Racial/ethnic differences in 21-gene recurrence score and survival among patients with estrogen receptor-positive breast cancer.

BACKGROUND: Despite numerous studies on racial/ethnic disparities among patients with breast cancer, there is a paucity of literature evaluating racial/ethnic differences in 21-gene recurrence score (RS) and survival differences stratified by RS risk categories. We thus performed an observational cohort study to examine racial/ethnic disparities in the context of RS. METHODS: The National Cancer Database (NCDB) was queried for female patients diagnosed between 2006 and 2018 with estrogen receptor (ER)-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy and had RS data available. Logistic multivariable analysis (MVA) was built to evaluate variables associated with RS ≥ 26. Cox MVA was used to evaluate OS. Subgroup analyses were performed to compare the magnitude of racial/ethnic differences stratified by RS. P values less than 0.017 were considered statistically significant based on Bonferroni correction. RESULTS: A total of 140,133 women were included for analysis. Of these, 115,651 (82.5%), 8,213 (5.9%), 10,814 (7.7%), and 5,455 (3.9%) were NHW, Hispanic, Black, and API women, respectively. Median (IQR) follow up was 66.2 months (48.0-89.8). Logistic MVA showed that, compared with NHW women, Black women were associated with higher RS (≥ 26 vs < 26: adjusted odds ratio [aOR] 1.19, 95% confidence interval [CI] 1.12-1.26, p < 0.001), while HW (aOR 0.93, 95% CI 0.86-1.00, p = 0.04) and API women (aOR 1.03, 95% CI 0.95-1.13, p = 0.45) were not. Cox MVA showed that, compared with NHW women, Black women had worse OS (adjusted hazards ratio [aHR] 1.10, 95% CI 1.02-1.19, p = 0.012), while HW (aHR 0.85, 95% CI 0.77-0.94, p = 0.001) and API (aHR 0.66, 95% CI 0.56-0.77, p < 0.001) women had better OS. In subgroup analysis, similar findings were noted among those with RS < 26, while only API women were associated with improved OS among others with RS ≥ 26. CONCLUSION: To our knowledge, this is the largest study using nationwide oncology database to suggest that Black women were associated with higher RS, while HW and API women were not. It also suggested that Black women were associated with worse OS among those with RS < 26, while API women were associated with improved OS regardless of RS when compared to NHW women.

Prediction of hematologic toxicity in luminal type breast cancer patients receiving neoadjuvant chemotherapy using CT L1 level skeletal muscle index.

This study aims to explore the correlation between the CT-L1 and L3 body composition parameters and analyze the relationship between L1 body composition and hematologic toxicity in luminal-type breast cancer patients undergoing neoadjuvant chemotherapy. Data from 140 luminal-type breast cancer patients who underwent surgical treatment after neoadjuvant chemotherapy were analyzed retrospectively. Spearman analysis was used to assess the correlation between CT-L1 and CT-L3 body composition parameters pre-neoadjuvant chemotherapy. Additionally, univariate and multivariate logistic regression analyses were performed to identify factors influencing hematologic toxicity. CT-L1 body composition parameters were positively correlated with CT-L3 body composition parameters in 34 patients. Severe hematological toxicity occurred in 46 cases among the patient cohort. A skeletal muscle index (SMI) of < 32.91 cm2/m2, initial tumor size ≥ 3.335 cm, and a glucose-to-neutrophil ratio (GLR) ≥ 2.88 were identified as independent risk factors for severe hematologic toxicity during neoadjuvant chemotherapy in luminal-type breast cancer patients. The sample size in this study is small, and the predictive capacity of GLR in hematologic toxicity requires further research for comprehensive validation. CT-L1 analysis represents a viable alternative to CT-L3 analysis for body composition assessment. Patients with a low skeletal muscle index were more prone to experiencing severe hematologic toxicity during neoadjuvant chemotherapy.

Maitake Beta-Glucan Enhances the Therapeutic Effect of Trastuzumab via Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

