Breast Cancer Initiation Research Articles

NSDHL contributes to breast cancer stem-like cell maintenance and tumor-initiating capacity through TGF-β/Smad signaling pathway in MCF-7 tumor spheroid

BackgroundNAD(P)-dependent steroid dehydrogenase-like protein (NSDHL), which is involved in breast tumor growth and metastasis, has been implicated in the maintenance of cancer stem cells. However, its role in regulating breast cancer stem-like cells (BCSCs) remains unclear. We have previously reported the clinical significance of NSDHL in patients with estrogen receptor-positive (ER +) breast cancer. This study aimed to elucidate the molecular mechanisms by which NSDHL regulates the capacity of BCSCs in the ER + human breast cancer cell line, MCF-7.MethodsNSDHL knockdown suppressed tumor spheroid formation in MCF-7 human breast cancer cells grown on ultralow-attachment plates. RNA sequencing revealed that NSDHL knockdown induced widespread transcriptional changes in the MCF-7 spheroids. TGF-β signaling pathway was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (fold change ≥ 2, P ≤ 0.05) identified in NSDHL-knockdown MCF-7 spheroids compared with the control. In orthotopic tumor models injected with NSDHL-knockdown MCF-7 spheroids, tumor initiation and growth were strongly suppressed compared with those in the control.ResultsBCSC populations with CD44+/CD24- and CD49f+/EpCAM + phenotypes and high ALDH activity were decreased in NSDHL-knockdown MCF-7 spheroids and xenograft tumors relative to controls, along with decreased secretion of TGF-β1 and 3, phosphorylation of Smad2/3, and expression of SOX2. In RNA-sequencing data from The (TCGA) database, a positive correlation between the expression of NSDHL and SOX2 was found in luminal-type breast cancer specimens (n = 998). Our findings revealed that NSDHL plays an important role in maintaining the BCSC population and tumor-initiating capacity of ER-positive MCF-7 spheroids, suggesting that NSDHL is an attractive therapeutic target for eliminating BCSCs, thus preventing breast cancer initiation and progression.ConclusionsOur findings suggest that NSDHL regulates the BCSC/tumor-initiating cell population in MCF-7 spheroids and xenograft tumors.

Bisphenol S exposure promoted stemness of triple-negative breast cancer cells via regulating Gli1-mediated Sonic hedgehog pathway

Bisphenol S (BPS), one of the most common alternatives for bisphenol A (BPA), has been implied to increase the risk of breast cancer. Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with a poor prognosis. However, the association between BPS and TNBC remains unclear. Cancer stem cells (CSCs) have a crucial role in breast cancer initiation, metastasis, and recurrence. Here, we proposed that BPS, equivalent to the human internal exposure and the environmental concentrations, enhanced CSC-like properties by upregulating sphere formation, self-renewal, the percentage of CD44+/CD24- cells, and the expression of CSC markers. Moreover, BPS promoted the migration, invasion, and epithelial-mesenchymal transition (EMT) in TNBC cells. Mechanistically, BPS activated the Sonic Hedgehog (SHH) signaling pathway in TNBC cells. Molecular docking analysis further showed that BPS upregulated SHH signaling pathway via directly binding Gli1 protein. Furthermore, inhibitor of SHH pathway or Gli1 siRNA attenuated the promoting effects of BPS on stemness, invasion, and migration of TNBC cells. In summary, our data firstly provide evidence that environmentally relevant BPS concentration treatment significantly enhanced TNBC malignant phenotype by activating the Sonic Hedgehog/Gli1 signaling pathway, raising high concerns about the potential population biology hazards of BPS.

Deletions Rate-Limit Breast and Ovarian Cancer Initiation.

