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Importance: Metastatic breast cancer (MBC) poses a substantial clinical challenge despite advancements in diagnosis and treatment. While tissue biopsies offer a static snapshot of disease, liquid biopsy-through detection of circulating tumor DNA (ctDNA)-provides minimally invasive, real-time insight into tumor biology. Objective: To determine the association between ctDNA and survival outcomes in patients with MBC. Data Sources: An electronic search was performed in 5 databases (CINAHL, Cochrane Library, Embase, Medline, and Web of Science) and included all articles published from inception until October 23, 2023. Study Selection: To be included in the meta-analysis, studies had to (1) include women diagnosed with MBC; (2) report baseline plasma ctDNA data; and (3) report overall survival, progression-free survival, or disease-free survival with associated hazards ratios. Data Extraction and Synthesis: Titles and abstracts were screened independently by 2 authors. Data were pooled using a random-effects model. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, and quality was assessed using the Newcastle-Ottawa Scale. Main Outcomes and Measures: The primary study outcome was the association between detection of specific genomic alterations in ctDNA with survival outcomes. Secondary objectives were associations of study methodology with survival. Results: Of 3162 articles reviewed, 37 met the inclusion criteria and reported data from 4264 female patients aged 20 to 94 years. Aggregated analysis revealed a significant association between ctDNA detection and worse survival (hazard ratio, 1.40; 95% CI, 1.22-1.58). Subgroup analysis identified significant associations of TP53 and ESR1 alterations with worse survival (hazard ratios, 1.58 [95% CI, 1.34-1.81] and 1.28 [95% CI, 0.96-1.60], respectively), while PIK3CA alterations were not associated with survival outcomes. Stratifying by detection method, ctDNA detection through next-generation sequencing and digital polymerase chain reaction was associated with worse survival (hazard ratios, 1.48 [95% CI, 1.22-1.74] and 1.28 [95% CI, 1.05-1.50], respectively). Conclusions and Relevance: In this systematic review and meta-analysis, detection of specific genomic alterations in ctDNA was associated with worse overall, progression-free, and disease-free survival, suggesting its potential as a prognostic biomarker in MBC. These results may help guide the design of future studies to determine the actionability of ctDNA findings.
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Neoplasias de la Mama , ADN Tumoral Circulante , Humanos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Metástasis de la Neoplasia , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Persona de Mediana EdadRESUMEN
Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumor progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumor immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1ß. While the release of IL-1ß is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, we show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, we induced breast cancer and hepatoma tumors in GSDMD-deficient mice. Contrary to our expectations, GSDMD deficiency had no effect on tumor growth, immune cell infiltration, or cytokine expression in the tumor microenvironment, except for Cxcl10 upregulation in hepatoma tumors. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumor type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumor microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer.
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Neoplasias de la Mama , Péptidos y Proteínas de Señalización Intracelular , Proteínas de Unión a Fosfato , Microambiente Tumoral , Animales , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Femenino , Humanos , Ratones , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Microambiente Tumoral/inmunología , Ratones Noqueados , Modelos Animales de Enfermedad , Línea Celular Tumoral , Citocinas/metabolismo , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/genética , GasderminasRESUMEN
Objectives: Rural patients have poor cancer outcomes and clinical trial (CT) enrollment compared to urban patients due to attitudinal, awareness, and healthcare access differential. Knowledge of cancer survival disparities and CT enrollment is important for designing interventions and innovative approaches to address the stated barriers. The study explores the potential disparities in cancer survival rates and clinical trial enrollments in rural and urban breast and lung cancer patients. Our hypotheses are that for both cancer types, urban cancer patients will have longer 5-year survival rates and higher enrollment rates in clinical trials than those in rural counties. Methods: We compared breast and lung cancer patients' survival rates and enrollment ratios in clinical trials between rural (RUCC 4-9) and urban counties in Georgia at a Comprehensive Cancer Center (CCC). To assess these differences, we carried out a series of independent samples t-tests and Chi-Square tests. Results: The outcomes indicate comparable 5-year survival rates across rural and urban counties for breast and lung cancer patients, failing to substantiate our hypothesis. While clinical trial enrollment rates demonstrated a significant difference between breast and lung cancer patients at CCC, no significant variation was observed based on rural or urban classification. Conclusion: These findings underscore the need for further research into the representation of rural patients with diverse cancer types at CCC and other cancer centers. Further, the findings have considerable implications for the initiation of positive social change to improve CT participation and reduce cancer survival disparities.
