Advanced Stage Breast Cancer Research Articles

Molecular mechanism of bone metastasis in breast cancer

Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. Here, we elucidate how bone metastasis arises from tumor cells that detach from the primary lesions and infiltrate into the surrounding tissue, as well as how these cells disseminate to distant sites. Specifically, we elaborate how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.

Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation

High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca2+ handling proteins, thereby boosting mitochondrial Ca2+ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca2+-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca2+ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.Graphical

Profiling Phenotypic Heterogeneity of Circulating Tumor Cells through Spatially Resolved Immunocapture on Nanoporous Micropillar Arrays.

The phenotype of circulating tumor cells (CTCs) offers valuable insights into monitoring cancer metastasis and recurrence. While microfluidics presents a promising approach for capturing these rare cells in blood, the phenotypic profiling of CTCs remains technically challenging. Herein, we developed a nanoporous micropillar array chip enabling highly efficient capture and in situ phenotypic analysis of CTCs through enhanced and tunable on-chip immunoaffinity binding. The nanoporous micropillar array addresses the fundamental limits in fluidic mass transfer, surface stagnant flow boundary effect, and interface topographic and multivalent reactions simultaneously within a single device, resulting in a synergistic enhancement of CTC immunocapture efficiency. The CTC capture efficiency increased by approximately 40% for cancer cells with low surface marker expressing. By manipulating fluidic velocity (hydrodynamic drag force) on the chip, a cell adhesion gradient was generated in the capture chamber, enabling individual CTCs with varying expression levels of epithelial cellular adhesion molecules to be immunocaptured at the corresponding spatial locations where equilibrium drag force is provided. The clinical utility of the nanoporous micropillar array was demonstrated by accurately distinguishing early and advanced stages of breast cancer and further longitudinally monitoring treatment response. We envision that the nanoporous micropillar array chip will provide an in situ capture and molecular profiling approach for CTCs and enhance the clinical application of CTC liquid biopsy.

Hematologic Predictors of Chemotherapy-Induced Neutropenia in Breast Cancer Patients Receiving Anthracycline- or Taxane-Based Chemotherapy

Background: Chemotherapy-induced neutropenia (CIN) is a common and serious complication of chemotherapy in breast cancer patients, leading to increased morbidity, mortality, and treatment disruptions. This study aimed to investigate the association between hematologic profiles and the occurrence of CIN in breast cancer patients receiving anthracycline-based or taxane-based chemotherapy. Methods: A retrospective observational analytic study with a cross-sectional design was conducted using medical records of breast cancer patients treated at the Oncology Surgery Clinic between 2022 and 2023. Sixty patients were included in the study. Hematologic profiles, including hemoglobin and leukocyte counts, were analyzed to assess their association with CIN in both anthracycline- and taxane-based chemotherapy groups. Results: The majority of patients were aged 15-64 years (86.67%), normoweight (65%), had luminal B subtype (63.3%), and were in the locally advanced breast cancer (LABC) stage (45%). Most patients were non-anemic (Hb ≥12 mg/dL) and leukopenic (71.7% and 80%, respectively). No significant association was found between age, nutritional status, or breast cancer stage and CIN (p > 0.05). However, hemoglobin and leukocyte profiles were significantly associated with CIN in both chemotherapy groups (p < 0.05). No association was found between the type of chemotherapy (anthracycline- or taxane-based) and CIN occurrence. Conclusion: Anemia (Hb <12 g/dL) and leukopenia are significant predictors of CIN in breast cancer patients, regardless of the chemotherapy regimen. These findings highlight the importance of monitoring hematologic profiles in these patients to identify those at higher risk of CIN and implement appropriate preventive and management strategies.

Association of Granulocyte Colony-Stimulating Factor Treatment with Risk of Brain Metastasis in Advanced Stage Breast Cancer.