Optimizing prevention and early detection of cancer requires understanding the number, types and timing of driver mutations. To quantify this, we exploited the elevated cancer incidence and mutation rates in germline BRCA1 and BRCA2 (gBRCA1/2) carriers. Using novel statistical models, we identify genomic deletions as the likely rate-limiting mutational processes, with 1-3 deletions required to initiate breast and ovarian tumors. gBRCA1/2 -driven hereditary and sporadic tumors undergo convergent evolution to develop a similar set of driver deletions, and deletions explain the elevated cancer risk of gBRCA1/2 -carriers. Orthogonal mutation timing analysis identifies deletions of chromosome 17 and 13q as early, recurrent events. Single-cell analyses confirmed deletion rate differences in gBRCA1/2 vs. non-carrier tumors as well as cells engineered to harbor gBRCA1/2 . The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.

Dendrosomal Curcumin Showed Cytotoxic Effects on Breast Cancer Cell Line by Inducing Mitochondrial Apoptosis Pathway and Cell Division Arrest

Background: Mutations in the p53 gene have been linked to the initiation and progression of breast cancer, as well as resistance to chemotherapy. Therefore, the development of novel treatment approaches is essential to combat this disease. Objectives: This study aimed to evaluate the effects of dendrosomal curcumin (DNC) on the breast cancer cell line MDA-MB231. Methods: MDA-MB231 cells were treated with 20 μM DNC, and the apoptosis rate and cell proliferation cycles were assessed using flow cytometry. Additionally, after RNA extraction and cDNA synthesis, the expression levels of Lnc-DANCR, EZH2, Noxa, bcl-2, bax, PUMA, p21, and p53 genes were analyzed using RT-PCR. Protein expression levels of P53, P21, Bcl-2, and Bax were evaluated through western blotting. Results: Dendrosomal curcumin induced apoptosis in MDA-MB231 cells and caused cell cycle arrest at the SubG1 phase. Dendrosomal curcumin treatment downregulated Lnc-DANCR, EZH2, bcl-2, and p53 gene expression, while upregulating bax, Noxa, PUMA, and p21 gene expression in a time-dependent manner. Bax and P21 protein levels were significantly upregulated following DNC treatment, whereas Bcl-2 and P53 protein levels were downregulated in DNC-treated breast cancer cells. Conclusions: In summary, dendrosomal nanocurcumin demonstrated potent anti-tumor effects against breast cancer cells, suggesting its potential as a therapeutic agent in breast cancer treatment.

Loss of STING impairs lactogenic differentiation.

Heightened energetic and nutrient demand during lactogenic differentiation of the mammary gland elicits upregulation of various stress responses to support cellular homeostasis. Here, we identify the stimulator of interferon genes (STING) as an immune supporter of the functional development of mouse mammary epithelial cells (MECs). An in vitro model of MEC differentiation revealed that STING is activated in a cGAS-independent manner to produce both type I interferons and proinflammatory cytokines in response to the accumulation of mitochondrial reactive oxygen species. Induction of STING activity was found to be dependent on the breast tumor suppressor gene single-minded 2 (SIM2). Using mouse models of lactation, we discovered that loss of STING activity results in early involution of #3 mammary glands, severely impairing lactational performance. Our data suggest that STING is required for successful functional differentiation of the mammary gland and bestows a differential lactogenic phenotype between #3 mammary glands and the traditionally explored inguinal 4|9 pair. These findings affirm unique development of mammary gland pairs that is essential to consider in future investigations into normal development and breast cancer initiation.

Exogenous Insulin Effect on the Initiation of Breast Cancer in Type 2 Diabetes Mellitus Patients

