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Background: The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%–20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL. Methods: In the cross‐sectional cohort (n = 180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra‐adrenal location, and secretory type (ASES) score in the longitudinal cohort (n = 114). Results: In the cross‐sectional cohort, pseudohypoxia group‐related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16 nmol/L, and tumor size >6.0 cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738–0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567–0.814, p = 0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio = 25.07, 95% CI: 5.65–111.20). A GMS score ≥2 (p < 0.001), but not ASES score ≥2 (p = 0.090), was associated with shorter progression‐free survival. Conclusion: The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL. [ABSTRACT FROM AUTHOR]

Purpose: Adherence to oral anticancer treatments (OATs) is a critical issue in metastatic breast cancer (MBC) to enhance survivorship and quality of life. The study is aimed to analyze the main themes and attributes related to OATs in MBC patients. This research is part of a project titled “Enhancing Therapy Adherence Among Metastatic Breast Cancer Patients" designed to produce a predictive model of non-adherence, a decision support system, and guidelines to improve adherence to OATs. Methods: The study consists of an exploratory observational and qualitative analysis using a focus group method. A semi-structured interview guide was developed to handle relevant OAT themes. Wordcloud plots, network analysis, and sentiment analysis were performed. Results: Nineteen female MBC patients participated in the protocol (age mean 55.95, SD = 6.87). Four main themes emerged: (theme 1) individual clinical pathway; (theme 2) barriers to adherence; (theme 3) resources to adherence; (theme 4) patients’ perception of new technologies. The Wordcloud and network analysis highlighted the important role of treatment side effects and the relationship with the clinician in the modulation of adherence behavior. This result is consistent with the sentiment analysis underscoring patients experience fear of issues related to clinical values and ineffective communication and discontinuity of the doctor in charge of the patient care. Conclusion: The study highlighted the key role of the individual, relational variables, and side effects as internal and external determinants influencing adherence to MBC. Finally, the opportunity offered by eHealth technology to connect with other patients with similar conditions and share experiences could be a relief for MBC patients. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) methylation modification affects the tumorigenesis and metastasis of breast cancer (BC). This study investigated the association between m6A regulator‐mediated methylation modification patterns and characterization of the tumour microenvironment in BC, as well as their prognostic importance. Public gene expression data and clinical annotations were collected from The Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus website and the METABRIC program. We analysed the genetic expression, gene–gene interactions, gene mutations and copy number variations using R software. The data were screened for risk genes using the Cox risk regression model, and we developed an algorithm for risk score and its predictive value. Compared to adjacent normal tissue, we identified 16 differentially expressed m6A regulators in BC, including six writers and 10 readers. Under unsupervised clustering, two distinguished modification patterns were identified, cluster C1 and C2. Compared to m6A cluster C2, cluster C1 was found to be more involved in immune‐related pathways, with a relatively higher immune score and stromal score (P < 0.05). Patients were divided into two groups based on their risk scores for survival analysis. The patients in the high‐risk score group had significantly worse overall survival than patients in the low‐risk score group, (P < 0.0001). The TCGA database validation revealed the same prognostic tendency. In summary, our study showed distinct m6A regulator modification patterns contribute to the immunological heterogeneity and diversity of BC. The development of m6A gene signatures and the m6A score aid in the prognostic prediction of patients with BC. [ABSTRACT FROM AUTHOR]

Aims and objectives: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear. Methods/materials: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression. Results: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094–3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups. Conclusions: The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker. [ABSTRACT FROM AUTHOR]

To develop and validate a predictive method for axillary lymph node (ALN) metastasis of breast cancer by using radiomics based on mammography and MRI. A retrospective analysis of 492 women from center 1 (The affiliated Hospital of Qingdao University) and center 2 (Yantai Yuhuangding Hospital) with primary breast cancer from August 2013 to May 2021 was carried out. The radscore was calculated using the features screened based on preoperative mammography and MRI from the training cohort of Center 1 (n = 231), then tested in the validation cohort (n = 99), an internal test cohort (n = 90) from Center 1, and an external test cohort (n = 72) from Center 2. Univariate and multivariate analyses were used to screen for the clinical and radiological characteristics most associated with ALN metastasis. A combined nomogram was established in combination with radscore that predicted the clinicopathological and radiological characteristics. Calibration curves were used to test the effectiveness of the combined nomogram. The receiver operating characteristic (ROC) curve was used to evaluate the performance of the combined nomogram and then compare with the clinical and radiomic models. The decision curve analysis (DCA) value was used to evaluate the combined nomogram for clinical applications. The constructed combined nomogram incorporating the radscore and MRI-reported ALN metastasis status exhibited good calibration and outperformed the radiomics signatures in predicting ALN metastasis (area under the curve [AUC]: 0.886 vs. 0.846 in the training cohort; 0.826 vs. 0.762 in the validation cohort; 0.925 vs. 0.899 in the internal test cohort; and 0.902 vs. 0.793 in the external test cohort). The combination nomogram achieved a higher AUC in the training cohort (0.886 vs. 0.786) and the internal test cohort (0.925 vs. 0.780) and similar AUCs in the validation (0.826 vs. 0.811) and external test (0.902 vs. 0.837) cohorts than the clinical model. A combined nomogram based on mammography and MRI can be used for preoperative prediction of ALN metastasis in primary breast cancer. [ABSTRACT FROM AUTHOR]

Objective: The Visiopharm artificial intelligence (AI) algorithm for oestrogen receptor (ER) immunohistochemistry (IHC) in whole slide images (WSIs) has been successfully validated in surgical pathology. This study aimed to assess its efficacy in cytology specimens. Methods: The study cohort comprised 105 consecutive cytology specimens with metastatic breast carcinoma. ER IHC WSIs were seamlessly integrated into the Visiopharm platform from the Image Management System (IMS) during our routine digital workflow, and an AI algorithm was employed for analysis. ER AI scores were compared with pathologists' manual consensus scores. Optimization steps were implemented and evaluated to reduce discordance. Results: The overall concordance between pathologists' scores and AI scores was excellent (99/105, 94.3%). Six cases exhibited discordant results, including two false‐negative (FN) cases due to abundant histiocytes incorrectly counted as negatively stained tumour cells by AI, two FN cases owing to weak staining, and two false‐positive (FP) cases where pigmented macrophages were erroneously counted as positively stained tumour cells by AI. The Pearson correlation coefficient of ER‐positive percentages between pathologists' and AI scores was 0.8483. Optimization steps, such as lowering the cut‐off threshold and additional training using higher input magnification, significantly improved accuracy. Conclusions: The automated ER AI algorithm demonstrated excellent concordance with pathologists' assessments and accurately differentiated ER‐positive from ER‐negative metastatic breast carcinoma cytology cases. However, precision in identifying tumour cells in cytology specimens requires further enhancement. [ABSTRACT FROM AUTHOR]

Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes. Author summary: Many therapies, especially small molecule drugs, inhibit the activity of a protein target. Not all proteins are druggable, however. When the proteins known to be involved in a disease process are not druggable, identifying a good target is difficult. In cancer, for example, the somatic driver mutations are often known, and the downstream changes in gene expression may be measured, but the driver gene and response genes may not be druggable. Here we present a method, NetPert, that selects candidate drug targets based on their ability to perturb interactions connecting a driver gene to response genes. Drugs already known to target these candidates are also reported. Applications to mouse models for metastatic breast cancer show that targets ranked highly by this method are highly active in wet-lab assays for dissemination and metastatic outgrowth. The NetPert method provides an interpretable data-driven approach to target selection and drug prioritization. [ABSTRACT FROM AUTHOR]

Locally advanced breast cancer (LABC) is a heterogeneous group of breast cancer that accounts for 10–30% of breast cancer cases. Despite the ongoing development of current treatment methods, LABC remains a severe and complex public health concern around the world, thus prompting the urgent requirement for innovative diagnosis and treatment strategies. The primary treatment challenges are inoperable clinical status and ineffective local control methods. With the rapid advancement of nanotechnology, inorganic nanoparticles (INPs) exhibit a potential application prospect in diagnosing and treating breast cancer. Due to the unique inherent characteristics of INPs, different functions can be performed via appropriate modifications and constructions, thus making them suitable for different imaging technology strategies and treatment schemes. INPs can improve the efficacy of conventional local radiotherapy treatment. In the face of inoperable LABC, INPs have proposed new local therapeutic methods and fostered the evolution of novel strategies such as photothermal and photodynamic therapy, magnetothermal therapy, sonodynamic therapy, and multifunctional inorganic nanoplatform. This article reviews the advances of INPs in local accurate imaging and breast cancer treatment and offers insights to overcome the existing clinical difficulties in LABC management. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment. KCNK1 is a potassium channel differentially expressed in many tumors, but the mechanisms underlying its function in breast cancer remain unclear. This study shows that KCNK1 is overexpressed in breast cancer promoting proliferation, invasion and metastasis by increasing glycolysis and activating Lactate Dehydrogenase A. [ABSTRACT FROM AUTHOR]

Simple Summary: A new class of therapy named cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) is the recommended preferred treatment for patients with metastatic breast cancer (MBC) who have the HR+/HER2− subtype; however, several barriers may still exist that prevent or delay the initiation of this treatment. In this observational study, we examined how the social determinants of health (SDOH) (e.g., income status, insurance coverage) and other patient characteristics are associated with the initiation of CDK4/6i for HR+/HER2− MBC in a Medicare population of patients aged 65 years or older. Our analysis showed that Medicare patients residing in areas with high vs. low median household income and those living in areas with a high vs. low proportion of Medicare-only coverage had higher rates of initiating treatment with CDK4/6i. Our study findings highlight the influence of SDOH on access to novel and effective cancer therapies and a need for strategies to improve equity in cancer care. In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC), cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) have replaced endocrine therapy alone as the standard of care; however, several barriers to treatment initiation still exist. We assessed social determinants of health (SDOH) and other factors associated with the initiation of CDK4/6i for HR+/HER2− MBC in the Medicare population. Using a retrospective cohort design, patients aged ≥65 years and diagnosed during 2015–2017 were selected from the SEER-Medicare database. Time from MBC diagnosis to first CDK4/6i initiation was the study outcome. The effect of SDOH measures and other predictors on the outcome was assessed using the multivariable Fine and Gray hazard modeling. Of 752 eligible women, 352 (46.8%) initiated CDK4/6i after MBC diagnosis (median time to initiation: 27.9 months). In adjusted analysis, SDOH factors significantly associated with CDK4/6i initiation included high versus low median household income (HHI) (hazard ratio [HR] = 1.70; 95% CI = 1.03–2.81) and the percentage of population with high versus low Medicare-only coverage (HR = 1.54; 95% CI = 1.04–2.27). In summary, older Medicare patients with HR+/HER2− MBC residing in areas with high median HHI and a high proportion of Medicare-only coverage had higher rates of initiating CDK4/6i, suggesting inequitable access to these novel, effective treatments and a need for policy intervention. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To estimate scenarios for survival for patients with estrogen receptor (ER) positive, metastatic breast cancer (MBC) and to help communicate prognosis to patients starting endocrine therapy (ET)We searched for randomized trials of ET for ER‐positive MBC and extracted the following percentiles (representative survival scenarios) from each overall survival (OS) curve: 90th (worst‐case), 75th (lower‐typical), 50th (median), 25th (upper‐typical), and 10th (best‐case). We then assessed the accuracy of estimating these percentiles for each OS curve by multiplying the median OS by four simple multiples: 0.25 (to estimate the 90th percentile), 0.5 (75th), 2 (25th), and 3 (10th). Estimates were deemed accurate if it fell within 0.75–1.33 times the actual value.We identified 25 trials with 10,566 patients. The median OS (interquartile range) was: 61.3 months (53.4–64.8) for first‐line ET with cyclin‐dependant kinase 4/6 inhibitors (four treatment groups); 42.6 months (40.9–50.4) for first‐line ET alone (21 treatment groups) and 29.2 months (24.8–33.4) for subsequent line ET (19 treatment groups). Simple multiples of the median OS accurately estimated the 90th percentile in 80%; 75th percentile in 93%; and 25th percentile in 76% of curves. The 10th percentile was only available for four OS curves and could not be evaluated.Simple multiples of the median OS are a helpful and accurate method to assist in estimating and discussing scenarios for survival for MBC patients starting ET. Longer follow‐up of trials is required to help clinicians estimate the best‐case scenario. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer. [ABSTRACT FROM AUTHOR]

This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system. [ABSTRACT FROM AUTHOR]

Background: Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer. Methods: Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families). Results: We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair. Conclusion: Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes. [ABSTRACT FROM AUTHOR]

Purpose: The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. Methods: Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups. Results: Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm. Conclusions: GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Importance: Among all US women, breast cancer is the second most common cancer and the second most common cause of cancer death. In 2023, an estimated 43 170 women died of breast cancer. Non-Hispanic White women have the highest incidence of breast cancer and non-Hispanic Black women have the highest mortality rate. Objective: The USPSTF commissioned a systematic review to evaluate the comparative effectiveness of different mammography-based breast cancer screening strategies by age to start and stop screening, screening interval, modality, use of supplemental imaging, or personalization of screening for breast cancer on the incidence of and progression to advanced breast cancer, breast cancer morbidity, and breast cancer–specific or all-cause mortality, and collaborative modeling studies to complement the evidence from the review. Population: Cisgender women and all other persons assigned female at birth aged 40 years or older at average risk of breast cancer. Evidence Assessment: The USPSTF concludes with moderate certainty that biennial screening mammography in women aged 40 to 74 years has a moderate net benefit. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of screening mammography in women 75 years or older and the balance of benefits and harms of supplemental screening for breast cancer with breast ultrasound or magnetic resonance imaging (MRI), regardless of breast density. Recommendation: The USPSTF recommends biennial screening mammography for women aged 40 to 74 years. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of supplemental screening for breast cancer using breast ultrasonography or MRI in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement) This 2024 Recommendation Statement from the US Preventive Services Task Force recommends biennial screening mammography for women aged 40 to 74 years (B recommendation) and concludes that evidence is insufficient to assess the balance of benefits and harms of screening mammography in women 75 years or older (I statement) and of screening using ultrasonography or MRI in women with dense breasts on a negative mammogram (I statement). [ABSTRACT FROM AUTHOR]