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Neoplasias de la Mama , Ensayos Clínicos como Asunto , Neoplasias Pulmonares , Población Rural , Población Urbana , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Femenino , Persona de Mediana Edad , Masculino , Tasa de Supervivencia , Georgia/epidemiología , Anciano , Adulto , Disparidades en Atención de SaludRESUMEN
BACKGROUND: Telomeres are a critical component of chromosome integrity and are essential to the development of cancer and cellular senescence. The regulation of breast cancer by telomere-associated lncRNAs is not fully known, though. The goals of this study were to describe predictive telomere-related LncRNAs (TRL) in breast cancer and look into any possible biological roles for these RNAs. METHODS: We obtained RNA-seq data, pertinent clinical data, and a list of telomere-associated genes from the cancer genome atlas and telomere gene database, respectively. We subjected differentially expressed TRLs to co-expression analysis and univariate Cox analysis to identify a prognostic TRL. Using LASSO regression analysis, we built a prognostic model with 14 TRLs. The accuracy of the model's prognostic predictions was evaluated through the utilization of Kaplan-Meier (K-M) analysis as well as receiver operating characteristic (ROC) curve analysis. Additionally, immunological infiltration and immune drug prediction were done using this model. Patients with breast cancer were divided into two subgroups using cluster analysis, with the latter analyzed further for variations in response to immunotherapy, immune infiltration, and overall survival, and finally, the expression of 14-LncRNAs was validated by RT-PCR. RESULTS: We developed a risk model for the 14-TRL, and we used ROC curves to demonstrate how accurate the model is. The model may be a standalone prognostic predictor for patients with breast cancer, according to COX regression analysis. The immune infiltration and immunotherapy results indicated that the high-risk group had a low level of PD-1 sensitivity and a high number of macrophages infiltrating. In addition, we've discovered a number of small-molecule medicines with considerable for use in treating high-risk groups. The cluster 2 subtype showed the highest immune infiltration, the highest immune checkpoint expression, and the worst prognosis among the two subtypes defined by cluster analysis, which requires more attention and treatment. CONCLUSION: As a possible biomarker, the proposed 14-TRL signature could be utilized to evaluate clinical outcomes and treatment efficacy in breast cancer patients.
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Biomarcadores de Tumor , Neoplasias de la Mama , ARN Largo no Codificante , Telómero , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Femenino , ARN Largo no Codificante/genética , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Telómero/genética , Tasa de Supervivencia , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Curva ROC , Estudios de Seguimiento , Perfilación de la Expresión Génica , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. METHODS: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. RESULTS: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. CONCLUSIONS: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.
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Biomarcadores de Tumor , Neoplasias de la Mama , Receptores Androgénicos , Receptores de Calcitriol , Receptores de Estrógenos , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Pronóstico , Receptores de Estrógenos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Estimación de Kaplan-Meier , TranscriptomaRESUMEN
IGFBP6, a member of the IGF binding protein (IGFBP) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism that can be regulated by IGF-related pathways. We performed bioinformatics analysis of the TCGA database to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis and collected clinical samples from BC patients with and without T2D to compare and verify the prognostic effect of IGFBP6. In our study, the levels of IGFBP1-6 were positively correlated with overall survival (OS) in patients with breast cancer. IGFBP6 was upregulated in estrogen receptor (ER)-positive BC, and ER-positive and progesterone receptor (PR) positive patients had a higher expression level of IGFBP6 than ER-negative and PR-negative patients. IGFBP6 could be used as an independent prognostic factor in BC. The expression of IGFBP6 was decreased in BC tissue, and BC tissue from patients with T2D had lower IGFBP6 expression levels than BC tissue from patients without T2D. IGFBP6 is mainly involved in the PI3K-Akt and TGF-ß signaling pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with that of most glucose metabolism-related genes. IGFBP6 expression was mainly correlated with mutations in TP53, PIK3CA, CDH1, and MAP3K1. In addition, the upregulation of IGFBP6 in BC increased the drug sensitivity to docetaxel, paclitaxel and gemcitabine. Overall, these results indicated that high expression of IGFBP6 is associated with a good prognosis in BC patients, especially in those without T2D. It is not only involved in the maintenance of the tumor microenvironment in BC but also inhibits the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognostic marker for BC.