Background: Growing evidence has indicated that women with type 2 diabetes mellitus are at an increased risk of developing breast cancer. However, as a major adjuvant treatment, the influence of hormone therapy such as exogenous insulin on type 2 diabetes mellitus in primary breast-cancer remains controversial. Objective: To explore the relationship between different types of hypoglycemic medications for diabetes and the factors that may contribute to the initiation of breast cancer. Methods: The study included 80 blood samples taken from 80 females recruited from Ibn Al-Bitar Center for Cardiac Surgery Hospital in Baghdad, Iraq, between November 2022 and February 2023. They were within the age range of 40 to 70 years. They were divided into three groups according to the treatment strategy and duration of disease as follows: Group 1: (20) patients who take insulin only, Group 2: (20) patients who take metformin with insulin, and G 3: (40) patients on metformin only for less than one year. An enzymatic oxidation technique was used to test the following biochemical parameters for all research groups: Total cholesterol, triglycerides, fasting blood glucose, and high-density lipoprotein cholesterol. Using the Friedewald formula, the very low-density lipoprotein cholesterol and low-density lipoprotein cholesterol were determined. Using an enzymatic process, Insulin levels and Insulin like growth factor-1(IGF-1), Estrogen receptor alpha (ERα) levels, and breast cancer susceptibility protein 1 (BRCA1) were measured with an enzyme-linked immunosorbent assay (ELISA). Glycated hemoglobin (HbA1c) level was measured with a sandwich immunodetection method. Finally, The Homeostasis Model Assessment for insulin resistance (HOMA-IR) was calculated according to the specific formula. Results: The values for HbA1C%, FBS, and lipid profile showed non-significant differences when compared between study groups. While BRCA-1, estrogen receptor alpha (ERα), insulin, insulin growth factor IGF-1, and HOMA IR All showed significant differences among all groups. Conclusion: Taking metformin only for less than one year seemed to contribute to higher levels of BRCA-1.

The Effect on Travel Distance of a Statewide Regionalization Policy for Initial Breast Cancer Surgery.

Reimbursement strategies to regionalize care can be effective for improving patient outcomes but may adversely affect access to care. We sought to determine the effect on travel distance for surgical treatment of a 2009 New York State (NYS) policy restricting Medicaid reimbursement for breast cancer surgery at low-volume hospitals. From a linked data set merging the NYS tumor registry with hospital discharge data, we identified women younger than 65 years with stage I-III first breast tumors from pre- and post-policy periods. We classified patients by urbanicity of their residence into four geographic areas (New York City, other large urban core, suburban/large town, and small town/rural). A multivariable difference-in-difference-in-differences model was used to estimate the policy effect on the distance traveled by Medicaid and non-Medicaid insured patients before and after the policy, by area of residence. Among the 46,029 study sample, 13.5% were covered by Medicaid. Regardless of insurance, women treated more recently traveled longer distances to their surgical facility than those in the prepolicy period. Regardless of time period, Medicaid beneficiaries drove fewer miles to treatment than women with other insurance. Although all women traveled greater distances postpolicy, the increase was not significantly different by insurance status (Medicaid or not), except for those living in suburban areas in which Medicaid patients traveled further postpolicy (+7.7 miles compared with +3.4 miles for non-Medicaid; P = .007). After a policy regionalizing surgical care, only suburban Medicaid patients experienced a statistically significant (albeit small) increase in travel distance compared with non-Medicaid patients. In the state of NY, regionalization of breast cancer care yielded improved outcomes with minimal decrease in access.

MammOnc-DB, an integrative breast cancer data analysis platform for target discovery.

Breast cancer (BCa) is one of the most common malignancies among women worldwide. It is a complex disease that is characterized by morphological and molecular heterogeneity. In the early stages of the disease, most BCa cases are treatable, particularly hormone receptor-positive and HER2-positive tumors. Unfortunately, triple-negative BCa and metastases to distant organs are largely untreatable with current medical interventions. Recent advances in sequencing and proteomic technologies have improved our understanding of the molecular changes that occur during breast cancer initiation and progression. In this era of precision medicine, researchers and clinicians aim to identify subclass-specific BCa biomarkers and develop new targets and drugs to guide treatment. Although vast amounts of omics data including single cell sequencing data, can be accessed through public repositories, there is a lack of user-friendly platforms that integrate information from multiple studies. Thus, to meet the need for a simple yet effective and integrative BCa tool for multi-omics data analysis and visualization, we developed a comprehensive BCa data analysis platform called MammOnc-DB (http://resource.path.uab.edu/MammOnc-Home.html), comprising data from more than 20,000 BCa samples. MammOnc-DB was developed to provide a unique resource for hypothesis generation and testing, as well as for the discovery of biomarkers and therapeutic targets. The platform also provides pre- and post-treatment data, which can help users identify treatment resistance markers and patient groups that may benefit from combination therapy.