Despite limited research on refractory and/or endocrine therapy failure in elderly metastatic breast cancer (MBC) patients, a prior study showed that low-dose oral cyclophosphamide (CY) can improve the overall survival rate of MBC patients, possibly through the immunoregulation of regulatory T cells (Tregs). We preliminarily investigated the combination of endocrine therapy (ET) with oral low-dose CY as salvage therapy in elderly patients via peripheral blood regulatory T-cell analyses. In addition, we evaluated the associations of tumor tertiary lymphoid structures (TLSs) with therapeutic outcomes. HR+/HER2− advanced breast cancer patients who received low-dose CY combined with ET or ET only from April 2015 to August 2021 were enrolled in this retrospective study. The primary outcome was the clinical control rate (CCR), and the secondary outcome was progression-free survival (PFS). Circulating T lymphocyte subpopulations represented by Tregs were monitored during treatment by flow cytometry methods. TLSs wereconfirmed by hematoxylin–eosin staining of pretreatment specimens, and CD3, CD4, and Foxp3 were detected using Opal multicolor immunofluorescence. A total of 85 patients who received CY + ET and 50 patients who received ET only were enrolled, the percentage of patients who received CCR was 73% (62/85) vs. 70% (45/50), and the objective response rate (ORR) was 28% (24/85) vs. 24% (12/50). No deaths occurred during the study period. The mean PFS time was 13 vs. 11 months (P = 0.03). In the CY + ET group, decreases in CD4+/CD25+/Foxp3+ T cells (P < 0.001) were favorable for both clinical control and prolonged PFS (P < 0.001). Compared with patients without TLSs, those with TLSs were more likely to have better clinical control and PFS (mean time = 6 months), and a greater number of Treg cells during TLS pretreatment correlated with longer PFS (P = 0.043). Oral low-dose CY combined with standard ET exerts immunological effects by decreasing Treg levels to achieve improved clinical responses. Moreover, patients with TLSs might benefit more from such therapy than those without TLSs, and a high Treg cell count in TLSs before treatment predicts better therapeutic efficacy. [ABSTRACT FROM AUTHOR]

The rapid emergence of anisotropic collagen fibers in the tissue microenvironment is a critical transition point in late-stage breast cancer. Specifically, the fiber orientation facilitates the likelihood of high-speed tumor cell invasion and metastasis, which pose lethal threats to patients. Thus, based on this transition point, one key issue is how to determine and evaluate efficient combination chemotherapy treatments in late-stage cancer. In this study, we designed a collagen microarray chip containing 241 high-throughput microchambers with embedded metastatic breast cancer cell MDA-MB-231-RFP. By utilizing collagen's unique structure and hydromechanical properties, the chip constructed three-dimensional isotropic and anisotropic collagen fiber structures to emulate the tumor cell microenvironment at early and late stages. We injected different chemotherapeutic drugs into its four channels and obtained composite biochemical concentration profiles. Our results demonstrate that anisotropic collagen fibers promote cell proliferation and migration more than isotropic collagen fibers, suggesting that the geometric arrangement of fibers plays an important role in regulating cell behavior. Moreover, the presence of anisotropic collagen fibers may be a potential factor leading to the poor efficacy of combined chemotherapy in late-stage breast cancer. We investigated the efficacy of various chemotherapy drugs using cell proliferation inhibitors paclitaxel and gemcitabine and tumor cell migration inhibitors 7rh and PP2. To ensure the validity of our findings, we followed a systematic approach that involved testing the inhibitory effects of these drugs. According to our results, the drug combinations' effectiveness could be ordered as follows: paclitaxel + gemcitabine > gemcitabine + 7rh > PP2 + paclitaxel > 7rh + PP2. This study shows that the biomimetic chip system not only facilitates the creation of a realistic in vitro model for examining the cell migration mechanism in late-stage breast cancer but also has the potential to function as an effective tool for future chemotherapy assessment and personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC. Methods: Relevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration's tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis. Results: Meta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49–0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72–0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable. Conclusion: Statistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 45-year-old woman with metastatic triple-negative breast cancer, initially diagnosed with a breast mass and subsequently developing brain metastases despite prior treatment with surgery, radiation, and chemotherapy. Topics discussed include the clinical presentation, diagnostic imaging findings, and treatment challenges in managing metastatic triple-negative breast cancer, highlighting the role of emerging therapies such as antibody-drug conjugates.

