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During the past two decades evidence has been developed that indicates a handful of viruses with known oncogenic capacity, have potential roles in breast cancer. These viruses are mouse mammary tumour virus (MMTV - the cause of breast cancer in mice), high-risk human papilloma viruses (HPV-the cause of cervical cancer), Epstein Barr virus (EBV-the cause of lymphomas and naso-pharyngeal cancer) and bovine leukemia virus (BLV - the cause of cancers in cattle). These viruses may act alone or in combination. Each of these viruses are significantly more prevalent in breast cancers than in normal and benign breast tissue controls. The odds ratios for the prevalence of these viruses in breast cancer compared to normal and benign breast controls, are based on case control studies - MMTV 13·40, HPV 5.56, EBV 4·43 and BLV 2·57. The odds ratios for MMTV are much greater compared to the other three viruses. The evidence for a causal role for mouse mammary tumour virus and high risk for cancer human papilloma viruses in human breast cancer is increasingly comprehensive. The evidence for Epstein Barr virus and bovine leukemia virus is more limited. Overall the evidence is substantial in support of a viral cause of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Squama Manis is a valuable traditional Chinese medicine with a long history of medicinal use in the treatment of breast-related diseases. However, owing to the excessive exploitation and utilization of the resources, Squama Manis has been included in the list of rare and endangered wild animals. The conservation of the resources of Squama Manis and continuing its clinical application has become an urgent problem, and the search for small-molecule substitutes for Squama Manis is an effective way to achieve this goal. Previous studies have identified PA3264 as a possible active ingredient in Squama Manis. In this study, we systematically investigated the pharmacological effects and mechanisms of PA3264 in the treatment of triple-negative breast cancer (TNBC), a representative breast-related disease. Methods: Cell viability and colony formation assays were performed after treatment with the target dipeptide PA3264 in vitro. Next, 4T1 orthotopic tumors and humanized PBMC-CDX mouse models were generated to examine the antitumor effect of PA3264 in vivo. Transcriptome sequencing and molecular docking experiments were performed to predict pathways to function. Western blotting and quantitative real-time PCR were used to validate the molecular mechanisms underlying the anticancer effects of PA3264. Results: PA3264 significantly inhibited cell viability and migration of breast cancer cells in vitro. Furthermore, PA3264 suppressed the tumor size and reduced the tumor weight in vivo. Finally, it was verified that PA3264 prevented the progression of breast cancer by inhibiting the PI3K/AKT/NF-κB pathway, causing cell cycle arrest, and promoting apoptosis. Conclusions: This study elucidated that PA3264 derived from rare and endangered Squama Manis was a novel bioactive peptide for treating triple-negative breast cancer from a scientific research perspective. [ABSTRACT FROM AUTHOR]

Background: Whole-body magnetic resonance imaging (WB-MRI) has shown its accuracy in the diagnosis of skeletal metastases in patients with known primary solid cancers. The standard protocol was a combination of T1 and short tau inversion recovery (STIR) sequences. Herein, this study was conducted to elucidate the role of the T2-Dixon sequence as a rapid alternative to the standard protocol with the assessment of its diagnostic accuracy and comparability to the established methodology. Methods: This prospective study included 30 patients with primary solid malignancies who underwent WB-MRI. The sequences obtained were T1WI, STIR, and T2-Dixon (fat-only and water-only images). Skeletal metastases were evaluated in each sequence. Results were compared between the T1-STIR combination and T2-Dixon fat and water reconstructions. Results: The sensitivity of fat and water reconstructions from a single T2-Dixon in the detection of lytic skeletal metastases was marginally superior to a combination of T1WI and STIR sequences (0–7%). Detection of mixed lesions demonstrated equally high sensitivity in both protocols. Sclerotic metastases detection in WB-MRI showed low sensitivity in both protocols. However, specificity surpassed 95% for all lesion types in both protocols. Overall image quality was favored (in 87–90% of patients) in T2-Dixon images. The overall estimated acquisition timing using T2-Dixon appeared to be approximately half that of the standard T1-STIR combination. Conclusions: WB-MRI using T2-Dixon fat and water reconstructions showed similar accuracy to T1WI and STIR combination in the evaluation of skeletal metastases in patients with primary solid cancers with significantly shorter acquisition time. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cause of death from cancer in women. Here, we present the case of a 43-year-old woman, who received a diagnosis of claudin-low luminal B breast cancer. The lesion revealed to be a poorly differentiated high-grade infiltrating ductal carcinoma, which was strongly estrogen receptor (ER)/progesterone receptor (PR) positive and human epidermal growth factor receptor (HER2) negative. Her tumor underwent in-depth chromosomal, mutational and gene expression analyses. We found a pathogenic protein truncating mutation in the TP53 gene, which is predicted to disrupt its transcriptional activity. The patient also harbors germline mutations in some mismatch repair (MMR) genes, and her tumor displays the presence of immune infiltrates, high tumor mutational burden (TMB) status and the apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) associated signatures, which, overall, are predictive for the use of immunotherapy. Here, we propose promising prognostic indicators as well as potential therapeutic strategies based on the molecular characterization of the tumor. [ABSTRACT FROM AUTHOR]

Background/Objective: Few Spanish mindfulness interventions have been evaluated in Latinx patients with cancer. We culturally adapted a mindfulness intervention for Spanish speaking Latinx patients. The objective was to measure feasibility and acceptability as primary outcomes, with changes in anxiety, depression, and sleep as secondary outcomes. Method: Spanish-speaking Latinx patients with breast cancer (n = 31) were randomized, between April 2021 and May 2022 to either intervention or wait-list control groups. The mindfulness intervention consisted of 6-weekly 1.5-hour sessions remotely delivered by a novice facilitator. Cultural adaptations included language, metaphor, goal, concept, trauma informed, and acknowledgement of spirituality. Feasibility was benchmarked as 75% of participants attending their first session, 75% of participants completing 4 of 6 sessions, and scoring ≥ 4 on a 5-point Likert feasability scale measuring ability to implement changes after 6-weeks. Acceptability was measured as scoring ≥ 4 on a 5-point Likert scale measuring usefulness and relevance of the mindfulness intervention for each session. An intention-to-treat, linear mixed model with repeated measures analysis examined changes in anxiety, depression, and sleep at week 6 and 18 (3 months post intervention). Results: All three feasibility benchmarks were met with 75% of first session attendance, 96% of participants completing 4 of 6 sessions, and 94% scoring ≥ 4, on the feasibility scale (Mean (SD) = 4.3 (0.6)). Acceptability scores for both usefulness and relevance questions were ≥ 4 across all 6 sessions. Anxiety was significantly reduced at 3 months (−3.6 (CI -6.9, −0.2), P =.04), but is of unclear clinical significance given the small change. Depression scores declined, but not significantly, and there were no changes in sleep. Conclusion: This culturally adapted, remotely delivered mindfulness intervention using a novice facilitator was acceptable and feasible and demonstrated associated reductions in anxiety amongst Spanish speaking Latinx patients with breast cancer. Trial Registration: ClinicalTrials.gov ID# NCT04834154. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most common cancers in women. Patient-reported outcome measures are used to evaluate patients' health-related quality of life in clinical breast cancer studies. This study evaluated the structure, validity, reliability, and responsiveness of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) subscales in a clinical trial featuring patients with advanced/metastatic breast cancer (aBC), and estimated NFBSI-16 meaningful change thresholds. Methods: Data from 101 patients with aBC enrolled in a phase II trial (Xenera-1) were included for psychometric evaluation of the NFBSI-16. Subscale structure was evaluated by assessing inter-item correlations, item-total correlations, and internal consistency (cycles 2 and 5). Validity was assessed using scale-level convergent validity (cycles 2 and 5) and known-groups (Baseline). Reliability was analysed via test-retest at cycles 3–4, and responsiveness to improvement and worsening was evaluated at cycles 5, 7, and 9. Meaningful change thresholds were estimated using anchor-based methods (supported by distribution-based methods) at cycles 5, 7, and 9. Results: NFBSI-16 internal consistency was acceptable, but item-total correlations suggested that its subscales and the GP5 item (side-effect of treatment) scores may be preferred over a total score. Convergent and known-groups evidence supported NFBSI-16 validity. Test-retest reliability was good to excellent for Total and DRS-P (disease-related symptoms: physical) scales, and moderate for the GP5 item. Responsiveness to worsening was generally demonstrated, but responsiveness to improvement could not be demonstrated due to limited observed improvement. Anchor-based meaningful change thresholds were estimated for DRS-P and Total scores. Conclusion: This study provides evidence that the NFBSI-16 has desirable psychometric properties for use in clinical studies in aBC. It also provides estimates of group- and individual-level meaningful change thresholds to facilitate score interpretation in future aBC research. [ABSTRACT FROM AUTHOR]