Abstract B134: Socioeconomic, social, and clinical factors associated with loneliness among African American breast cancer survivors

Abstract Importance: Social connections are an important driver of cancer risk and outcomes and animal studies have shown that social isolation is important to breast cancer initiation and progression. However, limited empirical data are available on perceived loneliness among patient groups who are at increased risk for breast cancer morbidity and mortality. Objectives: The purpose of this study was to characterize the nature and distribution of loneliness in a sample of African American breast cancer patients and identify clinical and social factors having significant independent associations with perceived loneliness among these survivors. Methods: The study included African American breast cancer patients (n=110) who provided self-reported data on loneliness as part of a participating in a prospective observational study and randomized trial that examined stress reactivity using the Trier Social Stress Test. Loneliness was measured using a short form of the Loneliness Scale; scores were dichotomized using the median split to characterize patients as experiencing high versus low levels of loneliness. Multivariate logistic regression analysis was used to identify factors having significant associations with loneliness. Results: Over half (51.82%) of patients reported experiencing high levels of loneliness. Clinical and social factors that had significant independent associations with loneliness included marital status (OR=2.853, CI=1.066, 7.635, p=0.037), financial strain (OR=3.240, CI=1.114, 9.422, p=0.031), and the number of co-morbidities. Compared to patients who did not have any co- morbidities, those who had one, two, or three or more comorbidities had seven (CI=1.066, 40.645; p=0.029), eleven (CI=1.858, 66.716, p=0.008), and eleven (CI=1.757, 65.244; p=0.010) times the odds, respectively, of experiencing loneliness. Conclusions and Relevance: Many African American breast cancer patients in this study reported high levels of loneliness. Greater efforts are needed to identify patients who may benefit from interventions that enhance social connections, especially if they are married, experiencing financial strain, and have co-morbid conditions. Citation Format: Kelsie Campbell, Fatimata Sanogo, Trista Beard, Melanie Jefferson, Bodhour Sahlia, Chanita Hughes Halbert. Socioeconomic, social, and clinical factors associated with loneliness among African American breast cancer survivors [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 B134.

Epigenetic Drug Interventions in Breast Cancer: A Narrative Review of Current Research and Future Directions

Breast cancer is a life-threatening disease known for its extensive molecular heterogeneity. The study of the breast cancer epigenome has revealed potential avenues for improving breast cancer treatment risk stratification, early detection, and treatment. With renewed interest in epigenetic-modifying pharmaceutical agents, namely DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), bromodomain and extra-terminal inhibitors (BETi), and enhancer of zeste homolog 2 inhibitors (EZH2i), there have been extensive preclinical and clinical studies to evaluate the safety and efficacy of these agents as potential treatments for breast cancer. In this review, we summarise and present the preclinical and clinical evidence for epigenetic drugs in treating breast cancer. We review the challenges associated with the translation of these findings into improved patient outcomes, namely the optimisation of dosage and treatment regimens, and the emergence of resistance. These challenges have been widely recognised in the field and are of utmost importance for the successful implementation of personalised medicine. While there is strong evidence that epigenetic alterations, consisting of changes in DNA methylation, histone modifications, and non-coding RNAs, play a crucial role in breast cancer initiation and development, additional research is warranted to elucidate the safety profile of long-term interventions involving epigenetic drugs and to validate the role of epigenetic markers in disease diagnosis, prognosis, and personalised treatment.

Surgical Management and Its Impact on Adjuvant Treatment in Recurrent Ipsilateral Breast Cancer: A Retrospective Cohort Study.