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Biomarcadores de Tumor , Neoplasias de la Mama , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Pronóstico , Biomarcadores de Tumor/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodos , Transducción de Señal , Glucosa/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Persona de Mediana Edad , Estimación de Kaplan-Meier , Bases de Datos GenéticasRESUMEN
BACKGROUND: To investigate the prognostic differences following the achievement of a pathological complete response (pCR) through neoadjuvant chemotherapy across different molecular subtypes of breast invasive ductal carcinoma. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) were identified for patients undergoing neoadjuvant chemotherapy who achieved pathological complete response for invasive ductal carcinoma of the breast between 2010 and 2019.Comparing the clinicopathological characteristics of patients across different molecular subtypes. Univariate and Cox multivariate analyses were utilized to identify independent predictors of overall survival (OS) and cancer-specific survival (CSS). The Kaplan-Meier method is used to compare OS and CSS among different molecular subtypes. After propensity score matching, subgroup analysis results were presented through forest plots. RESULTS: This study included 9,380 patients diagnosed with invasive ductal carcinoma, who were categorized into four molecular subtypes: 2,721 (29.01%) HR + /HER-2 + , 1,661 (17.71%) HR + /HER2-, 2,082 (22.20%) HR-/HER2 + , and 2,916 (31.08%) HR-/HER-2-. HR + /HER-2- subgroup exhibited a significantly higher proportion of patients under 50 years old than the other subtype groups (54.67% vs 40.2%, 50.35% and 51.82%, p < 0.01), and had a higher N2 + N3 stage (11.2% vs 7.24%, 8.69% and 7.48%, p < 0.01). Univariate and multivariate analysis revealed that molecular subtype was the independent risk factor for OS and CSS in patients(p < 0.05). The Kaplan-Meier curves indicated that the HR + /HER-2 + subtype had the highest OS and CSS(p < 0.05). Next, were the HR-/HER-2 + and HR-/HER-2- subtypes, with the HR + /HER-2- group having the lowest OS and CSS(p < 0.05). After propensity score matching, the OS and CSS of patients in the HR + /HER-2 + group remained higher compared to HR + /HER-2- group(p < 0.05). CONCLUSIONS: Patients with invasive ductal carcinoma of different molecular subtypes exhibit varying prognoses after achieving pCR to neoadjuvant chemotherapy. Those in the HR + /HER-2- group are younger, have a higher lymph node stage, and the lowest OS and CSS, whereas patients in the HR + /HER-2 + group have the highest OS and CSS.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Terapia Neoadyuvante , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/mortalidad , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/metabolismo , Persona de Mediana Edad , Tasa de Supervivencia , Pronóstico , Receptor ErbB-2/metabolismo , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Receptores de Progesterona/metabolismo , Programa de VERF , Receptores de Estrógenos/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Quimioterapia Adyuvante/métodos , Estudios RetrospectivosRESUMEN