Background: Breast cancer-related lymphedema (BRCL) is one of the most common causes of upper extremity (UE) lymphedema in developed nations and substantially impacts health-related quality of life. To advance our understanding of the epidemiology and treatment of BRCL, rigorously developed and validated patient-reported outcome measures (PROMs) are needed. This study aimed to demonstrate the iterative content validity of a modular UE lymphedema-specific PROM called the LYMPH-Q UE module. Methods: A multi-step iterative qualitative approach was used. Semi-structured interview data from in-depth qualitative interviews with adult women (18 years and older) with BCRL were used to develop the first set of the LYMPH-Q UE scales. The content validity of these scales was demonstrated with patient and clinician feedback. Over the course of cognitive debriefing interviews, additional concepts of lymphedema worry and impact on work were identified as missing from the LYMPH-Q UE module. Subsequently, two new qualitative studies (a focus group and in-depth concept elicitation interviews with patients) were conducted, and two new scales were developed to measure lymphedema worry and impact on work life and their content validity was demonstrated. Results: Qualitative data from in-depth and cognitive interviews with 15 (age 40–74 years) and 16 (age 38–74 years) women with BRCL, respectively, and feedback from 12 clinical experts, were used to develop and demonstrate the content validity of six LYMPH-Q UE scales measuring symptoms, function, appearance, psychological, information, and arm sleeve. Additionally, data from in-depth interviews with 12 (age 35–72 years) women with UE lymphedema and four focus groups (n = 16 women; age 35–74 years) was used to develop and assess the content validity of two new LYMPH-Q UE scales measuring lymphedema worry and impact on work life. The content validity of the previously established six scales was also demonstrated in these subsequent qualitative studies. Conclusion: The LYMPH-Q UE is a modular PROM developed using international guidelines for PROM development and can be used in clinical practice, research, and quality improvement to enhance patient-centered shared decision-making. This study's innovative and iterative approach to content validation demonstrates that the LYMPH-Q UE is a comprehensive measure that includes important concepts relevant to patients with UE lymphedema. [ABSTRACT FROM AUTHOR]

Radiotherapy demonstrates a synergistic effect with immunotherapy by inducing a transformation of "immune cold" tumors into "immune hot" tumors in triple negative breast cancer (TNBC). Nevertheless, the effectiveness of immunotherapy is constrained by low expression of tumor‐exposed antigens, inadequate inflammation, and insufficient tumor infiltrating lymphocyte (TILs). To address this predicament, novel lutecium‐based rare earth nanoparticles (RENPs) are synthesized with the aim of amplifying radiation effect and tumor immune response. The nanoprobe is characterized by neodymium‐based down‐conversion fluorescence, demonstrating robust photostability, biocompatibility, and targetability. The conjugation of RENPs with a CXCR4 targeted drug enables precise delineation of breast tumors using a near‐infrared imaging system and improves radiation efficacy via lutetium‐based radio‐sensitizer in vivo. Furthermore, the study shows a notable enhancement of immune response through the induction of immunogenic cell death and recruitment of TILs, resulting in the inhibition of tumor progression both in vitro and in vivo models following the administration of nanoparticles. Hence, the novel multifunctional nanoprobes incorporating various lanthanide elements offer the potential for imaging‐guided tumor delineation, radio‐sensitization, and immune activation post‐radiation, thus presenting an efficient radio‐immunotherapeutic approach for TNBC. [ABSTRACT FROM AUTHOR]

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models. Antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by their targeting ability and retention to tumor sites. Here the authors design the reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC nanoparticles with selective penetration into tumors for degradation of BRD4 to suppress breast and head and neck cancer progression. [ABSTRACT FROM AUTHOR]

Aim: The PREDICT tool is used to estimate survival in breast cancer patients according to the types of treatment given. This study aimed to assess the accuracy of the PREDICT tool and identify the prognostic factors for survival in patients with breast cancer. Material and Methods: A retrospective study was performed based on data collected from the Hospital Sultanah Nur Zahirah, Terengganu, Malaysia. All female patients diagnosed with stage I to IV breast cancer were identified from the year 2011 to 2017. Results: Based on data from 355 eligible patients, the predicted and observed 5-year overall survival rates were 75.8% and 75.2%, respectively. The model performed fairly well, with the area under the curve (AUC) of 0.747 (95% confidence interval (CI): 0.69-0.81) in the predicted 5-year overall survival. Among the 585 patients diagnosed with stage I to IV breast cancer, stage at the presentation (stage III hazard ratio (HR): 5.80, 95% CI: 1.69-19.94, p=0.005, stage IV HR: 10.61, 95% CI: 3.09-36.49, p<0.001), without surgical treatment (HR: 2.29, 95% CI: 1.73-3.00, p<0.001), without radiotherapy (HR: 1.92, 95% CI: 1.41-2.62, p<0.001), and without neoadjuvant chemotherapy (HR: 0.63, 95% CI: 0.47-0.86, p=0.003) were associated with death in breast cancer patients. Conclusion: The PREDICT tool accurately estimated the 5-year overall survival in the study center. It might serve as a useful prognostication tool during consultation. Late stages of the disease, patients without surgical treatment, and patients without radiotherapy were associated with a higher risk of death in breast cancer. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is the most prevalent cancer among women worldwide. Although advances have been made in the identification of predictive biomarkers, current options for early diagnosis and prognostic analysis are still suboptimal. Recently, transfer-RNA-derived RNA fragments (tRFs) have emerged as a class of small noncoding RNAs that play a role in the cancer progression. The authors aimed to identify a specific class of tRFs as a molecular marker for BC diagnosis and prognosis in clinical management. Methods: The levels of 5′-tRF-His-GTG were quantified in BC tissue (n = 101) and inflammatory normal breast tissue (n = 22) using in situ hybridization. Clinicopathological parameters were obtained, including age, tumor node metastasis stage, hormone receptor status, histopathological grade, lymphovascular invasion, and recurrence. The correlation between the expression of 5′-tRF-His-GTG and these parameters in different BC subtypes was analyzed. Patient death and cancer progression were regarded as clinical endpoints in the survival analysis. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also performed to predict the involvement in pivotal biological process. Results: The expression of 5′-tRF-His-GTG was significantly downregulated in BC tissues and was in connection with T stage in human epidermal growth factor 2-positive and basal-like BC, as well as N stage and histopathological grade in luminal BC. Patients with low expression of 5′-tRF-His-GTG had a poor overall survival rate. Statistics of GO and KEGG pathway revealed that cation channel activity, protein catabolic process, response to temperature stimulus, cell cycle, focal adhesion, and glycerophospholipid metabolism were significantly enriched. Conclusions: This study suggests that the assessment of 5′-tRF-His-GTG expression could serve as a novel biomarker for individual diagnosis and prognosis in BC. [ABSTRACT FROM AUTHOR]

