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Simple Summary: Research continues to show that exercising at recommended levels is associated with lower mortality rates and decreased risk of recurrence in breast cancer survivors (BCS). Moreover, those BCS exercising at levels meeting guidelines have higher self-reported health-related quality of life (HR-QOL) than those that do not. This includes lowered levels of perceived global stress. However, which modalities of exercise are most effective has yet to be determined. Our study investigates changes in stress experienced by breast cancer survivors participating in one of three different exercise modalities conducted over six months, as indicated by self-report and salivary cortisol measures. The revealed improvement in constructs of Health Related-Quality of Life (HR-QOL) suggest that engagement in exercise had a greater impact on outcomes than any particular modality. Background/Objectives: Extensive evidence suggests that exercise is physically and mentally beneficial for cancer survivors. This study reports on changes in self-reported stress, physiological biomarkers for stress (salivary cortisol), and HR-QOL constructs for fifty breast cancer survivors participating in one of three different exercise programs over 6 months. Methods: Fifty post-treatment breast cancer survivors were randomized to either therapeutic yoga-based exercise (YE), comprehensive exercise (CE) (aerobic, resistance, flexibility), or choosing (C) their own exercise activities. Participants completed the Perceived Stress Scale (PSS), Medical Outcomes Short-Form 36® (SF-36), and the Pittsburgh Sleep Quality Index (PSQI). Five samples of salivary cortisol were collected on two consecutive days. The 10 samples were used to calculate the diurnal rhythm slope. Outcome measures were repeated after six months. Results: All groups improved in HR-QOL measures of PSS; PSQI sleep quality components of latency and daytime functioning; and five of the ten SF-36 scales (Mental Component Scale, Social Functioning subscale, Mental Health subscale, Physical Component Scale, Physical Functioning subscale). Although the CE group observed the most favorable change in cortisol (−0.183), where cortisol slope changes approached significance (p = 0.057), but no significant decrease in cortisol between groups were noted. Conclusions: Our results suggest that it is the engagement of, rather than the specific type of exercise, which is associated with improved HR-QOL. However, longer-term studies with better adherence monitoring and larger sample sizes are needed to better determine clinical impact. [ABSTRACT FROM AUTHOR]

Simple Summary: Exogenous ketone esters (KEs) are compounds that elevate blood ketones without dietary restriction and they show promise as anti-cancer agents. This study examined the effects of an exogenous ketone ester-supplemented (eKET) diet in mouse models of metastatic breast and kidney cancers. Our eKET diet slowed tumor growth and reduced metastatic spread to the lungs in both cancer types. The mechanisms behind these effects differed: the eKET diet downregulated genes involved in Wnt and TGFβ signaling in mammary cancers, whereas it downregulated genes related to hypoxia and DNA damage repair in tumor-bearing kidneys. The diet was safe for use overall but was associated with some negative physiological effects in mice with renal cancer. Thus, eKET diets could be an effective addition to current cancer treatments, but additional work is needed to fully understand their limitations. Background/Objectives: Ketone esters (KEs) exhibit promise as anti-cancer agents but their impact on spontaneous metastases remains poorly understood. Although consumption of a ketogenic diet (KD) that is low in carbohydrates and high in fats can lead to KE production in vivo, the restrictive composition of KDs may diminish adherence in cancer patients. Methods: We investigated the effects of an exogenous ketone ester-supplemented (eKET), carbohydrate-replete diet on tumor growth, metastasis, and underlying mechanisms in orthotopic models of metastatic breast (4T1-Luc) and renal (Renca-Luc) carcinomas. Mice were randomized to diet after tumor challenge. Results: Administration of KEs did not alter tumor cell growth in vitro. However, in mice, our eKET diet increased circulating β-hydroxybutyrate and inhibited primary tumor growth and lung metastasis in both models. Body composition analysis illustrated the overall safety of eKET diet use, although it was associated with a loss of fat mass in mice with renal tumors. Immunogenetic profiling revealed divergent intratumoral eKET-related changes by tumor type. In mammary tumors, Wnt and TGFβ pathways were downregulated, whereas in renal tumors, genes related to hypoxia and DNA damage repair were downregulated. Conclusions: Thus, our eKET diet exerts potent antitumor and antimetastatic effects in both breast and renal cancer models, albeit with different modes of action and physiologic effects. Its potential as an adjuvant dietary approach for patients with diverse cancer types should be explored further. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the real-world efficacy and safety of combining pembrolizumab, a novel immunotherapy agent, with chemotherapy in early-stage triple-negative breast cancer treatment. We specifically aimed to validate clinical trial results in routine practice. A total of 108 Turkish patients receiving neoadjuvant therapy were examined. The combined regimen demonstrated high efficacy, with 64% of patients achieving pathological complete response, and exhibited generally favorable safety profiles with predominantly mild adverse events. These findings support the use of this combination as a standard treatment for this aggressive breast cancer subtype. However, the results underscore the need for further research to identify optimal patient selection criteria, which can inform oncologists' decision-making and potentially enhance outcomes for patients with triple-negative breast cancer. Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1–2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy in early-stage TNBC, complementing evidence from randomized trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Idiopathic granulomatous mastitis (IGM) is a rare breast disease that can be mistaken for inflammatory breast cancer. It requires a tissue biopsy for an accurate diagnosis. Even though it is not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. It is important to distinguish IGM from other breast inflammations caused by infections. IGM is mostly found in premenopausal women, often after pregnancy or breastfeeding. Smoking and contraceptive use might be risk factors, but the evidence is unclear. The treatment options include NSAIDs, steroids, immunosuppressants, surgery, prolactin suppressants, and antibiotics; many patients relapse, making treatment challenging. This review summarizes current information, which mostly comes from case reports and small studies, and presents GRAMAREG as a registry for IGM initiated by the EUBREAST Study Group, which aims to collect detailed data on IGM to improve the knowledge base for diagnosis and treatment. Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign inflammatory breast condition often mistaken for inflammatory breast cancer and, therefore, requires a biopsy for accurate diagnosis. Although not cancerous, IGM can cause emotional distress because of severe pain and ensuing breast deformity. Differentiating IGM from other breast inflammations caused by infections is essential. IGM mostly affects premenopausal women and is potentially associated with recent pregnancies and breastfeeding. The risk factors, including smoking and contraceptive use, have inconsistent associations. Steroid responses suggest an autoimmune component, though specific markers are lacking. Methods: We performed a narrative review on potential risk factors, diagnostics, and therapy of IGM. Results: Diagnostics and clinical management of IGM are challenging. The treatment options include NSAIDs, steroids, surgery, antibiotics, immunosuppressants, prolactin suppressants, and observation, each with varying effectiveness and side effects. Conclusions: Current IGM treatment evidence is limited, based on case reports and small series. There is no consensus on the optimal management strategy for this disease. The GRAMAREG study by the EUBREAST Study Group aims to collect comprehensive data on IGM to improve diagnostic and treatment guidelines. By enrolling patients with confirmed IGM, the study seeks to develop evidence-based recommendations, enhancing patient care and understanding of this condition. [ABSTRACT FROM AUTHOR]

Simple Summary: Limited knowledge exists on the effects of the COVID-19 pandemic and the pandemic lockdown on cancer detection and diagnoses in Switzerland. Population-based Swiss cantonal cancer registry data of the cantons of Zurich and Zug from 2018/19 to 2021 were used. Differences in cancer diagnoses were analyzed descriptively and using multivariate regression models. A decrease in all-cancer incidence was observed in 2020 compared to 2018/19, mainly during the lockdown phase in April. Meanwhile, higher all-cancer incidence rates were observed in 2021 compared to 2018/19. The impact in Switzerland was less severe than in other countries. Our findings may inform the decisions of policymakers and the public health system during future pandemics. Background/Objectives: This study aims to investigate differences in cancer diagnosis based on absolute case numbers and age-standardized incidence rate ratios (IRRs) in the pre-Coronavirus disease 2019 (COVID-19) years (2018/19) and the first two years of the COVID-19 pandemic (2020, 2021) in two Swiss cantons. Methods: Data of the Swiss cantonal cancer registry of the cantons of Zurich (ZH) and Zug (ZG) were used to descriptively investigate differences in annual and monthly absolute numbers regarding all-cancer and the five most common cancer types. Directly age-standardized monthly incidence rates (IRs) were calculated. Multivariate Quasipoisson regression models were fitted to determine the IRRs with 95% confidence intervals (95% CI). Results: Annual absolute numbers of all investigated cancers were similar in 2018/19, 2020, and 2021, except for prostate cancer (increase of 20.8% in 2021 compared to 2018/19). In 2020, there were generally more cancer diagnoses in January and February followed by a decrease in April and May. Compared to the pre-COVID-19 period, lower IRs were observed in 2020 for all-cancer (IRR = 0.96 [95% CI 0.96, 0.97]) and female breast cancer (0.92 [0.89, 0.96]), whereas higher IRs were observed in 2021 for all-cancer (1.02 [1.02, 1.02]) and prostate cancer (1.23 [1.18, 1.28]). Conclusions: Cancer detection and diagnoses decreased during the first year of the pandemic, especially during the most stringent lockdown phase in April. The findings of this study may inform the decisions of policymakers and public health system during future pandemics. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The most dangerous breast cancer is triple-negative breast cancer (TNBC). TNBC is very diverse, with 12 underlying subtypes. This great deal of patient diversity, along with the lack of broad-application targetable mechanistic markers (such as ER, PR, and HER2, which are present in other breast cancer subtypes but missing in TNBC), gives TNBC patients the worst outcomes of any breast cancer type. We aim to remedy this by exploring the molecular mechanisms across TNBC samples and subtypes. Molecular mechanisms are potentially targetable for treatment. We explore these options as part of our RNA-sequencing analysis. Our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone). Additionally, we found TNBC subtype-differentiating mechanistic markers, including PDE3B, CFD, IFNG, and ADM, which are targets with known therapeutics and potential for drug repurposing. Background/Objectives: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The prognosis for many breast cancer subtypes has improved due to treatments targeting the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In contrast, patients with triple-negative breast cancer (TNBC) tumors, which lack all three commonly targeted membrane markers, more frequently relapse and have lower survival rates due to a lack of tumor-selective TNBC treatments. We aim to investigate TNBC mechanistic markers that could be targeted for treatment. Methods: We performed a secondary TNBC analysis of 196 samples across 10 publicly available bulk RNA-sequencing studies to better understand the molecular mechanism(s) of disease and predict robust mechanistic markers that could be used to improve the mechanistic understanding of and diagnostic capabilities for TNBC. Results: Our analysis identified ~12,500 significant differentially expressed genes (FDR-adjusted p-value < 0.05), including KIF14 and ELMOD3, and two significantly modulated pathways. Additionally, our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone), CD300LG, ASPM, and RGS1 (98.9% combined accuracy), as well as TNBC subtype-differentiating mechanistic markers, including the targets PDE3B, CFD, IFNG, and ADM, which have associated therapeutics that can potentially be repurposed to improve treatment options. We then experimentally and computationally validated a subset of these findings. Conclusions: The results of our analyses can be used to better understand the mechanism(s) of disease and contribute to the development of improved diagnostics and/or treatments for TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer patients frequently encounter significant emotional and psychological challenges that can adversely affect their overall well-being and treatment outcomes. To address these challenges, we developed the Cancer Patient Empowerment Program (CancerPEP), a comprehensive, home-based intervention that incorporates physical exercise, nutritional guidance, and social support. CancerPEP builds on the success of the Prostate Cancer Patient Empowerment Program (PC-PEP), which has demonstrated positive effects on psychological well-being in prostate cancer patients. In this study, we also evaluated whether adding a Heart Rate Variability (HRV) biofeedback device could enhance the effectiveness of CancerPEP. Our findings indicate that while CancerPEP significantly reduced psychological distress and improved emotional well-being across cancer patients—including a breast cancer subgroup—at the end of the intervention (the 6-month point), the addition or lack of an HRV device did not significantly contribute to these improvements for the full sample. These results suggest that CancerPEP, similar to PC-PEP, is a valuable addition to standard cancer care, providing a holistic approach to support patients both mentally and emotionally. However, the inclusion of the HRV device may not be necessary to achieve these benefits. Background/Objectives: Psychological distress is a significant concern among cancer patients, negatively affecting their quality of life and adherence to treatment. The Cancer Patient Empowerment Program (CancerPEP) was developed as a comprehensive, home-based intervention aimed at reducing psychological distress by incorporating physical activity, dietary guidance, and social support. This study aimed to evaluate the feasibility, accrual and attrition rates, safety, and effectiveness of the CancerPEP intervention, with and without the biofeedback device, on psychological distress from baseline to 6 months, specifically focusing on the effects of group randomization and the difference between pre- and post-intervention results. Methods: This single-site, crossover randomized clinical trial included 104 cancer patients who were randomized to receive the CancerPEP intervention, with or without a Heart Rate Variability (HRV) biofeedback monitor. At 6 months, participants who did not receive the device were allowed to use one until the end of the year, while those who did receive the device were followed up to 12 months. Randomization was stratified by the presence or absence of clinically significant psychological distress and metastatic status. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10) at baseline, 6 months, and 12 months. The primary endpoint was the presence of nonspecific psychological distress, as measured by the K10 scale at 6 months from the trial start, based on group randomization. A secondary exploratory analysis assessed psychological distress at baseline, 6 months, and 12 months for both groups, while controlling for group randomization and prognostic covariates. Prognostic covariates included age; comorbidities; time between diagnosis and randomization; treatment modality; relationship status; and use of prescribed medications for anxiety, depression, or both. An exploratory sub-analysis was conducted for the breast cancer subgroup, based on the sample size available after recruitment. The trial is registered at ClinicalTrials.gov (NCT05508412). Results: The provision of the HRV biofeedback monitor in conjunction with the CancerPEP intervention did not significantly affect the primary outcome in either the full sample or the breast cancer subgroup, indicating that the HRV biofeedback provision was not beneficial in this trial. No self-reported or otherwise discovered adverse events at the 6-month mark were observed. About 10% of participants were lost to follow-up in both the early and late HRV monitor provision groups. Participation in the CancerPEP program led to a significant reduction in psychological distress over time. The odds of psychological distress were significantly higher at the start of the trial than at the end of the intervention (aOR = 2.64, 95% CI: 1.53–4.56) or 6 months after the intervention (aOR = 2.94, 95% CI: 1.62–5.30). Similarly, in the breast cancer subgroup, distress was higher at the trial's start than at 6 months, i.e., after the intervention (aOR = 2.25, 95% CI: 1.24–4.08), or at the end of the trial at 12 months (aOR = 2.73, 95% CI: 1.35–5.52). Conclusions: CancerPEP significantly reduces psychological distress in cancer patients, with consistent improvements noted across various cancer types and stages, including benefits specifically for breast cancer patients. These findings build upon the success of the Prostate Cancer Patient Empowerment Program (PC-PEP), indicating that a similar comprehensive intervention can be advantageous for all cancer patients and may be further tailored to address specific needs. With its holistic approach—encompassing physical, dietary, and psychosocial support—CancerPEP shows promise as a vital component of survivorship care. Ongoing 24-month evaluations will yield critical data on its long-term benefits. Additionally, a randomized trial with a control group (usual care without intervention) for breast cancer patients is currently under way and could potentially guide the integration of CancerPEP into standard oncology care to enhance patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer chemotherapy is dominated by cytotoxic drugs that non-selectively kill proliferating cells by blocking DNA replication and inducing apoptosis. Some natural anticancer products are less toxic to normal, slow-replicating cells but kill aggressive tumor cells. The combination of two structural isomers of pentacyclic triterpenes, oleanolic acid and ursolic acid, showed potent cytotoxic activity in human breast cancer cells in vitro by inducing cytotoxic autophagy at a significantly lower dose than previously reported. They were nontoxic to breast epithelial cells. Their activity was mainly due to the inhibition of AKT-mediated cell survival and the inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, a central regulator of cell metabolism, growth, and proliferation. The compounds were equally effective against ER+ and triple-negative breast cancer cells. Combining low doses of nontoxic inhibitors of PI3k kinase increased the activities of these compounds. In contrast, inhibition of autophagy by 3-methyl adenine annulled their activity, demonstrating that cytotoxic autophagy may be the dominant mechanism of cell death. These compounds have potential for cancer therapy in neoadjuvant or adjuvant settings. Background: Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. Materials and Methods: The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. Results: The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. Discussion: Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. Conclusion: These results suggest it would be worthwhile testing combined OA and UA in clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Axillary management in breast cancer has undergone significant changes over the past decades, especially with the introduction of neoadjuvant chemotherapy (NACT). NACT aims to shrink tumors before surgery, allowing for less invasive axillary approaches such as sentinel lymph node biopsy (SLNB) and targeted axillary dissection (TAD). These techniques help reduce the need for axillary lymph node dissection (ALND), which is associated with higher risks of complications like lymphedema. However, patient selection for these procedures depends on factors such as tumor biology, response to NACT, and the extent of nodal disease. This review discusses the latest evidence supporting de-escalation strategies in axillary surgery and highlights ongoing research that aims to further refine the selection criteria for these approaches. Multidisciplinary collaboration remains key to implementing personalized treatments that optimize patient outcomes while minimizing surgical morbidity. Background. In breast cancer (BC) patients, axillary management has undergone major improvements over the last few years, and efforts to identify the optimal strategy for the management of axillary surgery are still ongoing. Methods. In current clinical practice, women with clinically node-positive (cN+) BC usually receive neoadjuvant chemotherapy (NACT) with the aim of reducing the extent of primary disease and, thus, allowing for axillary-conservative surgery. Remarkably, after NACT, up to one out of three patients achieves an axillary pathologic complete response, which, in turn, is associated with a more favorable prognosis than residual axillary disease. However, NACT is not without drawbacks, as NACT-associated inflammation can damage lymphatic vessels. Furthermore, varying degrees of response may occur in the axillary lymph nodes, increasing the false negative rate for sentinel biopsy. Results. At present, there is no consensus on the optimal approach in patients with cN+ BC undergoing NACT, although multidisciplinary management seems to be recommended. Conclusions. This narrative review provides a comprehensive overview of axillary management in cN+ BC patients undergoing NACT. It uses a multidisciplinary approach that encompasses the oncological management perspectives, as well as surgical and chemotherapeutic viewpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondria as peculiar cellular "powerhouses" comprise a source of ATP produced by an oxidative phosphorylation (OXPHOS) system. Additionally, they are implicated in several crucial cellular processes such as regulating the cellular levels of metabolites, Reactive Oxygen Species (ROS) homeostasis, apoptosis, and many others. Thus, it is not surprising that mitochondrial function in cancer cells appears to be a potential promising target in chemotherapy. A substantial amount of evidence indicates that both apoptosis and ROS production could involve a small p66Shc adaptor protein, which can play a dual role as an oxidative stress sensor or "redox" enzyme. The main objective of this work was to determine the role of the p66Shc protein in mitochondrial physiology in MDA-MB-231 breast cancer cells. Thus, the data obtained in our study expanded the knowledge regarding the function of p66Shc protein in cancer cells, indicating the p66Shc protein as a potential therapeutic target for breast cancer treatment. This work presents a comprehensive evaluation of the role of p66Shc protein in mitochondrial physiology in MDA-MB-231 breast cancer cells. The use of human breast cancer cell line MDA-MB-231 and its genetically modified clones (obtained with the use of the CRISPR-Cas9 technique), expressing different levels of p66Shc protein, allowed us to demonstrate how the p66Shc protein affects mitochondrial metabolism of human breast cancer cells. Changes in the level of p66Shc (its overexpression, and overexpressing of its Serine 36-mutated version, as well as the knockout of p66Shc) exert different effects in breast cancer cells. Interestingly, knocking out p66Shc caused significant changes observed mostly in mitochondrial bioenergetic parameters. We have shown that an MDA-MB-231 (which is a strong metastatic type of breast cancer) clone lacking p66Shc protein is characterized by a significant shift in the metabolic phenotype in comparison to other MDA-MB-231 clones. Additionally, this clone is significantly more vulnerable to doxorubicin treatment. We have proved that p66Shc adaptor protein in human breast cancer cells may exert a different role than in noncancerous cells (e.g., fibroblasts). [ABSTRACT FROM AUTHOR]