INTRODUCTION: Hotspots (HS) mutations in the PIK3CA gene may lead to poorer oncological outcomes and endocrine resistance in advanced breast cancer (BC), but their prognostic role in early-stage disease remains controversial. The overall agreement within plasma and tissue methods has not been well explored. Our aim was to correlate tissue and plasma approaches and to analyze the prognostic impact of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. METHODS: A retrospective and unicentric analysis of PIK3CA mutational status in tissue and plasma samples by Cobas®PIK3CA Mutation Kit in patients with HR+/HER2- BC. RESULTS: We analyzed 225 samples from 161 patients with luminal BC. PIK3CA mutations were identified in 62 patients (38.5%), of which 39.6% were found in tissue and 11.8% in plasma. In advanced disease, plasma and tissue correlation rate was performed in 64 cases, with an overall agreement of 70.3%. Eighty patients were treated with CDK4/6 inhibitors + endocrine therapy. We observed a moderately worse progression-free survival (PFS) in PIK3CAm versus wild-type (WT) (24 m vs. 30 m; HR = 1.39, p = 0.26). A subanalysis was carried out based on exons 9 and 20, which showed a statistically poorer PFS in PIK3CAm exon 9 versus 20 population (9.7 m vs. 30.3 m; HR = 2.84; p = 0.024). Furthermore, detection of PIK3CAm in plasma was linked to a worse PFS vs PIK3CAm detection just in tissue (12.4 vs. 29.3; HR = 2.4; p = 0.08). CONCLUSIONS: Our findings suggest the PIK3CA evaluation in tissue as the diagnostic method of choice, however, additional investigations are required to improve the role of liquid biopsy in the PIK3CA assessment. PIK3CAm show worse outcomes in advanced luminal BC, especially in exon 9 mutation carriers, despite visceral involvement, prior exposure to endocrine therapy or detection of PIK3CAm in plasma, with an unclear prognosis in early-stage disease. Nonetheless, this should be validated in a prospective cohort study.
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Biomarcadores de Tumor , Neoplasias de la Mama , Fosfatidilinositol 3-Quinasa Clase I , Mutación , Receptor ErbB-2 , Humanos , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Anciano , Estudios Retrospectivos , Adulto , Anciano de 80 o más Años , Receptores de Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Estrógenos/metabolismoRESUMEN
In this study, the necessity of radiotherapy (RT) for hormone receptor-negative older breast cancer patients after breast-conserving surgery (BCS) was investigated. The data of hormone receptor-negative invasive breast cancer patients who underwent BCS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. All patients were separated into two groups, namely, the RT group and the no radiotherapy (No RT) group. The 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) rates were compared between the No RT and RT groups after propensity score matching (PSM). The nomograms for predicting the survival of patients were constructed from variables identified by univariate or multivariate Cox regression analysis. A total of 2504 patients were enrolled in the training cohort, and 630 patients were included in the validation cohort. After PSM, 738 patients were enrolled in the No RT group and RT group. We noted that RT can improve survival in hormone receptor-negative older breast cancer patients who undergo BCS. Based on the results of multivariate Cox analysis, age, race, tumour grade, receipt of RT and chemotherapy, pathological T stage, N status, M status and HER2 status were linked to OS and CSS for these patients, and nomograms for predicting OS and CSS were constructed and validated. Moreover, RT improved OS and CSS in hormone receptor-negative older breast cancer patients who underwent BCS. In addition, the proposed nomograms more accurately predicted OS and CSS for hormone receptor-negative older breast cancer patients after BCS.
