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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]

Background: The axillary lymph-node metastatic burden is closely associated with treatment decisions and prognosis in breast cancer patients. This study aimed to explore the value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT)–based radiomics in combination with ultrasound and clinical pathological features for predicting axillary lymph-node metastatic burden in breast cancer. Methods: A retrospective analysis was conducted and involved 124 patients with pathologically confirmed early-stage breast cancer who had undergone 18F-FDG PET/CT examination. The ultrasound, PET/CT, and clinical pathological features of all patients were analysed, and radiomic features from PET images were extracted to establish a multi-parameter predictive model. Results: The ultrasound lymph-node positivity rate and PET lymph-node positivity rate in the high nodal burden group were significantly higher than those in the low nodal burden group (χ2 = 19.867, p < 0.001; χ2 = 33.025, p < 0.001). There was a statistically significant difference in the PET-based radiomics score (RS) for predicting axillary lymph-node burden between the high and low lymph-node burden groups. (-1.04 ± 0.41 vs. -1.47 ± 0.41, t = -4.775, p < 0.001). The ultrasound lymph-node positivity (US_LNM) (odds ratio [OR] = 3.264, 95% confidence interval [CI] = 1.022–10.423), PET lymph-node positivity (PET_LNM) (OR = 14.242, 95% CI = 2.960–68.524), and RS (OR = 5.244, 95% CI = 3.16–20.896) are all independent factors associated with high lymph-node burden (p < 0.05). The area under the curve (AUC) of the multi-parameter (MultiP) model was 0.895, which was superior to those of US_LNM, PET_LNM, and RS models (AUC = 0.703, 0.814, 0.773, respectively), with statistically significant differences (Z = 2.888, 3.208, 3.804, respectively; p = 0.004, 0.002, < 0.001, respectively). Decision curve analysis indicated that the MultiP model provided a higher net benefit for all patients. Conclusion: A MultiP model based on PET-based radiomics was able to effectively predict axillary lymph-node metastatic burden in breast cancer. Trial registration: This study was registered with ClinicalTrials.gov (registration number: NCT05826197) on May 7, 2023. [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]

Purpose: Neuropilin-1 (NRP-1) is a multifunctional protein involved in a variety of biological processes such as angiogenesis, tumorigenesis and immunomodulation. It was usually overexpressed in many cancer cell lines and correlated with poor prognosis of breast cancer. Positron emission tomography (PET) is an advanced imaging technique for detecting the function and metabolism of tumor-associated molecules in real time, dynamically, quantitatively and noninvasively. To improve the level of early diagnosis and evaluate the prognosis of breast cancer, an NRP-1 targeting peptide-based tracer [68 Ga]Ga-NOTA-PEG4-CK2 was designed to sensitively and specifically detect the NRP-1 expression in vivo via PET imaging. Methods: In silico modeling and microscale thermophoresis (MST) assay were carried out to design the NRP-1 targeting peptide NOTA-PEG4-CK2, and it was further radiolabeled with 68 Ga to prepare the tracer [68 Ga]Ga-NOTA-PEG4-CK2. The radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), lipid-water partition coefficient (Log P) and stability of [68 Ga]Ga-NOTA-PEG4-CK2 were assessed. The targeting specificity of the tracer for NRP-1 was investigated by in vitro cellular uptake assay and in vivo PET imaging as well as blocking studies. The sensitivity of the tracer in monitoring the dynamic changes of NRP-1 expression induced by chemical drug was also investigated in vitro and in vivo. Ex vivo biodistribution, autoradiography, western blot, and immunofluorescence staining were also performed to study the specificity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1. Results: [68 Ga]Ga-NOTA-PEG4-CK2 was designed and synthesized with high RCY (> 98%), high stability (RCP > 95%) and high affinity to NRP-1 (KD = 25.39 ± 1.65 nM). In vitro cellular uptake assay showed that the tracer [68 Ga]Ga-NOTA-PEG4-CK2 can specifically bind to NRP-1 positive cancer cells MDA-MB-231 (1.04 ± 0.04% at 2 h) rather than NRP-1 negative cancer cells NCI-H1299 (0.43 ± 0.05%). In vivo PET imaging showed the maximum tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 in MDA-MB-231 xenografts (4.16 ± 0.67%ID/mL) was significantly higher than that in NCI-H1299 xenografts (1.03 ± 0.19%ID/mL) at 10 min post injection, and the former exhibited higher tumor-to-muscle uptake ratio (5.22 ± 0.18) than the latter (1.07 ± 0.27) at 60 min post injection. MDA-MB-231 xenografts pretreated with nonradioactive precursor NOTA-PEG4-CK2 showed little tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 (1.67 ± 0.38%ID/mL at 10 min post injection). Both cellular uptake assay and PET imaging revealed that NRP-1 expression in breast cancer MDA-MB-231 could be effectively suppressed by SB-203580 treatment and can be sensitively detected by [68 Ga]Ga-NOTA-PEG4-CK2. Ex vivo analysis also proved the high specificity and sensitivity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1 expression in MDA-MB-231 xenografts. Conclusion: A promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was successfully prepared. It showed remarkable specificity and sensitivity in monitoring the dynamic changes of NRP-1 expression. Hence, it could provide valuable information for early diagnosis of NRP-1 relevant cancers and evaluating the prognosis of cancer patients. A novel promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was developed based on a series of in vitro and in vivo investigations. The tracer showed remarkable specificity and sensitivity in detecting the expression of NRP-1. It could be applied for noninvasively and dynamically monitoring the NRP-1 expression in tumors and predicting the prognosis of breast cancer. [ABSTRACT FROM AUTHOR]

Machine‐learning algorithms have the potential to revolutionise diagnostic and prognostic tasks in health care, yet algorithmic performance levels can be materially worse for subgroups that have been underrepresented in algorithmic training data. Given this epistemic deficit, the inclusion of underrepresented groups in algorithmic processes can result in harm. Yet delaying the deployment of algorithmic systems until more equitable results can be achieved would avoidably and foreseeably lead to a significant number of unnecessary deaths in well‐represented populations. Faced with this dilemma between equity and utility, we draw on two case studies involving breast cancer and melanoma to argue for the selective deployment of diagnostic and prognostic tools for some well‐represented groups, even if this results in the temporary exclusion of underrepresented patients from algorithmic approaches. We argue that this approach is justifiable when the inclusion of underrepresented patients would cause them to be harmed. While the context of historic injustice poses a considerable challenge for the ethical acceptability of selective algorithmic deployment strategies, we argue that, at least for the case studies addressed in this article, the issue of historic injustice is better addressed through nonalgorithmic measures, including being transparent with patients about the nature of the current epistemic deficits, providing additional services to algorithmically excluded populations, and through urgent commitments to gather additional algorithmic training data from excluded populations, paving the way for universal algorithmic deployment that is accurate for all patient groups. These commitments should be supported by regulation and, where necessary, government funding to ensure that any delays for excluded groups are kept to the minimum. We offer an ethical algorithm for algorithms—showing when to ethically delay, expedite, or selectively deploy algorithmic systems in healthcare settings. [ABSTRACT FROM AUTHOR]

Background Many studies have examined patient-related factors affecting adjuvant hormone therapy adherence in patients with breast cancer. Our study aimed to examine associations of family-related factors with adjuvant hormone therapy discontinuation and breast cancer–specific mortality. Methods By cross-linking 7 Swedish health registers, we performed a cohort study that included all patients with breast cancer who initiated adjuvant hormone therapy during 2006-2019 in Sweden (N = 10 701). A group-based multitrajectory model was used to identify familial adversity groups based on 3 dimensions: material deprivation, negative family dynamics, and loss or threat of loss. Cox proportional hazard models were used to investigate associations of familial adversity with hormone therapy discontinuation and breast cancer–specific mortality. Results We identified 5 distinctive familial adversity groups among the cohort participants. Compared with women who had low familial adversity, higher risks to discontinue adjuvant hormone therapy were observed among women with material deprivation (hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.20 to 1.43), negative family dynamics (HR = 1.16, 95% CI = 1.06 to 1.28), loss or threat of loss (HR = 1.15, 95% CI = 1.00 to 1.32), or high familial adversity (HR = 1.53, 95% CI = 1.40 to 1.68). Furthermore, women with material deprivation (HR = 1.37, 95% CI = 1.05 to 1.79), negative family dynamics (HR = 1.41, 95% CI = 1.01 to 1.97), or high adversity (HR = 1.67, 95% CI = 1.26 to 2.23) were at higher risk of dying from breast cancer. Conclusion Familial adversity is associated with a higher risk of adjuvant hormone therapy discontinuation and breast cancer–specific mortality. Family-related factors identified in our study may help identify high-risk patients for interventions to prevent treatment discontinuation and subsequently improve breast cancer outcomes. [ABSTRACT FROM AUTHOR]

Evidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. A retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients' age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. 56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0–132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3–28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5–158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. There are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities. • This study reported SABR treatment outcomes for multisite OM and OP diseases originating from metastatic breast cancer • It showed modest local control and post-treatment toxicities on the SABR of extracranial OM and OP from metastatic breast cancer. • The types of follow-up imaging, OM vs OP, oestrogen receptor status, and number of metastases for SABR can be used as PFS prognostic factors. [ABSTRACT FROM AUTHOR]

Simple Summary: The manual assessment and identification of tumor-associated macrophages (TAMs) with a single marker limits a thorough analysis of their spatial distribution and density. We applied a digital workflow to compare the features of TAM populations identified by CD163 and CD206 and showed that these markers highlighted TAM populations with distinct clinical implications. The spatial distribution of CD163 TAMs and their interactions with tumor-infiltrating lymphocytes (TILs) refined the prognostic value in breast cancer. Conversely, CD206 TAMs may not have any unfavorable prognostic impact. Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors (p = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis (p = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) (p = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, p = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, p = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Hereditary breast cancer represents a significant proportion of breast cancer cases worldwide, and BRCA1 and BRCA2 explain the majority of these. Less frequent genes with variable penetrance remain less characterized in Colombia. This study explores the characteristics and outcomes of 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Instituto Nacional de Cancerología, Colombia (INC-C) from 2018 to 2021 as part of an Institutional Hereditary Cancer Program implementation. We described the distribution of germline PVs among the different breast cancer molecular subtypes in this cohort of carriers. We observed that most PVs were in known breast cancer susceptibility genes, and PVs in BRCA2 were the most frequent. Notably, we observed that patients with disease progression were predominantly carriers of PVs in the BRCA2 gene. This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. This study looked for markers in breast cancer cells linked to glutamine metabolism, an important fuel source for cancer cells. It found a protein called TRIM2 to be highly expressed alongside a key glutamine metabolism enzyme in TNBC. High levels of TRIM2 were linked to a worse chance of spread of cancer to distant sites. This association was particularly strong in patients who received chemotherapy. These findings suggest TRIM2 could be a valuable prognostic marker for TNBC patients, especially those undergoing chemotherapy. Further research is needed to understand how TRIM2 functions and its connection to glutamine metabolism in breast cancer. Background: Breast cancer (BC) remains heterogeneous in terms of prognosis and response to treatment. Metabolic reprogramming is a critical part of oncogenesis and a potential therapeutic target. Glutaminase (GLS), which generates glutamate from glutamine, plays a role in triple-negative breast cancer (TNBC). However, targeting GLS directly may be difficult, as it is essential for normal cell function. This study aimed to determine potential targets in BC associated with glutamine metabolism and evaluate their prognostic value in BC. Methods: The iNET model was used to identify genes in BC that are associated with GLS using RNA-sequencing data. The prognostic significance of tripartite motif-containing 2 (TRIM2) mRNA was assessed in BC transcriptomic data (n = 16,575), and TRIM2 protein expression was evaluated using immunohistochemistry (n = 749) in patients with early-stage invasive breast cancer with long-term follow-up. The associations between TRIM2 expression and clinicopathological features and patient outcomes were evaluated. Results: Pathway analysis identified TRIM2 expression as an important gene co-expressed with high GLS expression in BC. High TRIM2 mRNA and TRIM2 protein expression were associated with TNBC (p < 0.01). TRIM2 was a predictor of poor distant metastasis-free survival (DMFS) in TNBC (p < 0.01), and this was independent of established prognostic factors (p < 0.05), particularly in those who received chemotherapy (p < 0.05). In addition, TRIM2 was a predictor of shorter DMFS in TNBC treated with chemotherapy (p < 0.01). Conclusions: This study provides evidence of an association between TRIM2 and poor patient outcomes in TNBC, especially those treated with chemotherapy. The molecular mechanisms and functional behaviour of TRIM2 and the functional link with GLS in BC warrant further exploration using in vitro models. [ABSTRACT FROM AUTHOR]

The presence of autoantibodies is closely associated with the occurrence and development of cancer. Autoantibodies can be used as biomarkers for early breast cancer diagnosis. However, the relationship between autoantibodies and the prognosis of breast cancer patients remains elusive. This retrospective study aimed to investigate the correlation between the presence of autoantibodies and outcomes in breast cancer patients. This study included a total of 155 patients from People's Hospital of Henan University (Zhengzhou, China) who were diagnosed with breast cancer from January 2017 to December 2021. The enrolled patients' clinicopathological features were collected, and 88 patients were ultimately involved in the analysis. Univariate and multivariate Cox regression analyses were performed to search for the risk factors related to the poor prognosis of breast cancer patients. The association between the presence of autoantibodies and patients' survival was analysed using Kaplan–Meier curves. After screening, there were 38 autoantibody‐positive cases and 50 autoantibody‐negative cases. Breast cancer patients with autoantibody‐positive had a 57% lower risk of death compared with autoantibody‐negative patients. Multivariate Cox regression analysis indicated that the presence of autoantibody could be a potential prognostic predictor for breast cancer, independent of age, histological grade, pathological classification, clinical stage, and the expression levels of hormonal receptors. In addition, autoantibody‐positive breast cancer patients had longer progression‐free survival and overall survival compared with autoantibody‐negative cases. Positive autoantibody was found as an independent biomarker of better prognosis in breast cancer patients, providing a new strategy for the prognostic assessment of breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. Methods: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). Results: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52–6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06–4.51) and non-obese (HR = 2.11, 95% CI = 1.05–4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. Conclusions: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between the Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors. [ABSTRACT FROM AUTHOR]

Basal‐like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer with worse prognosis and fewer treatment options. The underlying mechanisms upon BLBC transcriptional dysregulation and its upstream transcription factors (TFs) remain unclear. Here, among the hyperactive candidate TFs of BLBC identified by bioinformatic analysis, POU4F1 is uniquely upregulated in BLBC and is associated with poor prognosis. POU4F1 is necessary for the tumor growth and malignant phenotypes of BLBC through regulating G1/S transition by direct binding at the promoter of CDK2 and CCND1. More importantly, POU4F1 maintains BLBC identity by repressing ERα expression through CDK2‐mediated EZH2 phosphorylation and subsequent H3K27me3 modification in ESR1 promoter. Knocking out POU4F1 in BLBC cells reactivates functional ERα expression, rendering BLBC sensitive to tamoxifen treatment. In‐depth epigenetic analysis reveals that the subtype‐specific re‐configuration and activation of the bivalent chromatin in the POU4F1 promoter contributes to its unique expression in BLBC, which is maintained by DNA demethylase TET1. Together, these results reveal a subtype‐specific epigenetically activated TF with critical role in promoting and maintaining BLBC, suggesting that POU4F1 is a potential therapeutic target for BLBC. [ABSTRACT FROM AUTHOR]