Background: Breast cancer (BC) recurrence, defined as the reappearance of cancer in the ipsilateral breast after primary treatment, poses significant challenges in clinical management. Despite advances in treatment, recurrence rates persist, ranging from 0.6 to 1.5% annually, reaching 10-15% at 20 years. This study aims to analyze the surgical and oncological characteristics of patients with BC recurrence. Methods: This retrospective study includes 56 patients diagnosed with recurrent BC between October 2018 and April 2022. Data were collected from a prospectively maintained surgical database. A descriptive analysis was performed on the initial BC, and the recurrence, including surgical complications, was classified using the Clavien-Dindo system. The success rates of selective sentinel lymph node (SLN) biopsies and aberrant drainages were assessed based on previous surgeries. Results: The cohort included 55 females and 1 male, with a median age of 65.3 years. The mean time to BC recurrence was 11.5 years. Among them, 26.8% underwent breast-conserving surgery, 41.1% had a mastectomy, 21.4% had a mastectomy with reconstruction, and 10.7% had an excision over a previous mastectomy. An SLN biopsy was performed in 78.6% of cases, with higher success rates in those without a previous axillary lymph node dissection (85.7% vs. 63.2%). Aberrant drainage was more frequent in patients with a previous ALND (44.4% vs. 20%). The median follow-up was 41.3 months, with 10.7% experiencing a second recurrence. Conclusions: Repeat breast-conserving surgery with re-irradiation for ipsilateral recurrence is feasible and does not significantly increase complications. SLN biopsy is valuable for restaging and tailoring adjuvant therapies, with ALND not being necessary if re-SLN biopsy shows no drainage. The management of aberrant drainage remains controversial.

Epigenetic Modulations in Breast Cancer: An Emerging Paradigm in Therapeutic Implications.

Breast cancer, a heterogeneous and intricate disease, ranks among the leading causes of mortality in women. Restricted therapeutic choices, drug resistance, recurrence, and metastasis are the predominant conditions that lead to mortality. Accumulating evidence has shown breast cancer initiation and progression happen through a multifaceted and intricate process that involves numerous genetic and epigenetic alterations. The modulation of gene expression through epigenetic modifications, encompassing DNA methylation, histone alterations, and non-coding RNA regulation, has emerged as a fascinating field that represents a new avenue for breast cancer therapy. This review emphasizes various aberrant epigenetic regulations implicated in the onset and advancement of breast cancer. The critical epigenetic modifications closely associated with estrogen signaling, epithelial-to-mesenchymal transition (EMT), cancer stemness, and drug resistance have been discussed extensively. Moreover, it highlights current epi-drugs, including DNA modifying agents, histone acetyltransferase inhibitors, histone deacetylase inhibitors, histone methyltransferase inhibitors, and histone demethyltransferase inhibitors used for breast cancer treatment. Nonetheless, we described current investigations pertaining to combination therapy employing epi-drugs and future challenges.

Predictive analysis of breast cancer metastasis and identification of genetic markers using machine learning.

4 Background: The study devises a framework integrating machine learning (ML) paradigms with explainable artificial intelligence (XAI) to prognosticate the metastatic trajectory of breast cancer (BC) and delineate critical genomic indicators pertinent to metastasis. Methods: An examination was conducted on 98 initial BC specimens, which included 34 instances evolving into distant metastasis within a quintennial monitoring phase and 44 instances evincing no recurrence for a minimum pentad post-diagnosis. Genomic datasets underwent rigorous biostatistical scrutiny, followed by the implementation of an elastic net algorithm for feature discernment, thereby constraining the scope to a salient subset of genomic markers implicated in BC metastasis. An ensemble of advanced predictive models encompassing Light Gradient Boosting Machine (LightGBM), Categorical Boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Gradient Boosting Trees (GBT), and Adaptive Boosting (AdaBoost) was deployed. Model efficacy was gauged through metrics such as accuracy, F1 score, precision, recall, the Area Under the Receiver Operating Characteristic Curve (AUC), and the Brier score. To elucidate the reasoning behind the ML predictions and to navigate the opacity inherent in such models, a SHapley Additive exPlanations (SHAP) approach was invoked. Results: The predictive acumen of the LightGBM model was superior, evidenced by a striking accuracy of 96% and an AUC of 99.3%. Parallel to biostatistical assessments, SHAP analysis leveraging XAI illuminated that augmented expression levels of specific genes, namely TSPYL5, ATP5E, CA9, NUP210, SLC37A1, ARIH1, PSMD7, UBQLN1, PRAME, and UBE2T (with statistical significance p ≤ 0.05), correlated with an escalated risk of BC metastasis. Conversely, diminished expression of CACTIN, TGFB3, SCUBE2, ARL4D, OR1F1, ALDH4A1, PHF1, and CROCC (p ≤ 0.05) was similarly associated with heightened metastatic susceptibility in BC. Conclusions: The insights garnered from this investigation may catalyze preventative strategies against BC progression and metastatic dissemination, thereby enhancing therapeutic efficacy through personalized intervention modalities for BC patients.