Background: Cancer-derived exosomes facilitate chemoresistance by transferring RNAs, yet their role in exosomal microRNA-221-3p (miR-221-3p) regulation of adriamycin resistance in breast cancer (BC) remains unclear. Methods: Adriamycin-resistant BC cells were developed from MCF-7 and MDA-MB-231 cells by incremental adriamycin exposure. The miR-221-3p levels were quantified by quantitative reverse transcription-polymerase chain reaction. Subsequently, exosomes were isolated and incubated with BC cells, and exosome-mediated adriamycin sensitivity was evaluated using Cell Counting Kit-8, colony formation, and flow cytometry assays. Sensitive cells were cocultured with miR-221-3p inhibitor-treated cells to assess adriamycin resistance. Moreover, the interaction between miR-221-3p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was validated using a dual luciferase reporter gene assay. Mimics and inhibitors were used to determine the effects of miR-221-3p on adriamycin resistance. Results: Elevated levels of miR-221-3p expression were observed in adriamycin-resistant BC cells and exosomes. Sensitive cells were cocultured with exosomes from resistant cells, resulting in increased half-maximal inhibitory concentration value and proliferation, and reduced adriamycin-induced apoptosis. However, the effects of coculturing sensitive cells with adriamycin-resistant cells were significantly weakened by miR-221-3p inhibitor transfection in adriamycin-resistant cells. PIK3R1 was found to be a target of miR-221-3p, and miR-221-3p mimics enhanced adriamycin resistance in sensitive cells. miR-221-3p inhibitors increased the expression of PIK3R1, p-AKT, c-Myc, HK2, and PKM2, decreased FOXO3 expression, and weakened the adriamycin resistance in resistant cells. Conclusions: miR-221-3p can be transferred between BC cells through exosomes. High levels of miR-221-3p were found to target PIK3R1 and promoted adriamycin resistance in BC cells. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between breast cancer susceptibility gene-1 (BRCA1) gene methylation and the radiosensitivity of breast cancer. Materials and Methods: The authors studied three breast cancer cell lines: MDA-MB-435, MDA-MB-231, and MCF-7 cells. They constructed five short hairpin RNAs (shRNAs) and five small interfering RNAs to target selected promoter loci and initiate sequence-specific methylation in breast cancer cells. Pyrosequencing was used to analyze the state of DNA methylation. Quantitative real-time polymerase chain reaction was used to detect BRCA1 mRNA expression and RNA-directed DNA methylation (RdDM)-related gene expression. Western blotting was performed to analyze BRCA1 protein expression. Colony formation assays and γ-histone H2A foci formation assays were conducted to assess the surviving fraction (SF) and double-strand break (DSB) repair ability of cells after irradiation. Results: The authors constructed five strains of lentivirus vectors and five plasmid vectors targeting BRCA1 promoter region. In MDA-MB-435 cells, lentivirus-mediated RNA interference targeting Site 1 of BRCA1 increased the methylation levels of BRCA1 and reduced BRCA1 mRNA and protein expression. The SF and the ability to repair DNA DSBs were reduced in the combined LV-BRCA1RNAi-Site 1 infection and irradiation group. Conclusions: The authors' findings suggest that the shRNA suppressed the expression levels of the BRCA1 gene and reduced the SF and DNA repair ability of cells after irradiation through RdDM. In summary, the radiosensitivity of breast cancer cells may correlate with BRCA1 methylation. Advances in Knowledge: The authors first utilized a lentivirus-based shRNA-mediated specific-sequence DNA methylation of the BRCA1 gene mediated by RdDM. [ABSTRACT FROM AUTHOR]

Engineering functional tissues and organs remains a fundamental pursuit in bio‐fabrication. However, the accurate constitution of complex shapes and internal anatomical features of specific organs, including their intricate blood vessels and nerves, remains a significant challenge. Inspired by the Matryoshka doll, here a new method called "Intra‐Embedded Bioprinting (IEB)" is introduced building upon existing embedded bioprinting methods. a xanthan gum‐based material is used which served a dual role as both a bioprintable ink and a support bath, due to its unique shear‐thinning and self‐healing properties. IEB's capabilities in organ modeling, creating a miniaturized replica of a pancreas using a photocrosslinkable silicone composite is demonstrated. Further, a head phantom and a Matryoshka doll are 3D printed, exemplifying IEB's capability to manufacture intricate, nested structures. Toward the use case of IEB and employing an innovative coupling strategy between extrusion‐based and aspiration‐assisted bioprinting, a breast tumor model that included a central channel mimicking a blood vessel, with tumor spheroids bioprinted in proximity is developed. Validation using a clinically‐available chemotherapeutic drug illustrated its efficacy in reducing the tumor volume via perfusion over time. This method opens a new way of bioprinting enabling the creation of complex‐shaped organs with internal anatomical features. [ABSTRACT FROM AUTHOR]

This study aims to investigate the potential association between serum levels of cytokines, HSP60, HSP70 and IR (HOMA-IR) in postmenopausal women. We conducted a cross-sectional study involving 381 postmenopausal women, including 94 with a breast cancer diagnosis and 278 without. We analyzed anthropometric and laboratory measurements. Immunoassays were used to measure cytokines (TNF-α, IL-10, and IL-6) as well as heat shock proteins (HSP) 60 and 70 in the serum using the ELISA technique. Women diagnosed with breast cancer showed higher levels of HOMA-IR, IL-6, TNF, and HSP60, and lower levels of IL-10 and HSP70 compared to women without cancer. An association was found between HSP70 and HOMA-IR only in women with breast cancer (β = 0.22, p =.030; without cancer: β = 0.04, p =.404), regardless of age, waist circumference, smoking, and physical activity. No associations were observed between cytokines, HSP60, and HOMA-IR in both groups of women. HSP70 is positively associated with IR in women diagnosed with breast cancer. [ABSTRACT FROM AUTHOR]

Clear cell hidradenoma is a rare benign tumor of the breast, its origin and pathogenesis are controversial. We have experienced a case of breast clear cell hidradenoma with mastermind like transcriptional coactivator 2 (MAML2) gene rearrangement. The patient found a painless mass with a hard texture in the left breast areola without nipple discharge. Microscopically, the tumor was cystic and solid, locally arranged in a glandular structure, covered by single cuboidal cells; it was composed of clear cells, epidermoid cells, and basaloid cells; there were no necrosis or mitotic figures. Immunohistochemical staining showed that the tumor cells positively expressed low‐molecular cytokeratin 7, low‐molecular cytokeratins (Cam5.2), high‐molecular cytokeratin 5/6, cytokeratin 14, CD117, and p63; and did not express calponin, and smooth muscle myosin heavy chain. The cuboidal cells were positive for SOX10 but negative for p63. Additionally, periodic acid‐Schiff reaction showed purple‐red granules in the tumor cytoplasm, but Alcian blue staining showed no blue mucus in the cytoplasm. The split signals of MAML2 gene were detected by fluorescence in situ hybridization. Subtle histological and immunophenotypical differences may help to distinguish breast clear cell hidradenoma from common breast tumors. Furthermore, the MAML2 gene rearrangement may be a molecular genetic characteristic of breast clear cell hidradenoma. [ABSTRACT FROM AUTHOR]