Accurate survival prediction is a critical goal in the prognosis of breast cancer patients because it can help physicians make more patient-friendly decisions and further guide appropriate treatment. Breast cancer is often caused by genetic abnormalities, which prompts researchers to consider information such as gene expression and copy number variation in addition to clinical data in their studies. The integration of these multi-modal data can improve the predictive power of models. However, with the highly unbalanced information of breast cancer patient data, it becomes a new challenge for breast cancer patient survival prediction to fully extract the characteristic information of these multi-modal data and to consider the complementarity of this information. To this end, we propose a deep multi-modal fusion network (DMMFN) to predict the five-year survival of breast cancer patients by integrating clinical data, copy number variation data, and gene expression data. The imbalanced dataset is first processed using the oversampling method SMOTE-NC. Then the abstract modal features of the multi-modal data are extracted by the two-layer one-dimensional convolutional neural network and the bi-directional long short-term memory network. Next, the weight coefficients of each modal data are dynamically adjusted using gated multimodal units to obtain fusion features. Finally, the fusion features are fed into the MaxoutMLP classifier to obtain the final prediction results. We conducted experiments on the METABRIC dataset to verify the validity of the multi-modal data and compared it with other methods. The comprehensive performance evaluation shows that DMMFN has better prediction performance. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasive lobular carcinoma represents a distinct histological type of breast cancer, characterised by morphological, genetic, and behavioural differences from other types. However, the behaviour of invasive lobular carcinomas is not uniform, and some tumours show poor outcome. This may attribute to the presence of aggressive variants. Therefore, we performed detailed investigation of a large series of cases to characterise this aggressive subtype of invasive lobular carcinoma. This subtype, which includes the pleomorphic and high-grade solid variants accounts for 14% of lobular carcinomas. It showed associations with unfavourable prognostic features, poor patient outcomes, and poor response to therapy when compared to classic lobular carcinoma and invasive ductal carcinoma of no special type. Background: Invasive lobular carcinoma (ILC), the most common special type of breast cancer (BC), has unique clinical behaviour and is different from invasive ductal carcinoma of no special type (IDC-NST). However, ILC further comprises a diverse group of tumours with distinct features. This study aims to examine the clinicopathological and prognostic features of different variants of ILC, with a particular focus on characterising aggressive subtypes. Methods: A large (n = 7140) well-characterised and histologically reviewed BC cohort with treatment and long-term follow-up data was investigated. The cohort was classified based on the WHO classification of tumours into main histological subtypes, including ILC and IDC-NST. ILCs were further classified into variants. Clinicopathological parameters and patient outcomes in terms of BC-specific survival (BCSS) and disease-free survival (DFS) were evaluated. Results: ILC constituted 11% of the cohort. The most common non-classic ILC variants were pleomorphic (pILC) and solid (sILC), constituting 19% of ILC. Compared to classic and related variants (alveolar, trabecular, papillary, and tubulolobular; cILC), pILC and sILC variants were associated with aggressive tumour characteristics. The histologic grade of ILC was an important prognostic variable. The survival patterns identified an aggressive ILC subtype encompassing pILC and high-grade sILC. These tumours, which comprised 14% of the cases, were associated with clinicopathological characteristics of poor prognosis and had high BC-specific death and recurrence rates compared not only to cILC (p < 0.001) but also to IDC-NST (p = 0.02) patients. Contrasting this, cILC patients had significantly longer BCSS and DFS than IDC-NST patients in the first 10 to 15 years of follow-up. Adjuvant chemotherapy did not improve the outcome of patients with aggressive ILC subtypes. Conclusions: pILC and high-grade sILC variants comprise an aggressive ILC subtype associated with poor prognostic characteristics and a poor response to chemotherapy. These results warrant confirmation in randomised clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite recent advancements in experimental technology for genome-wide molecular profiling, our understanding of the dynamic mechanism underlying cancer drug resistance remains limited. In this study, we present an approach that combines mathematical modeling with the pseudotime analysis of single-cell time-series transcriptome data of drug-treated breast cancer cells. Our method identifies approximately 600 genes out of 6000 exhibiting multistable expression states, including RPS6KB1, a predictor of poor prognosis, cell survival, and growth in estrogen-receptor-positive breast cancers. The bifurcation analysis elucidates the regulatory mechanisms of the key regulatory genes, which can also be mapped into a molecular network based on cell survival and metastasis-related pathways, providing a comprehensive understanding of the interplay between signaling pathways and regulatory genes. Our method serves as a powerful tool for deciphering the complexities of drug resistance mechanisms in human diseases. Single-cell RNA-sequencing (scRNA-seq) technology has provided significant insights into cancer drug resistance at the single-cell level. However, understanding dynamic cell transitions at the molecular systems level remains limited, requiring a systems biology approach. We present an approach that combines mathematical modeling with a pseudotime analysis using time-series scRNA-seq data obtained from the breast cancer cell line MCF-7 treated with tamoxifen. Our single-cell analysis identified five distinct subpopulations, including tamoxifen-sensitive and -resistant groups. Using a single-gene mathematical model, we discovered approximately 560–680 genes out of 6000 exhibiting multistable expression states in each subpopulation, including key estrogen-receptor-positive breast cancer cell survival genes, such as RPS6KB1. A bifurcation analysis elucidated their regulatory mechanisms, and we mapped these genes into a molecular network associated with cell survival and metastasis-related pathways. Our modeling approach comprehensively identifies key regulatory genes for drug resistance acquisition, enhancing our understanding of potential drug targets in breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-Hispanic Black breast cancer survivors have poorer outcomes than White survivors, but the biological mechanisms underlying these disparities are unclear. We discovered novel race-based differences in systemic DNA damage and repair activity among breast cancer survivors. This finding suggests DNA damage and repair are important basic science mechanisms in cancer disparities. Non-Hispanic Black breast cancer survivors have poorer outcomes and higher mortality rates than White survivors, but systemic biological mechanisms underlying these disparities are unclear. We used circulating leukocytes as a surrogate for measuring systemic mechanisms, which might be different from processes in the target tissue (e.g., breast). We investigated race-based differences in DNA damage and repair, using a novel CometChip assay, in circulating leukocytes from breast cancer survivors who had completed primary cancer therapy and were cancer free. We observed novel race-based differences in systemic DNA damage and repair activity in cancer survivors, but not in cells from healthy volunteers. Basal DNA damage in leukocytes was higher in White survivors, but Black survivors showed a much higher induction after bleomycin treatment. Double-strand break repair activity was also significantly different between the races, with cells from White survivors showing more sustained repair activity compared to Black leukocytes. These results suggest that cancer and cancer therapy might have long-lasting effects on systemic DNA damage and repair mechanisms that differ in White survivors and Black survivors. Findings from our preliminary study in non-cancer cells (circulating leukocytes) suggest systemic effects beyond the target site, with implications for accelerated aging-related cancer survivorship disparities. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic triple-negative breast cancer is an aggressive cancer with an average survival of 8 to 13 months. However, survival varies significantly among patients. We studied a large group of women in the National Cancer Database to better understand these survival differences. We found that the key factors influencing survival were comorbidity score (overall health status), histology (cancer subtype), number of metastatic sites (extent of cancer spread), and whether or not they received chemotherapy or immunotherapy. Our study's findings can help better predict survival based on an individual's specific factors and guide treatment strategies. Background: Metastatic triple-negative breast cancer (TNBC) is aggressive with poor median overall survival (OS) ranging from 8 to 13 months. There exists considerable heterogeneity in survival at the individual patient level. To better understand the survival heterogeneity and improve risk stratification, our study aims to identify the factors influencing survival, utilizing a large patient sample from the National Cancer Database (NCDB). Methods: Women diagnosed with metastatic TNBC from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, and treatment data and overall survival (OS) outcomes were collected. Kaplan–Meier curves were used to estimate OS. The log-rank test was used to identify OS differences between groups for each variable in the univariate analysis. For the multivariate analysis, the Cox proportional hazard model with backward elimination was used to identify factors affecting OS. Adjusted hazard ratios and 95% confidence intervals are presented. Results: In this sample, 2273 women had a median overall survival of 13.6 months. Factors associated with statistically significantly worse OS included older age, higher comorbidity scores, specific histologies, higher number of metastatic sites, presence of liver or other site metastases in those with only one metastatic site (excluding brain metastases), presence of cranial and extra-cranial metastases, lack of chemotherapy, lack of immunotherapy, lack of surgery to distant sites, lack of radiation to distant sites, and receipt of palliative treatment to alleviate symptoms. In the multivariate analysis, comorbidity score, histology, number of metastatic sites, immunotherapy, and chemotherapy had a statistically significant effect on OS. Conclusions: Through NCDB analysis, we have identified prognostic factors for metastatic TNBC. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future clinical trials. [ABSTRACT FROM AUTHOR]