Trastuzumab, an anti-HER2 monoclonal antibody, is the mainstay treatment for of HER2-positive breast cancer. However, trastuzumab resistance is often observed during treatment. Therefore, new therapeutic strategies are needed to enhance the clinical benefits of trastuzumab. Maitake ß-glucan MD-Fraction, isolated from Grifola frondosa, inhibits tumor growth by enhancing immune responses. In this study, we examined the effect of MD-Fraction on trastuzumab treatment of HER2-positive breast cancer. MD-Fraction did not directly inhibit the survival of HER2-positive breast cancer cells, alone or in the presence of trastuzumab in vitro. In HER2-positive xenograft models, the combination of MD-Fraction and trastuzumab was more effective than trastuzumab alone. Peripheral blood lymphocytes and splenic natural killer cells isolated from BALB/c nu/nu mice treated with MD-Fraction showed enhanced trastuzumab-induced antibody-dependent cellular cytotoxicity (ADCC) ex vivo. MD-Fraction-treated macrophages and neutrophils did not show enhanced trastuzumab cytotoxicity in the presence of heat-inactivated serum, but they showed enhanced cytotoxicity in the presence of native serum. These results suggest that MD-Fraction-treated macrophages and neutrophils enhance trastuzumab-induced complement-dependent cellular cytotoxicity (CDCC). Treatment of HER2-positive breast cancer cells with MD-Fraction in the presence of trastuzumab and native serum increased C3a release and tumor cell lysis in a dose-dependent manner, indicating that MD-Fraction enhanced trastuzumab-induced complement-dependent cytotoxicity (CDC) by activating the complement system. This study demonstrates that the combination of trastuzumab and MD-Fraction exerts a greater antitumor effect than trastuzumab alone by enhancing ADCC, CDCC, and CDC in HER2-positive breast cancer.

Investigating the level of vitamin D receptor gene expression in two tumoral and healthy breast tissues in breast cancer patients and its association with prognostic factors.

BACKGROUND: Breast cancer is one of the most common cancers known among women. This study aimed to investigate the level of vitamin D receptor gene expression in two tumoral and healthy breast tissues in breast cancer patients and its association with prognostic factors. METHODS: This descriptive cross-sectional study was conducted in 2022 on 50 patients with high suspicion of breast cancer who were candidates for mastectomy and lumpectomy in a learning hospital. From the patients, two tissue samples were prepared, and there was a total of 100 samples. The samples were subjected to H/E staining and evaluated by a pathologist. The presence or absence of malignancy in each sample was confirmed by two pathologists, and HER2/ER/PR indices were determined. Descriptive and analytical statistical methods and SPSS version 22 software were used. RESULTS: The average age of the patients was 51.60 ± 11.22 years old, and the average tumor size was 3.17 ± 1.28. Most tumors were grade 2 (48%). The expression of HER2, ER, and PR was positive in 24, 64, and 54%, respectively. The largest number of cases were in stage 2A. The expression level of vitamin D receptor (VDR) gene in healthy tissue (2.08 ± 1.01) was higher than tumoral tissue (0.25 ± 1.38) (P = 0.001). In tumoral and healthy tissue, VDR expression was not significant according to tumor grade, HER2, ER, PR, LVI, LN, disease stage, age, and tumor size. CONCLUSIONS: The expression level of VDR in healthy tissue was significantly higher than tumoral tissue. However, there was no significant relationship between VDR and tumor grade, HER2, ER, PR, LVI, LN, disease stage, age, and tumor size.

Gut microbiota and female health.

The gut microbiota is recognized as an endocrine organ with the capacity to influence distant organs and associated biological pathways. Recent advancements underscore the critical role of gut microbial homeostasis in female health; with dysbiosis potentially leading to diseases among women such as polycystic ovarian syndrome, endometriosis, breast cancer, cervical cancer, and ovarian cancer etc. Despite this, there has been limited discussion on the underlying mechanisms. This editorial explores the three potential mechanisms through which gut microbiota dysbiosis may impact the development of diseases among women, namely, the immune system, the gut microbiota-estrogen axis, and the metabolite pathway. We focused on approaches for treating diseases in women by addressing gut microbiota imbalances through probiotics, prebiotics supplementation, and fecal microbiota transplantation (FMT). Future studies should focus on determining the molecular mechanisms underlying associations between dysbiosis of gut microbiota and female diseases to realize precision medicine, with FMT emerging as a promising intervention.

Effects of sleep disturbance, cancer-related fatigue, and psychological distress on breast cancer patients' quality of life: a prospective longitudinal observational study.

More attention has gone to researching the cancer-related fatigue (CRF)-sleep disturbance (SD)-psychological distress (PD) symptom cluster in breast cancer patients during the chemotherapy period, but the change trend and heterogeneous development track in the whole treatment stage remain unclear, and it is also unclear whether the appearance of and changes in one symptom cause changes in other symptoms and quality of life (QoL). This study, using breast cancer patients' data collected through a validated questionnaire, examined the relationships between SD, CRF, PD, and QoL using latent growth modeling analyses. CRF developmental trajectories showed an upward trend over five surveys (slope = 0.649, P < 0.001); PD showed a significant weakening trend (slope = - 0.583, P < 0.001); SD showed an increasing trend (slope = 0.345, P < 0.001), and QoL showed a statistically significant weakening trend (slope = - 0.373, P < 0.001). The initial CRF (coefficient = - 0.233, P < 0.01), PD (coefficient = - 0.296, P < 0.01), and SD (coefficient = - 0.388, P < 0.001) levels had a statistically significant negative effect on initial QoL level. The linear development rate of PD was statistically significant and negatively affected that of QoL (coefficient = - 0.305, P < 0.05), whereas the quadratic development rate of SD negatively affected that of QoL (coefficient = - 0.391, P < 0.05). Medical staff should identify the change characteristics of different variables based on SD, CRF, PD, and QoL change trajectories, and advance the intervention time, as changes in variables affect other variables' subsequent changes.

