX). Inhibition of activated FX (FXa) can inhibit chemotherapy-induced lung metastasis. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the modulation of BM-derived monocytes/macrophages and extravascular clotting in lung tissues. Supported by grants from NIH (P20GM135004)

Glycoalkaloid Solasonine Targets SHH Signaling to Block MED12 Mutant Breast Cancer Oncogenesis

As breast cancer is the second leading cause of cancer deaths among American women, there is a strong need to find improved treatment strategies for this disease. Radiation and chemotherapy are the frontline choice of treatment; however, personalized treatment is rapidly on the rise as a superior treatment method. Through prior studies, it has been found that 67% of breast cancer tumors carry a mutation in the Mediator subunit MED12 thus indicating that MED12 likely has a critical tumor suppressive role in the breast. Interestingly, previous results from our lab, and others, have indicated that MED12 plays a role in restricting GLI3‐dependent SHH signaling. This finding is of importance to this study as hyper‐activated SHH signaling is known to play a role in promoting breast cancer oncogenesis. We thus hypothesize that MED12 mutations cause breast cancer oncogenenesis through hyperactivated SHH signaling, and furthermore, that drugs which target the SHH signaling pathway could prove to be beneficial for MED12 mutant breast cancer. Through proliferation assays and quantitative PCR analysis, we were able to conclude that MED12 mutations, as mimicked by a MED12 knockdown setting, enhance breast cancer cell growth and promote GLI3‐dependent SHH signaling. Through a MTT screening strategy, we found that the natural compound Solasonine can differentially target MED12 knockdown breast cancer cells. Solasonine is a known glycoalkaloid that has previously been shown to potentially target anti‐inflammatory signaling pathways. To study the effect of Solasonine on MED12 knockdown breast cancer cells, quantitative PCR was used to measure the levels of GLI3 target genes in cells treated with either vehicle or Solasonine. We found that Solasonine treatment significantly decreased the GLI3 target genes GLI1 and CREB 5 thus suggesting that Solasonine could target the GLI3‐dependent SHH signaling pathway to block breast cancer oncogenesis. These findings were further complemented by colony formation assays which showed that Solasonine treatment leads to a significant reduction in the formation of colonies in vitro. Overall, our findings suggest that Solasonine targets the SHH signaling pathway to block breast cancer oncogenesis and may therefore prove to be a superior treatment method for MED12 mutant breast cancer.

A Wrapper based feature extraction framework based on AlexNet deep convolutional neural network parameters optimized using gradient‐based optimizer for mammogram images

AbstractIn this manuscript, a Wrapper based feature extraction framework based on AlexNet deep convolutional neural network (ADCNN) with gradient‐based optimizer (GBO) is proposed for early detection of breast cancer. In this input images are occupied as mini‐mammography image analysis society (MIAS) database. Then the images are pre‐processed to eliminate that noises using Markov random field (MRF) method. Image features are extracted by the process of Wrapper based feature extraction framework with ADCNN. Then, the weight parameters of ADCNN are optimizing through the aid of GBO. Then the mammogram images are characterized as normal or abnormal (malignant and benign) with SVM classifier. The simulation process is implemented on MATLAB platform. The proposed ADCNN‐SVM‐GBO attains higher accuracy 34.64%, 28.86%, 19.86%, 24.64%, 32.86%, higher Precision 28.07%, 18.96%, 16.86%, 25.86%, 26.86%, higher recall 27.86%, 32.54%, 27.86%, 23.95%, 19.97%, and the efficiency of the proposed method FE‐ADCNN‐GBO‐SVM is likened with the existing processes. Classification of mammograms depends features removal processes with support vector machine (FE‐LBP‐GLCM‐SVM), breast cancer classification with global discriminate features on mammographic images (FE‐GLCM‐ANN), enhancing breast cancer classification with (SMOTE) technique and pectoral muscle removal on mammographic images (FE‐SMOTE‐RF), application of artificial intelligence depends deep learning on breast cancer screening and imaging diagnosis (FE‐CNN‐CDCNN) respectively.