Background: Older breast cancer survivors (BCS, age ≥ 65) are vulnerable to experiencing persistent symptoms and associated declines in health‐related quality of life (HRQOL). In research trials, cancer rehabilitation interventions (physical or occupational therapy, PT/OT) have been shown to enhance HRQOL, but the impact of community‐based PT/OT services for older BCS is unknown. We performed a retrospective, observational study to better understand the impact of PT/OT services on the HRQOL of older BCS. Methods: Outcomes and covariates were extracted from the outpatient rehabilitation medical record. HRQOL outcomes included: PROMIS® global physical health (GPH), global mental health (GMH), physical function (PF), and ability to participate in social roles and activities (SRA). Linear mixed‐effect models were used to examine change in HRQOL outcomes and explore the influence of patient age and service type (PT/OT). ICD‐10 codes were examined and compared between service types to describe the impairments treated. Results: PT/OT cases (N = 694) were 71.79 ± 5.44 years old and participated in a median of 11 visits (IQR: 7.0–17.25) over 9.71 weeks (IQR: 6.29–15.29). Most (84.4%) attended PT (n = 579; 84%) versus OT (n = 115; 16%). Overall, significant improvement was observed in each HRQOL outcome (GPH: +3.00, p < 0.001; GMH: +1.80, p < 0.001; PF: +1.97, p < 0.001; SRA: +2.34, p < 0.001). Service type influenced only GPH (p = 0.041); mean improvement was +3.24 (SE: 0.290, p < 0.001) for PT cases and + 1.78 for OT cases (SE: 0.651, p = 0.007). PT cases commonly received treatment for weakness/atrophy, pain, walking, and posture; OT cases commonly received treatment for lymphedema and scarring/fibrosis. No age effects were observed. Conclusions: In this large study of older BCS who participated in community‐based PT/OT services across the United States, we observed significant improvements in HRQOL outcomes that are important to older BCS and their providers. Although more research is needed, these findings suggest that improved access to PT/OT could help address unmet HRQOL needs among this population. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-positive breast cancer occurs in 15–30% of cases and has a poor prognosis. Digital image analysis of HER2 is promising, but its implementation in real clinical practice remains unclear. This systematic review evaluates the effectiveness of digital image analysis algorithms for HER2 in breast cancer and their performance, with a focus on testing them in real-world clinical settings. The authors aim to assess the applicability of these algorithms in practical clinical scenarios. By analyzing 25 papers from the period 2013–2024 and emphasizing mostly deep learning approaches, the review underscores the importance of standardized evaluation criteria, study designs tailored for clinical applications, and clinical validation. While direct evidence of clinical application was not found, the findings aim to guide future research and the implementation of digital image analysis in breast cancer diagnosis within clinical settings, potentially impacting the research community by advancing algorithmic applications in real clinical practice. This systematic review aims to address the research gap in the performance of computational algorithms for the digital image analysis of HER2 images in clinical settings. While numerous studies have explored various aspects of these algorithms, there is a lack of comprehensive evaluation regarding their effectiveness in real-world clinical applications. We conducted a search of the Web of Science and PubMed databases for studies published from 31 December 2013 to 30 June 2024, focusing on performance effectiveness and components such as dataset size, diversity and source, ground truth, annotation, and validation methods. The study was registered with PROSPERO (CRD42024525404). Key questions guiding this review include the following: How effective are current computational algorithms at detecting HER2 status in digital images? What are the common validation methods and dataset characteristics used in these studies? Is there standardization of algorithm evaluations of clinical applications that can improve the clinical utility and reliability of computational tools for HER2 detection in digital image analysis? We identified 6833 publications, with 25 meeting the inclusion criteria. The accuracy rate with clinical datasets varied from 84.19% to 97.9%. The highest accuracy was achieved on the publicly available Warwick dataset at 98.8% in synthesized datasets. Only 12% of studies used separate datasets for external validation; 64% of studies used a combination of accuracy, precision, recall, and F1 as a set of performance measures. Despite the high accuracy rates reported in these studies, there is a notable absence of direct evidence supporting their clinical application. To facilitate the integration of these technologies into clinical practice, there is an urgent need to address real-world challenges and overreliance on internal validation. Standardizing study designs on real clinical datasets can enhance the reliability and clinical applicability of computational algorithms in improving the detection of HER2 cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a major health concern worldwide, with mortality rates varying between ethnic groups. In Israel, Jewish and Muslim Arab women have different socioeconomic backgrounds and lifestyle factors that may influence breast cancer outcomes. This study investigates disparities in breast cancer mortality between these two groups and examines how factors such as number of children, socioeconomic status, and place of residence affect mortality rates. By analyzing data from over 800,000 Israeli women over a 30-year period, the researchers aim to understand the complex interplay among ethnicity, sociodemographic factors, and breast cancer mortality. The findings of this study could help identify key risk factors and protective elements specific to each ethnic group. This information is crucial for developing targeted intervention programs to reduce disparities and improve breast cancer outcomes for both Jewish and Muslim Arab women in Israel. Breast cancer mortality rates vary across ethnic groups in Israel, where protective factors such as high fertility and breastfeeding rates may be moderated by socioeconomic factors and mammography rates. We aim to investigate disparities in breast cancer mortality between Jewish and Muslim Arab women in Israel and examine how sociodemographic variables and number of children are associated with mortality. Our retrospective follow-up study uses data from the Israeli Central Bureau of Statistics and multivariable Cox regression models, adjusting for age, number of children, country of origin, locality size, and socioeconomic status. Compared to Jewish women, Muslim Arab women exhibited lower breast cancer mortality rates. However, after adjusting for multiple sociodemographic variables, no significant differences persisted between Jewish and Muslim Arab women. Having more than three children was associated with lower mortality among Muslim Arab women but not among Jewish women. European/American origin, larger localities, and medium socioeconomic status were associated with higher mortality. Sociodemographic factors may therefore explain the disparities in breast cancer mortality between Jewish and Muslim Arab women in Israel. Targeted intervention programs that consider the unique characteristics and risk factors of different ethnic groups are needed to reduce disparities and improve outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examines the relationship between subjective and objective measures of cognitive function and physical function, frailty, and quality of life (QoL) in older breast cancer survivors. Older breast cancer survivors who reported concerns participated in online surveys that included assessment of patient-reported cognitive function, physical function, frailty, and QoL. Participants then completed objective tests assessing visuospatial working memory and sustained attention. A total of 219 breast cancer survivors completed the study. Overall, older breast cancer survivors with higher perceived cognitive impairment reported poorer physical functioning, increased frailty, and poorer QoL (p ≤ 0.001). Poorer visuospatial working memory and sustained attention exhibited increased frailty (p ≤ 0.001–0.01); while poorer sustained attention was associated with poorer physical function (p < 0.01). The findings of this study suggest a need for a thorough assessment of cognitive concerns and their associated outcomes in older breast cancer survivors. Background: Older cancer survivors in general are at greater risk for cancer-related cognitive impairment (CRCI), yet few studies have explored its association with health outcomes. This study examined the association between subjective and objective measures of cognitive function and physical function, frailty, and quality of life (QoL) among older breast cancer survivors. Materials and Methods: Older breast cancer survivors who reported cognitive concerns completed surveys on patient-reported cognitive function, physical function, frailty, and QoL as well as objective tests of visuospatial working memory and sustained attention. Data were analyzed using descriptive statistics and separate linear regression models. Results: A total of 219 female breast cancer survivors completed the study. Perceived cognitive abilities were associated with better physical function, frailty, and QoL (p ≤ 0.001) while cognitive concerns were negatively related with these metrics (p ≤ 0.001). Poorer visuospatial working memory and sustained attention were linked to increased frailty (p ≤ 0.001–0.01), whereas poorer sustained attention was associated with poorer physical function (p < 0.01). Conclusions: Older breast cancer survivors with perceived cognitive impairment and poorer cognitive performance reported poorer physical functioning, increased frailty, and poorer QoL. These findings underscore the importance of assessing cognitive concerns and their associated outcomes in older breast cancer survivors. [ABSTRACT FROM AUTHOR]