The routine use of granulocyte colony-stimulating factor (GCSF) is not recommended for the prevention or treatment of chemotherapy-induced neutropenia or febrile neutropenia because risks associated with certain types of cancers, distant organ metastases, and primary tumor growth cannot be excluded. We examined the association between GCSF use and the incidence of brain metastasis (BM), as well as BM-free survival (BMFS). This retrospective cohort study included 121 stage IV breast cancer patients without confirmed BM at the time of diagnosis and who received at least one course of systematic chemotherapy or target therapy at a tertiary teaching hospital between 1 January 2014 and 31 December 2022. The effect of GCSF use on BM was assessed with other confounding factors in Cox regression analyses. In this retrospective cohort, patients who received GCSF treatment had a significantly higher incidence of BM than those who did not (34.9% vs. 13.8%, p = 0.011). Univariate Cox regression analysis showed that GCSF use, menopause status, hormone treatment, HER2 treatment, cumulative dosage, dosage density, and neutropenia were independent risk factors for BMFS (p < 0.05). GCSF users had a higher risk of BM (adjusted HR: 2.538; 95% CI: 1.127-5.716, p = 0.025) than nonusers. BM risk was significantly associated with those with neutropenia (RR: 1.84, 95% CI: 1.21, 2.80) but not with those without neutropenia (RR: 0.59, 95% CI: 0.41-0.84, Interaction p-value < 0.05). The higher the dose density of GCSF, the higher the risk compared with those who do not use GCSF (p for trend < 0.01). These preliminary results suggest that GCSF is associated with BM in patients with stage IV breast cancer who did not have BM at initial diagnosis. Further comprehensively designed large-scale observational studies are needed to confirm our preliminary results.

The Social Reality of Meaning Making: The Dichotomy in the Illness Narratives of Women With Breast Cancer and Biomedical Practitioners in Nigeria.

Despite the increasing burden of breast cancer in the developing world, there is a misunderstanding of the complex and multifaceted relationship between culture and cancer, particularly breast cancer. Hence, a dichotomy of illness narratives exists due to differential meaning making concerning breast cancer. While clinicians always recommend biomedical treatment, women with breast cancer often seek alternative treatment pathways. To explore the experiences of women with breast cancer and clinicians in Nigeria on the dichotomy in the illness narratives. This qualitative study used in-depth interviews and focus group discussion to explore the experiences of 22 women with breast cancer and 7 clinicians in Nigeria on the dichotomy in the illness narratives using grounded theory method analysis. This study revealed that many women living with breast cancer (WLBC) hold health beliefs that are contradictory to the biomedical norm. They mostly sought treatment based on the perceived aetiology of breast cancer. The treatment pathway follows faith and traditional healing as alternatives or sometimes in combination with biomedicine. WLBC reported a constant fear of biomedical treatment, perceived to be harmful to women's sexuality, fertility and body image. Hence, after perceived treatment failure from alternative care, biomedical care becomes the last resort, usually at an advanced stage of breast cancer, often responsible for poor prognosis. There is a dichotomy of illness construction between sufferers and health practitioners. To guide women with breast cancer on the path of care, modern care practitioners should consider some cultural norms and practices without compromising professional ethos.

Characteristics of Chemotherapy Treatments for Breast Cancer Patients at Bhayangkara Tk.1 Pudsdokkes Polri Hospital, Jakarta

Background: Breast cancer is a malignant breast tumor that develops in the ductal or lobular epithelium and usually attacks women. Chemotherapy is a cornerstone of breast cancer treatment, particularly for patients with advanced disease or those who are not candidates for surgery or radiation therapy. This research aims to observe the use of chemotherapy drugs for breast cancer patients in terms of chemotherapy regimens and cycles at Bhayangkara Tk.1 Pudsdokkes Polri Hospital. Methods: This study employs descriptive quantitative approaches. Data were gathered retrospectively from medical records of breast cancer patients receiving chemotherapy at Bhayangkara Tk.1 Pudsdokkes Polri Hospital Jakarta from July to December 2021. Results: From 110 patients, 86 (78.18%) patients used the CAF regimen, 18 (16.36%) patients used the AC regimen, and 3 (2.73%) patients used the TAC regimen, while the regimen that did not comply with the guidelines was 2 (1.82%) patients using the combination of paclitaxel and epirubicin, 1 patient utilizing the combination of paclitaxel and doxorubicin. Forty-six (41.82%) patients with the CAF regimen had completed six cycles of chemotherapy with intervals of 3 weeks or 21 days, while only 5 patients (3.63%) completed four cycles of the AC regimen at 3-week or 21-day intervals. At the time of data collection, 11 patients, and 1 patient utilizing the AC regimen. This was because 59 patients had not yet finished the chemotherapy cycle, specifically in the advanced stage. Conclusions: The CAF regimen was the most commonly used chemotherapy regimen, followed by the AC and TAC regimens. This finding aligns with current clinical guidelines for breast cancer treatment. A significant number of patients had not yet completed their chemotherapy cycles, particularly those with advanced-stage breast cancer. This highlights the challenges associated with treating advanced disease and the need for more effective and less toxic treatment options.