Effect of inpatient breast cancer education and risk assessment on mammography utilization among hospitalized women post discharge

ABSTRACT Objective To evaluate prevalence of nonadherence to breast cancer screening guidelines after bedside educational intervention and informed individualized risk assessment score during an inpatient stay. Methods A prospective intervention study was conducted among 507 cancer-free (except skin cancer) women aged 50–75 years hospitalized to a general medicine service. Study intervention included one-on-one bedside education via handout and videos about breast cancer screening and informed individualized risk assessment using the Gail risk model to predict 5-year risk for breast cancer development. Study outcomes were measured using posthospitalization follow-up survey to determine if intervention resulted in improved adherence to breast cancer screening. Chi-square and unpaired t-tests were utilized to compare population characteristics. Results The mean age for the study population was 60.5 years (SD = 6.9), the mean 5-year Gail risk score was 1.77 (SD = 1), and 36% of women were African American. One hundred sixty nine (33%) hospitalized women were nonadherent to breast cancer screening recommendations. Only 15% of the nonadherent women were reachable for follow-up survey, and 42% of these women self-reported adherence to screening mammography after a mean follow-up period of 27 months. Conclusion This study provides evidence that most women who are nonadherent to breast cancer screening remain nonadherent after hospital discharge despite educational interventions. Our study intervention was only partially successful in enhancing breast cancer screening among hospitalized women who were overdue and at high risk. Further studies need to evaluate strategies to overcome the barriers and improve adherence whenever patients encounter health care system regardless of clinical locale.

Glycoprotein hormone α-subunit promotes cell proliferation and tumorigenesis in breast cancer.

The glycoprotein hormone α-subunit (CGA) is implicated in the occurrence and progression of a number of solid tumors. However, its role in breast cancer remains unclear. The present study aimed to investigate the biological functions and mechanisms of action of CGA in breast cancer. CGA protein expression was evaluated in clinical breast cancer specimens using immunohistochemistry. The association between CGA expression and patient prognosis was determined using the Kaplan-Meier method and Mantel-Cox test. At the same time, CGA mRNA and protein expression was explored in a normal mammary epithelial cell line and breast cancer cell lines. Breast cancer cell lines overexpressing or deficient in CGA were established, and the effect of CGA on cell proliferation was evaluated in vitro, and in vivo using a mouse xenograft tumor model. Intracellular signaling pathway activities were evaluated using western blotting in CGA-overexpressing or -depleted cells. Increased CGA protein expression was significantly associated with a poor prognosis in patients with breast cancer. Furthermore, while CGA mRNA and protein expression level was negligible in normal mammary epithelial cells, it was elevated in breast cancer cell lines. In vitro and in vivo experiments showed that CGA overexpression enhanced breast cancer cell proliferation via activation of the epidermal growth factor receptor, extracellular signal-regulated kinase 1/2 and serine/threonine kinase Akt signaling cascades. The present results suggest that CGA is upregulated in breast cancer tissues and that it is associated with a poor prognosis. CGA may serve as a candidate for developing targeted therapies for breast cancer.

Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.

Tumourigenesis and cancer progression require enhanced global protein translation1–3. Such enhanced translation is caused by oncogenic and tumour suppressive events that drive the synthesis and activity of translational machinery4,5. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer. Monoallelic genetic deletion of LARS in mouse mammary glands enhanced breast cancer tumour formation and proliferation. LARS repression reduced the abundance of select leucine tRNA isoacceptors, leading to impaired leucine codon-dependent translation of growth suppressive genes including epithelial membrane protein 3 (EMP3) and gamma-glutamyltransferase 5 (GGT5). Our findings uncover a tumour suppressive tRNA synthetase and reveal that dynamic repression of a specific tRNA synthetase—along with its downstream cognate tRNAs—elicits a downstream codon-biased translational gene network response that enhances breast tumour formation and growth.