Shear-wave elastography as a supplementary tool for axillary staging in patients undergoing breast cancer diagnosis

BackgroundPreoperative evaluation of axillary lymph node status is crucial for the selection of both systemic and surgical treatment in early breast cancer. This study assessed the particular role of additional shear wave elastography (SWE) in axillary staging in patients undergoing initial breast cancer diagnostics.MethodsOne hundred patients undergoing axillary lymph node biopsy due to a sonographically suspicious axillary lymph node were prospectively evaluated with SWE using virtual touch tissue imaging quantification (VTIQ). Mean values of tissue stiffness for axillary tissue and lymph node tissue were measured prior to core-cut biopsy of the lymph node. All lymph nodes were clip-marked during the biopsy. Cut-off values to differentiate between malignant and benign lymph nodes were defined using Youden’s index.ResultsLymph nodes with evidence of malignant tumor cells in the final pathological examination showed a significantly higher velocity as measured by SWE, with a mean velocity of 3.48 ± 1.58 m/s compared to 2.33 ± 0.62 m/s of benign lymph nodes (p < 0.0001). The statistically optimal cutoff to differentiate between malignant and benign lymph nodes was 2.66 m/s with a sensitivity of 69.8% and a specificity of 87.5%.ConclusionsLymph node metastases assessed with SWE showed significantly higher elasticity values compared to benign lymph nodes. Thus, SWE provides an additional useful and quantifiable parameter for the sonographic assessment of suspicious axillary lymph nodes in the context of pre-therapeutic axillary staging in order to differentiate between benign and metastatic processes and support the guidance of definitive biopsy work-up.Critical relevance statementShear-wave elastography provides an additional useful and quantifiable parameter for the assessment of suspicious axillary lymph nodes in the context of pre-therapeutic axillary staging in order to differentiate between benign and metastatic processes and support guiding the definitive biopsy work-up.Key PointsSWE is a quantifiable ultrasound parameter in breast cancer diagnosis.SWE shows a significantly higher velocity in malignant lymph nodes.SWE is useful in improving the sensitivity and specificity of axillary staging.Graphical

Detection of Contralateral Malignancies on Breast MRI.

Women with unilateral breast cancer are at increased risk for having simultaneous cancer of the contralateral breast. Overall, earlier detection of contralateral breast cancer prevents the burden of additional surgery or chemotherapy rounds and is associated with higher overall survival. However, MRI screening for the contralateral breast is seldom done following an initial unilateral breast cancer diagnosis. The purpose of this study is to retrospectively evaluate patients with known, biopsy-proven malignancy who went on to obtain a breast MRI and were later found to have cancer of the contralateral breast. Methods: This was a retrospective study that reviewed the charts of women aged over 18 years who were determined to have synchronous bilateral breast cancer from January 2017 to January 2022 at the University of Florida, Gainesville, FL. The study extracted data from this institution's cancer registry database, which provided information on patients with breast cancer diagnoses. The study conducted a review of mammography (MAM) and MRI imaging reports to ascertain the presence or absence of contralateral breast cancer identified by each respective imaging modality. Surgical pathology reports from the biopsy of the contralateral breast were reviewed to obtain information on the histological type of cancer and TNM (tumor, node, metastasis) staging. Of the 17 cases in which MAM missed contralateral cancer, follow-up MRI detected contralateral malignancy in 12 cases (70.59%) and subsequently changed management, resulting in additional imaging, biopsy, and eventual diagnosis and treatment of contralateral breast cancer. Examining the number of contralateral breast cancers detected by patients who had undergone MAM followed by MRI and those who had only undergone MAM, the study found that the detection rate of contralateral breast cancer from MAM was 45.45% (15/33). The tumor stages of the missed cancers were all T1 or Tis stage with one T1mi, and there was no nodal involvement. Conclusion: In addition to its utility in staging breast cancers, MRI also has the superior ability to detect otherwise undetected contralateral breast malignancy. This retrospective study found that MRI imaging led to a considerable increase in the detection of contralateral cancer. The study found that these undetected contralateral breast cancers by MAM were often of lower staging with no nodal involvement, highlighting the opportunity for MRI to assist in early cancer detection while the patient's prognosis is still good. Its high cost should be balanced with staging and occult malignancy detection utility in future practice.