A retrospective analysis suggests PTEN expression is associated with favorable clinicopathological features of breast cancer

The phosphatase and tensin homolog (PTEN) gene acts as a tumor suppressor by regulating the PI3K/AKT pathway, crucial for cell growth and survival. Mutations or loss of PTEN are common in breast cancer, leading to uncontrolled cell growth. Understanding PTEN’s role is vital for targeted therapies. 276 formalin-fixed paraffin-embedded (FFPE) breast cancer tissue blocks from 2012 to 2016 were analyzed for PTEN expression. Immunohistochemistry was performed to identify and assess tumor related clinicopathological characteristics as well as patient demographics. These were statistically matched with PTEN expression. Only 27.5% of the breast cancer tumors were PTEN-positive. PTEN expression correlated significantly with smaller tumor size, lower tumor grade, positive estrogen and progesterone receptor status, and favorable/unfavorable Ki67 status (p < 0.001). No significant association was found with vascular invasion, histologic type, age, HER2 status, staging, or lymph node involvement (p > 0.05). The study confirms PTEN's association with favorable clinicopathological features in breast cancer, supporting its role as a prognostic marker. These findings underscore the importance of PTEN in breast cancer biology and its potential as a therapeutic target. Furthermore these findings confirm the prevalence of advanced stage and aggressive breast cancer tumors in Ghana.

Meaningful engagement of people living with cancer: Leveraging breast cancer survivors in a stigma reduction intervention in Tanzania.

Cancer-related stigma is a key driver of advanced breast cancer stage in Sub-Saharan Africa (SSA). We developed and tested the impact of a breast cancer survivor-led Stigma reduction intervention (SRI) on stigma and treatment adherence of newly diagnosed patients with breast cancer in Tanzania. Breast cancer survivors were trained on breast cancer knowledge and motivational interviewing. A total of 4 trained survivors delivered a SRI (standardized flipchart breast education talk, personal testimony, and motivational interviewing) to 30 newly diagnosed patients with breast cancer before treatment. Pre- and post-intervention knowledge surveys and stigma scale surveys were analyzed via Fisher's exact test and Wilcoxon rank-sum tests. A discussion was held with a group of survivors after the intervention period to elicit feedback on their intervention experience. Among the 30 patients, breast cancer knowledge (median overall percent correct) increased from 28% (IQR: 18%-45%) to 85% (IQR: 79%-88%) (p<0.001) and stigma (median score) decreased from 75 (IQR: 57-81) to 53 (IQR: 44-66) (p<0.01) following the intervention. All participants were willing to pursue hospital-based treatment after undergoing the intervention. Eighty-seven percent (n=26) initiated treatment at 8-week follow-up after the intervention. All survivors endorsed feeling empowered and valued in their role in this intervention. Breast cancer survivors are a powerful group to combat the lack of knowledge and stigma in community and healthcare settings. Expanding the scope and scale of this intervention holds promise for improving treatment-seeking behavior and ultimately breast cancer outcomes in SSA.

Transformable self-delivered supramolecular nanomaterials combined with anti-PD-1 antibodies alleviate tumor immunosuppression to treat breast cancer with bone metastasis

Breast cancer is the most common malignant tumor that threatens women’s life and health, and metastasis often occurs in the advanced stage of breast cancer, leading to pathological bone destruction and seriously reducing patient quality of life. In this study, we coupled chlorin e6 (Ce6) with mono-(6-amino-6-deoxy)-beta-cyclodextrin (β-CD) to form Ce6-CD, and combined ferrocene with the FFVLG3C peptide and PEG chains to form the triblock molecule Fc-pep-PEG. In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF). After laser irradiation, Ce6 produced robust reactive oxidative species to induce tumor cell apoptosis. Simultaneously, ferrocene became charged, and Fc-pep-PEG dissociated from the spherical nanoparticles, enabling their transformation into nanofibers, which increased both the retention effect and the induction of ferroptosis. The released NLG919 reduced the number of regulatory T cells (Tregs) and restored the function of cytotoxic T lymphocytes (CTLs) by inhibiting the activity of IDO-1. Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis.Graphical

Modeling the management of patients with human epidermal growth factor receptor 2-positive breast cancer with liquid biopsy: the future of precision medicine.