Impact of neurofibromatosis type 1 in an adult community population.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome with varying manifestations and severity. Adult NF1 patients often experience fragmented care, so we sought to characterize the health and demographic features of a community-based population of adults with NF1 and hypothesized that lack of a specialty clinic for adult NF1 patients correlates with unmet needs. Retrospective case-control study of all adult cases of NF1 among 4.06 million medical records in a Pacific Northwest population. 122 case charts were reviewed to ascertain NF1 disease features, comorbidities, and severity of disease. A 1:1 control cohort was selected by matching case/control by age, sex, and ZIP code to compare demographic features and health status. Adult NF1 patients were less likely to have private insurance, be employed, and have children, but were equally likely to be married. One half of cases had disease features compromising health and well-being, and care involved 26 different specialties. Excluding neurofibromas, 43% of cases had cancer compared to 10% of controls [P < .0001, OR 5.38 (2.53-11.4)]. Only 27% of women ages 30-50 had undergone age-appropriate enhanced breast cancer surveillance. Behavioral health problems were found in 60% of NF1 patients compared to 37% of controls [P < .001, OR 2.61 (1.52-4.50)]. 93% of cases referred to a NF1 specialty center underwent a change in management upon establishing care. NF1 patients may benefit from coordinated management of care in a specialty center.

Biodegradable Nanoprobe for NIR-II Fluorescence Image-Guided Surgery and Enhanced Breast Cancer Radiotherapy Efficacy.

Positive resection margin frequently exists in breast‐conserving treatment (BCT) of early‐stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus‐like gadolinium (Gd)‐based indocyanine green (R&HV‐Gd@ICG) nanoprobe is developed to improve fluorescence image‐guided surgery and breast cancer RT efficacy. R&HV‐Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near‐infrared (NIR‐II) window multimodal imaging in vivo. The nanoprobe‐based NIR‐II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X‐ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long‐term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies.

Abstract P4-12-09: Implications of protocol modifications and treatment delays for breast cancer patient experiences during Covid-19

Abstract The Covid-19 pandemic put a considerable strain on U.S. healthcare resources, resulting in significant disruptions in breast cancer care. Treatment protocols across the cancer care continuum were modified to permit continued delivery of critical cancer care with the lowest risk of Covid-19 transmission for both patients and healthcare providers. These deviations from standard treatment protocols revealed to patients the complexity of navigating cancer treatment, including critical dependencies and care coordination. While much of the research on cancer treatment protocols during the pandemic focuses on effectiveness or health outcomes, this research investigates the experiences of breast cancer survivors as they navigated the uncertainties and complexities of their cancer care during the Covid-19 pandemic. Method: We conducted a qualitative content analysis of survey data documenting patient experiences of the impact of Covid-19 related disruptions in cancer care and the challenges of navigating breast cancer treatment during the pandemic. Data for this analysis come from a larger data set collected from a national survey of adult breast cancer survivors, distributed online from 4/2/20 to 4/27/20. We used snowball sampling to recruit adult (&amp;gt;18 years old) breast cancer survivors in the US. A 50-item survey instrument was administered to breast cancer survivors in the U.S to assess the impact of COVID-19 on breast cancer care. Results: A total of 633 respondents completed the survey. We analyzed data from seven questions eliciting free-text responses detailing the nature of the delays in care and the impact of the delays on the physical, psycho-social, and practical aspects of life, yielding a sample size of 421 respondents. Patients reported experiencing a broad range of challenges across the cancer care continuum based on factors such as tumor type, disease stage, age, location and type of cancer care facility, and whether they were newly diagnosed, in active treatment, or completed active treatment. Respondents reported changes in the sequence, type, frequency, or location of treatment, follow-up, and symptom management. These changes were initiated by both providers and patients. Changes were associated with limited access to ancillary or supportive services such as imaging, labs, physical therapy and mental health care, and restricted availability of medical facilities such as operating rooms or emergency rooms. Balancing the risks of cancer and Covid-19 infection generated considerable uncertainty and anxiety for patients and their families, which they often attributed to feeling unable to reliably assess individual risk or prognosis. Respondents noted that navigating treatment protocol changes was further exacerbated by limitations on usual support services and resources, most notably restrictions prohibiting a companion or caregiver to accompany patients to appointments and changes in the frequency and channels of communication between survivors and their cancer care team. Conclusion: Our results point to the complex challenges and dependencies patient experienced in navigating cancer care during the Covid-19 pandemic. We suggest that a detailed understanding of patient experiences is critical to assessing the impact of the pandemic on cancer care, especially modifications to treatment protocols and other disruptions in care. These findings have implications beyond the crisis of the pandemic and can inform interventions to improve care coordination and communication between patients and providers and identify evidence-based opportunities to enhance breast cancer support and patient navigation in the U.S. Citation Format: Tamara Hamlish, Elizabeth L Papautsky. Implications of protocol modifications and treatment delays for breast cancer patient experiences during Covid-19 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-09.