• The nipple-areolar complex (NAC) is a major landmark anatomically and when performing breast ultrasound. • However, the nipples themselves do not seem to be closely observed unless there are any special symptoms or changes in the shape of the nipple. • It is also not easy to view the protruding nipple as a linear ultrasound probe. • Therefore, we aim to help in diagnosis by introducing examination methods that allow for good observation of the nipple area with ultrasound and the characteristics of ultrasound images for each disease in the NAC. • In addition, ultrasound-guided aspiration or biopsy may be helpful for accurate diagnosis, including exclusion of malignancy, and determination of treatment method. Categories of nipple-areolar complex (NAC) lesions 1. Anatomy and variation 2. Tips for ultrasonographic evaluation of the nipple 3. Benign conditions 4. Malignant conditions 1. Anatomy And Variation 3) Montgomery glands and tubercles Montgomery glands (areolar glands) • sebaceous glands in the areola • make oily secretions (lipoid fluid) to keep the areola and the nipple lubricated and protected • The portions of the gland visible on the skin's surface (1–2-mm-diameter) • The round bumps are found in the areola, and on the nipple itself. • They can become exposed and raised when the nipple is stimulated. • The skin over the surface opening is lubricated and tends to be smoother than the rest of the areola. • The tubercles become more pronounced during pregnancy. 4) Polythelia (accessory nipples) • most commonly in the axilla or inframammary fold • may occur anywhere along the embryologic milk line, from the axilla to the groin • pigmented accessory nipples may be mistaken for moles • Polythelia is uncommon, also may be seen in males Polymastia (Supernumerary breasts; formation of an accessory true mammary gland) also may occur when involution of the milk line is incomplete, but it is rare. Accessory breasts may have normal tissue and even function during lactation. 5) Nipple retraction or inversion • Nipple inversion should only be used when the entire nipple is pulled inward, whereas retraction should be used when the nipple only has an inward slit like area. • Nipple retraction and inversion are either congenital or acquired and either unilateral or bilateral. Nipple inversion • typically occur during puberty • normal variants of the nipple position or result from the development of fibrous tissue between the nipple and the subareolar parenchyma • hinders breast-feeding and predisposes to mastitis and abscess formation • when inverted nipples are detected on mammography, radiologists must not confuse them with subareolar masses Grade 1 Inverted nipple is easily pulled out maintains its projection fairly well without traction Grade 2 Inverted nipple can be pulled out, but not as easily after releasing traction, the nipple tends to fall back and invert again. Grade 3 Nipple is severely retracted and inverted difficult to physically force this nipple out and hold it there. 2. Tips for ultrasonographic evaluation of the nipple 1) Clinical examination; symptoms, inspection 2) Bilateral assessment 3) Linear & high frequency transducer (17–5-MHz) 4) Using a generous amount of jelly around the nipple 5) Intraductal lesion evaluation with radial scan 6) Doppler mode increase the specificity of conventional B-mode US and improve its diagnostic performance 3. Benign conditions 1) Dermal lesions 2) Subareolar abscess 3) Papillomas 4) Benign masses with calcifications • Eczema of the nipple-areolar complex typically occurs bilaterally and may be associated with systemic symptoms of atopic dermatitis, including (but not limited to) flexural dermatitis. Eczema is responsive to topical application of a moderate-dose steroid cream. However, if the symptoms do not improve, a biopsy may be necessary to exclude Paget disease of the nipple, which may have a similar appearance. • Psoriasis also may cause nipple changes, including excoriation and ulceration. A complete clinical history may be helpful for differential diagnosis, as patients may have other manifestations of disease. • Nevoid hyperkeratosis, a benign idiopathic condition that is characterized by slowly growing verrucous thickening and hyperpigmentation of the nipple, areola, or both; and periareolar fistula, an extraintestinal cutaneous manifestation of Crohn disease. • Pathogenesis • -Epidermalization or squamous metaplasia of the cuboidal epithelium lining the ducts -Leading to obstruction of the ducts by keratin plugs -Dilatation of the duct and ampulla occurs -Rupture of the thin columnar epithelial lining of the major duct formation of an abscess • MG: Negative in young patients with dense breast parenchyma • US: Most common imaging option for detecting abscess • Ill-defined or a well-defined outline • Anechoic or low echoic lesion with posterior enhancement • Treatment; Abscess drainage, Surgical therapy (warranted) Central papillomas • arise in the subareolar space and are usually solitary, within major ducts • spontaneous, unilateral, bloody nipple discharge • intraductal proliferation of epithelial and myoepithelial cells overlying a fibro-vascular stalk • less associated with a coexisting malignancy • US findings; mass, a complex cystic-solid mass or duct changes only ; internal vascularity • Calcifications may develop in the nipple areolar complex in some patients and typically are benign. • Calcifications may occur in the skin of the areola, within the Montgomery glands, within hair follicles, in association with a mass, or in the context of Paget disease. • Calcifications in the skin of the areola may be secondary to surgery such as reduction mammoplasty but also may occur in patients without a history of such surgery. • Calcified cutaneous horns are typically asymptomatic and benign but also have been associated with malignant lesions, including Paget disease and squamous cell carcinoma. 1) Paget disease 2) Invasion and recurrence of carcinoma • Malignant masses of the nipple-areolar complex may be more difficult to diagnose than cancers elsewhere in the breast because subareolar masses can be easily confused with normal nipple structures on mammography. • On sonography, subareolar masses or intraductal lesions may be more easily identified than on mammography. • Contrast- enhanced MRI is useful when mammographic and sonographic findings are inconclusive. • Underlying cancer may originate immediately deep to the nipple or extend from another location in the breast to the nipple-areolar complex. • Nipple retraction and ulceration are secondary signs of malignancy and may occur with the extension of advanced breast cancer to the skin surface. • a rare disorder of the nipple-areolar complex • 0.5% to 5% of all breast cancer (often associated with an underlying in situ or invasive carcinoma) • Infiltration of the nipple epidermis by adenocarcinoma cells - characteristic eczematous eruption on the nipple and areola. • Clinical features - Early; erythema and scaling of the nipple, eczematiod change - Late; nipple erosion or ulceration, bloody nipple discharge, nipple retraction - palpable mass(50%) or thickening in the breast • Histologic hallmark of Paget disease - involvement of the epidermis by malignant cells called Paget cells • MG - skin thickening, nipple retraction, subareolar or more diffuse malignant microcalcifications - discrete mass or masses - negative (50%) • US - parenchymal heterogeneousness, hypoechoic areas, discrete masses, skin thickening or dilated ducts • MRI - abnormal nipple enhancement, thickening of the nipple-areolar complex - linear clumped enhancement indicative of DCIS in association with Paget disease [ABSTRACT FROM AUTHOR]

Background: Locally advanced breast cancer (LABC) can be caused by a variety of breast neoplasms. The use of mammography with sonography to estimate pathological complete response (PCR) after neoadjuvant chemotherapy (NAC) has a good degree of precision. Aim of work: To evaluate the precision of breast sonomammography in determining LABC response to neoadjuvant chemotherapy. Subjects and methods: A total of 54 female patients with locally advanced breast cancer were included in the study, which was conducted prospectively from August 2019 to May 2020, they were sent to the Zagazig University Radiology Department and hospitals by the General Surgery and Oncology Departments. A thorough medical history (personal, past, present, and family) was collected, as well as a thorough physical examination. All subjects had bilateral digital mammography as well as a traditional B-mode ultrasonography examination. Before neoadjuvant treatment, a sonomammographic evaluation of the tumour size and morphometric criteria was performed. Biopsy processes were done for suspected breast masses. after finishing the NAC 1:4 weeks previous to surgery, a sonomammographic evaluation of the tumour size and morphological criteria was conducted. Results: There was significant association between post chemotherapy diameters and different breast subtypes in radiological assessment. HR-/HER2-were the most subtype to show radiological response followed by HR+/HER2-while none of HR+/HER2+ show response to NAC. Conclusion: In patients with LABC, mammography and breast ultrasonography are regarded more reliable techniques for assessing tumour size and nodal staging of breast cancer subtypes prior to or after treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVES In patients with oligometastatic non-small-cell lung cancer (NSCLC), systemic therapy in combination with local ablative treatment of the primary tumour and all metastatic sites is associated with improved prognosis. For patient selection and treatment allocation, further knowledge about the molecular characteristics of the oligometastatic state is necessary. Here, we performed a genetic characterization of primary NSCLC and corresponding brain metastases (BM). METHODS We retrospectively identified patients with oligometastatic NSCLC and synchronous (<3 months) or metachronous (>3 months) BM who underwent surgical resection of both primary tumour and BM. Mutation profiling of formalin-fixed paraffin-embedded tumour cell blocks was performed by targeted next-generation sequencing using the Oncomine Focus Assay panel. RESULTS Sequencing was successful in 46 paired samples. An oncogenic alteration was present in 31 primary tumours (67.4%) and 40 BM (86.9%). The alteration of the primary tumours was preserved in the corresponding BM in 29 out of 31 cases (93.5%). The most prevalent oncogenic driver in both primary tumours and BM was a KRAS (Kirsten rat sarcoma viral oncogene) mutation (s  = 21). In 16 patients (34.8%), the BM harboured additional oncogenic alterations. The presence of a private genetic alteration in the BM was an independent predictor of shorter overall survival. CONCLUSIONS In oligometastatic NSCLC, BM retain the main genetic alterations of the primary tumours. Patients may profit from targeted inhibition of mutated KRAS. Additional private genetic alterations in the BM are dismal. [ABSTRACT FROM AUTHOR]