Purpose. Breast cancer is a heterogeneous disease. Exploring new prognostic and therapeutic targets in patients with breast cancer is essential. This study investigated the expression of MET, ESR1, and ESR2 genes and their association with clinicopathologic characteristics and clinical outcomes in patients with breast cancer. Methods. The METABRIC dataset for breast cancer was obtained from the cBioPortal public domain. Gene expression data for MET, ESR1, and ESR2, as well as the putative copy number alterations (CNAs) for MET were retrieved. Results. The MET mRNA expression levels correlated inversely with the expression levels of ESR1 and positively with the expression levels of ESR2 (r = −0.379, p < 0.001 and r = 0.066, and p = 0.004 , respectively). The ESR1 mRNA expression was significantly different among MET CNAs groups p < 0.001 . Patients with high MET/ESR1 coexpression had favorable clinicopathologic tumor characteristics and prognosticators compared to low MET/ESR1 coexpression in terms of greater age at diagnosis, reduced Nottingham Prognostic Index, lower tumor grade, hormone receptor positivity, HER2-negative status, and luminal subtype p < 0.001 . In contrast, patients with high MET/ESR2 coexpression had unfavorable tumor features and advanced prognosticators compared to patients with low MET/ESR2 coexpression p < 0.001 . No significant difference in overall survival was observed based on the MET/ESR coexpression status. However, when data were stratified based on the treatment type (chemotherapy and hormonal therapy), survival was significantly different based on the coexpression status of MET/ESR. Conclusions. Findings from our study add to the growing evidence on the potential crosstalk between MET and estrogen receptors in breast cancer. The expression of the MET/ESR genes could be a novel prognosticator and calls for future studies to evaluate the impact of combinational treatment approaches with MET inhibitors and endocrine drugs in breast cancer. [ABSTRACT FROM AUTHOR]

Background: Developing countries have a significantly higher incidence of breast cancer in patients younger than 40 years as compared to developed countries. This study aimed to examine if young age at diagnosis is an independent prognostic factor for worse survival outcomes in breast cancer as well as the effect of age on Disease-free survival (DFS) and local recurrence free survival (LRFS) after adjusting for various tumor characteristics, local and systemic treatments. Methods: This is a secondary analysis of prospective cohort of patients from two existing databases. We identified patients with breast cancer aged 40 years or less and we matched them to those older than 40 years. We also matched based on stage and molecular subtypes. In cohort 1, we matched at a ratio of 1:1, while in cohort 2 we matched at a ratio of 1:3. Results: In cohort 1, Disease-free survival (DFS) at 5 years was significantly shorter for those younger than 40 years (75.6% and 92.7% respectively; p < 0.03). On multivariate analysis, only chemotherapy was found to be significant, while age was not found to be an independent predictor of prognosis. Local recurrence free survival at 5 years was similar between both age categories. Only hormonal therapy is a significant predictor for LRFS at 5 years. In the second cohort, DFS and LRFS at 3 years were similar between those younger and those older than 40 years. On multivariate analysis, no factor including age was found to be an independent predictor of prognosis. Conclusion: Data in the literature is controversial on the effect of young age on breast cancer prognosis. Our findings could not demonstrate that age is an independent prognostic factor in our population. There is a need for outcomes from larger, prospective series that have longer follow-ups and more data from our region. [ABSTRACT FROM AUTHOR]

Breast cancer screening programmes frequently detect early, good prognosis breast cancers with significant treatment burden for patients, and associated health-cost implications. Emerging evidence suggests a role for minimally invasive techniques in the management of these patients enabling many women to avoid surgical intervention. Minimally invasive techniques include vacuum-assisted excision, cryoablation, and radiofrequency ablation. We review published evidence in relation to the risks and benefits of each technique and discuss ongoing trials. Data to date are promising, and we predict a trend towards minimally invasive treatment for early, good-prognosis breast cancer as technical skills, suitability criteria, and follow-up protocols are established. [ABSTRACT FROM AUTHOR]

Ferroptosis and apoptosis are key cell‐death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron‐dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis‐to‐apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA‐assaociated protein 1(PDAP1), is found to suppress basal‐like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)‐stress and phosphatidylethanolamine (PE)‐to‐phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer is the most common and deadly female cancer. In breast cancer cases, survival is closely related to muscle mass, which is one of the components of body composition. Our aim was to investigate the usefulness of computed-tomography (CT)-based pectoral muscle measurements in detecting sarcopenia in patients with non-metastatic breast cancer and the relationship of these measurements with survival. Patients and Methods: Our study included 62 adult female breast cancer cases diagnosed with breast cancer between January 2012 and January 2018 and without metastasis in positron emission tomography/CT (PET/CT) examination obtained for pre-treatment staging. To evaluate sarcopenia, skeletal muscle index (SMI) and pectoral muscle index (PMI) were calculated by measuring pectoral muscle area and skeletal muscle area at L3 vertebra level on PET/CT images. Results: Deceased patients were significantly older (Median=73.90, IQR=27.04) than surviving patients (Median=54.60, IQR=13.37, p=0.025) and were diagnosed with cancer later in life (Median=63.92 IQR=30.16' vs. Median=47.51 IQR=15.0, p=0.030). When the threshold of 31 cm2/m2 was selected, there was a statistically significant difference in survival between sarcopenic and non-sarcopenic groups (p=0.031). Conclusion: In conclusion, the presence of sarcopenia in female breast cancer cases is a parameter that affects survival and can be measured using radiological imaging methods. In addition to the measurements accepted in the literature regarding sarcopenia, pectoral muscle measurements can be chosen as an alternative method in the diagnosis of sarcopenia. [ABSTRACT FROM AUTHOR]