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Neoplasias de la Mama , Mastectomía Segmentaria , Programa de VERF , Humanos , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Femenino , Anciano , Nomogramas , Anciano de 80 o más Años , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Radioterapia AdyuvanteRESUMEN
OBJECTIVE: To explore the high-risk factors affecting the prognosis of pT1 - 2N1M0 patients after mastectomy, establish a nomogram prediction model, and screen the radiotherapy benefit population. METHOD: The clinical data of 936 patients with pT1 - 2N1M0 who underwent mastectomy in the fourth hospital of Hebei Medical University from 2010 to 2016 were retrospectively analyzed. There were 583 patients received postmastectomy radiotherapy(PMRT), and 325 patients without PMRT. Group imbalances were mitigated using the propensity score matching (PSM) method, and the log-rank test was employed to compare overall survival (OS) and disease-free survival (DFS) between the cohorts. The efficacy of PMRT across various risk groups was evaluated using a nomogram model. RESULT: The median follow-up period was 98 months, Patients who received PMRT demonstrated significantly improved 5-year and 8-year OS and DFS compared to those who did not (P < 0.001). Multivariate analysis revealed that age, primary tumor site, positive lymph node, stage, and Ki-67 level independently influenced OS, while age, primary tumor site, and stage independently affected DFS. PMRT drastically enhanced OS in the high-risk group (P = 0.001), but did not confer benefits in the low-risk and intermediate risk groups (P = 0.057, P = 0.099). PMRT led to a significant improvement in disease-free survival (DFS) among patients in the intermediate and high-risk groups (P = 0.036, P = 0.001), whereas the low-risk group did not experience a significant benefit (P = 0.475). CONCLUSION: Age ≤ 40 years, tumor located in the inner quadrant or central area, T2 stage, 2-3 lymph nodes metastasis, and Ki67 > 30% were the high-risk factors affecting the prognosis of this cohort of patients. In OS nomogram, patients with a risk score of 149 or higher who received PMRT exhibited improved OS. Similarly, in DFS nomogram, patients with a risk score of 123 or higher who received PMRT demonstrated enhanced DFS.
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Neoplasias de la Mama , Mastectomía , Nomogramas , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Radioterapia Adyuvante , Adulto , Pronóstico , Anciano , Medición de Riesgo , Tasa de Supervivencia , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Neoadjuvant chemotherapy (NAC) is an effective treatment for locally advanced breast cancer (BC). However, there are no effective biomarkers for evaluating its efficacy. CDR1-AS, well known for its important role in tumorigenesis, is a famous circular RNA involved in the chemosensitivity of cancers other than BC. However, the predictive role of CDR1-AS in the efficacy and prognosis of NAC for BC has not been fully elucidated. We herein aimed to clarify this role. METHODS: The present study included patients treated with paclitaxel-cisplatin-based NAC. The expression of CDR1-AS was detected by real-time quantitative reverse transcription polymerase chain reaction testing. The predictive value of CDR1-AS expression was examined in pathological complete response (pCR) after NAC using logistic regression analysis. The relationship between CDR1-AS expression and survival was demonstrated using the Kaplan-Meier method, and tested by log-rank test and Cox proportional hazards regression model. RESULTS: The present study enrolled 106 patients with BC. Multivariate logistic regression analysis revealed that CDR1-AS expression was an independent predictive factor for pCR (odds ratio [OR] = 0.244; 95% confidence interval [CI] 0.081-0.732; p = 0.012). Furthermore, pCR benefits with low CDR1-AS expression were observed across all subgroups. The Kaplan-Meier curves and log-rank test suggested that the CDR1-AS high-expression group showed significantly better disease-free survival (DFS; log-rank p = 0.022) and relapse-free survival (RFS; log-rank p = 0.012) than the CDR1-AS low-expression group. Multivariate analysis revealed that CDR1-AS expression was an independent prognostic factor for DFS (adjusted HR = 0.177; 95% CI 0.034-0.928, p = 0.041), RFS (adjusted HR = 0.061; 95% CI 0.006-0.643, p = 0.020), and distant disease-free survival (adjusted HR = 0.061; 95% CI 0.006-0.972, p = 0.047). CONCLUSIONS: CDR1-AS may be a potential novel predictive biomarker of pCR and survival benefit in patients with locally advanced BC receiving NAC. This may help identify specific chemosensitive individuals and build personalized treatment strategies.
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Biomarcadores de Tumor , Neoplasias de la Mama , Terapia Neoadyuvante , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Estudios Prospectivos , Adulto , ARN Circular/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , China/epidemiología , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Pueblos del Este de AsiaRESUMEN
BACKGROUND: The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. METHODS: The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. RESULTS: In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients. CONCLUSION: After HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.