Simple Summary: Improved outcomes have been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative breast cancer, regardless of age. In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. A higher discontinuation rate for abemaciclib was reported in patients ≥65 years and it can be assumed that discontinuation rates may increase with more older patients. If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. [ABSTRACT FROM AUTHOR]

Simple Summary: Change in protein expression is the key driving force for tumorigenesis. Increased expression of Ankyrin Repeat Domain 1 (ANKRD1) acts as a co-activator of the p53 tumor suppressor protein and is associated with cancer drug resistance and poor survival of cancer patients. In this study, we found increased levels of ANKRD1 in highly metastatic breast cancer cell lines and human tissues of high-grade breast cancer. We also demonstrated that ANKRD1 is upstream of NF-κB-MAGE-A6 and plays a role in cancer metastasis. Our results show that the expression of ANKRD1 has significant clinical diagnostic significance in breast cancer metastasis. Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Research shows that Black women generally have poorer breast cancer survival rates than White women in the U.S. Our study aims to identify genomic variants and socioeconomic determinants that might explain this racial disparity using mediation analysis. Based on the All of US research program, we identified 15 gene mutations along with factors age, general health, and general quality of life that can explain the observed racial disparity. By studying how these genes behave differently in Black and White breast cancer patients, researchers can gain important insights into the mechanism underlying the cancer development and prognosis among different populations. This understanding could help create better, personalized treatments, especially to address the differences in breast cancer outcomes among racial groups. Background: Breast cancer outcomes are worse among Black women in the U.S. compared to White women. While extensive research has focused on risk factors contributing to breast cancer; the role of genomic elements in health disparities between these racial groups remains unclear. This study aims to identify genomic variants and socioeconomic status (SES) determinants influencing racial disparities in breast cancer survival through multiple mediation analyses. Methods: Our investigation is based on the NIH-supported All of Us (AoU) program and analyzes 7452 female participants with malignant tumors of breast, including 5073 with genomic data. A log-rank test reveals significant racial differences in overall survival time between Black and White participants (p-value = 0.04). Multiple mediation analysis examines the effects of 9481 genetic variables across 23 chromosomes in explaining the racial disparity in survival, adjusting for SES variables. Results: 15 gene mutations, in addition to age, general health, and general quality of life, have significant effects (p-values < 0.001) in explaining the observed racial disparity. Mutations in TMEM132B, NARFL, SALL1, PAD12, RIPK1, ASB14, DCX, GNB1L, ARHGAP32, AL135787.1, WBP11, SLC16A12AS1, AP000345.1, IKBKB, and SUPT20H have significantly different distributions between Black and White participants. The disparity is completely explained by the included variables as the direct effect is insignificant (p-value = 0.73). Conclusions: The combined impact of SES determinants and genetic mutations can explain the observed differences in breast cancer survival among Black and White participants. Future studies will explore pathways and design in vivo and in vitro experiments to validate the functions of these genes [ABSTRACT FROM AUTHOR]

Simple Summary: The studies highlighted in this commentary demonstrate the significant role of wild-type IDH2 in both cancer progression and immune cell function. In triple-negative breast cancer (TNBC), it was found that wild-type IDH2 is essential for tumor survival, as its inhibition leads to disrupted energy metabolism and reduced tumor growth. Additionally, inhibiting IDH2 in CD8+ T cells and CAR T cells enhances the differentiation of memory T cells, improving the efficacy of cell-based immunotherapies. These findings suggest that wild-type IDH2 is a promising therapeutic target, potentially impacting cancer treatment and immunotherapy by providing new avenues for therapy development. This research underscores the urgent need for specific inhibitors targeting wild-type IDH2, which could revolutionize cancer immunotherapy and broaden treatment options for various cancer types. The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies wild-type IDH2 as a crucial factor in the survival of triple-negative breast cancer (TNBC) cells, with its inhibition leading to disrupted energy metabolism, reduced tumor growth, and enhanced apoptosis. The second analysis examines the role of IDH2 in CD8+ T cells, revealing that its inhibition promotes the differentiation of memory T cells, thereby enhancing the efficacy of cell-based immunotherapies like CAR T cells. A third investigation supports these findings, demonstrating that IDH2 inhibition in CAR T cells reduces exhaustion, enhances memory T cell formation, and improves anti-tumor efficacy. Collectively, these reports highlight wild-type IDH2 as a promising therapeutic target, with potential applications as a two-edged sword in both cancer treatment and immunotherapy. The development of specific wild-type IDH2 inhibitors could offer new avenues for therapy, particularly in tumors reliant on IDH2 activity as well as in enhancing the effectiveness of CAR T cell therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Menopause remains a complex challenge after breast cancer. Menopausal symptoms, whether iatrogenic or premature due to cancer treatment, significantly affect health and quality of life. Menopausal hormone therapy is currently deemed unsafe in hormone-sensitive breast cancer. Unfortunately, the alternative non-hormonal therapies are not as effective in controlling menopausal symptoms. The aim of our narrative review was to determine the risk of recurrence of breast cancer in breast cancer survivors taking menopausal hormone therapy. Data on this topic are of low quality and outdated. This review highlights the need for future research to help navigate this difficult path. Menopausal symptoms negatively impact quality of life in breast cancer survivors. The paucity of data on the impact of Menopausal Hormone Therapy (MHT) on oncological outcomes in these patients limits informed clinical discussion. Defining the risk of cancer recurrence with MHT is central to the appraisal of risk/benefit, particularly with low-risk disease (based on genomic profile). The aim of this review is to summarize the current data evaluating MHT in breast cancer patients. A systematic review of the literature was performed to evaluate the impact of MHT on oncological outcomes in breast cancer survivors. Three major databases (PubMed, EMBASE and Medline) were searched. The review included all prospective studies published in English. Four randomized control trials and four non-randomized prospective studies were identified. An increase in breast cancer recurrence with MHT was observed in the early randomized trials whilst no increased risk of recurrence was reported in the observational studies. There remains a need to quantify MHT-related recurrence risk in patients with molecularly favorable disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has changed the way we treat triple-negative breast cancer (TNBC), a type of breast cancer that does not have common markers like estrogen, progesterone, or HER2. TNBC has the worst outlook among breast cancers, but it may respond better to immunotherapy because it often shows higher levels of PD-L1 and has more immune cells attacking the tumor. Recently, the FDA approved pembrolizumab (Keytruda) combined with chemotherapy for advanced TNBC, offering new hope for patients. However, not all patients respond equally well, mainly because not everyone has high PD-L1 levels. To improve treatment success, combining immunotherapy with other treatments like chemotherapy, targeted therapies, or radiation seems promising. This review explains TNBC and immunotherapy, discusses current and future combination treatment strategies, and explores the challenges and potential new approaches that might soon be available for treating TNBC. Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are the most recent breakthrough in cancer treatments. Several drugs have been approved by the FDA including anti-PD-1 antibodies (Nivolumab, Pembrolizumab, and Cemiplimab). Their treatment is most effective for melanoma, non-small cell lung cancer, or bladder cancer. However, ICI response rates are very low for breast cancer patients, even for those with triple negative breast cancer (TNBC) who are expected to be more responsive to ICI treatment. Improved treatments are in demand for patient benefits. Our armed oncolytic virus is one therapeutic agent that can improve the outcome of TNBC treatment, especially in combination with ICIs, as demonstrated by this study. It has been shown that the response rate of TNBC is dependent on the level of PD-L1 and the tumor microenvironment (TME). Approaches that alter the TME can improve the efficacy of ICIs. Background: We have engineered a Smac-armed oncolytic virus by inserting a Smac transgene into the genome of a vesicular stomatitis virus to generate VSV-S. Our previous study shows that the anticancer efficacy of VSV-S is more potent than that of wild-typed VSV in a subcutaneous TNBC mouse model. VSV-S treatment reverts the immunosuppressive TME by reducing MDSCs and TAMs, while increasing infiltration of neutrophils and CD8+ T cells. Methods: VSV-S was used to treat TNBC in an orthotopic mouse model, and in a combination therapy with an anti-PD-1 antibody to treat metastatic TNBC in a mouse model. Changes in the TME were evaluated. Results: In this current study, we show that neoadjuvant VSV-S treatment of primary orthotopic TNBC tumors in mice drastically lowered lung metastasis after surgical removal of the primary tumor, and significantly increased the survival rate. The mechanism of action and changes to the TME were delineated, among which one significant marker is the elevation of PD-L1 expression in tumors. In the TNBC lung metastasis mouse model, pulmonary treatment with VSV-S greatly enhanced the efficacy of ICI treatment. Conclusions: Our results suggest that the combination of oncolytic virus and ICI therapies has the potential to substantially improve the outcome of TNBC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer remains a major health issue in the United States and around the world. While progress has been made in curing most types of breast cancer, there are currently no effective cures for a subtype called 'triple-negative' breast cancer. We have identified a gene named BORG that, based on experiments in cultured human cells and mice, plays an important role in triple-negative breast cancer. Here, we study the function of this gene in a large group of human triple-negative breast cancers and show that when the level of expression of this gene is high, tumors become more invasive and develop 'triple-negative'-like properties. Even in non-triple-negative tumors, high levels of expression of this gene are associated with more aggressive tumor behavior and poor response to therapy. Based on these validation studies in human tumors, we hope to leverage mechanistic vulnerabilities in BORG action to one day advance novel therapeutic strategies to alleviate hard-to-cure triple-negative breast tumors. Background/Objectives: Long noncoding RNAs (lncRNAs) are known to play key roles in breast cancers; however, detailed mechanistic studies of lncRNA function have not been conducted in large cohorts of breast cancer tumors, nor has inter-donor and inter-subtype variability been taken into consideration for these analyses. Here we provide the first identification and annotation of the human BORG lncRNA gene. Methods/Results: Using multiple tumor cohorts of human breast cancers, we show that while BORG expression is strongly induced in breast tumors as compared to normal breast tissues, the extent of BORG induction varies widely between breast cancer subtypes and even between different tumors within the same subtype. Elevated levels of BORG in breast tumors are associated with the acquisition of core cancer aggression pathways, including those associated with basal tumor and pluripotency phenotypes and with epithelial–mesenchymal transition (EMT) programs. While a subset of BORG-associated pathways was present in high BORG-expressing tumors across all breast cancer subtypes, many were specific to tumors categorized as triple-negative breast cancers. Finally, we show that genes induced by heterologous expression of BORG in murine models of TNBC both in vitro and in vivo strongly overlap with those associated with high BORG expression levels in human TNBC tumors. Conclusion: Our findings implicate human BORG as a novel driver of the highly aggressive basal TNBC tumor phenotype. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant therapy, used before surgery, is an important part of breast cancer treatment. Not only can it shrink tumors, but it can also provide valuable information on how the cancer responds to treatment, which can help physicians tailor further therapy. For aggressive types of breast cancer, such as HER2-positive and triple-negative breast cancers, targeted therapies and immunotherapy are often added to standard chemotherapy. Achieving a complete response to treatment (i.e., total absence of viable tumor from tissue removed during surgery) is usually a good sign, but it does not always mean better long-term outcomes for every patient. This review examines the evolution of neoadjuvant therapy in high-risk breast cancer and discusses recent clinical trials focused on optimizing treatment. It also highlights the need for new approaches to improve outcomes, especially for patients whose cancer does not fully respond to initial treatments. The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a huge problem in modern medicine, even surpassing breast cancer in women. A very common method of treatment is mastectomy which is, in most cases, followed by breast reconstruction, the course of which changes dynamically. The process is aimed at improving patient satisfaction, minimizing the risk of tumor recurrence, and preventing complications. That is why we decided to look at the trend in the abovementioned procedures. We have described important types of surgical treatment of breast cancer, such as modified radical mastectomy, breast-conserving surgery, contralateral prophylactic mastectomy, and robotic mastectomy. We have also discussed breast reconstruction, focusing on implants, acellular dermal matrix, autologous reconstruction, robotic breast reconstruction, and fat grafting. Background: Breast cancer continues to be a significant diagnostic and therapeutic problem. Mastectomy is still a frequently used treatment method, but its form is changing with progress in medicine. Methods: We have described important types of surgical treatments for breast cancer, such as modified radical mastectomy, breast-conserving surgery, contralateral prophylactic mastectomy, and robotic mastectomy. Breast reconstruction is also a very important element of treatment because it directly affects the mental state of patients after the procedure. We have also described types of breast reconstruction, such as implants, acellular dermal matrices, autologous reconstruction, robotic breast reconstruction, and fat grafting. Results: The aim of our study was to compare available types of surgical treatment for breast cancer and breast reconstruction to help tailor personalized treatment to patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Protein tyrosine kinase 7 (PTK7) is a conserved catalytically defective transmembrane receptor that is a potential therapeutic target in triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer. The aim of this retrospective study was to determine if PTK7 expression levels in breast tumours were associated with the clinical outcome of breast cancer patients. We determined PTK7 expression in patient tumours using immunohistochemistry and assessed PTK7 mRNA expression in the METABRIC and TCGA cohorts. We determined that PTK7 expression was not clearly linked with survival in unselected patient cohorts; however, it was associated with breast cancer-specific survival of patients with poor and moderate Nottingham Prognostic Index values. Protein tyrosine kinase 7 (PTK7), originally known as colon carcinoma kinase (CCK4), is an evolutionary conserved, catalytically defective transmembrane receptor involved in Wnt signalling. PTK7 has been identified as a potential therapeutic target, and a PTK7 antibody drug conjugate (PF-06647020; cofetuzumab pelidotin) has been investigated in phase I clinical trials for triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer. PTK7 protein expression was evaluated in 1136 early-stage invasive breast tumours by immunohistochemistry. In addition, PTK7 mRNA expression in the METABRIC (n = 1980) and the TCGA breast cancer cohorts (n = 1082) was evaluated. Associations between PTK7 expression and clinicopathological criteria and patient outcome were determined. No association between PTK7 protein expression and breast cancer-specific survival was observed; however, PTK7 mRNA expression in the METABRIC cohort was associated with breast cancer-specific survival (p < 0.001). PTK7 protein and mRNA expression were associated with breast cancer-specific survival of patients with a poor prognostic Nottingham Prognostic Index (NPI) and a moderate prognostic NPI, respectively. Taken together, these data indicate that PTK7 expression is associated with patient outcome in subgroups of breast cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This research is the first comprehensive study in New Zealand to categorise and examine the characteristics of breast cancer based on HER2 status. We explored three HER2 categories: HER2-zero, HER2-low, and HER2-positive, in women diagnosed with invasive breast cancer. Utilising Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), our study analysed data spanning 21 years, revealing that most women underwent HER2 testing. Significantly, many cases previously not recognised as having significant HER2 levels were in fact HER2-low, qualifying them for newer, targeted drug therapies. These findings are particularly crucial as they suggest that newer therapies could benefit a larger segment of patients, notably those with advanced breast cancer; approximately 60% of these women might now benefit from these innovative HER2-targeted treatments. The study underscores the urgent need for standardised HER2 testing to personalise and optimise treatment, enhancing outcomes for patients with invasive breast cancer. Objectives: To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low, and HER2-zero invasive breast cancers in New Zealand. The study will reveal the proportion of women who may benefit from new HER2-targeted antibody drug conjugate (ADC) therapies. Methods: Utilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories—HER2-zero, HER2-low, HER2-positive. Results: From 2009–2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% of those formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates that 60% of women with advanced breast cancer may potentially benefit from the new HER2-directed ADCs (approximately 120 women per year). Conclusions: The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Sentinel lymph node assessment is becoming a standard of care procedure in patients with surgically treatable endometrial cancer due to its cost-effectiveness and the advantages it offers in guiding post-operative management. Unlike in breast cancer, however, several key aspects regarding this technique's employment in endometrial cancer remain unclear, such as tracer injection volume and final pathology interpretation. The aim of this paper is to investigate the current literature on this technique in order to provide simple and clear insight on the matter and to facilitate the reproducibility of this technique, ultimately resulting in improving patients' oncological outcomes. As the number of patients diagnosed with endometrial cancer rises, so does the number of patients who undergo surgical treatment, consisting of radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy or lymph node sampling. The latter entail intra- and post-surgical complications, such as lymphedema and increased intra-operative bleeding, which often outweigh their benefits. Sentinel Lymph Node (SLN) sampling is now common practice in surgical management of breast cancer, as it provides important information about the disease without jeopardizing surgical radicality and patient outcomes. While this technique has also been shown to be feasible in patients with endometrial cancer, there is little consensus on several aspects, such as tracer injection volume and site, pathological ultrastaging, and result interpretation. The aim of this review is to analyze the current literature on SLN assessment in order to help standardize the procedure. [ABSTRACT FROM AUTHOR]

Simple Summary: Diabetes rapidly advances the growth and spread of breast cancer. This study explores how high-glucose conditions in diabetes affect the structure of cancer cells, which makes them more aggressive and more likely to spread to other parts of the body. This is partly due to the involvement of two proteins associated with cytoskeletal structure, Rho kinase (ROCK) and focal adhesion kinase (FAK), which are important for cell movement. Cell shape and stiffness were studied using advanced microscopic techniques in cancer cells and normal cells exposed to varying glucose levels. It was found that cancer levels made the cancer cells less stiff and more likely to move, which can lead to the cancer spreading. However, when the ROCK or FAK proteins were blocked, these harmful changes were lessened. Diabetes greatly reduces the survival rates in breast cancer patients due to chemoresistance and metastasis. Reorganization of the cytoskeleton is crucial to cell migration and metastasis. Regulatory cytoskeletal protein kinases such as the Rho kinase (ROCK) and focal adhesion kinase (FAK) play a key role in cell mobility and have been shown to be affected in cancer. It is hypothesized that diabetes/high-glucose conditions alter the cytoskeletal structure and, thus, the elasticity of breast cancer cells through the ROCK and FAK pathway, which can cause rapid metastasis of cancer. The aim of the study was to investigate the role of potential mediators that affect the morphology of cancer cells in diabetes, thus leading to aggressive cancer. Breast cancer cells (MDA-MB-231 and MCF-7) were treated with 5 mM glucose (low glucose) or 25 mM glucose (high glucose) in the presence of Rho kinase inhibitor (Y-27632, 10 mM) or FAK inhibitor (10 mM). Cell morphology and elasticity were monitored using atomic force microscopy (AFM), and actin staining was performed by fluorescence microscopy. For comparative study, normal mammary breast epithelial cells (MCF-10A) were used. It was observed that high-glucose treatments modified the cytoskeleton of the cells, as observed through AFM and fluorescence microscopy, and significantly reduced the elasticity of the cells. Blocking the ROCK or FAK pathway diminished the high-glucose effects. These changes were more evident in the breast cancer cells as compared to the normal cells. This study improves the knowledge on the cytoarchitecture properties of diabetic breast cancer cells and provides potential pathways that can be targeted to prevent such effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Drugs work by binding to a specific 3D structure on a protein. Drug discovery has historically been driven by prior knowledge of function, either of a protein or chemical. This knowledge of function then drives investigations to probe chemical/protein interactions. We undertook a different approach. We first identified unique 3D structures, agnostic of function, and investigated whether they could lead us to innovative therapeutics. Using a synchrotron-based X-ray source, we first determined high-resolution structures of hundreds of proteins. With a supercomputer running analytical programs created by us, we identified novel 3D structures and screened for chemicals binding them. We then tested their ability to inhibit cancer growth without damaging normal cells. We identified a potent inhibitor of a deadly cancer, melanoma. It was not toxic to normal cells even at 2100-fold higher doses. It worked by inducing anoikis, a fundamental process of known importance for cancer. Therapeutics that selectively induce anoikis are needed. In summary, we demonstrate the power of using a 3D protein structure as the starting point to discover new biology and drugs. Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable. [ABSTRACT FROM AUTHOR]