According to the World Health Organization, breast cancer became the most common cancer in the world in 2020 and accounted for 685,000 deaths globally. In this article, breast cancer risk factors, considerations for genetic testing for BRCA1 and BRCA2 variants, signs and symptoms, and treatment are briefly discussed. Factors that impact the well-being and quality of life of women who have or have had breast cancer are also explored in depth, and practice implications for primary care providers are noted. According to the World Health Organization, breast cancer became the most common cancer in the world in 2020 and accounted for 685,000 deaths globally. In this article, breast cancer risk factors, considerations for genetic testing, signs and symptoms, and treatment are briefly discussed. Factors that impact the well-being and quality of life of women who have or have had breast cancer are also explored in depth, and practice implications for primary care providers are noted. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we investigated the effectiveness of the targeted cancer medication CDK4/6 inhibitors, in patients with breast cancer. These medicaments have been used for nearly a decade, but how well they work can vary greatly from one patient to another. By examining the experiences of 86 patients over a period from November 2016 to May 2020, we aimed to understand what factors might predict better or worse outcomes for patients. We discovered that certain characteristics, like the level of the progesterone receptor in the tumor and whether the cancer had spread to multiple locations or the liver, played a significant role in how long patients benefited from treatment without progression. The study also found that management characteristics during treatment could significantly affect patient outcomes. These insights are crucial for developing personalized management strategies that could lead to better outcomes for people with breast cancer. Background: The quest to comprehend the real-world efficacy of CDK4/6 inhibitors (CDKis) in breast cancer continues, as patient responses vary significantly. Methods: This single-center retrospective study evaluated CDKi use outside the trial condition from November 2016 to May 2020. Progression-free survival (PFS), time-to-treatment failure (TTF), short-term and prolonged treatment benefit (≥4 and ≥10 months), as well as prognostic and predictive markers were assessed with Kaplan–Meier and multivariate regression analyses. Results: Out of 86 identified patients, 58 (67.4%) had treatment failure of which 40 (46.5%) were due to progression. Median PFS and TTF were 12 and 8.5 months, respectively. A total of 57 (66.3%) and 42 (48.8%) patients experienced short-term and prolonged treatment benefit. Independent, significant predictors for PFS were progesterone receptor expression (HR: 0.88), multiple metastatic sites (HR: 2.56), and hepatic metastasis (HR: 2.01). Significant predictors for TTF were PR expression (HR: 0.86), multiple sites (HR: 3.29), adverse events (HR: 2.35), and diabetes (HR: 2.88). Aside from tumor biology and adverse events, treatment modifications like pausing and switching of CDKi were predictive for short-term (OR: 6.73) and prolonged (OR: 14.27) therapeutic benefit, respectively. Conclusions: These findings emphasize the importance of tailored treatment strategies, highlighting the role of PR expression, metastatic burden, and therapeutic adjustments in optimizing patient outcomes in real-world breast cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: Although women 70 years of age and older represent a large percentage of newly diagnosed breast cancer cases, older individuals are drastically underrepresented in clinical trials. Most women diagnosed with breast cancer at 70 years of age and older present with hormone receptor-positive (HR+) breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy has become the standard of care for metastatic HR+ breast cancer. This study reports that metastatic breast cancer patients ≥70 years of age receiving CDK4/6 inhibitor-based treatment, particularly when combined with an aromatase inhibitor, experience prolonged progression-free survival but display no such prolongation in overall survival and report more frequent adverse effects to treatment. The reported findings can aid in the development of optimized treatments based on age and help older patients weigh treatment options. The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but effective biomarkers has yet been developed. Here, we identified ATP1A1 as prognostic marker and therapeutic target via integrated analysis of DNA methylome and transcriptome of TNBC. These data will provide new insight into not only developing specific biomarker for TNBC but also understanding TNBC pathogenesis. Dysregulated DNA methylation in cancer is critical in the transcription machinery associated with cancer progression. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, but no treatment targeting TNBC biomarkers has yet been developed. To identify specific DNA methylation patterns in TNBC, methyl-binding domain protein 2 (MBD) sequencing data were compared in TNBC and the three other major breast cancer subtypes. Integrated analysis of DNA methylation and gene expression identified a gene set showing a correlation between DNA methylation and gene expression. ATPase Na+/K+-transporting subunit alpha 1 (ATP1A1) was found to be specifically hypomethylated in the coding sequence (CDS) region and to show increased expression in TNBC. The Cancer Genome Atlas (TCGA) database also showed that hypomethylation and high expression of ATP1A1 were strongly associated with poor survival in patients with TNBC. Furthermore, ATP1A1 knockdown significantly reduced the viability and tumor-sphere formation of TNBC cells. These results suggest that the hypomethylation and overexpression of ATP1A1 could be a prognostic marker in TNBC and that the manipulation of ATP1A1 expression could be a therapeutic target in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiplex digital spatial profiling is a newly emerging approach for investigating multiple RNA transcripts and proteins simultaneously in the context of intact tissue. This review describes the different spatial technologies for the study of breast cancer, providing examples of their applicability in research and clinical settings to guide diagnosis and prognosis and to inform treatment decisions. While RNA sequencing and multi-omic approaches have significantly advanced cancer diagnosis and treatment, their limitation in preserving critical spatial information has been a notable drawback. This spatial context is essential for understanding cellular interactions and tissue dynamics. Multiplex digital spatial profiling (MDSP) technologies overcome this limitation by enabling the simultaneous analysis of transcriptome and proteome data within the intact spatial architecture of tissues. In breast cancer research, MDSP has emerged as a promising tool, revealing complex biological questions related to disease evolution, identifying biomarkers, and discovering drug targets. This review highlights the potential of MDSP to revolutionize clinical applications, ranging from risk assessment and diagnostics to prognostics, patient monitoring, and the customization of treatment strategies, including clinical trial guidance. We discuss the major MDSP techniques, their applications in breast cancer research, and their integration in clinical practice, addressing both their potential and current limitations. Emphasizing the strategic use of MDSP in risk stratification for women with benign breast disease, we also highlight its transformative potential in reshaping the landscape of breast cancer research and treatment. [ABSTRACT FROM AUTHOR]

To look for links between diffusion and IVIM parameters and different molecular subtypes and prognostic factors through histogram analysis. A total of 139 patients with breast cancer who had pre-operative MRI examinations were enrolled in this retrospective study. Histograms of the diffusion and IVIM parameters were analyzed for the whole tumor, and an association was investigated between the parameters and the different molecular prognostic factors and subtypes using the nonparametric test, Spearman's rank correlation, and receiver operating characteristic (ROC) curve. The histogram metrics of the diffusion and IVIM parameters were significantly different for molecular prognostic factors such as human epidermal receptor factor-2 (HER2), progesterone receptor, estrogen receptor, and ki-67. All histogram metrics displayed a poor correlation with all groups (r = −0.28-0.29). There were significant differences in the histogram metrics for the Luminal B-HER2 (−) vs. HER2-positive (non-luminal) subtypes in the mean and 10th percentile D, with the area under the curves (AUCs) of 0.742 and 0.700, respectively, and for the Luminal A and HER2-positive (non-luminal) subtypes in the 90th percentile and entropy of D*, with AUCs of 0.769 and 0.727, respectively. The histogram metrics of IVIM parameters exhibited links with breast cancer prognosis factors and combined subtypes. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer. Methods: We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed. Results: Gap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta‐2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta‐2 are rare in breast cancer. The gap junction beta‐2 transcription level in the p110α subunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type subgroup. Gap junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells. Conclusions: Gap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The two major histological subtypes of breast cancer are ductal and lobular cancers. Histology impacts the biological behavior of breast cancer, so it is imperative to study its influence on the overall survival of breast cancer patients. The existing literature reports conflicting conclusions regarding the impact that histology might have on survival, so we aimed to study a large sample of patient data obtained from the National Cancer Database to determine if histology and several other clinical factors have an impact on the survival of early-stage breast cancer patients who have T1–T2 tumors, are clinically node-negative and have no metastatic activity. These results may help clinicians better understand the behaviors of different subtypes of breast cancer and will help them take a more tailored approach to breast cancer treatment. Histology is an important predictor of the behavior of breast cancer. We aim to study the impact of histology on the overall survival (OS) of breast cancer patients. We studied 11,085 breast cancer patients diagnosed with T1–T2 tumors, clinically node-negative and non-metastatic, from 2004 to 2019 included in the National Cancer Database. Kaplan–Meier curves, log-rank tests and Cox regression models were used to study the impact of histology and other variables on OS. In our patient population, 8678 (78.28%) had ductal cancer (IDC), while 2407 (21.71%) had lobular cancer (ILC). ILC patients were significantly more likely to be older, Caucasian, have a lower grade at diagnosis and be hormone receptor-positive compared to IDC patients. There was no statistically significant difference in the 5-year OS of early stage ductal (16.8%) and lobular cancer patients (16.7%) (p = 0.200). Patients of Hispanic and African American origin had worse OS rates compared to non-Hispanic and Caucasian patients, respectively. For node-positive disease, HER2+ tumors and triple-negative tumors, chemotherapy had a positive influence on OS (HR 0.85, 95% CI 0.77–0.93, p = 0.0012). Histology did not have a significant impact on the 5-year OS of early stage breast cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) ranks as among the top two commonly diagnosed cancers in women worldwide. Triple-negative breast cancer (TNBC) is recognized globally as the most lethal subtype of BC, with patients often building resistance to conventional chemotherapy treatments. This study assesses the relationship between taxane-based chemotherapy resistance in BC and the oncoprotein epithelial membrane protein 2 (EMP2), with an emphasis on the aggressive TNBC group. Analyses of preclinical models and human tissue samples reveal that EMP2 may not only be used to predict patient response to taxanes but also serve as a therapeutic target for resistant disease. Our findings demonstrate a correlation between elevated EMP2 expression post-chemotherapy and reduced survival outcomes and reveal that targeting EMP2 in conjunction with chemotherapy yields a synergistic reduction in TNBC tumor volume. Thus, results shed light on a novel biomarker for guiding the personalized, targeted treatment of intractable and recurrent TNBC. Breast cancer (BC) remains among the most commonly diagnosed cancers in women worldwide. Triple-negative BC (TNBC) is a subset of BC characterized by aggressive behavior, a high risk of distant recurrence, and poor overall survival rates. Chemotherapy is the backbone for treatment in patients with TNBC, but outcomes remain poor compared to other BC subtypes, in part due to the lack of recognized functional targets. In this study, the expression of the tetraspan protein epithelial membrane protein 2 (EMP2) was explored as a predictor of TNBC response to standard chemotherapy. We demonstrate that EMP2 functions as a prognostic biomarker for patients treated with taxane-based chemotherapy, with high expression at both transcriptomic and protein levels following treatment correlating with poor overall survival. Moreover, we show that targeting EMP2 in combination with docetaxel reduces tumor load in syngeneic and xenograft models of TNBC. These results provide support for the prognostic and therapeutic potential of this tetraspan protein, suggesting that anti-EMP2 therapy may be beneficial for the treatment of select chemotherapy-resistant TNBC tumors. [ABSTRACT FROM AUTHOR]