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Biomarcadores de Tumor , Neoplasias de la Mama , Terapia Neoadyuvante , Receptor ErbB-2 , Humanos , Femenino , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Tasa de Supervivencia , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Estudios de Seguimiento , Terapia Neoadyuvante/métodos , Adulto , AncianoRESUMEN
Objectives: Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate, regulates various biological processes related to tumor progression. We explore the prognostic value of HPSE and its relationship with immunotherapy response in patients with breast cancer, to improve the effectiveness of immunotherapy and increase the survival outcomes. Methods: In the study, we explored the prognostic value of HPSE through the The Cancer Genome Atlas (TCGA) database. By using the single-sample gene set enrichment analysis (ssGSEA) method, we measured the infiltration levels of 24 immune cell types in the tumor microenvironment. Cancer Therapeutics Response Portal (CTRP) and PRISM datasets provide the area under the dose-response curve (AUC) to measure drug sensitivity. Using nomograms, we predicted overall survival ability. In vivo studies, we investigated the relationship between HPSE and immune checkpoint proteins and pro-inflammatory cytokines by immunohistochemistry of Triple-Negative Breast Cancer tumors in mice. Results: Our model demonstrated that the integrating of HPSE with the clinical stage effectively predicts patients' survival time, highlighting high HPSE expression as a prognostic risk factor for breast cancer. Then the Receiver Operating Characteristic (ROC) curve [AUC of 1 year = 0.747, AUC of 3 years = 0.731] and Decision Curve Analysis (DCA) curve illustrated the satisfactory discriminative capacity of our model, emphasizing its valuable clinical applicability. Immune-related results showed that HPSE correlates strongly with immune infiltrating cells, immune-related genes, and the anti-cancer immunity cycle. In vivo studies have demonstrated that HPSE in breast cancer is associated with increased expression of immune checkpoint proteins CD274 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and is positively correlated with the pro-inflammatory cytokine TNF-α. Meanwhile, we analyzed the 11 types of drugs that are sensitive to the HPSE gene. Conclusion: Our results show that HPSE can serve as an effective biomarker to predict the prognosis of breast cancer patients and reflect the impact of immunotherapy.
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Antígeno B7-H1 , Biomarcadores de Tumor , Neoplasias de la Mama , Antígeno CTLA-4 , Regulación Neoplásica de la Expresión Génica , Glucuronidasa , Microambiente Tumoral , Humanos , Femenino , Pronóstico , Glucuronidasa/metabolismo , Glucuronidasa/genética , Animales , Ratones , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Microambiente Tumoral/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Proteínas de Punto de Control Inmunitario/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Curva ROC , Nomogramas , Biología Computacional/métodos , Perfilación de la Expresión Génica , Bases de Datos GenéticasRESUMEN
PURPOSE: Survival rates of breast cancer (BC) patients are particularly low in rural regions in sub-Saharan Africa (SSA) which is due to limited access to therapy. In recent years, gene expression profiling (GEP) of BC showed a strong prognostic value in patients with local tumour surgery and (neo)adjuvant treatment. The aim of this study was to evaluate the impact of intrinsic subtypes on survival of patients in rural Ethiopia without any (neo)adjuvant therapy. METHODS: In total, 113 female patients from Aira Hospital with histologically proven BC and treated only with surgery were included in this study. All samples were analysed by immunohistochemistry (IHC) for estrogen receptor, progesterone receptor, HER2 and Ki67, as well as RNA-expression analysis for PAM50 subtyping. RESULTS: A positive hormone receptor status was found in 69.0% of the tumours and intrinsic subtyping demonstrated Luminal B to be the most common subtype (34.5%). Follow-up data was available for 79 of 113 patients. Two-year overall survival (OS) was 57.3% and a considerably worse OS was observed in patients with Basal-like BC compared to Luminal A BC. Moreover, advanced tumours showed an increased risk of mortality. CONCLUSION: The OS was very low in the patient cohort that received no (neo)adjuvant treatment. Immunohistochemistry and GEP confirmed endocrine-sensitive tumours in more than half of the patients, with a large proportion of Luminal B, HER2-enriched and Basal-like tumours so that adjuvant chemotherapy should be recommended.