In the evolving landscape of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) management, liquid biopsy offers unprecedented opportunities for guiding clinical decisions. Here, we review the most recent findings on liquid biopsy applications in HER2-positive BC and its potential role in addressing challenges specific to this BC subtype. Recent studies have highlighted the significance of liquid biopsy analytes, primarily circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), in stratifying patients' prognosis, predicting treatment response, and monitoring tumor evolution in both early and advanced stages of BC. Liquid biopsy holds promise in studying minimal residual disease to detect and potentially treat disease recurrence before it manifests clinically. Additionally, liquid biopsy may have significant implication in the management of brain metastasis, a major challenge in HER2-positive BC, and could redefine parameters for determining HER2 positivity. Combining ctDNA and CTCs is crucial for a comprehensive understanding of HER2-positive tumors, as they provide complementary insights. Research efforts are needed to address analytical challenges, validate, and broaden the application of liquid biopsy in HER2-positive BC. This effort will ultimately facilitate its integration into clinical practice, optimizing the care of patients with HER2-positive tumors.

Expression of p53 and ki-67 in Breast Carcinomas and Their Association with Histopathological Type, Grade, and Stage

Background &amp; objective: Recently many laboratories are evaluating the usefulness of determining p53, and Ki67 proliferation activities using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might help make treatment decisions in cancer patients, their clinical usefulness is still controversial. The present study was undertaken to see the expression of p53 and Ki-67 in breast carcinoma and their associations with histopathological variables. Methods: This cross-sectional analytical study was conducted in the Department of Pathology, in collaboration with the Department of Surgery, Rajshahi Medical College Hospital and the Department of Pathology, Bangobandhu Sheikh Mujib Medical University (BSMMU), Dhaka over a period of one and a half year from July 2018 to December 2019. Resected specimens of breast tissue, histopathologically confirmed as breast carcinoma, were the study population. Histological grading of breast carcinoma was done according to Nottingham modification of the Bloom-Richardson system, while staging was done using Tumor-Node-Metastasis (TNM) classification of malignant tumors, as recommended by the Union for International Cancer Control (UICC). The Ki67 and p53 expressions were assessed by immunohistochemistry. Based on the Ki67 labeling index (Ki67-LI), the patients were divided into two groups – Ki 67 &gt; 30% (considered as over-expressed) and ≤ 30% (considered as less expressed). Likewise, p53 immuno-expression was grouped as over-expressed (score ≤ 8) and low-expressed (score &gt; 8). The histological grade, type, and stage were then compared between patients with tumours of high and low proliferating activities to find the associations of Ki67 and p53 with tumor grade, type, and stage. Result: In the present study, almost three-quarters (74%) of the specimen of the breast had high Ki67-LI and 26% intermediate and low Ki67-LI. The p53 was found to be highly expressed in the majority (86%) of the cases. Analyses of the association of biomarkers with histological grade, stage, and type revealed that advanced-stage breast cancers (Stage-IIIA) were more likely to be associated with high Ki67-LI than the early-stage breast cancers (Stage-IIA and Stage-IIB) (p = 0.023). Poorly differentiated (G3) carcinoma also more often tends to be associated with high Ki67-LI than with low and intermediate Ki67-LI (p = 0.066). Likewise, stage IIIA tumors and poorly differentiated carcinoma were also considerably higher in the p53 over-expressed group (23.3%) than in the low p53 expression group (14.3%) (p = 0.023). Conclusion: The study concluded that a substantial proportion of breast carcinomas demonstrates high Ki67-LI. The p53 overexpression is also found in the majority (86%) of the breast carcinoma cases. Both Ki67 and p53 proliferation activities show their significant presence in high-grade and advanced-stage tumours. Ibrahim Card Med J 2023; 13 (1&amp;2): 11-18

Emerging drugs in breast cancer: a focus on antibody–drug conjugates and novel treatment options in luminal disease