Women around the world are most frequently afflicted with breast cancer, and it is one of the most frequent causes of cancer death in females. Breast cancer is usually classified according to biomarker status, triple‐negative breast cancer (TNBC) represents a distinct subtype characterized by immunohistochemical findings that denote negativity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her-2) on cancer tissue. It is more common in younger women than in other subtypes. As an invasive breast cancer subtype with a unique drug-resistant phenotype and metastatic burden, it has limited treatment options, and patients have a poor prognosis with high rates of local, distant recurrence and mortality, and there is still a lack of standardized treatment protocols for TNBC. In this review, we delve into the current treatment strategies for TNBC and explore the potential for new approaches and targets in the future. This trial is registered with NCT03997123. [ABSTRACT FROM AUTHOR]

OBJECTIVE Breast carcinoma (BC) is the most common cancer in women, and, in particular, some subtypes are established as suitable for immunotherapy strategies targeting immune checkpoints. Programmed cell death-1 (PD-1), as well as cytotoxic T lymphocyte-associated protein-4 (CTLA-4), has an important role in the tumor microenvironment to escape from the immune system. In this study, we examined the relationship of Programmed cell death-1 (PD-L1) expression with survival, recurrence, and other prognostic factors. METHODS This retrospective cohort comprised tissue microarray blocks of 391 cases examined at the same institute between 2000-2012. All cases were completely resected tumors, without neoadjuvant therapy, with more than 5 years of follow-up. Clinical follow-up and all pathologic parameters were recorded. PD-L1 immunohistochemistry (SP263) was applied, then staining details including density, percentage, and patterns were noted for tumor areas and immune cells. PD-L1 expression results were analyzed, and its relationship with prognostic parameters and survival was investigated. RESULTS PD-L1 expression was detected in 90 (24.8%) cases: 55 in only tumor-infiltrating lymphocytes (TILs), 35 in both tumor and TILs. Statistically, there was no significant relationship between PD-L1 expression and survival. However, high histologic grade, high scores in pleomorphism and mitosis, mild stromal reaction, dense immune cell infiltration, perineural invasion, absence of lymph node metastasis, negativity of ER and PR, HER2 expression, and high Ki-67 results had a significant relationship with PD-L1 expression. CONCLUSION Consistent with the literature, our results showed that PD-L1 expression in triple-negative and HER2 overexpressed types and in the presence of TILs is higher than in other breast cancers. [ABSTRACT FROM AUTHOR]

Background: pregnancy-associated breast cancer (PABC) affects one in 3000 pregnancies, often presenting with aggressive features. Methods: We retrospectively evaluated a cohort of 282 young BC patients (≤45 years old) treated between 1995 and 2019, dividing them into three groups: nulliparous women, women with PABC (diagnosed within 2 years since last pregnancy) and women with BC diagnosed > 2 years since last pregnancy. This last group was further stratified according to the time between pregnancy and BC. The analysis encompassed histological factors (tumor size, histotype, grading, nodal involvement, multifocality, lympho-vascular invasion, hormone receptor expression, Ki-67 index, and HER2 expression), type of surgery and recurrence. Results: Age at diagnosis was younger in nulliparous than in parous women (p < 0.001). No significant differences were noticed regarding histological characteristics and recurrences. At univariate analysis, nodal involvement (OR = 2.4; p < 0.0001), high tumor grade (OR = 2.6; p = 0.01), and lympho-vascular invasion (OR = 2.3; p < 0.05), but not pregnancy (OR = 0.8; p = 0.30), influenced DFS negatively. Multivariate analysis confirmed nodal involvement as the only negative independent prognostic factor for a worse DFS (OR = 2.4; p = 0.0001). Conclusions: in our experience, pregnancy is not an independent adverse prognostic factor for BC DFS. [ABSTRACT FROM AUTHOR]

BACKGROUND: The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011 or Z11) trial demonstrated no survival advantage with completion axillary lymph node dissection (ALND) for patients with T1-2 breast cancer, 1 to 2 positive SLNs who received adjuvant chemoradiation therapy. More than 70% of the cohort had estrogen receptor (ER)+ tumors. There is paucity of data on the adherence rate to Z11, as well as a dearth of data on the applicability of Z11 for the different subtypes. We conducted a large hospital-based study to evaluate the adherence rate to Z11 based on subtypes. STUDY DESIGN: The National Cancer Database was queried to evaluate 33,859 patients diagnosed with T1-2, N1, and M0 breast cancer treated with lumpectomy with negative margins, and adjuvant chemoradiation therapy between 2012 and 2018. Patients were classified into 3 groups: (1) ER+/HER2-, (2) ER-/HER2-, and (3) HER2+ regardless of ER status. The revised Scope of the Regional Lymph Node Surgery 2012 was used to classify patients into those who underwent an SLN or ALND. Differences in use of ALND by subtypes were compared. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS). A p value of <0.05 was considered statistically significant. RESULTS: For ER+/human epidermal growth factor receptor 2 (HER2)-, ER-/HER2-, and HER2+ tumors, the rate of ALND was 43.6%, 50.2%, and 47.8%, respectively. The 5-year OS for SLN and ALND for the entire cohort was 94.0% and 93.1% (p = 0.0004); for ER+/HER2-, it was 95.4% and 94.7% (p = 0.04); for ER-/HER2-, it was 84.1% and 84.3% (p = 0.41); for HER2+, it was 94.2% and 93.2% (p = 0.20). Multivariable cox proportional hazard regression analysis demonstrated no significant survival differences between SLN and ALND (p = 0.776). CONCLUSIONS: Z11 is applicable for women with early N1 disease, regardless of subtypes. ALND did not confer a survival advantage over SLN. Despite this, up to 50% of patients who fit Z11 criteria continue to undergo ALND. [ABSTRACT FROM AUTHOR]

Blood cell biomarkers, such as the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR), have been recently used as prognostic markers in tumors. In this study, we investigated the association between NLR and PLR with sociodemographic, clinical, anthropometric, and quality of life factors of hospitalized women with non-metastatic breast cancer. A cross-sectional observational study was conducted at a reference center for oncological treatment in Southeast Brazil. Female participants aged over 18 years, with a histopathological diagnosis of stage I, II or III breast cancer, in any phase of antineoplastic treatment, were included. Our study revealed a high risk for participants, with high mean values of NLR and PLR, indicating low antitumor activity and worse prognosis. The binary logistic regression model showed that there was a significant association of the NLR marker and marital status (OR = 3.1; 95%CI = 1.06-8.57; p = 0.03) and, in relation to PLR, a trend was shown for a higher chance in women of black ethnicity to have increased PLR compared to white women (OR = 4.13; 95%CI = 0.96-17.70; p = 0.05). However, the inflammatory markers (NLR and PLR) did not show any significant association with nutritional factors. NLR and PLR are inflammatory biomarkers that can be easily obtained and measured in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Despite the relatively high cure rates in early-stage breast cancer, advanced and metastatic breast cancer cases are associated with more inauspicious patient outcomes. Fortunately, with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors (e.g. palbociclib, ribociclib, and abemaciclib) with endocrine therapy, survival in advanced and metastatic breast cancer has appreciably improved. In the current review, we discuss these distinctions and the concomitant implications associated with the individual CDK4/6 inhibitors. Data sources: We conducted an extensive PubMed search comprising several review articles on the topic of advanced or metastatic breast cancer treatment, with specific terms that included CDK4/6 inhibitors, treatment, and breast cancer. Data summary: Palbociclib, ribociclib, and abemaciclib have exhibited superior progression-free survival differences compared to endocrine therapy alone. However, there are differences among the various CDK4/6 inhibitors with regard to overall survival, tolerability and quality of life. Conclusions: Ribociclib may be indicated for pre/perimenopausal patients, whereas abemaciclib is potentially recommended to address endocrine-resistant or visceral disease. Alternatively, palbociclib is associated with lower discontinuation rates than abemaciclib and unlike ribociclib, QTc prolongation is not observed with palbociclib. [ABSTRACT FROM AUTHOR]