Simple Summary: Aquaporins (AQPs) have emerged as potential predictors of response to cancer therapy and as targets for increasing sensitivity to treatment. However, systemic therapeutic inhibition using pan-AQP or AQP-specific inhibitors has not been characterized for efficacy in treating breast cancer or as a component of combination treatment. We evaluated AQP inhibition using established AQP inhibitors in cytotoxicity and pharmacologic assays. This study identified AQPs as a targetable vulnerability in breast cancer. AQP inhibitors can increase therapeutic efficacy, both as single agents and in a combination therapy strategy, in treating breast cancer progression and metastasis. These results provide significant insights that support the future development of improved AQP inhibitors. AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: The management of the axilla for post-mastectomy breast cancer patients who develop a chest wall recurrence (CWR) remains to be established. This study aimed to determine if omitting axillary staging surgery for these patients resulted in an increased risk of second recurrence. A total of 194 patients with CWR, with a median follow-up of 59.5 (IQR 27.3–105) months, were analysed. There was no statistically significant difference in second recurrences between patients with or without axillary surgery during the excision of the CWR. Background: The management of the axilla in breast cancer patients with isolated chest wall recurrence (CWR) after mastectomy remains controversial. Although sentinel lymph node biopsy (SLNB) for restaging is feasible, its role is unclear. We aimed to determine if the omission of axillary restaging surgery in female patients with operable presumably isolated CWRs could result in an increased risk of second recurrences. Methods: In this retrospective multicentre study, patients who developed CWRs were reviewed. We excluded patients with suspected or concomitant regional/distant metastases, bilateral cancers and patients without CWR surgery. Patients' demographics, pathological data and subsequent recurrences were collected from a prospective database and were compared between patients with axillary lymph node dissection (ALND) and/or SLNB versus no axillary operation at CWR. Findings: A total of 194 patients with CWRs were eligible. The median age at CWR was 56.0 (IQR 47.0–67.0) years old. At recurrence, 8 (4.1%), 5 (2.6%) and 181 (93.3%) patients had ALND, SLNB and no axillary operation, respectively. Patients with no axillary surgery during CWR were associated with, at primary cancer, a lower incidence of ductal carcinoma in situ as diagnosis (p = 0.007) and older age (p = 0.022). Subsequent ipsilateral axillary (p = 0.768) and second recurrences (p = 0.061) were not statistically different between patients with and without axillary surgery at CWR on median follow-up of 59.5 (IQR 27.3–105) months. Interpretation: In patients without evidence of concomitant regional or distant metastasis at CWR diagnosis, omission of axillary restaging surgery was not associated with an increased ipsilateral axillary or second recurrences on long-term follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone metastases represent a serious and common challenge in advanced cancer patients, making early detection crucial. The growing implementation of artificial intelligence (AI) in various medical fields is revolutionizing healthcare by enhancing diagnostic accuracy. This systematic review includes 59 articles and sought to assess the potential of machine learning models in the fields of nuclear medicine, clinical research, radiology, and molecular biology. The review provides a comprehensive analysis of AI's effectiveness in detecting bone metastases, which had not yet been thoroughly conducted. The findings highlight the benefits of integrating AI technologies in the inspected fields, encouraging further advancements and adoption of AI to ultimately improve patient care and treatment planning. This study provides invaluable perceptions into the promising application of computational intelligence in the detection of bone metastases, demonstrating its superiority over standard tests. However, further research is necessary to substantiate these findings with the aim of developing better-trained data-driven models soon. Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. Methods: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. Results: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. Conclusions: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved. [ABSTRACT FROM AUTHOR]

Simple Summary: The indications for neoadjuvant chemotherapy (NAT) have expanded in recent years both for locally advanced and early-stage breast cancer, with different pathological complete response (pCR) rates among different molecular subtypes. This retrospective two-center study aims to evaluate the diagnostic performance of Contrast-Enhanced Mammography (CEM) in assessing the response to NAT in breast cancer patients. The CEM sensitivity and specificity were 66.2% and 75.2%, with the highest specificity (80.9%) in HR+/HER2− and the highest sensitivity (70%) in triple-negative breast cancer. CEM is a valid tool to assess the pCR with different performances among the molecular subtypes and may be reliable in the decisional process of de-escalating surgical management. Neoadjuvant chemotherapy (NAT) plays a crucial role in breast cancer (BC) treatment, both in advanced BC and in early-stage BC, with different rates of pathological complete response (pCR) among the different BC molecular subtypes. Imaging monitoring is mandatory to evaluate the NAT efficacy. This study evaluates the diagnostic performance of Contrast-Enhanced Mammography (CEM) in BC patients undergoing NAT. This retrospective two-center study included 174 patients. The breast lesions were classified based on the molecular subtypes in hormone receptor (HR+)/HER2−, HER2+, and triple-negative breast cancer (TNBC). The histopathological analysis performed following surgery was used as a reference standard for the pCR. Sensitivity, specificity, PPV, and NPV were measured overall and for the different subtypes. We enrolled 174 patients, 79/174 (46%) HR+/HER2−, 59/174 (33.9%) HER2+, and 35/174 (20.1%) TNBC; the pCR was found in 64/174 (36.8%), of which 57.1% were TNBCs. In the total population, the CEM sensitivity and specificity were 66.2% and 75.2%, with a PPV of 61.4% and an NPV of 78.8%. The highest specificity (80.9%) and NPV (91.7%) were found in HR+/HER2−, while the highest sensitivity (70%) and PPV appeared (73.7%) in TNBC. The results indicate that CEM is a valid tool to assess the pCR, with different performances among the subtypes of BC. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a major global issue, ranking as the second most common cancer among women. Various factors such as genetics, epigenetics, obesity, sedentary lifestyle, tobacco use, and vitamin D deficiency have been implicated in its prevalence. Toll-like receptor 9 (TLR9) has emerged as a potential key factor, yet its role in breast cancer has not been fully explored. TLR9, a component of the innate immune system, recognizes unmethylated CpG motifs, thus initiating immune responses. Understanding TLR9 expression and function in breast tissue, particularly in distinguishing between normal and cancerous tissue, is crucial. This review examines the existing literature on TLR9 expression in both normal and cancerous breast tissue, aiming to identify knowledge gaps and enhance our understanding of TLR9's role in breast cancer. The ultimate goal is to enhance our understanding of TLR9's involvement in breast cancer pathogenesis, which could potentially lead to novel diagnostic markers or therapeutic targets, thereby improving patient outcomes and advancing breast cancer treatment strategies. Breast cancer is a significant global issue, ranking as the second most common cancer among women worldwide and a leading cause of cancer-related deaths. Although the exact causes of this increase remain unclear, factors such as genetics, epigenetics, obesity, sedentary lifestyle, tobacco use, and vitamin D deficiency have been implicated. The Toll-like receptor 9 (TLR9) is recognized for its role in inflammation and innate immunity; however, its specific involvement in breast cancer pathogenesis requires further investigation. This study aims to systematically review the existing literature on TLR9 expression in normal and cancerous breast tissue, providing current knowledge and identifying gaps. Relevant articles in English were from PubMed, Scopus, and Google Scholar, with the inclusion criteria focusing on studies evaluating TLR9 mRNA and protein expression. The review found that TLR9 mRNA and protein exhibit variable expressions in both normal and cancerous breast tissue, highlighting the need for further research to clarify TLR9's role in breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is discussed. We evaluated the impact of cALND omission on survival in breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 BC, the non-SN involvement rate was 13.2%. With a median follow-up of 66.46 months, multivariate analysis showed that cALND omission was significantly associated with overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly impacted by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative patients, DFS, OS, RFS, and MFS were also significantly affected (HR: 2.358, 3.317, 2.538, 2.756). For 161 patients ≤ 50 years with ER-positive/Her2-negative BC, OS and BCSS were notably associated with cALND omission (HR: 103.47 and 50.874). These findings suggest a negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated the survival impact of cALND omission in a cohort of breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 early BC patients (391 pN1mi, 163 ITC), the NSN involvement rate was 13.2% (49/371). With a median follow-up of 66.46 months, multivariate analysis revealed significant associations between cALND omission and overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly affected by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative BC, DFS, OS, recurrence-free survival (RFS), and MFS were significantly associated with cALND omission (DFS HR: 2.358, p = 0.043; OS HR: 3.317; RFS HR: 2.538; MFS HR: 2.756). For 161 patients aged ≤50 years with ER-positive/Her2-negative cancer, OS and breast cancer-specific survival (BCSS) were notably impacted by cALND omission (OS HR: 103.47, p = 0.004; BCSS HR: 50.874, p = 0.035). These findings suggest a potential negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Further randomized trials are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: The overexpression of c-MYC is implicated in many cancers, and it drives the tumors' aggressiveness and metastatic progression, but there is no clinically approved drug that targets MYC. We discovered that the MYC mRNA is stabilized by the poly U sequences on its 3′UTR. We engineered these stable elements into unstable forms in a way such that they degraded the target MYC mRNA through a process called nonsense-mediated decay. We developed the drug 3′UTRMYC1-18 and evaluated its therapeutic efficacy in a metastatic model of c-MYC-driven TNBC in vivo by delivering it with iron oxide nanocages. The constructs inhibited primary and metastatic lung and liver cancers by degrading the c-MYC-STAT5A/5B-PD-L1 complex and achieved significant survival outcomes. The in vivo data strongly suggests that this new drug is therapeutically effective in inhibiting c-MYC-driven triple-negative breast cancer and metastatic tumors. The drug was well tolerated and represents a new arsenal to target the deadly TNBC and will offer hope to patients who need it. c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most prevalent forms of cancer diagnosed in women worldwide. Since the estradiol receptor (ER) is overexpressed in 75% of breast tumors, it is a reasonable target for tumor diagnosis and therapy. This study focuses on the development and preclinical evaluation of readily synthesized 18F-labeled estradiol derivatives with different lipophilicity. The least hydrophilic derivative, 18F-TA-Glyco-EE, showed the highest cellular uptake in ER-positive breast cancer cells. The in vivo PET imaging of breast tumor-bearing mice demonstrated the desired rapid clearance of the tracer from the excretory organ through the liver. The in vitro autoradiography of ER-positive tumor sections confirmed the high specific binding of 18F-TA-Glyco-EE. In conclusion, 18F-TA-Glyco-EE may be a promising candidate for imaging of ER-positive breast cancer. About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[18F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER+) breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three 18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by 18F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER+ MCF-7 tumor cells was highest for the less hydrophilic derivative (18F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER+ MCF-7 and T47D versus ER− MDA-MB-231), 18F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of 18F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of 18F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of 18F-TA-Glyco-EE to ER+ tumor slices. We conclude that 18F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of HER2-inhibitors for the treatment of HER2-positive breast cancer represented a breakthrough in targeted tumor therapy. However, as for other targeted therapeutics, drug resistance remains a serious challenge to the treatment of HER2+ BC. Recent research has identified critical biomarkers for HER2-inhibitor resistance and explored more effective treatment regimens in HER2+ breast cancer to overcome drug resistance; however, research on several potential biomarkers and promising alternative therapies remains incomplete. HER2 (human epidermal growth factor receptor 2) is highly expressed in a variety of cancers, including breast, lung, gastric, and pancreatic cancers. Its amplification is linked to poor clinical outcomes. At the genetic level, HER2 is encoded by the ERBB2 gene (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), which is frequently mutated or amplified in cancers, thus spurring extensive research into HER2 modulation and inhibition as viable anti-cancer strategies. An impressive body of FDA-approved drugs, including anti-HER2 monoclonal antibodies (mAbs), antibody–drug conjugates (ADCs), and HER2-tyrosine kinase inhibitors (TKIs), have demonstrated success in enhancing overall survival (OS) and disease progression-free survival (PFS). Yet, drug resistance remains a persistent challenge and raises the risks of metastatic potential and tumor relapse. Research into alternative therapeutic options for HER2+ breast cancer therefore proves critical for adapting to this ever-evolving landscape. This review highlights current HER2-targeted therapies, discusses predictive biomarkers for drug resistance, and introduces promising emergent therapies—especially combination therapies—that are aimed at overcoming drug resistance in the context of HER2+ breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal receptors. This lack of receptors renders TNBC unsuitable for targeted-based treatment, making it the most fatal and aggressive subtype of breast cancer. TNBC has a greater relapse rate, worse prognosis, and increased metastasis rate compared to non-TNBC because of its tendency to resist apoptosis, a programmed cell death triggered by most chemotherapeutic drugs, producing anticancer efficacy. This work describes two new drugs, TPH104c, and TPH104m, that induce a non-apoptotic form of cell death in TNBC. The incubation of TNBC cells with TPH104c or TPH104m causes cellular expansion and rupture without producing apoptotic characteristics, such as nuclear fragmentation, apoptotic blebbing, or caspase activation. TPH104c and TPH104m decreased the mitochondrial protein, division regulator, and dynamin-related protein 1 (DRP1). The level of DRP1 in TNBC cells affects the magnitude of cytotoxicity produced by TPH104c and TPH104m. Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC. [ABSTRACT FROM AUTHOR]

Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis. [ABSTRACT FROM AUTHOR]

This study determined the relationship between death anxiety and COVID-19 related fear and anxiety in women with breast cancer. This is a descriptive correlation-seeking study. The research included 140 women with breast cancer who visit the day treatment unit of the oncology department of a state university hospital. Personal Information Form, Fear of COVID-19 Scale (FCV-19S), Coronavirus Anxiety Scale (CAS), and Death Anxiety Scale (DAS) were used to collect data. A significant difference was found between the DAS score and body mass index (p =.019) and between FCV-19S score and COVID-19 vaccination status (p =.007). As the fear of COVID-19 and coronavirus anxiety of women with breast cancer increase, death anxiety also increases. In conclusion, death anxiety should be taken into consideration for this patient group while maintaining the continuity of care for these patients now and in future pandemics. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the long-term outcomes of stage I breast cancer (BC) patients diagnosed during the current era of screening mammography, immunohistochemistry receptor testing, and systemic adjuvant therapy. Methods: A retrospective cohort study was conducted on 328 stage I BC patients treated consecutively in a single referral center with a follow-up period of at least 12 years. The primary endpoints were invasive disease-free survival (IDFS) and overall survival (OS). The influence of tumor size, grade, and subtype on the outcomes was analyzed. Results: Most patients were treated by lumpectomy, sentinel node biopsy, and adjuvant endocrine therapy, and most (82%) were of subtype luminal A. Adjuvant chemotherapy was administered to 25.6% of our cohort. Only 24 patients underwent gene expression testing, which was introduced toward the end of the study period. Mean IDFS was 14.64 years, with a 15-year IDFS of 75.6%. Mean OS was 15.28 years with a 15-year OS of 74.9%. In a Cox multivariate analysis, no clinical or pathologic variable impacted on OS and only tumor size (<1 cm vs. 1–2 cm) impacted significantly on IDFS. During follow-up, 20.1% of the cohort developed second primary cancers, including BC. The median time to diagnosis of a second BC was 6.49 years. Conclusion: The study results emphasize the importance of long-term follow-up and screening for subsequent malignancies of patients with stage I BC and support the need for using prognostic and predictive indicators beyond the routine clinicopathological characteristics in luminal A patients. [ABSTRACT FROM AUTHOR]

To use the bibliographic data of publications regarding the association between orofacial cleft (OC) and cancer to examine the implications of publication growth, co-citation, co-words, and authorship networks using bibliometric indicators and network visualization. Bibliometric study analyzed documents related to the association between OC and cancer. Data were obtained in October 2023 from the Scopus, Pubmed, Web of Science. The search strategy was developed, and data obtained were imported into R ("bibliometrix") for analysis. Results: 70 documents were found from 1977 to 2023. Most were journal articles (90.0%) designed as case–control studies (42.8%). American Journal of Epidemiology was the most relevant source. The most cited document was Frebourg T, et al. (2006). Vieira A, Martelli-Junior were the most cited author. Most authors were affiliated to Brazil (University of Montes Claros) and United States (University of Pittsburgh). Research in this thematic has included children and adults of both sexes. Research trend points to gastric cancer, leukemia and breast cancer as the most investigated cancers in association to OC. This bibliometric analysis helps fill research gaps regarding the knowledge of the relationship between OC and cancer, providing some clues for selecting future research in this topic. Analysis of publications regarding the association between orofacial cleft and cancer highlighted: The majority of publications as journal articles (90.0%) designed as case–control studies (42.8%). American Journal of Epidemiology was the most relevant source. The most global cited documents were Frebourg T, et al. (2006). Vieira A, Martelli-Junior was the top author of the published literature and the most local cited author. Most of the authors were mainly affiliated to Universities from Brazil (University of Montes Claros) and United States (University of Pittsburgh). Motor themes of study include genetic association studies, investigating single nucleotides polymorphisms shared by OC and cancer types. Research in this thematic has included children and adults of both sexes. Research trend points to gastric cancer, leukemia and breast cancer as the most investigated cancers in association to OC. [ABSTRACT FROM AUTHOR]