Simple Summary: Peripheral blood analyses can offer a minimally invasive view into systemic immunity during cancer and can lead to the identification of biomarkers for cancer screening and therapeutic management. While a limited number of studies have reported blood transcriptome in breast cancer (BC) using RNA-seq analysis, our study is the first that aimed to identify potential BC biomarkers by analyzing transcriptome at an isoform level in peripheral blood mononuclear cells (PBMCs) from BC patients and healthy women. Our approach has led to the identification of an isoform of the RASGEF1A gene, the ENST00000374459 transcriptional variant, as a promising blood mRNA biomarker for distinguishing BC and healthy subjects. Additionally, our association analysis with clinicopathological characteristics revealed that lower ENST00000374459 expression in PBMCs of breast cancer patients was associated with higher proliferation and circulating tumor DNA (ctDNA) shedding, thereby linking expression of this isoform in blood immune cells to cancer progression and spreading. Background: Breast cancer (BC) comprises multiple subtypes with distinct molecular features, which differ in their interplay with host immunity, prognosis, and treatment. Non-invasive blood analyses can provide valuable insights into systemic immunity during cancer. The aim of this study was to analyze the expression of transcriptional isoforms in peripheral blood mononuclear cells (PBMCs) from BC patients and healthy women to identify potential BC immune biomarkers. Methods: RNA sequencing and isoform-level bioinformatics were performed on PBMCs from 12 triple-negative and 13 luminal A patients. Isoform expression validation by qRT-PCR and clinicopathological correlations were performed in a larger cohort (156 BC patients and 32 healthy women). Results: Transcriptional analyses showed a significant (p < 0.001) decrease in the ENST00000374459 RASGEF1A isoform in PBMCs of BC compared to healthy subjects, indicating disease-related expression changes. The decrease was associated with higher ctDNA and Ki-67 values. Conclusions: The levels of the RASGEF1A transcriptional isoform ENST00000374459 may have the potential to distinguish between BC and healthy subjects. The downregulation of ENST00000374459 in breast cancer is associated with higher proliferation and ctDNA shedding. Specialized bioinformatics analyses such as isoform analyses hold significant promise in the detection of biomarkers, since standard RNA sequencing analyses may overlook specific transcriptional changes that may be disease-associated and biologically important. [ABSTRACT FROM AUTHOR]

Simple Summary: This study evaluates the long-term oncological outcomes of sentinel lymph node biopsy (SLNB) compared to axillary lymph node dissection (ALND) in clinically node-positive (cN+) breast cancer patients treated with neoadjuvant therapy (NAT). Analyzing data from 322 patients, the study found that SLNB is associated with better long-term outcomes, including recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS), compared to ALND. The axillary recurrence rates for SLNB ranged between 0.9% and 2.1%, comparable to those reported in other studies. Despite the high false-negative rates previously associated with SLNB, this study's findings support its safety and effectiveness in this patient population. Overall, SLNB is a viable alternative to ALND, offering better long-term oncological outcomes without increasing the risk of axillary recurrence. Backgrounds: This study compares the long-term outcomes of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB) in clinically node-positive (cN+) breast cancer (BC) patients treated with neoadjuvant therapy (NAT).Methods: We conducted a retrospective analysis of 322 cN+ BC patients who became clinically node-negative (ycN0) post-NAT. Patients were categorized based on the final type of axillary surgery performed: ALND or SLNB. Recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were evaluated and compared between the two groups. Results: Patients in the SLNB group had significantly better 3-, 5-, and 10-year RFS, DDFS, OS, and BCSS compared to those in the ALND group. The SLNB group also had a higher proportion of patients achieving pathologic complete response (pCR). Multivariate analysis identified pCR, ypN0 status, and SLNB as favorable prognostic factors for all survival metrics. Axillary recurrence rates were low for both groups (0.6–2.1%). Conclusions: SLNB may be a safe and effective alternative to ALND for selected cN+ BC patients who convert to ycN0 after NAT. These findings suggest that careful patient selection is crucial, and further research is needed to validate these results in more comparable populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Neutrophil granulocytes in the vicinity of malignant tumors are referred to as tumor-associated neutrophils (TANs). Knowledge about the role of TANs in the disease progression of early hormone-receptor-positive breast cancer is limited but essential to the development of new immunotherapies and biomarkers. In this work, we counted immunohistochemically stained TANs in sections of 144 early-stage breast cancer tumors and correlated these results with disease-free survival. Our results indicate that not only intratumoral TANs but also those in adjacent normal tissue and in sentinel lymph nodes were associated with shorter disease-free survival. Combined analysis with other immune cells from previous studies revealed that intratumoral TANs were only associated with prognosis in tumors that did not express an unfavorable macrophage polarization profile, providing a clinical example of the known interactions between different types of immune cells within the tumor microenvironment. This indicates that future research in the field should evaluate the two types of immune cells together. Background: Tumor-associated neutrophils (TANs) are important modulators of the tumor microenvironment with opposing functions that can promote and inhibit tumor progression. The prognostic role of TANs in early luminal breast cancer is unclear. Methods: A total of 144 patients were treated for early-stage hormone-receptor-positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment. Results: High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. TANs were a negative prognostic factor in tumors with an elevated M1/M2 TAM ratio, while this impact on patient outcome was lost in tumors with a low M1/M2 ratio. A combined multivariate analysis of TAM and TAN density revealed that only TAM polarization status was an independent prognostic factor. Conclusions: CD66b+ neutrophils were a negative prognostic factor in early-stage luminal breast cancer in single-marker analysis. Combined analysis with TAMs could be necessary to correctly evaluate their prognostic impact in future studies. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors that are unable to sufficiently attract and polarize TAMs. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the past years, the introduction of various anti-HER2 therapies has significantly improved the outcome for patients with HER2-positive breast and gastroesophageal carcinomas. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers, focusing on the published studies, the scoring systems, and assays used and analyzing the clinical parameters and therapeutic approaches used. The evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal remains investigational but is increasing due to a tumor site-related prognostic and predictive value of the different types of HER2 alterations. The major limitation was that standardized and validated scoring system assays are not well-established for many organs. The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody–drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-low breast cancer is a newly recognized subtype that has shown promising responses to treatment with antibody–drug conjugates (ADCs). However, there is still little known about its clinical and molecular characteristics. In this study, we examined the clinical and pathological features, survival rates, and expression of HER2-related genes in Colombian patients with HER2-low breast cancer, comparing them to HER2-negative and positive groups. We found that HER2-low tumors were better differentiated and had a lower proliferation index compared to HER2-positive tumors. Additionally, compared to HER2-negative cases, HER2-low patients had higher mRNA expression of the ERBB2 gene and longer overall survival rates. Despite these findings, there were no significant differences in survival when adjusted for estrogen receptor status and clinical stage. These results highlight the need for further research on HER2-low breast cancer to optimize treatment strategies for this unique group. HER2-low tumors have shown promise in response to antibody–drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group's clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes (ERBB2, GRB7 and MIEN1), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy is the standard of care for locally advanced breast cancer; however, it is less effective in hormone receptor (HR)-positive tumors. Therefore, we aimed to evaluate the safety and efficacy of adding an aromatase inhibitor to standard neoadjuvant chemotherapy in patients with stage II or stage III HR-positive, HER2-negative breast cancer. Adding letrozole to standard neoadjuvant chemotherapy did not significantly increase the pathologic complete response (pCR) rate; however, it enhanced the overall response rate with acceptable safety. Further research is necessary to determine the optimal neoadjuvant therapy for HR-positive, HER2-negative breast cancer to address the ongoing unmet need compared with recent advances in clinical outcomes observed in HER2-positive and triple-negative subtypes. The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33–63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo–endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is difficult to treat. This is partly because each tumor is different and there are few drugs that are effective against this disease. Further, the high mortality from TNBC is primarily attributable to its spread beyond the primary tumor site, or metastasis. There has been a lack of understanding of common factors affecting metastasis in TNBC and, consequently, continued difficulty in effectively treating this deadly disease. A re-emerging concept regarding the broad regulation of factors affecting disease is that of competitive endogenous RNA networks. The recent study of these networks and how they regulate metastatic processes in TNBC is providing new insights into the predominant molecular factors and cellular signaling pathways involved in the progression of this disease. Here, we review this research and what it may mean for patients with metastatic TNBC (mTNBC) and advancements that may improve their treatment. Triple-negative breast cancer is aggressive and challenging to treat because of a lack of targets and heterogeneity among tumors. A paramount factor in the mortality from breast cancer is metastasis, which is driven by genetic and phenotypic alterations that drive epithelial–mesenchymal transition, stemness, survival, migration and invasion. Many genetic and epigenetic mechanisms have been identified in triple-negative breast cancer that drive these metastatic phenotypes; however, this knowledge has not yet led to the development of effective drugs for metastatic triple-negative breast cancer (mTNBC). One that may not have received enough attention in the literature is post-translational regulation of broad sets of cancer-related genes through inhibitory microRNAs and the complex competitive endogenous RNA (ceRNA) regulatory networks they are influenced by. This field of study and the resulting knowledge regarding alterations in these networks is coming of age, enabling translation into clinical benefit for patients. Herein, we review metastatic triple-negative breast cancer (mTNBC), the role of ceRNA network regulation in metastasis (and therefore clinical outcomes), potential approaches for therapeutic exploitation of these alterations, knowledge gaps and future directions in the field. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women globally, with over 2.26 million new cases in women in 2020. Male breast cancer, while rare (less than 1% of cases), is treated similarly to female breast cancer despite some clinical differences. Advances in treatment, such as using genomic and immunohistochemical markers, have significantly improved survival rates for women. Men with breast cancer are often older at diagnosis, and their prognosis may differ due to age and other factors. The survival analysis conducted on 2162 patients (19 males and 2143 females) suggests that male breast cancer may have a poorer prognosis compared to female breast cancer. Breast cancer is one of the most common cancers and the leading cause of cancer death in women. Less than 1% of breast cancer cases are male breast cancers. Although there has been significant progress made in the management of breast cancer, due to its rarity among men, the question of whether men and women with breast cancer have the same treatment response and survival rate still needs to be answered. The primary goal of this study is to compare survival outcomes between male and female breast cancer patients. Material and Method: This cohort study represents a retrospective and anonymized data analysis of 2162 breast cancer cases (19 males and 2143 females), registered over a period of 12 years, from 1 January 2010 to 31 December 2021, in the Clinic of Obstetrics and Gynecology, Diakoneo Diak Klinikum Schwäbisch Hall, Germany. Results: According to the Kaplan–Meier survival analysis, the estimated overall 3-year survival rate was 91.1% for women and 88.9% for men. The log-rank test of equality of survival distributions indicated a statistically significant difference in survival times between the two groups (p = 0.009). In the subsequent age-matched Kaplan–Meier analysis, the p-value was below the significance threshold (p = 0.068). Conclusions: Male breast cancer is a rare disease that may show some particularities in terms of survival compared to female breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we demonstrate an essential role for the RAS downstream effectors RALA and RALB in TNBC and describe a promising novel small molecule RAL inhibitor. We report that TNBC, but not HER2+BC, cell lines are dependent upon RAL expression for growth in vitro and in vivo. Surprisingly, we found little correlation between RAL-dependency and the cytotoxicity of commercially available RAL inhibitors, suggesting that these inhibitors kill through effects other than RAL inhibition. Finally, we identified a novel small molecule RAL inhibitor, OSURALi, which is more toxic to RAL-dependent TNBC cell lines than RAL-independent HER2+BC or normal cell lines. Our results highlight the RALs as key molecular targets in TNBC and introduce a novel RAL inhibitor. Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Simple Summary: Screening for breast, colorectal, and cervical cancer is correlated with diagnosis at an earlier stage, less extensive surgery, and reduced mortality and fewer complications. Adherence rates to cancer screening are lower for individuals with low socio-economic conditions and educational attainment. These social disparities are only partially reduced by free screening through national initiatives. Education and information and appropriate expenditure for preventive care have the potentials to increase adherence to screening for colorectal, breast, and cervical cancer with the possibility of reduced cancer mortality. The findings of our study highlight the importance of the implementation of nationally organized screening programs for several other types of cancers that are often detected after the occurrence of symptoms. Nationally organized screening programs for several types of cancers, like esophageal, gastric, and pancreatic cancer, in regions with a high prevalence may increase the possibility of diagnosis at earlier stages and improved early and late results. The objective of this study was to determine the correlation between adherence to cancer screening programs and earlier diagnosis of the 14 most common types of cancers in the adult population, before and during the COVID-19 pandemic. National data concerning number of admissions and operations in Italy for adult patients admitted with oncologic problems during the COVID-19 pandemic (2020 to 2022) and in the pre-pandemic period (2015 to 2019) were analyzed. We selected 14 types of cancer that present the most common indications for surgery in Italy. This study included 1,365,000 adult patients who had surgery for the 14 most common types of cancer in the period 2015–2022, and interviews concerning adherence rates to screening for breast, colorectal, and cervical cancer were conducted for 133,455 individuals. A higher decrease in the number of operations for the 14 types of cancer (−45%) was registered during the first three acute phases of the pandemic, and it was more evident for screenable cancers like breast, colorectal, and cervical cancer (p < 0.001). During the first year of the COVID-19 pandemic, the number of screened individuals for breast, colorectal, and cervical cancer decreased by 33.8% (from 7,507,893 to 4,969,000) and the number of diagnoses and operations for these three types of cancer decreased by 10.5% (from 107,656 to 96,405). The increase and return to normality of the number of screened individuals in the last year of the pandemic (2022) and in the first post-pandemic year (2023) was associated with a return to the pre-pandemic levels of diagnoses and operations. The adherence rates were lower for individuals living in rural areas, with low socio-economic status, and unmarried persons; however, the most statistically significant factor for reduced adherence was a lower level of educational attainment. Free screening through nationally organized programs reduced social disparities. There were no significant differences between the pre-pandemic and pandemic periods for several types of cancers (stomach, esophagus, pancreas, liver) that are diagnosed for the occurrence of symptoms and for which nationally organized programs might increase the possibility of earlier diagnosis and improved clinical outcomes. Education, information, and appropriate expenditure for preventive care have the potential to reduce cancer mortality. Nationally organized screening programs for several types of cancers, which are often detected for the occurrence of symptoms, may increase the possibility of diagnosis at earlier stages. [ABSTRACT FROM AUTHOR]

Simple Summary: It has long been known that breast tumors harbor various types of microbes. However, it was little known where these tumor-resident microbes came from and how they could contribute to breast cancer pathogenesis. Now, recent discoveries have unveiled that these tumor-resident microbes come from different parts of the body and live inside tumor cells to participate not only in tumorigenesis events, i.e., DNA damage and genomic instability, but also in tumor progression and metastasis. Such important findings have helped identify these intratumoral microbes as potential new targets for breast cancer treatment and prevention. Cumulative evidence attests to the essential roles of commensal microbes in the physiology of hosts. Although the microbiome has been a major research subject since the time of Luis Pasteur and William Russell over 140 years ago, recent findings that certain intracellular bacteria contribute to the pathophysiology of healthy vs. diseased tissues have brought the field of the microbiome to a new era of investigation. Particularly, in the field of breast cancer research, breast-tumor-resident bacteria are now deemed to be essential players in tumor initiation and progression. This is a resurrection of Russel's bacterial cause of cancer theory, which was in fact abandoned over 100 years ago. This review will introduce some of the recent findings that exemplify the roles of breast-tumor-resident microbes in breast carcinogenesis and metastasis and provide mechanistic explanations for these phenomena. Such information would be able to justify the utility of breast-tumor-resident microbes as biomarkers for disease progression and therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of breast cancer patients have axillary lymph node metastases present at the time of diagnosis. Historically, axillary lymph node dissection was performed in these patients with significant morbidity associated with the procedure including permanent lymphedema. These patients are now often treated with neoadjuvant chemotherapy to attempt to downstage the axilla and avoid axillary lymph node dissection. To reduce the false negative rate of a sentinel lymph node biopsy, a targeted axillary dissection is often performed to ensure that biopsy-proven metastatic axillary nodes are removed. The aim of our study was to determine how often the clipped node was also a sentinel lymph node, to identify factors that were associated with pathologic complete response following neoadjuvant chemotherapy, and to assess how the clipped node impacted final treatment decisions. These findings aim to help understand and guide surgeons on axillary evaluation after neoadjuvant chemotherapy. We examined clinically node-positive (cN+) breast cancer patients undergoing neoadjuvant chemotherapy and clipped lymph node (CLN) localization to determine the rate of CLN = non-sentinel lymph node (SLN), the factors associated with cN+ to pN0 conversion, and the treatment impact. We conducted a single institution review of cN+ patients receiving NAC from 2016 to 2022 with preoperative CLN localization (N = 81). Demographics, hormone receptor (HR) and HER2 status, time to surgery, staging, chemotherapy regimen, localization method, pathology, and adjuvant therapy were analyzed. Pathologic complete response (pCR) of the CLN was observed in 41 patients (50.6%): 18.8% HR+/HER2−, 75% HR+/HER2+, 75% HR−/HER2+, and 62.5% triple-negative breast cancer (p-value = 0.006). CLN = SLN in 68 (84%) patients, while CLN = non-SLN in 13 (16%). In 14 (17.3%) patients, the final treatment was altered based on +CLN status: 11 patients underwent axillary lymph node dissection (ALND), and 3 had systemic treatment changes. pCR rates varied, with the highest conversion rates observed in HER2+ disease and the lowest in HR+/HER2− disease. In 2 (2.5%) patients, adjuvant therapy changes were made based on a non-sentinel CLN, while in 97.5% of patients, a SLN biopsy alone represented the status of the axilla. This demonstrates that a +CLN often alters final plans and that, despite also being a SLN in most cases, a subset of patients will be undertreated by SLN biopsy alone. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, cancer has gradually become a terrible killer of human health. Due to various factors such as tumor heterogeneity and the complexity of the microenvironment, completely conquering cancer has always been a major problem in the scientific research community. Therefore, more detailed research and individualized treatment are essential. Everyone knows that tumor cells in the process of rapid proliferation need replenishing nutrients to sustain their energy supply. Intervention of tumor cell metabolism is gradually becoming a way to treat cancer. As an important transporter of glutamine, ASCT2 can uptake glutamine from the tumor microenvironment to support the growth and metabolism of cancer cells. Deficiency of ASCT2 can significantly inhibit tumor progression. However, not all patients benefit from this treatment. Our study aims to explore the metabolic heterogeneity of breast cancer and its related mechanisms, as well as to find metabolic-sensitive populations for further precision treatment. As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine–lipid feedback loop. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer in females. Although rare in the younger population, individuals with a susceptible genetic background are at higher risk of breast cancer. A study was conducted on 63 Finnish breast cancer patients without any BRCA1/2 variants who had an onset of breast cancer at age 40 or younger. These patients were sequenced, and variants in DNA repair genes were identified. These variants were then prioritized based on their allele frequency in the population and pathogenicity prediction scores to identify potential new risk variants. Seventy-two deleterious variants were found, including eight novel variants. For the novel variants, protein structure modeling was conducted, and all deleterious variants were validated in another Finnish BRCA1/2-negative breast cancer population. Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes. [ABSTRACT FROM AUTHOR]