The biological behavior and prognosis of breast cancer is often unpredictable with a number of factors contributing to the outcome. Nottingham's Prognostic Factor (NPI) takes into account the tumor size, nodal status, and histological grade of tumor. The receptor status considers the hormone receptor and HER2 status. The aim of the study was to correlate the NPI score with the receptor status expression in Indian women with breast cancer. A total of 78 breast cancer patients who underwent upfront modified radical mastectomy were recruited. NPI score and receptor status assessment was done at histopathological examination of the specimen. Hormone receptor negative breast cancer tended to have a higher NPI score compared to hormone receptor positive patients. However, this difference did not achieve statistical significance. NPI score parameters except for the histological grade are a reflection of the duration or time span of the tumor. On the contrary, the receptor status is indicative of the tumor biology and not of its time duration. A scoring system which incorporates the three parameters of the NPI as well as the receptor status would be the best prognostic index as well as predictive regarding the choice of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer affects one out of every eight women worldwide. Although the Nottingham Prognostic Index (NPI) is an important tool for forecasting, its accuracy remains a matter of contention. The Src protein, which has been linked to cancer proliferation and metastasis, may provide improved prognostic information. Aim: The aim of the study was to investigate the relationship between Src expression levels and the NPI in breast cancer patients. Methods: From January 2019 to December 2022, breast cancer samples were collected retrospectively. Immunohistochemistry was used to quantify Src expression, followed by digital image analysis using ImageJ software. To assure consistency, expression levels were standardized to a control protein. The samples were then stratified according to their NPI scores, and t-test was used to determine the relationship between Src expression and NPI. P <0.05 was considered statistically significant. Results: Src expression demonstrated a wide range across the 60 samples analyzed. Although there were no significant associations between Src expression and age, tumor size, or lymphovascular invasion, there was a significant correlation between the NPI and Src expression (P = 0.046). Conclusion: Increased Src expression frequently indicated a worse prognosis. Despite the absence of significant correlations with conventional factors, the study discovered a crucial relationship between NPI and Src expression. [ABSTRACT FROM AUTHOR]

Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer. Methods: We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people's Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan–Meier method and further analyzed with multivariate analysis. Results: Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes. Conclusion: The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer among women. Metaplastic breast carcinoma is a rare, heterogeneous group of invasive breast carcinomas that are more aggressive, poorly responsive to neoadjuvant chemotherapy, and have higher rates of chemoresistance than most other breast tumors. This article aims to provide an overview and summary of the current knowledge regarding the translational aspects of metaplastic breast carcinoma that could open the possibility of discovering specific treatment targets and knowing prognostic factors. Breast cancer is the most common cancer among women. Metaplastic breast carcinoma (MpBC) is a rare, heterogeneous group of invasive breast carcinomas, which are classified as predominantly triple-negative breast carcinomas (TNBCs; HR-negative/HER2-negative). Histologically, MpBC is classified into six subtypes. Two of these are considered low-grade and the others are high-grade. MpBCs seem to be more aggressive, less responsive to neoadjuvant chemotherapy, and have higher rates of chemoresistance than other TNBCs. MpBCs have a lower survival rate than expected for TNBCs. MpBC treatment represents a challenge, leading to a thorough exploration of the tumor immune microenvironment, which has recently opened the possibility of new therapeutic strategies. The epithelial–mesenchymal transition in MpBC is characterized by the loss of intercellular adhesion, downregulation of epithelial markers, underexpression of genes with biological epithelial functions, upregulation of mesenchymal markers, overexpression of genes with biological mesenchymal functions, acquisition of fibroblast-like (spindle) morphology, cytoskeleton reorganization, increased motility, invasiveness, and metastatic capabilities. This article reviews and summarizes the current knowledge and translational aspects of MpBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is recognized as the most common cancer within the female population. In this context, cholesterol is recognized as a vital component for the proliferation and survival of cancer cells. These cells primarily acquire cholesterol through the receptor-mediated uptake from external sources, including low-density lipoprotein (LDL), utilizing the endocytosis pathway. Thus, this observational study aimed to test the effectiveness of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in cancer onset. Although PCSK9 correlated with lipid parameters (e.g., cholesterol, LDL) and with 17 β-estradiol, our results do not portend PCSK9 is a prognostic biomarker, at least, in the context of breast neoplastic events. Background and aim: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. Methods: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. Results: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170–252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999–1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = −0.305), maintained even after partial adjustment for BMI and age (r = −0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. Conclusions: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant therapy, which reduces advanced breast tumours before surgery, is common in medical practice. However, accurately mapping lymph nodes post-therapy is challenging and affects staging accuracy. One solution is marking the affected lymph nodes in the armpit before therapy, then removing the marked nodes during surgery via targeted axillary dissection (TAD), which combines standard sentinel lymph node biopsy (SLNB) with pre-neoadjuvant marked lymph node biopsy (MLNB). Radar reflector localisation (RRL) is a promising technology for locating tumours. Our study found that using RRL in TAD is reliable and accurate. This reduces the need for extensive armpit surgery in responsive patients, minimising surgical complications and improving their quality of life without compromising cancer outcomes. SAVI SCOUT® or radar reflector localisation (RRL) has proven accurate in localising non-palpable breast and axillary lesions, with minimal interference with MRI. Targeted axillary dissection (TAD), combining marked lymph node biopsy (MLNB) and sentinel lymph node biopsy (SLNB), is becoming a standard post-neoadjuvant systemic therapy (NST) for node-positive early breast cancer. Compared to SLNB alone, TAD reduces the false negative rate (FNR) to below 6%, enabling safer axillary surgery de-escalation. This systematic review evaluates RRL's performance during TAD, assessing localisation and retrieval rates, the concordance between MLNB and SLNB, and the pathological complete response (pCR) in clinically node-positive patients post-NST. Four studies (252 TAD procedures) met the inclusion criteria, with a 99.6% (95% confidence [CI]: 98.9–100) successful localisation rate, 100% retrieval rate, and 81% (95% CI: 76–86) concordance rate between SLNB and MLNB. The average duration from RRL deployment to surgery was 52 days (range:1–202). pCR was observed in 42% (95% CI: 36–48) of cases, with no significant migration or complications reported. Omitting MLNB or SLNB would have under-staged the axilla in 9.7% or 3.4% (p = 0.03) of cases, respectively, underscoring the importance of incorporating MLNB in axillary staging post-NST in initially node-positive patients in line with the updated National Comprehensive Cancer Network (NCCN) guidelines. These findings underscore the excellent efficacy of RRL in TAD for NST-treated patients with positive nodes, aiding in accurate axillary pCR identification and the safe omission of axillary dissection in strong responders. [ABSTRACT FROM AUTHOR]