Context.--: The American Society of Clinical Oncology/College of American Pathologists 2018 update of the human epidermal growth factor receptor 2 (HER2) testing guideline includes a fluorescence in situ hybridization (FISH) group with a HER2 to chromosome 17 centromere (CEP17) ratio less than 2.0 and HER2 copy number 6.0 or greater (group 3), which requires integrated review of HER2 immunohistochemistry (IHC). Objective.--: To assess the clinicopathologic features of group 3 patients and determine features associated with HER2-positive status after workup. Design.--: Cases submitted for HER2 FISH between January 2019 and June 2022 were identified, and relevant clinicopathologic information was obtained. Results.--: One hundred forty-two HER2 FISH cases (1.6%) were group 3. In 52 cases (36.6%) IHC was negative (0/1+), in 3 (2.8%) IHC was positive (3+), and in 86 (60.6%) IHC was 2+. Annotated IHC 2+ slides were recounted by a second reviewer in targeted areas, where 16 of 86 (18.6%) had a HER2:CEP17 ratio less than 2.0 and a HER2 copy number of 4.0 or greater to less than 6.0 (HER2 negative). After combined IHC/FISH review, 74 of 142 (52.1%) were classified as HER2 positive. HER2 copy number/cell was higher in HER2-positive compared with HER2-negative cases after the workup. The extent and intensity of staining in IHC 2+ cases did not correlate with the level of gene amplification. Twenty percent of HER2-positive patients achieved pathologic complete response. Conclusions.--: About half of group 3 cases were classified as HER2 positive after additional workup. Pathologic complete response rates in HER2-positive cases were lower than expected for group 1 (HER2:CEP17 ratio ≥2.0; HER2 copy number ≥4.0) patients. IHC-targeted FISH recounts may be redundant and may potentially lead to classification of some patients as HER2 negative, resulting in withholding of targeted therapy. [ABSTRACT FROM AUTHOR]

Background To assess the amount of breast cancer overdiagnosis associated with the National Health Service Breast Screening Programme (NHSBSP) that started in 1988 in England. Methods First, numbers of breast cancers in women eligible for breast screening not attending screening were estimated for the period 1995–2019, which were extrapolated to all women. A second method was based on ratios of incidence rates of breast cancers in women aged 50–69 to women aged 70 years or more in 1971–1985. The ratio was used for estimating expected numbers of cancers in 1988–2019, and 1995–2019. Results From 1995 to 2019, 506,607 non-invasive and invasive breast cancers were diagnosed among women aged 50–64 years (1995–2001) and 50–70 years (2002–2019). A first method estimated that 95,297 cancers were in excess to the number of cancers that would be expected had the NHSBSP not existed. 42,567 screen-detected non-invasive and micro-invasive cancers represented 45.8% of the total excess cancer. 18.8% of all cancers diagnosed among women invited to screening, 25.1% of cancers found in women attending screening, and 35.1% of cancers detected by screening would represent overdiagnosis. A second method estimated that, 18.0% of all cancers diagnosed in 1988–2019, and 18.2% of all cancers diagnosed in 1995–2019 among women invited to screening would represent overdiagnosis. Conclusion The two independent methods obtained similar estimates of overdiagnosis. The NHS Breast Screening Programme in England is associated with substantial amount of overdiagnosis. [ABSTRACT FROM AUTHOR]

Background The recommendation for the implementation of mammography screening in women aged 45–49 and 70–74 is conditional with moderate certainty of the evidence. The aim of this study is to simulate the long-term outcomes (2020–50) of using different age range scenarios in the breast cancer screening programme of the Valencia Region (Spain), considering different programme participation rates. Methods Three age range scenarios (S) were simulated with the EU-TOPIA tool, considering a biennial screening interval: S1, 45–69 years old (y); S2, 50–69 y and S3, 45–74 y. Simulations were performed for four participation rates: A = current participation (72.7%), B = +5%, C = +10% and D = +20%. Considered benefits: number (N°) of in situ and invasive breast cancers (BC) (screen vs. clinically detected), N° of BC deaths and % BC mortality reduction. Considered harms: N° of false positives (FP) and % overdiagnosis. Results The results showed that BC mortality decreased in all scenarios, being higher in S3A (32.2%) than S1A (30.6%) and S2A (27.9%). Harms decreased in S2A vs. S1A (N° FP: 236 vs. 423, overdiagnosis: 4.9% vs. 5.0%) but also benefits (BC mortality reduction: 27.9% vs. 30.6%, N° screen-detected invasive BC 15/28 vs. 18/25). In S3A vs. S1A, an increase in benefits was observed (BC mortality reduction: 32.2% vs. 30.6%), N° screen-detected in situ B: 5/2 vs. 4/3), but also in harms (N° FP: 460 vs. 423, overdiagnosis: 5.8% vs. 5.0%). Similar trends were observed with increased participation. Conclusions As the age range increases, so does not only the reduction in BC mortality, but also the probability of FP and overdiagnosis. [ABSTRACT FROM AUTHOR]

Background The value equation of value-based healthcare (VBHC) as a single figure remains ambiguous, closer to a theoretical framework than a useful tool for decision making. The challenge lies in the way patient-centred outcomes (PCOs) might be combined to produce a single value of the numerator. This paper aims to estimate the weights of PCOs to provide a single figure in the numerator, which ultimately will allow a VBHC figure to be reached. Methods A cohort of patients diagnosed with breast cancer (n  = 690) with a 6-month follow-up recruited in 2019–20 across six European hospitals was used. Patient-reported outcomes (PROs), clinical-related outcomes (CROs), and clinical and socio-demographic variables were collected. The numerator was defined as a composite indicator of the PCOs (CI-PCO), and regression analysis was applied to estimate their weights and consequently arrive at a single figure. Results Pain showed as the highest weight followed by physical functioning , emotional functioning , and ability to work , and then by a symptom, either arm or breast. PCOs weights were robust to sensitivity analysis. The CI-PCO value was found to be more informative than the health-related quality of life (HRQoL) value. Conclusions To the best of our knowledge, this is the first research to combine the PCOs proposed by ICHOM to provide a single figure in the numerator of the value equation. This figure shows a step forward in VBHC to reach a holistic benchmarking across healthcare centres and a value-based payment. This research might also be applied in other medical conditions as a methodological pathway. [ABSTRACT FROM AUTHOR]

Breast cancer is especially prevalent among women. It can affect patients' sexual function, body image, and marital relations. The aim of present study was to investigate the relationship between body image and sexual function among women with breast cancer. This case–control study was done online on patients admitted to the clinic of breast cancer in 2021 in Jahrom, Iran. The sample consisted of 222 women (111 with breast cancer who had undergone mastectomy and 111 without breast cancer). To collect data, two questionnaires, female sexual function index and body image scale, were used. p < 0.05 was significant. Sexual dysfunction among women with breast cancer was 91%. The most common disorder was sexual arousal. Comparing sexual domains: desires disorder (OR: 3.11, 95% CI: 1.63–5.49), arousal disorder (3.31, 95% CI: 1.16–9.45), orgasm (OR: 4.08, 95% CI: 1.57–10.55), vaginal lubrication (OR: 2.68, 95% CI: 1.06–6.76), sexual satisfaction (OR: 2.65, 95% CI: 1.11–6.36), and painful intercourse (OR = 2.03 95% CI = 0.95–4.35) saw a decrease in the women with breast cancer group compared to the control group. The body image concern among women with breast cancer (51.56 ± 15.09) compared to the control (45.80 ± 16.82) was significant (OR = OR: 2.66, 95% CI: 1.22–5.81). Women with breast cancer undergo problems in sexuality and are afraid of their body image. Moreover, there is a correlation between sexuality and body image. Therefore, it is necessary to inform patients about the effects of treatments and the side effects of breast cancer on sexuality. Sexual dysfunctions are highly prevalent among women with breast cancer, and have been associated with body image. This study examined the relationship between body image and sexual function among women with breast cancer. Orgasm and libido, lubrication, and satisfaction decrease in women with breast cancer compared to healthy women. [ABSTRACT FROM AUTHOR]