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Neoplasias de la Mama , Receptor ErbB-2 , Receptores de Estrógenos , Humanos , Femenino , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Etiopía/epidemiología , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Anciano , Receptores de Estrógenos/metabolismo , Receptor ErbB-2/metabolismo , Población Rural , Receptores de Progesterona/metabolismo , Pronóstico , Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Inmunohistoquímica , Quimioterapia Adyuvante/métodosRESUMEN
BACKGROUND: Our systematic review aimed to critically evaluate empirical literature describing the association of muscle-strengthening exercise (MSE) with recurrence and/or mortality among breast cancer survivors. METHODS: We included English-language empirical research studies examining the association between MSE and recurrence and/or mortality among females diagnosed with breast cancer. Seven databases (MEDLINE, PsycINFO, Embase, Scopus, Web of Science, Cochrane CENTRAL, and CINAHL) were searched in September 2023. Quality was appraised using the Mixed Methods Appraisal Tool. Results are summarized descriptively. RESULTS: Five sources were identified. MSE measurement differed in relation to the description of the MSE (i.e., muscle-strengthening vs. strength training), examples of activities (e.g., sit-ups or push-ups vs. calisthenics vs. circuit training), and exercise frequency (i.e., days vs. times/week). Findings offer provisional evidence that some MSE may lower the hazards of recurrence and mortality. This association may vary by race, weight status, and menopausal status. CONCLUSIONS: In summary, limited available evidence suggests that MSE may lower the hazards of recurrence and mortality. More consistent measurement and analyses would help generate findings that are more readily comparable and applicable to inform clinical practice. Further research is needed to improve understanding of the strength and differences of these associations among underserved and underrepresented women.
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Neoplasias de la Mama , Supervivientes de Cáncer , Fuerza Muscular , Recurrencia Local de Neoplasia , Entrenamiento de Fuerza , Humanos , Neoplasias de la Mama/mortalidad , Femenino , Ejercicio FísicoRESUMEN
BACKGROUND: Breast cancer (BRCA) remains to be among the main causes of cancer-associated mortality in women globally. HGH1 homolog (HGH1) has been reported to be associated with tumor immunity. However, the function of HGH1 in BRCA remains unclear. Therefore, the present study examined the potential role of HGH1 in BRCA. METHODS: The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) were used to obtain RNA-seq data for BRCA. A protein localization of HGH1 was determined by using the Human Protein Atlas (HPA), and immunohistochemistry (IHC) staining revealed an upregulation in the expression of HGH1 in clinical BRCA tissues. Xenograft mice were used to test tumor growth and HGH1 expression in breast cancer cells. The protein interaction information of HGH1 was analyzed using the GeneMANIA website. Based on univariate Cox regression and Kaplan-Meier methods, we evaluated the role of HGH1 in BRCA prognosis. HGH1-related differentially expressed genes were analyzed using GO, KEGG, and GSEA. We also examined the relationship between HGH1 expression, immune checkpoints, and immune infiltration. CCK-8, EdU, and colony formation assays were used to measure cell proliferation, and western blot analysis was used to evaluate HGH1's role in BRCA. RESULTS: IHC results showed that the expression of HGH1 was significantly upregulated in BRCA tissues compared to normal tissues. High levels of HGH1 expression was associated with worse clinical features and a worse prognosis. HGH1 expression was an independent predictor of BRCA outcomes in both univariate and multivariate analyses. Functionally, western blot analysis showed that HGH1 is implicated in cell cycle. As well, knocking down HGH1 significantly reduced BRCA cells' proliferative abilities. Crucially, HGH1 expression levels were positively correlated with Th2 cell infiltration and negatively correlated with Tcm cell infiltration. CONCLUSION: Biomarkers such as HGH1 can reliably predict prognosis in BRCA patients.