Simple Summary: An important component in the study of survival in breast cancer patients is how the tumor is detected. This involves examining whether and to what extent survival differs when the tumor is detected, for example, by screening or by symptoms. In such an analysis, it is important to note that survival times are influenced by several biases. One important factor is the bias due to the so-called lead time, i.e., the time by which the diagnosis has been brought forward by screening. Therefore, survival may appear to be longer even if earlier diagnosis did not affect disease progression. We examine whether there is a remaining survival difference after correction for bias that could be attributable to the mode of detection, for example, because of higher quality of care. These results can then be used to further improve the survival of breast cancer patients. (1) Background: Screen-detected breast cancer patients tend to have better survival than patients diagnosed with symptomatic cancer. The main driver of improved survival in screen-detected cancer is detection at earlier stage. An important bias is introduced by lead time, i.e., the time span by which the diagnosis has been advanced by screening. We examine whether there is a remaining survival difference that could be attributable to mode of detection, for example, because of higher quality of care. (2) Methods: Women with a breast cancer (BC) diagnosis in 2000–2022 were included from a population-based cancer registry from Schleswig-Holstein, Germany, which also registers the mode of cancer detection. Mammography screening was available from 2005 onwards. We compared the survival for BC detected by screening with symptomatic BC detection using Kaplan–Meier, unadjusted Cox regressions, and Cox regressions adjusted for age, grading, and UICC stage. Correction for lead time bias was carried out by assuming an exponential distribution of the period during which the tumor is asymptomatic but screen-detectable (sojourn time). We used a common estimate and two recently published estimates of sojourn times. (3) Results: The analysis included 32,169 women. Survival for symptomatic BC was lower than for screen-detected BC (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.21–0.25). Adjustment for prognostic factors and lead time bias with the commonly used sojourn time resulted in an HR of 0.84 (CI: 0.75–0.94). Using different sojourn times resulted in an HR of 0.73 to 0.90. (4) Conclusions: Survival for symptomatic BC was only one quarter of screen-detected tumors, which is obviously biased. After adjustment for lead-time bias and prognostic variables, including UICC stage, survival was 27% to 10% better for screen-detected BC, which might be attributed to BC screening. Although this result fits quite well with published results for other countries with BC screening, further sources for residual confounding (e.g., self-selection) cannot be ruled out. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant treatment refers to therapy given before surgery for early-stage breast cancer. It has several benefits, especially for patients with specific subtypes like HER2+ and triple-negative cancers. By using neoadjuvant treatment, tumors can shrink before surgery, allowing for less invasive surgical procedures in the breast and axilla. Achieving complete tumor disappearance after neoadjuvant treatment is associated with better survival outcomes. Researchers studied 92 patients initially diagnosed with node-positive disease. A key finding is that patients with HER2+ and triple-negative subtypes who have achieved complete tumor disappearance in the breast have a higher chance of achieving complete tumor disappearance in the axilla, which allows for less aggressive axillary surgery. In this study, more than half the patients did not need a removal of all the nodes in the axilla. In summary, neoadjuvant treatment improves outcomes, reduces surgical morbidity, and benefits patients with HER2+ and triple-negative subtypes. Neoadjuvant systemic treatment (NST) is the standard treatment for HER2+, triple-negative (TN), and highly proliferative luminal HER2− early breast cancer. Pathologic complete response (pCR) after NST is associated with improved outcomes. We evaluated the predictive factors for axillary-pCR (AXpCR) and its impact on the extent of axillary node surgery. This retrospective study included 92 patients (median age of 50.4 years) with an initially node-positive disease. Patients were treated with molecular subtype-specific NST (4.3% were luminal A-like, 28.3% luminal HER2−, 26.1% luminal HER2+, 18.5% HER2+ non-luminal, and 22.8% TN). Axillary-, breast- and total-pCR were achieved in 52.2%, 48.9%, and 38% of patients, respectively. In a binary logistic regression model for the whole population, the only independent factor significantly associated with AXpCR was breast-pCR (OR 7.4; 95% CI 2.6–20.9; p < 0.001). In patients who achieved breast-pCR, aggressive subtypes (HER2+ and TN; OR 11.24) and clinical tumor stage (OR 0.10) had a significant impact on achieving AXpCR. Axillary lymph node dissection was avoided in 53.3% of patients. In conclusion, in node-positive patients with HER2+ and TN subtypes, who achieved breast-pCR after NST, de-escalation of axillary surgery could be considered in most cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a significant global health challenge, ranking as the second leading cause of death worldwide. Current treatment modalities, such as invasive surgery and chemotherapy, while effective to some extent, pose notable risks to patient well-being. High-intensity focused ultrasound (HIFU) offers a non-invasive alternative, utilizing precise acoustic energy for targeted tumor ablation while sparing surrounding healthy tissues. However, HIFU's efficacy depends on various factors, necessitating comprehensive research for optimization. The research focuses on in vitro thermal ablation of epithelial breast cancer cell lines, exploring the impact of HIFU on both 2D monolayer and 3D spheroidal cell configurations. The investigation assesses ultrasound parameters, including acoustic intensity, duty cycle, and sonication duration, evaluating their influence on temperature elevation and tumor cell ablation. Empirical findings are compared with numerical simulations, contributing to a deeper understanding of HIFU's potential in breast cancer treatment and paving the way for more effective therapeutic strategies. High-intensity focused ultrasound (HIFU) is a non-invasive therapeutic modality that uses precise acoustic energy to ablate cancerous tissues through coagulative necrosis. In this context, we investigate the efficacy of HIFU ablation in two distinct cellular configurations, namely 2D monolayers and 3D spheroids of epithelial breast cancer cell lines (MDA-MB 231 and MCF7). The primary objective is to compare the response of these two in vitro models to HIFU while measuring their ablation percentages and temperature elevation levels. HIFU was systematically applied to the cell cultures, varying ultrasound intensity and duty cycle during different sonication sessions. The results indicate that the degree of ablation is highly influenced by the duty cycle, with higher duty cycles resulting in greater ablation percentages, while sonication duration has a minimal impact. Numerical simulations validate experimental observations, highlighting a significant disparity in the response of 2D monolayers and 3D spheroids to HIFU treatment. Specifically, tumor spheroids require lower temperature elevations for effective ablation, and their ablation percentage significantly increases with elevated duty cycles. This study contributes to a comprehensive understanding of acoustic energy conversion within the biological system during HIFU treatment for 2D versus 3D ablation targets, holding potential implications for refining and personalizing breast cancer therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer patients whose tumor has already developed metastases are now living longer and longer in studies. These results are encouraging but must be viewed with caution because study participants are in most cases very special, i.e., they are younger or have fewer concomitant diseases than the average patient. For this reason, we analyzed all patients who were diagnosed with metastases between 1995 and 2022. The analysis showed that survival has also improved continuously in this real-world patient group. In a comparison of the periods 2018–2022 vs. 1995–2000, patients live about 1.5 years longer, a total of approximately 48 months. Overall survival (OS) of patients with metastatic breast cancer (MBC) has improved within controlled clinical trials. Whether these advances translate into improved OS in routine care is controversial. We therefore analyzed retrospectively unselected female patients from five oncology group practices and one university outpatient clinic, whose initial diagnosis of MBC was between 1995 and 2022. A total of 1610 patients with a median age of 63 years (23–100) were evaluated. In all, 82.9% had hormone-receptor-positive disease, and 23.8% were HER2-positive. Evaluation in time cohorts by initial MBC diagnosis date showed a continuous prolongation of median OS from 31.6 months (0.5–237.3+) (1995–2000) to 48.4 months (0.4–61.1+) (2018–2022) (p = 0.003). Univariable analyses showed a significant dependence on the time cohort of diagnosis, metastatic status at initial diagnosis, age at metastasis, hormone and HER2 status, general condition, metastasis localization, and the number of affected organs. A multivariable analysis revealed a significant dependence of survival probability on receptor status, general condition, and number of metastatic sites, as well as the time between initial breast cancer diagnosis and the diagnosis date of MBC in months. In sum, OS of patients with MBC has improved continuously and significantly in routine care over the last 27 years. [ABSTRACT FROM AUTHOR]

Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a marker of systemic inflammation with a prognostic impact in patients with various cancers, including breast cancer. The aim of this study was to investigate the relationships between the preoperative NLR and breast cancer prognosis in the patients before and after menopausal age, and its relationship with other prognostic factors. A total of 1868 patients with clinical Stage I-III primary breast cancer were enrolled. The associations between clinicopathological factors and the preoperative NLR were analyzed, and relapse-free survival (RFS) and overall survival (OS) were estimated. Statistical analyses stratified by the menopausal status revealed that a high NLR was significantly associated with worse RFS (P < 0.001) and OS (P = 0.001) in postmenopausal patients, but not in premenopausal patients. Although the postmenopausal patients with relapsed cancer tended to have higher NLR levels than those without relapse (P = 0.079), NLR levels of premenopausal patients with relapsed cancer were significantly lower than that of relapse-free patients (P = 0.024). In postmenopausal patients, a high NLR was only associated with worse RFS in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer (P < 0.001), in those managed without adjuvant chemotherapy (P = 0.003); this association was not observed in patients who received adjuvant chemotherapy. The preoperative NLR can be a useful prognostic marker, especially in postmenopausal breast cancer patients. The relationships between the NLR and breast cancer prognosis may be more evident when patients are assessed according to their menopausal status. [ABSTRACT FROM AUTHOR]