Background: Although there is evidence that cognitive behavioral therapy (CBT)-based group interventions can improve quality of life (QoL) in women undergoing treatment for breast cancer (BC) little is known about factors that mediate and moderate these effects. We examined a) the mediating role of benefit finding on QoL changes after a Cognitive Behavioral Stress Management (CBSM) intervention, and b) whether this mediation effect differed based on baseline optimism in the first year following surgery for BC. Methods: We used data from a prior CBSM trial in 240 women with stage 0–3 BC who completed measures of benefit finding (Benefit Finding Scale, BFS), QoL (Functional Assessment of Cancer Treatment, FACT-G), and optimism (Life Orientation Test-Revised) at baseline (2 – 10 weeks post-surgery), 6-months and 12-months after randomization. CBSM-related changes and mediation and moderation effects were assessed using latent growth curve models. Results: We found CBSM increased benefit finding (b = 2.65, p < 0.01), emotional (b = 0.53, p < 0.01), and functional QoL (b = 0.71, p < 0.05) over time. CBSM-related changes in emotional QoL were mediated by increased benefit finding (indirect effect = 0.68, 95% bootstrapped CI: 0.17, 1.56) but only among participants with low to moderate optimism at baseline. Conclusion: CBSM intervention improved emotional QoL over the first year of breast cancer treatment by increasing benefit finding among women who reported low trait optimism suggesting those who will most likely benefit from improving benefit finding during this stressful period. [ABSTRACT FROM AUTHOR]

This quality improvement project implemented a nurse-led high-risk screening referral protocol for earlier identification of women at increased risk for breast cancer. The Breast Cancer Risk Assessment Tool was used at the mammography appointment, which led to improved electronic communication and significant increases in high-risk clinic consultations, breast magnetic resonance imaging, genetic counseling, and additional testing. Patients reported high satisfaction with advanced practice providers, which indicates increased comfort levels. [ABSTRACT FROM AUTHOR]

Metaphors are pervasive in cancer discourse. However, little is known about how metaphor use develops over time within the same patient, and how metaphor use and its content relate to the mental health of the patient. Here, we analyzed metaphor use in personal essays written by breast cancer patients shortly after the time of diagnosis and nine months later, in relation to their depressive symptoms at both time points. Results show that metaphor use can provide important insight into a patient's current mental state. Specifically, patients who had no change in their depressive symptom levels used metaphors more densely after nine months. In addition, metaphor valence in the later essay was associated with depressive symptoms at study entry and nine months after. Lastly, we observed a shift in metaphor reference pattern for different symptom trajectories, such that those who recovered from initially elevated depressive symptoms used fewer self-referencing metaphors and more cancer-referencing metaphors in their later essay. Our work suggests that metaphor use reflects how a patient is coping with their diagnosis. [ABSTRACT FROM AUTHOR]

Alcohol is a causal factor in about 10% of breast cancer (BCa) cases, but awareness of this link is low. This study explored how to raise awareness and inform the development of an intervention using the COM-B model (capability, opportunity, motivation, behavior) framework. Eight online focus groups were conducted with 36 participants (6 expert stakeholders,and 30 women aged 40–65). Participants reflected on a package of information about alcohol and BCa and discussed how to impart this information and encourage women to reduce drinking. Thematic analysis of focus group transcripts was undertaken. Three themes were identified: understanding ineffective messaging; transitions and challenges; and message acceptability. Current health information about alcohol was perceived as judgmental and BCa was put down to chance. Mid-life consisted of many challenges that could lead to increased consumption, but menopause transition may be a key moment for alcohol reduction. Barriers and enablers to communicating risk information and encouraging alcohol reduction were mapped onto the COM-B model. Psychological capability (relating to knowledge), social opportunity (in the form of social pressure) and automatic motivation (relating to drinking to cope) were barriers to behavior change. These will be targeted in an alcohol reduction intervention. It is important to tailor information to women's experiences, taking into account the social benefits of drinking, and encourage the development of healthy coping strategies. Acceptable intervention messages may include personal stories, clear statistics, and suggest healthy alternatives to drinking. It is vital that messaging does not appear judgmental or patronizing. [ABSTRACT FROM AUTHOR]

Aim: To obtain an in‐depth understanding of the lived experiences, values, and beliefs of Taiwanese women with breast cancer who withdrew from cancer treatment. Background: Fear of side effects, negative experiences and personal beliefs were identified as reasons for withdrawing from cancer treatments. Body–mind consciousness and body autonomy play a crucial role in cancer treatment decisions. Design: Descriptive phenomenological approach. Methods: We conducted semi‐structured, face‐to‐face and in‐depth interviews with 16 women diagnosed with breast cancer. Participants were purposefully selected from the Cancer Registry database. Employing a phenomenological approach, our aim was to explore the lived experiences of these individuals. Data analysis followed Giorgi's five‐step process. To ensure a comprehensive report the COREQ checklist was applied. Findings: 'The Determination to Preserve Me' is the essence of treatment withdrawal, identified by three themes and seven sub‐themes. 'Raising Body‐Mind Consciousness' was generated using body autonomy and preventing repeated psychological trauma from the participant's view. Their lifestyles, maintaining the family role, and returning to a normal trajectory help develop 'Maintaining Stability for Being a Patient and a Family Carer'. 'Self‐Defending Against the Body Harm' was generated by concerns about maintaining health and preventing harm. Conclusion: Women's behaviours became transformed by suffering. Actions were influenced by physical and psychological distress, misconceptions about treatments, and appearance changes by self‐determination through self‐protection. Relevance to clinical practice: Healthcare professionals should respect women's autonomy and work collaboratively to ensure their decision‐making with accurate information and awareness of the potential risks and benefits of treatment withdrawal need to concern. [ABSTRACT FROM AUTHOR]

Inhibiting breast cancer stem cell (BCSC) signaling pathways is a strategic method for successfully treating breast cancer. Nobiletin (NOB) is a compound widely found in orange peel that exhibits a toxic effect on various types of cancer cells, and inhibits the signaling pathways that regulate the properties of BCSCs; however, the effects of NOB on BCSCs remain elusive. The purpose of this study was to determine the target genes of NOB for inhibiting BCSCs using in vitro three-dimensional breast cancer cell culture (mammospheres) and in silico approaches. We combined in vitro experiments to develop mammospheres and conducted cytotoxicity, next-generation sequencing, and bioinformatics analyses, such as gene ontology, the Reactome pathway enrichment, network topology, gene set enrichment analysis, hub genes selection, genetic alterations, prognostic value related to the mRNA expression, and mRNA and protein expression of potential NOB target genes that inhibit BCSCs. Here, we show that NOB inhibited BCSCs in mammospheres from MCF-7 cells. We also identified CDC6, CHEK1, BRCA1, UCHL5, TOP2A, MTMR4, and EXO1 as potential NOB targets inhibiting BCSCs. NOB decreased G0/G1, but increased the G2/M cell population. These findings showed that NOB is a potential therapeutic candidate for BCSCs treatment by regulating cell cycle. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis of breast cancer. Thiostrepton exerts anti-tumor activities against several cancers including TNBC. Herein we discussed the new molecular mechanisms of thiostrepton in TNBC. Thiostrepton inhibited MDA-MB-231 cell viability, accompanied by a decrease of c-FLIP and p-SMAD2/3. c-FLIP overexpression reduced the sensitivity of MDA-MB-231 cells to thiostrepton, while SMAD2/3 knockdown increased the sensitivity of MDA-MB-231 cells to thiostrepton. Moreover, c-FLIP overexpression significantly increased the expression and phosphorylation of SMAD2/3 proteins and vice versa. In conclusion, our study reveals c-FLIP/SMAD2/3 signaling pathway as a novel mechanism of antitumor activity of thiostrepton. [ABSTRACT FROM AUTHOR]

Background: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. Methods: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. Results: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). Conclusions: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.) [ABSTRACT FROM AUTHOR]

Morning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 53-year-old woman with a history of breast cancer who presented with abnormal axillary lymph nodes detected on surveillance imaging. Using history, physical examination, and diagnostic workup, an illness script for her presentation emerges. A differential diagnosis is developed and refined until a final diagnosis is confirmed. [ABSTRACT FROM AUTHOR]