Background: Palliative care improves cancer patients' quality of life. Limited research has investigated racial/ethnic disparities in palliative care utilization and its associated survival among metastatic breast cancer (MBC) patients. Objectives: To examine racial/ethnic palliative care use disparities and assess racial/ethnic overall survival differences in MBC patients stratified by palliative care use. Design: A retrospective study of MBC patients from the 2004–2020 National Cancer Database. Measurements: Palliative care was defined as noncurative cancer treatment, including surgery, radiotherapy, systemic therapy, and/or pain management; utilization was coded "yes/no." Racial/ethnic groups included Asian, American Indian or Alaska Native (AIAN), Black, Hawaiian or Other Pacific Islander (HPI), Hispanic, and White. Logistic regression was performed to assess palliative care use disparities. Overall survival was modeled using Cox regression. Results: Of 148,931 patients, the mean age was 62 years; 99% were female; 73% identified as White, 17% as Black, 6% as Hispanic, 3% as Asian, 0.3% as AIAN, and 0.3% as HPI; 42% and 39% had Medicare and private insurance, respectively. Overall, 21% used palliative care, with an increasing utilization rate from 2004 to 2020 (3.6% increase per year, p-trend <0.001). Black (adjusted odds ratio [aOR] = 0.89; 95% confidence interval [CI]: 0.84 to 0.94), Asian (aOR = 0.76; 95% CI: 0.68 to 0.86), and Hispanic (aOR = 0.68; 95% CI: 0.62 to 0.74) patients had a lower likelihood of palliative care utilization than White patients. Among palliative care users, compared with White patients, Black (adjusted hazard ratio [aHR] = 1.14, 95% CI: 1.07 to 1.21) patients had a greater mortality risk, while Asian (aHR = 0.83, 95% CI: 0.71 to 0.97) and Hispanic (aHR = 0.77, 95% CI: 0.69 to 0.87) patients had a lower mortality risk. Conclusions: Palliative care utilization among MBC patients significantly increased but remained suboptimal. Racial/ethnic minority patients were less likely to use palliative care, and Black patients had worse survival, than White patients, suggesting the need for improving palliative care access and ameliorating disparities in MBC patients. [ABSTRACT FROM AUTHOR]

A joint modeling framework was developed using data from 75 patients of early amcenestrant phase I–II AMEERA‐1‐2 dose escalation and expansion cohorts. A semi‐mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure‐driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of treatment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of amcenestrant. This joint modeling framework integrated complex RECISTv1.1 criteria information, linked TS metrics to progression‐free survival (PFS), and was externally evaluated using the randomized phase II trial AMEERA‐3. We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I–II data. This provides a good modeling and simulation tool to inform early development decisions. [ABSTRACT FROM AUTHOR]

We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2− advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45–78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p =.002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24–2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04–1.37). The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression. [ABSTRACT FROM AUTHOR]

Background: Altered body composition has been attributed to major health problems globally, particularly in patients with cancer. To date, there have not been sufficient indices for body compositions in predicting the survival of locally advanced breast cancer (LABC). Purpose: To assess the association between body composition and overall survival (OS) as well as disease-free survival (DFS) in patients with LABC. Material and Methods: A retrospective study was conducted of patients with LABC diagnosed between 2010 and 2018. Body composition parameters, including skeletal muscle and adiposity parameters, were measured using computed tomography at the L3 vertebra using in-house software developed by MATLAB and freeware Python 3.6.13. The association between body composition and OS and DFS were analyzed using a log-rank test and multivariate Cox-proportional hazard regression. Results: Of 199 patients, 72 (36%) died during the follow-up period (range = 3.8–150.7 months). Median survival was 101 months. Low visceral-to-subcutaneous ratio ≤0.3 (adjusted hazard ratio [aHR] = 2.57, 95% confidence interval [CI] = 1.51−4.37; aHR = 2.46, 95% CI = 1.33−4.56), and high composite fat (aHR = 3.26, 95% CI = 1.69−6.29; aHR = 2.19, 95% CI = 1.11−4.3) were associated with lower OS and DFS. Positive lymph nodes ≥3, progesterone receptor negative, and total radiation dose >5000 cGy significantly decreased both OS and DFS. A history of previous treatment before body composition assessment and surgery had a protective effect on OS and DFS. No association of sarcopenia, body mass index, and adiposity areas with survival outcomes was observed. Conclusion: Low visceral-to-subcutaneous ratio and high composite fat were independent prognostic factors for OS and DFS in patients with LABC. However, other body composition parameters showed no effect on survival. [ABSTRACT FROM AUTHOR]

Molecular probes with the ability to differentiate between subcellular variations in acidity levels remain important for the investigation of dynamic cellular processes and functions. In this context, a series of cyclic peptide and PEG bio-conjugated dual near-infrared emissive BF2-azadipyrromethene fluorophores with maxima emissions at 720 nm (at pH > 6) and 790 nm (at pH < 5) have been developed and their aqueous solution photophysical properties determined. Their inter-converting emissions and fluorescence lifetime characteristics were exploited to track their spatial and temporal progression from first contact with the plasma membrane to subcellular locales to their release within extracellular vesicles. A pH-dependent reversible phenolate/phenol interconversion on the fluorophore controlled the dynamic changes in dual emission responses and corresponding lifetime changes. Live-cell confocal microscopy experiments in the metastatic breast cancer cell line MDA-MB-231 confirmed the usability of the dual emissive properties for imaging over prolonged periods. All three derivatives performed as probes capable of real-time continuous imaging of fundamental cellular processes such as plasma membrane interaction, tracking endocytosis, lysosomal/large acidic vesicle accumulation, and efflux within extracellular vesicles without perturbing cellular function. Furthermore, fluorescence lifetime imaging microscopy provided valuable insights regarding fluorophore progression through intracellular microenvironments over time. Overall, the unique photophysical properties of these fluorophores show excellent potential for their use as information-rich probes. [ABSTRACT FROM AUTHOR]

Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Purpose: Adolescent and young adults (AYAs) with metastatic breast cancer (MBC) experience high physical and psychosocial burdens compounded by a disrupted life trajectory. We sought to determine the psychosocial and supportive care concerns of this population to better understand and address unmet needs. Methods: AYAs diagnosed with MBC (18–39 years) participating in a prospective interventional study (Young, Empowered, and Strong) at Dana-Farber Cancer Institute completed an electronic survey following enrollment. Measures evaluated sociodemographics, health behaviors, quality of life, and symptoms, among others. We used two-sided Fisher’s exact tests to determine associations between concerns (e.g., cancer progression, side effects, lifestyle, finances, fertility) and demographic variables. Results: Among 77 participants enrolled from 9/2020–12/2022, average age at MBC diagnosis and survey was 35.9 (range: 22–39) and 38.3 years (range: 27–46), respectively. Most were non-Hispanic white (83.8%) and 40.3% reported their diagnosis caused some financial problems. Many were concerned about fertility (27.0%), long-term treatment side effects (67.6%), exercise (61.6%), and diet (54.1%). Select concerns varied significantly by age, race/ethnicity, and education. Younger women at survey reported greater concern about familial cancer risk (p = 0.028). Women from minority racial/ethnic groups more frequently reported issues talking about their cancer to family/friends (p = 0.040) while those with more education were more frequently concerned with long-term effects of cancer on their health (p = 0.021). Conclusion: Young women living with MBC frequently report psychosocial, health, and cancer management concerns. Tailoring supportive care and communications to address prevalent concerns including disease progression and treatment side effects may optimize wellbeing. [ABSTRACT FROM AUTHOR]

Purpose: Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US). Methods: HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported. Results: Of the 312 patients initiating 2L treatment, had a median age of 59 years (interquartile range [IQR], 50–66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6 months (95% CI, 8.8–13.3) and real-world progression-free-survival was 7.9 months (95% CI, 7.0–9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively. Conclusion: This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression. [ABSTRACT FROM AUTHOR]

BACKGROUND: The management of and monitoring for hematologic adverse events associated with oral cyclin-dependent kinase (CDK) 4/6 inhibitors present unique challenges for providers and patients. Oncology pharmacists need to be familiar with drug manufacturers' recommendations and advance their clinical practice by assisting providers in the care of women with advanced breast cancer. This article highlights one institution's experience of using a pharmacist-driven approach to monitor the hematologic adverse events of CDK4/6 inhibitors and supplements the current literature with real-world patient outcomes. OBJECTIVE: To evaluate the outcomes of a pharmacist-driven approach in the monitoring for hematologic adverse events after receiving CDK4/6 inhibitors in women with advanced breast cancer. METHODS: Women aged ≥18 years with advanced breast cancer who initiated treatment with a CDK4/6 inhibitor at St Luke's Cancer Institute between September 26, 2022, and March 26, 2023, were identified. The prospective analysis identified and excluded patients if they did not initiate treatment with a CDK4/6 inhibitor within the study period. A total of 2 cohorts were identified, including patients who received CDK4/6 inhibitors within a medically integrated pharmacy who were managed by oncology clinical pharmacists (pharmacist-driven approach) and patients who received drugs through external fulfillment and were managed per usual care (non-pharmacist-driven). Data on the demographics and adverse events, such as diarrhea, that resulted from treatment with a CDK4/6 inhibitor were collected from the patients who met the inclusion criteria. RESULTS: A total of 32 patients were analyzed in the prospective chart review, with palbociclib and abemaciclib accounting for the majority of new prescriptions. Overall, >50% of patients managed by oncology clinical pharmacists in the medically integrated pharmacy achieved the manufacturer-recommended laboratory monitoring for neutropenia. Less than 20% of the patients receiving follow-up care outside the medically integrated pharmacy achieved the recommended monitoring, which represents a stark contrast compared with pharmacist-driven management. A total of 4 events of grade 3 neutropenia were observed, and early interventions by oncology clinical pharmacists occurred during treatment cycle 1. CONCLUSION: The results of this observational study show that patients receiving CDK4/6 inhibitors who were monitored by oncology clinical pharmacists obtained the recommended laboratory monitoring, which led to more timely interventions of neutropenia during treatment cycle 1. [ABSTRACT FROM AUTHOR]

Background: The role of surgery in metastatic breast cancer (MBC) is currently controversial. Several novel statistical and deep learning (DL) methods promise to infer the suitability of surgery at the individual level. Objective: The objective of this study was to identify the most applicable DL model for determining patients with MBC who could benefit from surgery and the type of surgery required. Methods: We introduced the deep survival regression with mixture effects (DSME), a semi‐parametric DL model integrating three causal inference methods. Six models were trained to make individualized treatment recommendations. Patients who received treatments in line with the DL models' recommendations were compared with those who underwent treatments divergent from the recommendations. Inverse probability weighting (IPW) was used to minimize bias. The effects of various features on surgery selection were visualized and quantified using multivariate linear regression and causal inference. Results: In total, 5269 female patients with MBC were included. DSME was an independent protective factor, outperforming other models in recommending surgery (IPW‐adjusted hazard ratio [HR] = 0.39, 95% confidence interval [CI]: 0.19–0.78) and type of surgery (IPW‐adjusted HR = 0.66, 95% CI: 0.48–0.93). DSME was superior to other models and traditional guidelines, suggesting a higher proportion of patients benefiting from surgery, especially breast‐conserving surgery. The debiased effect of patient characteristics, including age, tumor size, metastatic sites, lymph node status, and breast cancer subtypes, on surgery decision was also quantified. Conclusions: Our findings suggested that DSME could effectively identify patients with MBC likely to benefit from surgery and the specific type of surgery needed. This method can facilitate the development of efficient, reliable treatment recommendation systems and provide quantifiable evidence for decision‐making. [ABSTRACT FROM AUTHOR]

18F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) is considered an accurate diagnostic tool to determine whole-body endocrine responsiveness. In the endocrine therapy (ET)-FES trial, we evaluated 18F-FES PET/CT as a predictive tool in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Eligible patients underwent an 18F-FES PET/CT at baseline. Patients with standardized uptake value (SUV) ≥ 2 received single-agent ET until progressive disease; patients with SUV < 2 were randomized to single-agent ET (arm A) or chemotherapy (ChT) (arm B). The primary objective was to compare the activity of first-line ET versus ChT in patients with 18F-FES SUV < 2. Overall, 147 patients were enrolled; 117 presented with 18F-FES SUV ≥ 2 and received ET; 30 patients with SUV < 2 were randomized to ET or ChT. After a median follow-up of 62.4 months, 104 patients (73.2%) had disease progression and 53 died (37.3%). Median progression-free survival (PFS) was 12.4 months [95% confidence interval (CI) 3.1-59.6 months] in patients with SUV < 2 randomized to arm A versus 23.0 months (95% CI 7.7-30.0 months) in arm B, [hazard (HR) = 0.71, 95% CI 0.3-1.7 months]; median PFS was 18.0 months (95% CI 11.2-23.1 months) in patients with SUV ≥ 2 treated with ET. Median overall survival (OS) was 28.2 months (95% CI 14.2 months-not estimable) in patients with SUV < 2 randomized to ET (arm A) versus 52.8 months (95% CI 16.2 months-not estimable) in arm B (ChT). Median OS was not reached in patients with SUV ≥ 2. 60-month OS rate was 41.6% (95% CI 10.4% to 71.1%) in arm A, 42.0% (95% CI 14.0% to 68.2%) in arm B, and 59.6% (95% CI 48.6% to 69.0%) in patients with SUV ≥ 2. In patients with SUV ≥ 2, 60-month OS rate was 72.6% if treated with aromatase inhibitors (AIs) versus 40.6% in case of fulvestrant or tamoxifen (P < 0.005). The ET-FES trial demonstrated that ER+/HER2− MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV. • 18F-FES PET/CT may be used as a predictive tool of efficacy of ET to assess overall endocrine sensitivity. • Endocrine-sensitive patients (SUVmax ≥ 2) treated with single-agent ET have a prolonged OS. • In endocrine-sensitive patients, PFS and OS related to the use of AI were significantly higher than ER-directed agents. • 18F-FES PET/CT can be used as a valid alternative to biopsy. [ABSTRACT FROM AUTHOR]