Imaging and Monitoring HER2 Expression in Tumors during HER2 Antibody-Drug Conjugate Therapy Utilizing a Radiolabeled Site-Specific Single-Domain Antibody Probe: 68Ga-NODAGA-SNA004-GSC.

The overexpression of HER2 is pivotal in the initiation and progression of breast cancer. Developing HER2-targeted radiotracers is crucial for noninvasive assessment of HER2 expression, patient selection for HER2-targeted therapy, monitoring treatment response, and identifying resistance. Here, we reported a nonsite-specific coupled radiotracer, 68Ga-NOTA-SNA004-His6, and a site-specific coupled radiotracer, 68Ga-NODAGA-SNA004-GSC, based on a novel HER2 nanobody, SNA004. Both radiotracers exhibited high affinity, specific targeting, and rapid clearance in vitro and in vivo. Additionally, these tracers and trastuzumab showed noncompetitive binding to HER2. Compared to 68Ga-NOTA-SNA004-His6, 68Ga-NODAGA-SNA004-GSC demonstrated significantly reduced renal and liver uptake. PET/CT imaging with 68Ga-NODAGA-SNA004-GSC sensitively detected the responsiveness of various tumor models to trastuzumab and its antibody-drug conjugates (ADCs). Overall, the site-specific coupled radiotracer 68Ga-NODAGA-SNA004-GSC offered significant advantages in biodistribution and signal-to-noise ratio, making it a valuable tool for monitoring HER2 expression levels before, during, and after trastuzumab and ADC treatment.

Online Charge-Generation Derivatization by Electrochemical Radical Cations of Thianthrene: Mass Spectrometry Imaging of Estrogens in Biological Tissues.

Estrogens play a significant role in endocrinology and oncology. Although separation methods coupled with mass spectrometry (MS) have emerged as a powerful tool for studying estrogens, imaging the spatial distributions of estrogens is crucial but remains challenging due to its low endogenous concentration and poor ionization efficiency. Charge-generation derivatization, such as N-alkylpyridinium quaternization and S-methyl thioetherification, represents a method wherein neutral molecules involving analytes and derivatization reagents undergo chemical reactions to establish permanent charges directly onto the analytes to improve detection sensitivity. Here, we developed a novel derivatization reagent, thianthrene (TT), which enabled oxidization to radical cations ([TT]•+) using an electrochemical method and completed the online charge-generation derivatization of estrogens on a mass spectrometry imaging platform. In this strategy, [TT]•+ can efficiently and selectively derivatize estrogens via an electrophilic aromatic substitution reaction. Results indicated that derivatization with [TT]•+ can significantly enhance imaging sensitivity (3 orders of magnitude), enabling the visualization of estrogen and its metabolites in ovarian and breast tissues. Furthermore, a higher mass intensity of these estrogens was captured in breast para-cancerous tissues than in cancerous tissues, which might provide estrogens spatial dimension information for further research on the initiation and progression of breast cancer.