Simple Summary: The naturally occurring derivative of estrogen, 2-methoxyestradiol (2-ME), has been shown to have good anti-cancer properties. However, it is broken down too quickly within the blood to be clinically useful. We designed 2-ME analogs with modifications which could avoid rapid metabolism, would preferably stay in the tumor, and were more toxic to cancer cells. Here, we looked more closely at how these compounds work within cancer cells, and how they communicate within themselves and with their environment. ESE-15-one and ESE-16 interfere with the functioning of the intracellular cytoskeleton (actin and microtubules), sending messages that stop cell division, intracellular transport of proteins, and cell migration and invasion, eventually inducing cell suicide. They also inhibited the movement of cells that make blood vessels that would support tumor growth. Using eggs with chicken embryos, we could show that the compounds reduced the tumor size and diminished the spread of cancer cells in a living system. The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast reconstruction is considered for any patient who is undergoing surgical treatment for breast cancer. Many factors must be considered when discussing reconstruction, including patient risk factors, the type of material used for breast restoration, and the timing of surgery relative to other adjuvant treatments, such as radiotherapy. Plans for post-mastectomy radiotherapy significantly impact whether a breast reconstruction may be performed at the same time as a mastectomy (immediate reconstruction) or delayed for a later time (delayed reconstruction). The risk of surgical complications from irradiating a reconstructed breast is often weighed against the benefits of fewer surgeries and the potential for an improved quality of life when discussing eligibility for immediate reconstruction. This narrative review covers the current trends and controversies regarding breast reconstruction and radiotherapy. We aim to provide the context and relevant evidence for general community-practice oncologists and oncology providers who counsel patients on the sequencing and modalities of radiotherapy and breast reconstruction. Immediate breast reconstruction (IBR) following a mastectomy, combined with radiotherapy, presents a multifaceted approach to breast cancer treatment, balancing oncological safety and aesthetic outcomes. IBR, typically involving the use of implants or autologous tissue, aims to restore breast morphology directly after a mastectomy, minimizing the psychological and physical impacts. However, integrating radiotherapy with IBR is complex due to the potential adverse effects on reconstructed tissues. Radiotherapy, essential for reducing local recurrence, can induce fibrosis, capsular contracture, and compromised aesthetic results. This narrative review covers the current trends in the sequencing of breast reconstruction and radiotherapy. We discuss patient selection, timing of radiotherapy, and reconstructive techniques, with special attention paid to quality-of-life outcomes that are increasingly reported in clinical trials. Emerging evidence supports the feasibility of IBR with careful patient selection and tailored therapeutic approaches, although ongoing research is necessary to refine protocols and enhance outcomes. Overall, IBR in the context of radiotherapy remains a promising but intricate treatment modality, requiring a nuanced balance between cancer control and aesthetic restoration. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aims to identify preoperative factors that may predict positive resection margins in patients undergoing breast-conserving surgery for early-stage breast cancer. By retrospectively analyzing patient records from 2009 to 2017, the study investigates preoperative factors associated with positive resection margins. The findings indicate that neoadjuvant chemotherapy and the presence of ductal carcinoma in situ are significantly associated with positive resection margins. These results underscore the importance of these preoperative factors in surgical planning and management, potentially leading to improved outcomes for breast cancer patients. The primary objective of this study was to identify preoperative factors that could be associated with positive resection margins. We also tried to analyze the local recurrence and overall survival in patients who received conservative treatment for early-stage breast cancer and correlate these parameters with preoperative factors. A retrospective examination was conducted on the medical records and pathological reports of 143 patients who underwent breast-conserving surgery (BCS) for breast cancer in our department from 2009 to 2017. Postoperative outcomes were assessed through phone contact and statistical analyses, including GraphPad Prism, and Fisher's exact test, the Chi-square test, and the log-rank test were employed. The results revealed positive resection margins in 7.69% (11 cases) of the 143 patients, with an overall mortality rate of 16.66% for those with positive margins and 6.59% for those with negative margins. Statistical analysis indicated no significant differences in the overall (p = 0.5) or specific (p = 0.53) survival between the positive and negative margin groups. The positive margins were significantly associated with neoadjuvant chemotherapy (p < 0.0001) and the presence of ductal carcinoma in situ (DCIS) (p = 0.01). Among the analyzed factors, two out of sixteen were significantly linked to positive resection margins in BCS, emphasizing their importance in surgical management planning for early-stage breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Postoperative adjuvant chemotherapy generally improves survival in patients with breast cancer. However, adjuvant chemotherapy does not benefit all patients. There are considerations and guidelines that guide us as to whether or not chemotherapy is recommended to a particular patient. The decision is based on clinicopathologic features and may be aided by multigene assays. The Oncotype DX test is used worldwide. It makes the recommendation more accurate; however, there are possibilities to refine the process to make a more accurate decision. We investigated how we could move forward in recommending adjuvant chemotherapy. Background: The use of the Oncotype DX test reduces the rate of adjuvant chemotherapy recommendations. Few in-depth analyses have been performed on this decision-making process. Methods: We retrospectively analyzed patient data based on available Oncotype DX test results (RS) irrespective of nodal status at a single center. We collected recommendations from six oncologists, first without RS (pre-RS) and then with RS results (post-RS). We investigated changes in recommendations, agreement between oncologist decisions, and the effect of different National Comprehensive Cancer Network (NCCN) recommendation categories (for, against, and considering chemotherapy). Results: Data from 201 patients were included in the analysis. Recommendation of chemotherapy decreased by an average of 39.5%. Agreement improved substantially with RS, with a kappa value pre-RS of 0.37 (fair agreement) and post-RS of 0.75 (substantial agreement). Discordance remained substantial in cases where the NCCN recommendations considered chemotherapy only (32%). Pre-RS consensus against chemotherapy predicted low RS results (50 out of 51 patients). Post-RS consensus was highest in the NCCN chemotherapy recommendation group. Conclusions: The Oncotype DX test substantially improves decision accuracy in recommending adjuvant chemotherapy. It may be further improved with a consensus decision. In the case of pre-RS consensus against chemotherapy, the test can be spared. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast-conserving therapy to resect only the tumor in breast cancer is a standard procedure. To replace loss of volume in the breast and to avoid dislocation of the nipple/areola, local flaps are useful. One technique that has only rarely been used is the local, pedicled rhombus-shaped flap, according to Limberg. The flap is easy and safe, and the donor site is always closed primarily. On the breast, the rhombus-shaped flap can be used as an all-layer flap to cover defects, or it can be deepithelialized to be used as a buried flap. The flap can be harvested from the breast itself or the chest wall. Especially in the lateral breast, the flap is very useful. In the axilla, it can be used to cover full-thickness defects after resection when skin is involved, avoiding a contracture in the axilla. Primarily, breast-conserving therapy is an oncological intervention, but eventually it is judged by its cosmetic result. Remaining cavities from tumor resection can promote seromas, delay healing and cause lasting discomfort. Additionally, volume loss, dislocation of nipple/areola and fat necrosis lead to (cosmetically) unfavorable results, aggravated by radiotherapy. Oncoplastic surgery can reduce these sequelae. A local flap that has rarely been used in breast cancer surgery is the Limberg rhombic flap. The tumor defect is planned as a rhombus. The sides of the rhombus are of equal length and ideally have an angle of 60° and 120°. The flap that closes the defect is planned as an extension of equal length of the short diagonal. The second incision of the flap is placed according to the defect angle of 60°, running parallel to the defect at the same length. This creates a second rhombus. The flap is transposed into the defect, and the donor area is primarily closed. It is axially perfused and safe with a 1:1 length-to-width ratio. Compared to local perforator flaps, defect closure is easily managed without microsurgical skills. In the breast, the flap can be used in volume replacement and volume displacement techniques as an all-layer flap to cover defects, or it can be deepithelialized and buried. In the axilla, it can cover full-thickness defects when skin is involved. The advantages of the rhombic flap are its safety and simplicity to add volume and close defects, thus reducing the complexity of oncoplastic surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of brain metastasis is extremely poor, partly because of the concurrence of multiple brain lesions and their limited access to current systemic therapies. Applying a phosphatidylserine (PS)-targeting antibody, we identified abundant PS on the vasculature of brain metastases in mouse models. Given its location on the luminal surface of tumor blood vessels, exposed PS appears to be an ideal target for both diagnostic and therapeutic agents, which otherwise have difficulty penetrating the blood–tumor barrier (BTB) of brain metastases. Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: Adolescents and young adults (AYAs) experiencing cancer have support needs that differ from older adult cancer patients. The aim of our qualitative study was to determine the holistic needs of AYA cancer survivors and to develop a patient-centered conceptual model of AYA survivorship care. Analysis of our interview results reveals eight key domains critical to holistic patient-centered AYA survivorship care. We offer a conceptual model that differs from current conceptual models of AYA survivorship care by centering the patient and their support systems, emphasizing the need for continuing supportive navigation, and the importance of repeated support along the identified domains over time. Purpose: Conceptual models provide frameworks to illustrate relationships among patient-, provider-, system-, and community-level factors that inform care delivery and research. Existing models of cancer survivorship care focus largely on pediatric or adult populations whose needs differ from adolescents and young adults (AYAs). We developed a patient-centered conceptual model of AYA survivorship care. Methods: We conducted a narrative literature review of current conceptual and theoretical models of care. We engaged AYA cancer survivors (n = 25) in semi-structured one-hour telephone interviews. Most participants were in their 20s and 30s, and the majority (84%) were women. Recruitment was stratified by age and time since cancer diagnosis. We conducted a thematic analysis of interview transcripts to identify themes that exemplified patient-centered care. Results: Most participants identified as white and female. Leukemia and breast cancer were the most common cancer types. Main themes included the need for (1) care coordination, (2) ongoing mental health support, (3) connection to AYA peer support, (4) support during fertility preservation efforts, (5) support with financial burden, (6) support for quality of life, (7) information about and support with side effects and late effects, and (8) attention to the unique needs of young adults. Conclusions: We present a patient-centered conceptual model of AYA survivorship care needs that can inform future cancer care delivery and research. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer significantly affects women globally, but physical activity (PA) has been shown to improve the quality of life, aid recovery, and enhance survival rates in patients. Studies reveal that PA influences DNA methylation, both globally and at gene-specific levels, potentially reversing abnormal methylation linked to cancer. This review compiles research on PA's impact on DNA methylation in breast cancer patients. The findings suggest that PA increases global DNA methylation in tumour tissues and alters gene-specific promoter methylation across various genes. Bioinformatic analysis indicates that these genes are primarily involved in metabolic pathways, cell cycle regulation, mitosis, cellular stress responses, and diverse binding processes. The Human Protein Atlas supports these findings, showing gene functionality in 266 tissues, including various breast tissues. Overall, PA's ability to modify DNA methylation patterns in breast cancer patients may aid in the restoration of normal cellular functions and enhance recovery and survival outcomes. Breast cancer (BC) continues to significantly impact women worldwide. Numerous studies show that physical activity (PA) significantly enhances the quality of life, aids recovery, and improves survival rates in BC patients. PA's influence extends to altering DNA methylation patterns on both a global and gene-specific scale, potentially reverting abnormal DNA methylation, associated with carcinogenesis and various pathologies. This review consolidates the findings of the current literature, highlighting PA's impact on DNA methylation in BC patients. Our systematic analysis indicates that PA may elevate global DNA methylation within tumour tissues. Furthermore, it appears to modify gene-specific promoter methylation across a wide spectrum of genes in various tissues. Through bioinformatic analysis, to investigate the functional enrichment of these affected genes, we identified a predominant enrichment in metabolic pathways, cell cycle regulation, cell cycle checkpoints, mitosis, cellular stress responses, and molecular functions governing diverse binding processes. The Human Protein Atlas corroborates this enrichment, indicating gene functionality across 266 tissues, notably within various breast tissues. This systematic review unveils PA's capacity to systematically alter DNA methylation patterns across multiple tissues, particularly in BC patients. Emphasising its influence on crucial biological processes and functions, this alteration holds potential for restoring normal cellular functionality and the cell cycle. This reversal of cancer-associated patterns could potentially enhance recovery and improve survival outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Germline mutation rates and spectra across three cohorts of Chinese patients: a high-risk breast cancer cohort, an unselected breast cancer cohort, and a benign breast lesion cohort were compared. The high-risk cohort had the highest mutation rate at 11.9%, while the unselected cancer and benign lesion cohorts had rates of 6.5% and 8.1%, respectively. Notably, 29.3% of the unselected breast cancer patients met genetic testing criteria, and this subgroup had a mutation rate similar to the high-risk cohort. High-penetrance gene mutations were only found in the high-risk and unselected cancer cohorts. Unexpectedly, a 2% mutation rate was observed in the benign lesion cohort. These findings highlight the need for broader genetic testing of all breast cancer patients, not just those deemed high-risk, to identify more individuals harboring clinically relevant germline mutations. Mutation study for high-risk breast and ovarian cancer (HBOC) has been extensively studied in patients of different ethnicities. Here we compared the germline mutation rate and mutation spectrum of patients (n = 4341) with benign breast diseases or breast cancers, with and without other risk factors. Three cohorts of Chinese patients were recruited. The first cohort, high-risk cohort (HR, n = 3935) included high-risk breast cancer patients fulfilling high-risk HBOC criteria and who are recruited at our genetics clinic. The second cohort, unselected cancer cohort (CC, n = 307) was from general recruitment of patients with breast cancer at breast surgery clinics. The third cohort, benign breast lesion cohort (NC, n = 99) comprised 99 patients with benign breast diseases such as fibroadenoma, fibroadenomatoid hyperplasia, and intraductal papilloma. Thirty HBOC related genes were sequenced on the above-mentioned patient cohorts. The germline mutation rates of HR, CC, and NC cohort were 11.9%, 6.5%, and 8.1%, respectively. In the CC cohort, 29.3% (90/307) of patients fulfilled the National Comprehensive Cancer Network (NCCN) high-risk genetic test criteria 2022 v.2. The mutation rate for this group of patients was 11.1%, similar to that of the HR cohort, while the mutation rate for those not fulfilling testing criteria was 4.6%, like that of the NC cohort. High penetrance genes (BRCA1/2, CDH1, PALB2, PTEN, and TP53) mutations were only found in the HR (10.6%) and CC (3.3%) cohorts but were not found in the NC cohort. ATM, BRIP1, RAD51C, and RAD51D mutations were identified in all cohorts. RAD51C and RAD51D mutations showed conflicting penetrance. An unexpectedly high mutation rate of total 2% was found in the NC cohort but it was only 0.3% and 0.5% in the HR cohort and CC cohort, respectively. Our results show a clinical need to enhance genetic testing of unselected breast cancer patients to identify the high-risk patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most frequent tumors worldwide, based on the number of new cases and deaths. Unfortunately, the low selectivity of action and the rapid development of multiple drug resistances remain the main disadvantages of anticancer compounds. The search for new agents with pronounced antitumor activity is an urgent task in modern biology and medicine. We focused on the investigation of the antitumor potential of novel hybrid pyrrolidinedione–thiazolidinone derivatives. The synthesized derivatives are effective and selective agents that exhibit their antitumor effects in breast carcinoma cells via (1) inhibiting viability, proliferation, and the ability to form colonies; (2) inducing extrinsic and intrinsic apoptotic pathways; and (3) decreasing the level of proteins associated with autophagy, invasion, and metastasis. Our results indicate that synthesized derivatives are potential candidates for deeper exploration of their therapeutic efficiency. The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione–thiazolidinone hybrid molecules Les-6287, Les-6294, and Les-6328 towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [3H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC50 ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC50 > 93.01 µM). Les-6287 at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, while Les-6294 and Les-6328 did that at 2.5 and 5 µM, respectively. Les-6287 suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower. Les-6287 induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells. Les-6287 decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione–thiazolidinones might be promising agents for treating breast tumors of different types. [ABSTRACT FROM AUTHOR]

Simple Summary: The study analyzed income disparities in 5-year survival rates (5YSR) among cancer patients in South Korea from 2002 to 2018. Overall, 5YSR improved from 2002–2006 to 2014–2018, particularly for lung, liver, and stomach cancers. The Slope Index of Inequality (SII) indicated significant income-related disparities, with higher survival rates associated with higher incomes, notably for lung and liver cancers. The SII for lung, liver, and stomach cancer increased, while that of thyroid, breast, cervical, prostate, and colorectal cancer decreased over the study period. The findings highlight persistent income-related gaps in cancer survival despite overall improvements, emphasizing the need for targeted interventions to address socioeconomic inequalities in cancer care outcomes. Background: The overall survival rates among cancer patients have been improving. However, the increase in survival is not uniform across socioeconomic status. Thus, we investigated income disparities in the 5-year survival rate (5YSR) in cancer patients and the temporal trends. Methods: This study used a national cancer cohort from 2002 to 2018 that was established by linking the Korea Central Cancer Registry and the National Health Insurance Service (NHIS) claim database to calculate the cancer survival rate by income level in the Republic of Korea. Survival data were available from 2002 onward, and the analysis was based on the actuarial method. We compared the survival of the earliest available 5-year period of 2002–2006 and the latest available 5-year period of 2014–2018, observing until 31 December 2021. Income level was classified into six categories: Medical Aid beneficiaries and five NHIS subtypes according to insurance premium. The slope index of inequality (SII) and relative index of inequality were used to measure absolute and relative differences in 5YSR by income, respectively. Results: The 5YSR between the 2002–2006 and 2014–2018 periods for all cancers improved. A significant improvement in 5-year survival rates (5YSR) over the study period was observed in lung, liver, and stomach cancer. The SII of survival rates for lung (17.5, 95% confidence interval (CI) 7.0–28.1), liver (15.1, 95% CI 10.9–19.2), stomach (13.9, 95% CI 3.2–24.7), colorectal (11.4, 95% CI 0.9–22.0), and prostate (10.7, 95% CI 2.5–18.8) cancer was significantly higher, implying higher survival rates as income levels increased. The SII for lung, liver, and stomach cancer increased, while that of thyroid, breast, cervical, prostate, and colorectal cancer decreased over the study period. Conclusions: Although substantial improvement in the 5YSR was observed across cancer types and income levels from 2002 to 2018, this increase was not uniformly distributed across income levels. Our study revealed persistent income disparities in the survival of cancer patients, particularly for lung and liver cancer. [ABSTRACT FROM AUTHOR]