Community cohesion looseness in gene networks reveals individualized drug targets and resistance.

Community cohesion plays a critical role in the determination of an individual's health in social science. Intriguingly, a community structure of gene networks indicates that the concept of community cohesion could be applied between the genes as well to overcome the limitations of single gene-based biomarkers for precision oncology. Here, we develop community cohesion scores which precisely quantify the community ability to retain the interactions between the genes and their cellular functions in each individualized gene network. Using breast cancer as a proof-of-concept study, we measure the community cohesion score profiles of 950 case samples and predict the individualized therapeutic targets in 2-fold. First, we prioritize them by finding druggable genes present in the community with the most and relatively decreased scores in each individual. Then, we pinpoint more individualized therapeutic targets by discovering the genes which greatly contribute to the community cohesion looseness in each individualized gene network. Compared with the previous approaches, the community cohesion scores show at least four times higher performance in predicting effective individualized chemotherapy targets based on drug sensitivity data. Furthermore, the community cohesion scores successfully discover the known breast cancer subtypes and we suggest new targeted therapy targets for triple negative breast cancer (e.g. KIT and GABRP). Lastly, we demonstrate that the community cohesion scores can predict tamoxifen responses in ER+ breast cancer and suggest potential combination therapies (e.g. NAMPT and RXRA inhibitors) to reduce endocrine therapy resistance based on individualized characteristics. Our method opens new perspectives for the biomarker development in precision oncology.

Laparoscopically harvested omental flap for immediate breast reconstruction: a retrospective single-center study of 300 cases.

BACKGROUND: The laparoscopically harvested omental flap (LHOF) has been used in partial or total breast reconstruction, but most studies on LHOF were case reports or small case series. However, the clinical feasibility and oncological safety of LHOF in oncoplastic breast surgery remains controversial. This study reported our experience applying LHOF for immediate breast reconstruction. METHODS: Between June 2018 and March 2022, 300 patients underwent oncoplastic breast surgery using LHOF at our institution. Their clinicopathological data, complications, cosmetic outcomes, and oncologic outcomes were evaluated. RESULTS: All patients underwent total breast reconstruction using LHOF after nipple-sparing mastectomy. The median operation time was 230 min (ranging from 155 to 375 min). The median operation time for harvesting the omental flap was 55 min (ranging from 40 to 105 min). The success rate of the laparoscopically harvested pedicled omental flap was over 99.0%. Median blood loss was 70 ml, ranging from 40 to 150 ml. The volume of the flap was insufficient in 102 patients (34.0%). The overall complication rate was 12.3%. Subcutaneous fluid in the breast area (7%) was the most common reconstruction-associated complication, but most cases were relieved spontaneously. The incidence rate of omental flap necrosis was 3.3%. LHOF-associated complications occurred in two cases, including one case of incisional hernia and one case of vascular injury. Cosmetic outcomes were satisfactory in 95.1% of patients on a four-point scale by three-panel assessment and 97.2% using the BCCT.core software. Two local and one systemic recurrence were observed during a median follow-up period of 32 months. CONCLUSIONS: The LHOF for immediate breast reconstruction is a safe and feasible method that involves minimal donor-site morbidity, satisfactory cosmetic outcomes, and promising oncologic safety.

Impact of doxorubicin-loaded ferritin nanocages (FerOX) vs. free doxorubicin on T lymphocytes: a translational clinical study on breast cancer patients undergoing neoadjuvant chemotherapy.