SummaryRecent years have seen the introduction of several new drugs and novel treatment approaches in early and advanced-stage breast cancer, leading to relevant improvements in outcome. Still, further reduction of recurrence risk in high-risk early breast cancer is required as is further improvement of disease control in metastatic disease, preferentially with parallel improvement of tolerability. Several antibody–drug conjugates are currently under clinical development, among them drugs targeting HER2, HER3 and TROP2; in addition, bispecific HER2-directed antibodies are a promising class of drugs. In hormone receptor-positive disease, optimizing treatment options in patients progressing on prior CDK4/6-inhibitor-based therapies is a focus of clinical research and recent developments encompass small molecule growth-factor pathway inhibitors such as the AKT inhibitor capivasertib, novel PIK3Ca inhibitors such as inavolisib as well as selective oestrogen receptor degraders and modulators. This article is intended as a short review of promising novel drugs in later clinical development in the field of breast cancer.

Evaluation of cyclin-dependent kinase 4/6 inhibitor-induced serum creatinine elevations in patients with hormone receptor positive breast cancer.

e23304 Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have improved the efficacy of endocrine therapy in hormone receptor-positive (HR+)/HER2- breast cancer (BC) and are now used in both early-stage and metastatic disease. In the MONARCH-3 trial, 98% of patients (pts) treated with abemaciclib (abema) experienced elevated serum creatinine (sCr). Chappell et al. reported that abema caused pseudo-elevation in sCr by inhibiting renal tubular secretion. This effect was not evaluated in trials of palbociclib (palbo) and ribociclib (ribo), but case reports suggest that pseudo-sCr elevations are likely a class effect of CDK 4/6i. In this retrospective study, we sought to evaluate the incidence of sCr elevation in pts being treated with CDK4/6i for early and advanced stage BC. Methods: This single-center retrospective analysis included pts aged ≥18 years who received at least one dose of palbo, ribo, or abema for the treatment (tx) of HR+/HER2- BC in the early or advanced setting at the University of Chicago Medicine from January 2015 to August 2023. Pts were categorized into subgroups based on the CDK4/6i received. The primary objective was to evaluate the incidence of pseudo-sCr elevation in the subgroups. sCr elevation was graded according to Common Terminology Criteria for Adverse Events Version 5. CDK4/6i-induced pseudo-sCr elevation was suspected when the sCr elevation could not be fully explained by other causes. Secondary endpoints included the grade, onset, duration, and clinical consequences of pseudo-sCr elevation. Incidence of pseudo-sCr elevation among the three groups were compared using the Chi-squared test. Descriptive statistics were used for pt characteristics and secondary endpoints. Results: In total, 143 pts were analyzed. Pseudo-sCr elevation was suspected in pts treated with palbo, ribo, and abema, with incidences of 16% (8/50), 14% (6/43), and 20% (10/50), respectively. Rates did not significantly differ between agents (p = 0.727). Among pts with CDK4/6i-induced pseudo-sCr elevation, all pts experienced either grade 1 (8.3%) or 2 (91.7%) events, with a median sCr increase from baseline to peak of 0.69 mg/dL (range, 0.39 – 2.9 mg/dL). The median onset from tx initiation to first sCr elevation was 33.5, 42, and 21.5 days, for palbo, ribo, and abema, respectively. Based on available data at study cutoff, 13 of the 24 pts with suspected pseudo-sCr elevation were still on tx with continued sCr elevation. Nine of 24 pts were no longer on CDK4/6i tx; none due to sCr elevation. Three of the 9 pts had sCr returned to baseline within 3 months of tx discontinuation. Conclusions: Pseudo-sCr elevation appears to be a class effect of CDK4/6i, with similar rates of sCr elevation observed across the three CDK4/6i currently FDA approved. Further analyses evaluating differences by age, race, and stage are ongoing.