Background: The combination of dual‐targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first‐line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan‐ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first‐line survival benefits and serve as a more affordable treatment option? Methods: This real‐world retrospective study included patients diagnosed with HER2‐positive mBC who received PyroC as a first‐line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. Results: A total of 64 patients received PyroC as first‐line therapy. The median progression‐free survival (PFS) was 19.6 months (95% CI 15.0–27.2), while overall survival (OS) has not yet been reached. Kaplan–Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti‐HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment‐related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand‐foot syndrome (n = 10, 15.6%). Conclusion: The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2‐positive mBC patients, with an acceptable safety profile and convenience. [ABSTRACT FROM AUTHOR]

Background: The most common route of breast cancer metastasis is through the mammary lymphatic network. An accurate assessment of the axillary lymph node (ALN) burden before surgery can avoid unnecessary axillary surgery, consequently preventing surgical complications. In this study, we aimed to develop a non-invasive prediction model incorporating breast specific gamma image (BSGI) features and ultrasonographic parameters to assess axillary lymph node status. Materials and methods: Cohorts of breast cancer patients who underwent surgery between 2012 and 2021 were created (The training set included 1104 ultrasound images and 940 BSGI images from 235 patients, the test set included 568 ultrasound images and 296 BSGI images from 99 patients) for the development of the prediction model. six machine learning (ML) methods and recursive feature elimination were trained in the training set to create a strong prediction model. Based on the best-performing model, we created an online calculator that can make a linear predictor in patients easily accessible to clinicians. The receiver operating characteristic (ROC) and calibration curve are used to verify the model performance respectively and evaluate the clinical effectiveness of the model. Results: Six ultrasonographic parameters (transverse diameter of tumour, longitudinal diameter of tumour, lymphatic echogenicity, transverse diameter of lymph nodes, longitudinal diameter of lymph nodes, lymphatic color Doppler flow imaging grade) and one BSGI features (axillary mass status) were selected based on the best-performing model. In the test set, the support vector machines' model showed the best predictive ability (AUC = 0.794, sensitivity = 0.641, specificity = 0.8, PPV = 0.676, NPV = 0.774 and accuracy = 0.737). An online calculator was established for clinicians to predict patients' risk of ALN metastasis (https://wuqian.shinyapps.io/shinybsgi/). The result in ROC showed the model could benefit from incorporating BSGI feature. Conclusion: This study developed a non-invasive prediction model that incorporates variables using ML method and serves to clinically predict ALN metastasis and help in selection of the appropriate treatment option. [ABSTRACT FROM AUTHOR]

In this study, we assess the impact of photodynamic therapy (PDT) using aluminum phthalocyanine tetrasulfonate (AlPcS4) on the viability and cellular stress responses of MCF-7 breast cancer cells. Specifically, we investigate changes in cell viability, cytokine production, and the expression of stress-related genes. Experimental groups included control cells, those treated with AlPcS4 only, light-emitting diode (LED) only, and combined PDT. To evaluate these effects on cell viability, cytokine production, and the expression of stress-related genes, techniques such as 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, enzyme-linked immunosorbent assays (ELISA), and real-time quantitative PCR (RT‒qPCR) were employed. Our findings reveal how PDT with AlPcS4 modulates mitochondrial activity and cytokine responses, shedding light on the cellular pathways essential for cell survival and stress adaptation. This work enhances our understanding of PDT's therapeutic potential and mechanisms in treating breast cancer. [ABSTRACT FROM AUTHOR]

Background: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression. Methods: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes. Discussion: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC. Trial registration: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC. Methods: MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens. Results: Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5–4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0–4.0 months), and 6.1 months (3.7–9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics. Conclusions: The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population. [ABSTRACT FROM AUTHOR]

Melanoma, with its diverse histopathologic characteristics, can mimic both benign nevi and neoplasms of various cell lineages. Immunohistochemistry (IHC) can play a vital role in melanoma diagnosis, particularly when the cell lineage is unclear on hematoxylin and eosin sections. Commonly utilized IHC stains for melanoma diagnosis include SOX10, Melan‐A, and S100. A relatively novel stain, PReferentially expressed Antigen in MElanoma (PRAME), is also proving useful in accurate melanoma diagnosis. However, none of these stains are completely specific to melanocytes or melanoma, and misinterpretation can lead to incorrect diagnoses. This report presents a unique case of triple‐negative breast carcinoma (TNBC) metastatic to the skin exhibiting histopathologic characteristics similar to melanoma, including positivity for SOX10 and PRAME. Our aim is to highlight TNBC metastatic to the skin as a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

The role of endothelial cells in promoting cancer cell extravasation to the brain during the interaction of cancer cells with the vasculature is not well characterised. We show that brain endothelial cells activate EGFR signalling in triple-negative breast cancer cells with propensity to metastasise to the brain. This activation is dependent on soluble factors secreted by brain endothelial cells, and occurs via the RAC1 GEF DOCK4, which is required for breast cancer cell extravasation to the brain in vivo. Knockdown of DOCK4 inhibits breast cancer cell entrance to the brain without affecting cancer cell survival or growth. Defective extravasation is associated with loss of elongated morphology preceding intercalation into brain endothelium. We also show that brain endothelial cells promote paracrine stimulation of mesenchymal-like morphology of breast cancer cells via DOCK4, DOCK9, RAC1 and CDC42. This stimulation is accompanied by EGFR activation necessary for brain metastatic breast cancer cell elongation which can be reversed by the EGFR inhibitor Afatinib. Our findings suggest that brain endothelial cells promote metastasis through activation of cell signalling that renders breast cancer cells competent for extravasation. This represents a paradigm of brain endothelial cells influencing the signalling and metastatic competency of breast cancer cells. Brain endothelial cells activate EGFR signaling in triple-negative breast cancer cells, promoting brain metastasis. DOCK4 is crucial for cancer cell extravasation to the brain, with EGFR activation driving cell elongation reversed by Afatinib. [ABSTRACT FROM AUTHOR]