Despite the advent of numerous targeted therapies in clinical practice, anthracyclines, including doxorubicin (DOX), continue to play a pivotal role in breast cancer (BC) treatment. DOX directly disrupts DNA replication, demonstrating remarkable efficacy against BC cells. However, its non-specificity toward cancer cells leads to significant side effects, limiting its clinical utility. Interestingly, DOX can also enhance the antitumor immune response by promoting immunogenic cell death in BC cells, thereby facilitating the presentation of tumor antigens to the adaptive immune system. However, the generation of an adaptive immune response involves highly proliferative processes, which may be adversely affected by DOX-induced cytotoxicity. Therefore, understanding the impact of DOX on dividing T cells becomes crucial, to deepen our understanding and potentially devise strategies to shield anti-tumor immunity from DOX-induced toxicity. Our investigation focused on studying DOX uptake and its effects on human lymphocytes. We collected lymphocytes from healthy donors and BC patients undergoing neoadjuvant chemotherapy (NAC). Notably, patient-derived peripheral blood mononuclear cells (PBMC) promptly internalized DOX when incubated in vitro or isolated immediately after NAC. These DOX-treated PBMCs exhibited significant proliferative impairment compared to untreated cells or those isolated before treatment initiation. Intriguingly, among diverse lymphocyte sub-populations, CD8 + T cells exhibited the highest uptake of DOX. To address this concern, we explored a novel DOX formulation encapsulated in ferritin nanocages (FerOX). FerOX specifically targets tumors and effectively eradicates BC both in vitro and in vivo. Remarkably, only T cells treated with FerOX exhibited reduced DOX internalization, potentially minimizing cytotoxic effects on adaptive immunity.Our findings underscore the importance of optimizing DOX delivery to enhance its antitumor efficacy while minimizing adverse effects, highlighting the pivotal role played by FerOX in mitigating DOX-induced toxicity towards T-cells, thereby positioning it as a promising DOX formulation. This study contributes valuable insights to modern cancer therapy and immunomodulation.

The Effect of Melatonin on Increasing the Health Related Quality of Life in Non-Metastatic Breast Cancer Patients: Three-Year Follow up a Clinical Trial.

INTRODUCTION: Although breast cancer is common worldwide, if diagnosed early and treated on time, the probability of recovery is high and patients often experience a long life. Reducing the quality of life is a common side effect in patients. Melatonin may have an important role in fatigue, sleep disorders and, as a result, the health-related quality of life (HRQoL) in people. About 184 patients with breast cancer were enrolled in 2 groups: intervention with daily melatonin intake of 18 mg for 3 years (93 patients) and the control group with placebo intake (91 patients). Health-related quality of life and the effect of melatonin on increasing that were evaluated with the EORTC QLQ-C30 questionnaire, third edition at the beginning, 2 months later and 3 years after the beginning of the study. RESULTS: The general score of the HRQoL was significantly different both in the passage of time and in the comparative study of the 2 groups, and it was better in the melatonin group (P < .05). CONCLUSION: Long-term use of 18 mg of melatonin for 3 years in patients with non-metastatic breast cancer can lead to an increase in the patients' quality of life.

[Oncological Rehabilitation for Breast Cancer]. / Onkologische Rehabilitation bei Mammakarzinom.

As a result of increasingly individualized and multimodal therapy, prognosis of breast cancer has improved significantly over the last years. However, multimodal treatment and the use of new medications can lead to a variety of somatic, sometimes new, side effects such as fatigue, polyneuropathy or autoimmune toxicities. This and the oncological diagnosis lead to a high level of psychological distress in the women affected and often to subsequent psychological disorders (sleep/anxiety disorders, depression, ...). Both the diverse complaints after oncological therapy and the increasingly improved overall prognosis underline the importance of multimodal rehabilitation concepts to improve quality of life and successful professional reintegration.In the following, these secondary disorders after breast cancer, their multimodal therapy and their significance for social-medical performance assessment are presented in more detail.

Chlordiazepoxide against signalling, receptor and regulatory proteins of breast cancer: a structure-based in-silico approach.

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others. In this study, we included four crucial proteins that perform signalling, receptor, and regulatory action, namely- NUDIX Hydrolases, Dihydrofolate Reductase, HER2/neu Kinase and EGFR and performed multitargeted molecular docking studies against human-approved drugs using HTVS, SP and extra precise algorithms and filtered the poses with MM\GBSA, suggested a benzodiazepine derivative chlordiazepoxide, used as an anxiolytic agent, can be a multitargeted inhibitor with docking and MM\GBSA score ranging from - 4.628 to - 7.877 and - 18.59 to - 135.86 kcal/mol, respectively, and the most interacted residues were 6ARG, 6GLU, 3TRP, and 3VAL. The QikProp-based ADMET and DFT computations showed the suitability and stability of the drug candidate followed by 100 ns MD simulation in water and MMGBSA on trajectories, resulting in stable performance and many intermolecular interactions to make the complexes stable, which favours that chlordiazepoxide can be a multitargeted breast cancer inhibitor. However, experimental validation is needed before its use.