Abstract PD1-09: Constitutively active estrogen receptor mutants enhance breast cancer pathogenesis by co-opting progesterone receptor activity, which can be countered by Giredestrant

Abstract ESR1 mutations contribute significantly to resistance against standard-of-care endocrine therapies and are associated with poor outcomes for estrogen receptor-positive (ER+) breast cancer patients. Structural, biochemical and cellular data all support a model in which such mutations trigger estrogen-independent ER activity, consistent with their emergence in patients who have been treated with Aromatase Inhibitors. Engineered cell line models have further suggested that the ESR1 mutations display gain-of-function effects that extend beyond constitutive canonical ER activity by influencing, for example, epithelial to mesenchymal transition and metastatic potential. However, concerns over potential engineering artifacts and limitations of in vitro conditions have challenged interpretation. Importantly, the mechanisms by which ER mutants might broadly impact cell behavior and whether the latest candidate ER therapeutics will inhibit the full spectrum of ESR1 mutant phenotypes are currently unknown. To address these questions, we generated conditional knock-in Esr1-mutant mice, allowing us to study the fundamental properties of the mutations under physiological conditions (equivalent to those experienced by wildtype ESR1) in the mammary gland, as a hormone-sensitive tissue and the origin of breast tumors. We find that ER mutations profoundly re-wire the transcriptional and cellular response of the mammary gland to hormones, including over the normal estrus cycle. In particular, mutant ER cells display hyper-sensitivity to progesterone, which triggers a proliferative program reminiscent of pregnancy (in nulliparous/virgin mice)- a phenotype that is entirely distinct from ESR1 wildtype mammary glands, both under physiological conditions and when stimulated with high levels of exogenous hormones. The ESR1 mutant-specific PR-mediated proliferative program does not reflect elevated Pgr expression but rather correlates with an altered PR cistrome and transcriptome. We found that this PR program also appears important for human tumor biology because progesterone stimulates the growth of ESR1-mutant patient-derived xenograft tumors (PDXs), in contrast to previous work showing progesterone to be generally tumor-suppressive in ESR1 wildtype tumor models. Importantly, Giredestrant (GDC-9545), a latest-generation orally bioavailable ER antagonist and degrader (SERD), counters the PR-mediated proliferative program, both in the mouse mammary model and in human PDXs. Taken together, these data suggest that in addition to promoting estrogen-independence, mutant ER collaborates with PR to drive a pro-tumorigenic proliferative program, perhaps co-opting a relationship between the hormone receptors established to be key for mammary gland development. Citation Format: Jackson Liang, Ciara Metcalfe. Constitutively active estrogen receptor mutants enhance breast cancer pathogenesis by co-opting progesterone receptor activity, which can be countered by Giredestrant [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-09.