Comprehensive molecular interaction map of TGFβ induced epithelial to mesenchymal transition in breast cancer

Breast cancer is one of the prevailing cancers globally, with a high mortality rate. Metastatic breast cancer (MBC) is an advanced stage of cancer, characterised by a highly nonlinear, heterogeneous process involving numerous singling pathways and regulatory interactions. Epithelial–mesenchymal transition (EMT) emerges as a key mechanism exploited by cancer cells. Transforming Growth Factor-β (TGFβ)-dependent signalling is attributed to promote EMT in advanced stages of breast cancer. A comprehensive regulatory map of TGFβ induced EMT was developed through an extensive literature survey. The network assembled comprises of 312 distinct species (proteins, genes, RNAs, complexes), and 426 reactions (state transitions, nuclear translocations, complex associations, and dissociations). The map was developed by following Systems Biology Graphical Notation (SBGN) using Cell Designer and made publicly available using MINERVA (http://35.174.227.105:8080/minerva/?id=Metastatic_Breast_Cancer_1). While the complete molecular mechanism of MBC is still not known, the map captures the elaborate signalling interplay of TGFβ induced EMT-promoting MBC. Subsequently, the disease map assembled was translated into a Boolean model utilising CaSQ and analysed using Cell Collective. Simulations of these have captured the known experimental outcomes of TGFβ induced EMT in MBC. Hub regulators of the assembled map were identified, and their transcriptome-based analysis confirmed their role in cancer metastasis. Elaborate analysis of this map may help in gaining additional insights into the development and progression of metastatic breast cancer.

Cost-Effectiveness Analysis of Digital Breast Tomosynthesis and Mammography in Breast Cancer Screening: A Markov Modeling Study

BackgroundMammography (MG) has demonstrated its effectiveness in diminishing mortality and advanced-stage breast cancer incidences in breast screening initiatives. Notably, research has accentuated the superior diagnostic efficacy and cost-effectiveness of digital breast tomosynthesis (DBT). However, the scope of evidence validating the cost-effectiveness of DBT remains limited, prompting a requisite for more comprehensive investigation. The present study aimed to rigorously evaluate the cost-effectiveness of DBT plus MG (DBT-MG) compared to MG alone within the framework of Taiwan’s National Health Insurance program.MethodsAll parameters for the Markov decision tree model, encompassing event probabilities, costs, and utilities (quality-adjusted life years, QALYs), were sourced from reputable literature, expert opinions, and official records. With 10,000 iterations, a 2-year cycle length, a 30-year time horizon, and a 2% annual discount rate, the analysis determined the incremental cost-effectiveness ratio (ICER) to compare the cost-effectiveness of the two screening methods. Probabilistic and one-way sensitivity analyses were also conducted to demonstrate the robustness of findings.ResultsThe ICER of DBT-MG compared to MG was US$5971.5764/QALYs. At a willingness-to-pay (WTP) threshold of US$33,004 (Gross Domestic Product of Taiwan in 2021) per QALY, more than 98% of the probabilistic simulations favored adopting DBT-MG versus MG. The one-way sensitivity analysis also shows that the ICER depended heavily on recall rates, biopsy rates, and positive predictive value (PPV2).ConclusionDBT-MG shows enhanced diagnostic efficacy, potentially diminishing recall costs. While exhibiting a higher biopsy rate, DBT-MG aids in the detection of early-stage breast cancers, reduces recall rates, and exhibits notably superior cost-effectiveness.

Advanced-stage breast cancer diagnosis and its determinants in Ethiopia: a systematic review and meta-analysis

IntroductionWorldwide, breast cancer is the primary cause of illness and death. Unless early detected and treated breast cancer is a life-threatening tumor. Advanced-stage presentation is greatly linked with short survival time and increased mortality rates. In Ethiopia nationally summarized evidence on the level of advanced-stage breast cancer diagnosis is scarce. Therefore, this systematic review and meta-analysis aimed to determine the pooled prevalence of advanced-stage breast cancer diagnosis and its determinants in Ethiopia.MethodBy following PRISMA guidelines, a systematic review and meta-analysis were carried out. To include relevant publications, a broad literature search was conducted in the African Online Journal, PubMed, Google Scholar, and Embase which are published until last search date; June 15, 2023. To prevent further duplication this review was registered in PROSPERO database with ID no of CRD42023435096. To determine the pooled prevalence, a weighted inverse variance random effect model was applied. I2 statistics and the Cochrane Q-test were computed to determine heterogeneity. To evaluate publication bias, a funnel plot, and Egger’s regression test were used.ResultA total of 924 articles were sought and finally 20 articles were included in this review. The pooled prevalence of advanced-stage breast cancer diagnosis in Ethiopia was 72.56% (95%CI; 68.46-76.65%). Use of traditional medicine as first choice (AOR = 1.32, 95% CI: (1.13–1.55)), delay of > 3 months in seeking care (AOR = 1.24, 95% CI: (1.09–1.41)), diagnosis or health system delay of > 2 months (AOR = 1.27, 95% CI: (1.11–1.46)), rural residence (AOR = 2.04, 95% CI: (1.42 − 2.92)), and chief complaint of a painless breast lump (AOR = 2.67, 95% CI: (1.76–4.06)) were significantly associated to advanced-stage diagnosis.ConclusionIn Ethiopia, more than two-thirds of breast cancer cases are diagnosed at an advanced stage. Use of traditional medicine before diagnostic confirmation, delay in seeking care, health system delay, rural residence, and chief complaint of painless breast lump were positively associated with an advanced-stage diagnosis. Policymakers and program designers give great focus to those delays so as to seek and access modern diagnosis and treatment as early as possible specifically focusing on those who are rurally residing.