Hinokitiol Inhibits Breast Cancer Cells In Vitro Stemness-Progression and Self-Renewal with Apoptosis and Autophagy Modulation via the CD44/Nanog/SOX2/Oct4 Pathway.

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (ß-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.

Molecular Research and Treatment of Breast Cancer 2.0.

Breast cancer is the primary contributor to cancer-related deaths among women [...].

B7-H3 Expression in Breast Cancer and Brain Metastasis.

Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management.

Small Non-Coding RNAs and Their Role in Locoregional Metastasis and Outcomes in Early-Stage Breast Cancer Patients.

Deregulation of small non-coding RNAs (sncRNAs) has been associated with the onset of metastasis. We evaluated the expression of sncRNAs in patients with early-stage breast cancer, performing RNA sequencing in 60 patients for whom tumor and sentinel lymph node (SLN) samples were available, and conducting differential expression, gene ontology, enrichment and survival analyses. Sequencing annotation classified most of the sncRNAs into small nucleolar RNA (snoRNAs, 70%) and small nuclear RNA (snRNA, 13%). Our results showed no significant differences in sncRNA expression between tumor or SLNs obtained from the same patient. Differential expression analysis showed down-regulation (n = 21) sncRNAs and up-regulation (n = 2) sncRNAs in patients with locoregional metastasis. The expression of SNHG5, SNORD90, SCARNA2 and SNORD78 differentiated luminal A from luminal B tumors, whereas SNORD124 up-regulation was associated with luminal B HER2+ tumors. Discriminating analysis and receiver-operating curve analysis revealed a signature of six snoRNAs (SNORD93, SNORA16A, SNORD113-6, SNORA7A, SNORA57 and SNORA18A) that distinguished patients with locoregional metastasis and predicted patient outcome. Gene ontology and Reactome pathway analysis showed an enrichment of biological processes associated with translation initiation, protein targeting to specific cell locations, and positive regulation of Wnt and NOTCH signaling pathways, commonly involved in the promotion of metastases. Our results point to the potential of several sncRNAs as surrogate markers of lymph node metastases and patient outcome in early-stage breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant sncRNAs and to validate our results in a larger cohort of patients.

Treatment Monitoring of a Patient with Synchronous Metastatic Angiosarcoma and Breast Cancer Using ctDNA.

Angiosarcoma is a rare and aggressive type of soft-tissue sarcoma with high propensity to metastasize. For patients with metastatic angiosarcoma, prognosis is dismal and treatment options are limited. To improve the outcomes, identifying patients with poor treatment response at an earlier stage is imperative, enabling alternative therapy. Consequently, there is a need for improved methods and biomarkers for treatment monitoring. Quantification of circulating tumor-DNA (ctDNA) is a promising approach for patient-specific monitoring of treatment response. In this case report, we demonstrate that quantification of ctDNA using SiMSen-Seq was successfully utilized to monitor a patient with metastatic angiosarcoma. By quantifying ctDNA levels using 25 patient-specific mutations in blood plasma throughout surgery and palliative chemotherapy, we predicted the outcome and monitored the clinical response to treatment. This was accomplished despite the additional complexity of the patient having a synchronous breast cancer. The levels of ctDNA showed a superior correlation to the clinical outcome compared with the radiological evaluations. Our data propose a promising approach for personalized biomarker analysis to monitor treatment in angiosarcomas, with potential applicability to other cancers and for patients with synchronous malignancies.

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era.

Precision oncology is based on deep knowledge of the molecular profile of tumors, allowing for more accurate and personalized therapy for specific groups of patients who are different in disease susceptibility as well as treatment response. Thus, onco-breastomics is able to discover novel biomarkers that have been found to have racial and ethnic differences, among other types of disparities such as chronological or biological age-, sex/gender- or environmental-related ones. Usually, evidence suggests that breast cancer (BC) disparities are due to ethnicity, aging rate, socioeconomic position, environmental or chemical exposures, psycho-social stressors, comorbidities, Western lifestyle, poverty and rurality, or organizational and health care system factors or access. The aim of this review was to deepen the understanding of BC-related disparities, mainly from a biomedical perspective, which includes genomic-based differences, disparities in breast tumor biology and developmental biology, differences in breast tumors' immune and metabolic landscapes, ecological factors involved in these disparities as well as microbiomics- and metagenomics-based disparities in BC. We can conclude that onco-breastomics, in principle, based on genomics, proteomics, epigenomics, hormonomics, metabolomics and exposomics data, is able to characterize the multiple biological processes and molecular pathways involved in BC disparities, clarifying the differences in incidence, mortality and treatment response for different groups of BC patients.

Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome.

Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.