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%5fBreast%5fCancer%5f1). 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. [ABSTRACT FROM AUTHOR]

The benefits of denosumab as an antiresorptive therapy and in reducing fragility fractures are well documented. However, its association with atypical femur fractures (AFFs), especially in the absence of prior bisphosphonate use, remains poorly understood and warrants further investigation. This case report presents a rare instance of bilateral AFFs in a 78-year-old bisphosphonate-naïve patient with a history of long-term denosumab therapy for previous metastatic breast cancer. Management involved intramedullary nail fixation after initial presentation with a unilateral AFF and a recommendation to cease denosumab therapy. However, the patient subsequently experienced a contralateral periprosthetic AFF below a total hip implant 5 months thereafter and was treated with open reduction internal fixation. This case report highlights the critical need for orthopedic surgeons to maintain a high level of suspicion and vigilance in screening for impending AFFs, especially in patients with a prolonged history of denosumab therapy without prior bisphosphonate use. Furthermore, the growing report of such cases emphasizes the urgent need for comprehensive research aimed at refining treatment protocols that balance the therapeutic benefits of denosumab and its associated risks of AFFs. [ABSTRACT FROM AUTHOR]

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases. [ABSTRACT FROM AUTHOR]

Breast cancer, when advancing to a metastatic stage, involves the liver, impacting over 50% of cases and significantly diminishing survival rates. Presently, a lack of tailored therapeutic protocols for breast cancer liver metastasis (BCLM) underscores the need for a deeper understanding of molecular patterns governing this complication. Therefore, by analyzing differentially expressed genes (DEGs) between primary breast tumors and BCLM lesions, we aimed to shed light on the diversities of this process. This research investigated breast cancer liver metastasis relapse by employing a comprehensive approach that integrated data filtering, gene ontology and KEGG pathway analysis, overall survival analysis, identification of the alteration in the DEGs, visualization of the protein–protein interaction network, Signor 2.0, identification of positively correlated genes, immune cell infiltration analysis, genetic alternation analysis, copy number variant analysis, gene-to-mRNA interaction, transcription factor analysis, molecular docking, and identification of potential treatment targets. This study's integrative approach unveiled metabolic reprogramming, suggesting altered PCK1 and LPL expression as key in breast cancer metastasis recurrence. [ABSTRACT FROM AUTHOR]

Metastasis in breast cancer is the major cause of death in females (about 30%). Based on our earlier observation that Vitamin D3 downregulates mTOR, we hypothesized that Vitamin D3 conjugated to gold nanoparticles (VD3-GNPs) reduces breast cancer aggressiveness by downregulating the key cancer controller PI3K/AKT/mTOR. Western blots, migration/invasion assays, and other cell-based, biophysical, and bioinformatics studies are used to study breast cancer cell aggressiveness and nanoparticle characterization. Our VD3-GNP treatment of breast cancer cells (MCF-7 and MDA-MB-231) significantly reduces the aggressiveness (cancer cell migration and invasion rates > 45%) via the simultaneous downregulation of ETV7 and the Hippo pathway. Consistent with our hypothesis, we, indeed, found a downregulation of the PI3K/AKT/mTOR pathway. It is surprising that the extremely low dose of VD3 in the nano formulation (three orders of magnitude lower than in earlier studies) is quite effective in the alteration of cancer invasiveness and cell signaling pathways. Clearly, VD3-GNPs are a viable candidate for non-toxic, low-cost treatment for reducing breast cancer aggressiveness. [ABSTRACT FROM AUTHOR]

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer may have poor prognoses and short overall and disease-free survival. Most previous studies focused on assessing the quality of life and health-state utility of the general population of breast cancer patients. The number of studies for HER2-positive breast cancer patients is negligible. This study investigated the health-state utility and its associated factors among Vietnamese patients with HER2-positive breast cancer. Methods: We conducted face-to-face interviews with 301 HER2-positive breast cancer patients to collect data. Their health-state utility was measured via the EQ-5D-5L instrument. The Mann-Whitney U and Kruskal-Wallis tests were employed to compare the differences in utility scores between two groups and among three groups or more, respectively. Factors associated with patients' heath-state utility were identified via Tobit regression models. Results: Pain/discomfort (56.1%) and anxiety/depression (39.5%) were the two issues that patients suffered from the most, especially among metastatic breast cancer patients. The severity of distress (depression, anxiety, and stress) in patients was relatively mild. Of 301 patients, their average utility score was 0.86±0.17 (range: 0.03–1.00), and the average EQ-visual analogue scale (VAS) score was 69.12±12.60 (range: 30–100). These figures were 0.79±0.21 and 65.20±13.20 for 102 metastatic breast cancer patients, significantly lower than those of 199 non-metastatic cancer patients (0.89±0.13 and 71.13±11.78) (p<0.001), respectively. Lower health-state utility scores were significantly associated with older age (p = 0.002), lower education level (p = 0.006), lower monthly income (p = 0.036), metastatic cancer (p = 0.001), lower EQ-VAS score (p<0.001), and more severe level of distress (p<0.001). Conclusions: Our findings showed a significant decrement in utility scores among metastatic breast cancer patients. Patients' health-state utility differed by their demographic characteristics (age, education level, and income) and clinical characteristics (stage of cancer and distress). Their utility scores may support further cost-effectiveness analysis in Vietnam. [ABSTRACT FROM AUTHOR]

Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial–mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures. [ABSTRACT FROM AUTHOR]

Background: This prospective real‐world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China. Patients and Methods: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo−/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m2) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression‐free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed. Results: One hundred and thirty‐four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3–15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first‐ or second‐line treatment was significantly better than those who received eribulin as ≥3‐line treatment (6.9 months [95% CI: 3.2–8.8] vs. 4.0 months [95% CI: 3.4–4.6], p = 0.006). The mPFS of patients with triple‐negative, HER2‐positive, and HER2(−)/HR(+) was 3.4 (95% CI: 2.7–4.1), 6.2 (95% CI: 2.3–10.1) and 5.0 months (95% CI: 4.1–5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6–6.3] vs. 4.0 months [95% CI: 3.3–4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non‐TNBC receiving eribulin as ≤2‐line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment‐related adverse events. Conclusion: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real‐world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials. [ABSTRACT FROM AUTHOR]

Background: Cyclin‐dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard‐of‐care for patients with hormone receptor‐positive, human epidermal growth factor receptor‐2 negative (HR+/HER2−) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib‐based ET in Chinese patients with HR+/HER2− MBC. Methods: From 414 consecutive patients with HR+/HER2− MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease‐free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression‐free survival (PFS) compared using the Kaplan–Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. Results: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94–8.06) in abemaciclib group and 4.0 months (95% CI, 2.52–5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first‐line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd‐line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). Conclusion: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2− MBC after progression on prior palbociclib‐based therapy in addition to chemotherapy. [ABSTRACT FROM AUTHOR]