Pleiotrophin serum level and metastasis occurrence in breast cancer patients.

Breast cancer (BC) cases in Makassar, Indonesia, are on the rise, with 2723 cases recorded in 2018. Tumor cells in the blood indicate metastasis, emphasizing the need for early diagnosis and monitoring. Pleiotrophin (PTN) is associated with various human malignancies, and recent studies suggest a correlation between PTN expression and advanced BC stages; therefore, PTN could serve as an independent predictor of metastasis. This study aimed to determine the correlation between serum PTN level, histopathological grading, and metastasis occurrence in BC patients in Makassar, Indonesia. This study used an observational cross-sectional design. Pleiotrophin serum levels were examined using enzyme-linked immunosorbent assays. This study used a t-test and ROC curve analysis for the statistical tests. Of the 64 samples used in this study, metastasis was present in 26 cases and absent in 38 samples. The mean PTN serum levels in metastatic and non-metastatic breast cancer patients were 4.311 and 1.253, respectively. The PTN receiver operating characteristic curve showed an area under the curve of 2.47 ng/dL, which was statistically significant (p < 0.001). A significant relationship was found between PTN level and metastasis (p < 0.001). The correlation coefficient was 0.791, indicating a positive correlation. This study revealed that the serum PTN level among breast cancer patients had a cut-off value of 2.47 ng/dL. The research established a clear correlation between PTN level and metastasis occurrence in breast cancer patients, indicating a higher likelihood of distant metastasis with elevated PTN concentration.

Abstract PO4-10-09: MBC Community Barriers and Patient Navigation Training Needs

Abstract Background Komen’s mission is to save lives by meeting the most critical needs in our communities and investing in breakthrough research to prevent and cure breast cancer. One method to achieve our mission is through patient navigation. Evidence supports the role of patient navigation in improving breast health outcomes. Patient navigators identify and address barriers to equitable cancer care delivery in a fragmented healthcare system and work to ease the burdens that patients diagnosed with breast cancer experience. As a valued member of a patient’s health care team, patient navigators contribute to improving the quality of cancer care and eliminating barriers throughout the continuum of care. However, not all breast cancer patients experience the same barriers. Metastatic breast cancer (MBC) is the most advanced stage of breast cancer, and there is some evidence that suggests those diagnosed with MBC have unique experiences and needs that often determine and/or contribute to their disease trajectory. Despite this, little in-depth systematic work has been done to understand the unique challenges faced by those diagnosed with MBC or to explore strategies to address those challenges, and there have been no known efforts to equip patient navigators to specifically address the unique barriers of those diagnosed with MBC. Methods Susan G. Komen®’s Center for Applied Research (CfAR) designed the MBC Patient Navigation Training research study to improve the health outcomes of those diagnosed with MBC through patient navigation. The study design includes 4 phases of qualitative methodology with MBC and patient navigator communities to accomplish the following objectives: Examine the needs and barriers of MBC patients (Phase 1) Identify what needs and barriers MBC patients face that can be addressed through patient navigation (Phase 2) Assess the gaps in Komen's Patient Navigation Training Programs' ability to prepare navigators across the United States to address the identified needs/barriers of MBC patients (Phase 3) Design a new module to fill the gaps in Komen's Patient Navigation Training Program to support patient navigators serving MBC communities across the U.S. (Phase 4) Participants were recruited through a grassroots approach to community engagement, with members of the study team, Komen staff, and other breast health advocates contacting individuals and organizations across the U.S. Individuals were invited to attend a virtual introductory call to meet study staff and each other before consenting to participate in the virtual focus groups. Results Participants diagnosed with MBC (n=17) attended one of four virtual focus groups held May 2023 to share their lived experiences. The focus groups were recorded, the recordings were transcribed and checked for accuracy, and study staff analyzed data using a constant comparison approach to qualitative data analysis with NVivo data management software. Those diagnosed with MBC identified challenges of their diagnosis, barriers within the healthcare system, financial toxicity, lack of support, and health inequities as factors limiting their access to care. These participants also identified the role patient navigators could serve to help address these challenges. Next Steps In Phase 2, the study team will examine to what extent patient navigators feel prepared to address the barriers of MBC communities. Based on the findings from this study, the team will identify areas where more training is needed (Phase 3) and design a training module for Komen’s Patient Navigation Training Program (Phase 4) to better prepare patient navigators across the U.S. to meet the needs of MBC communities and improve health outcomes and cancer care delivery. Citation Format: Stephanie McCoy, Kyandra Fox, Kasey Volpe, Toni Lee, Janet Okamoto, Julie McMahon, Kari Wojtanik. MBC Community Barriers and Patient Navigation Training Needs [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-09.