Preoperative psychological factors influence analgesic consumption and self-reported pain intensity following breast cancer surgery

BackgroundPsychological factors such as anxiety and mood appear to influence acute postoperative pain; however, there is conflicting evidence on the relationship between preoperative psychological parameters and the severity of postoperative pain. In the context of the stressful setting of initial surgery for breast cancer, we conducted a prospective observational study of patients who were scheduled to undergo initial breast cancer surgery.MethodsThe objectives were to examine the potential associations between predefined preoperative psychological parameters and (i) Self-reported pain scores at discharge from the postoperative acute care unit, (ii) Cumulative perioperative opioid consumption at four hours postoperatively and (iii) Self-reported pain as measured during the first seven days after surgery. Patients completed the following questionnaires during the three hours prior to surgery: the Spielberger State Trait Anxiety Inventory (STAI State and Trait), the Pain Catastrophizing Scale (PCS), the Cohen Stress Questionnaire (CSQ), the Hospital Anxiety and Depression Scale (HADS A and D), and the short-form McGill Pain Questionnaire. Postoperative pain experience was assessed using patient self-reports of pain (SF Magill Pain questionnaire on discharge from the postanaesthesia care unit and a pain diary for seven days postoperatively) and records of analgesic consumption.ResultsPre- to postoperative self-reported pain was significantly different with respect to the STAI State, Cohen score and PCS for both low and high values (p < 0.001), but only patients categorized as having low STAI Trait, HADS A, and HADS D values achieved significant differences (p < 0.001). A significant positive correlation was demonstrated between preoperative state anxiety (STAI) and the most severe pain reported during the first seven days postoperatively (r = 0.271, p = 0.013). Patients who were categorized preoperatively as having a “high value” for each of the psychological parameters studied (HADS A and D, STAI State and Trait and PCS) tended to have greater perioperative opioid consumption (up to four hours postoperatively); this trend was statistically significant for HADS D and HADS A only. Using a linear regression model, state anxiety was found to be a significant predictor of postoperative pain based on self-reports during the first seven postoperative days (standardized β = 0.271, t = 2.286, p = 0.025).ConclusionPreoperative state anxiety, in particular, is associated with the severity of postoperative pain experienced by women undergoing initial breast cancer surgery. Formal preoperative assessment of anxiety may be warranted in this setting with a view to optimize perioperative analgesia and wellbeing.

Feasibility of Monitoring Global Breast Cancer Initiative Framework Key Performance Indicators in 21 Asian Countries

Feasibility of Monitoring Global Breast Cancer Initiative Framework Key Performance Indicators in 21 Asian Countries

The Role of Civil Society in the Implementation of the Global Breast Cancer Initiative (GBCI) Framework: Takeaways from Southeast Asia.

In 2021, the World Health Organization (WHO) launched the Global Breast Cancer Initiative (GBCI) with the aim of strategically guiding and coordinating efforts to reduce breast cancer mortality in low- and middle-income countries (LMICs). At the country level, GBCI requires adaptation to local contexts based on a systematic assessment of barriers faced by breast cancer patients and the health system's capacity. This requires engaging stakeholders with civil society organizations being key. During the 7th Southeast Asia Breast Cancer Symposium (SEABCS) held in Hue, Vietnam, breast cancer clinicians, policy makers, patients, advocates, and caregivers were invited to participate in a workshop to discuss the role civil society organizations will play in the implementation of GBCI. The workshop objective was to identify the needs of CSOs to effectively support the domestic implementation of GBCI principles and strategies. Twenty-two people registered for the workshop, with eight civil society organizations represented by one or more members. Participants were assigned to three groups and were asked to describe; (a) the ways in which civil society could use the GBCI framework document, advocate for its implementation at the country level, and support the implementation of recommended interventions; and (b) what would be needed for civil society to use, advocate for, or implement GBCI. This report outlines the main discussion points, the roles that civil society can play in countries' implementation efforts, and the resources needed so they can efficiently support their governments in their implementation strategy. By including civil society as a key element of breast cancer control, countries in the region and beyond can accelerate the domestic implementation of the GBCI principles and strategies, making significant progress in breast cancer control and improving the lives of those affected by the disease.