Abstract PO2-18-06: Targeting fibroblast growth factor receptor (FGFR1) expression through G-quadruplex stabilization inhibits metastatic breast cancer

Abstract Metastatic breast cancer (MBC) is the most advanced stage of breast cancer. Our understanding of the molecular mechanisms which drive MBC remain incomplete. Epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) promote drug resistance and metastasis. It has been reported that fibroblast growth factor receptor 1 (FGFR1) plays a key role during the EMT:MET cycle. Furthermore, FGFR1 is amplified in 13% of primary and 20% of metastatic breast cancer patients. Therefore, optimizing inhibition of FGFR1 is crucial for the therapeutic targeting of the late stage breast cancer. First, we examined the efficacies of FGFR kinase inhibitors in the murine based dormant 4T07 tumor model. Inhibition of FGFR kinase activity leads to tumor growth inhibition but fail to eradicate dormant breast cancer cells. Therefore, we explored broader approaches to inhibit FGFR1 expression in addition to blockade of its kinase activity. G-quadruplex (G4) structures are secondary DNA structures commonly found upstream of transcriptional start sites (TSS) of oncogenes restricting their expression. Consequently, pharmacological stabilization of G4 structures within the promoters of cancer-related genes via use of small molecules has emerged as a promising therapeutic approach in cancer. Results herein demonstrate that the proximal promoter of FGFR1 contains sequences that form G4. Circular dichroism was used to verify formation of G4 in the FGFR1 proximal promoter. Importantly, use of the G4-binding compound CX-5461 stabilized the FGFR1 G4 structure, blocked the transcriptional activity of the FGFR1 proximal promoter and decreased FGFR1 expression. Therefore, we implemented the G4 stabilizers in FGFR1 expressing and metastatic drug-resistant BC cell lines. This approach results in dramatic downregulation of FGFR1 at the protein level after treatment with the G4 stabilizer. G4 stabilizing agents also interfere with ectopic FGFR1 expression and EMT-driven FGFR1 expression. Importantly, use of the G4-targeting compound CX5461 effectively blocked FGFR1 expression and inhibited FGFR1 downstream signaling, resulting in eradication of dormant breast cancer cells. Finally, in vivo application of CX5461 reduced FGFR1 expression, blocked pulmonary tumor formation and prolonged animal survival. In conclusion, consistent with the clinical observations our evaluation of FGFR kinase inhibitors validates the resistance to FGFR kinase inhibitors in MBC. Our findings indicate that targeting FGFR1 expression through G4 stabilization may be a potential strategy for MBC. Citation Format: Muhammad Safdar, Hang Lin, Sarah Dagher, Jonathan Dickerhoff, Mitchell Ayers, Luis Solorio, Danzhou Yang, Michael Wendt, Saeed Akhand. Targeting fibroblast growth factor receptor (FGFR1) expression through G-quadruplex stabilization inhibits metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-06.