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Neoplasias de la Mama , Ciclo Celular , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Femenino , Pronóstico , Animales , Ratones , Ciclo Celular/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular TumoralRESUMEN
PURPOSE: Breast cancer progression varies across molecular subtypes, and treatment options for human epidermal growth factor receptor 2 (HER2)-low expression tumors are limited compared with those of HER2 overexpression tumors. Comprehensive information regarding the epidemiology and clinical outcomes of metastatic HER2-low expression breast cancer in a Southeast Asian population is lacking. METHODS: This retrospective cohort study was performed to analyze data from patients with de novo advanced breast cancer, including HER2 expression, tumor stage, and metastatic pattern. Statistical analyses, including chi-square tests and survival analyses, were used to compare HER2-low expression and HER2-negative groups. RESULTS: Of the 491 patients, 21.2% had HER2-low expression, 30% had HER2 overexpression, and 50% had HER2-negative expression. Among the hormone receptor (HR)-positive patients, 34% had HER2-low expression; in the triple-negative patients, the HER2-low incidence was 20.6%. No significant differences in clinical characteristics between HER2-low and HER2-negative groups were observed, except for more HR-positive patients in the HER2-low group. HER2-low patients had a longer overall survival (OS) than HER2-negative patients (43 v 23 months; hazard ratio, 0.7; P < .001), especially in HR-positive patients. After adjusting for HR status, HER2-low patients maintained improved outcomes. HR-positive HER2-low patients showed nonsignificant OS gains compared with HR-positive HER2-negative patients, regardless of first-line chemotherapy or endocrine therapy. CONCLUSION: This study revealed the incidence and clinical outcomes of HER2-low expression in de novo advanced breast cancer, suggesting favorable outcomes, particularly in HR-positive breast cancer. These findings may inform personalized treatment strategies. Further research into the mechanisms and implications of HER2-low expression in breast cancer is required.
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Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Femenino , Estudios Retrospectivos , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Pronóstico , Incidencia , Adulto , Anciano , Asia Sudoriental/epidemiología , Metástasis de la Neoplasia , Biomarcadores de Tumor/metabolismo , Pueblos del Sudeste AsiáticoRESUMEN
BACKGROUND: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. PATIENTS AND METHODS: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. RESULTS: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. CONCLUSIONS: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. CLINICALTRIALS: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).
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Neoplasias de la Mama , Recurrencia Local de Neoplasia , Receptor ErbB-2 , Receptores de Progesterona , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Medición de Riesgo/métodos , Factores de Riesgo , Trastuzumab/uso terapéuticoRESUMEN
OBJECTIVE: Breast-conserving therapy (BCT) includes breast-conserving surgery (BCS) combined with radiation therapy (RT). RT plays a crucial role in improving the prognosis of patients who undergo BCS. However, obesity is a potential risk factor for resistance to radiation. The aim of this study was to evaluate any difference in the long-term prognosis of patients with early stage breast cancer and obesity treated with BCT or total mastectomy (TM). DESIGN, SETTING AND PARTICIPANTS: This was a retrospective cohort study involving 1125 patients diagnosed with early stage breast cancer and obesity at the Shanghai Cancer Center of Fudan University from 2013 to 2016. OUTCOME MEASURES: Obesity in the Chinese population was defined as a body mass index ≥28 kg/m2. Surgical options included BCT and TM. The primary survival outcomes were overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS). Inverse probability of treatment weighting (IPTW) was used to control for the impact of confounding factors on prognosis. RESULTS: The median follow-up times in the BCT group and TM group without postoperative RT were 51.1 months (IQR of 40.6-68.1 months) and 61.8 months (IQR of 46.5-76.7 months), respectively. After IPTW, the baseline data were balanced. Compared with those in the TM cohort, patients in the whole IPTW cohort in the BCT cohort had worse DFS (HR 4.280, 95% CI 2.180 to 8.400; p<0.001), RFS (HR 4.380, 95% CI 2.370 to 8.120; p<0.001) and OS (HR 3.590, 95% CI 1.620 to 7.950; p=0.002). CONCLUSION: In patients with early stage breast cancer and obesity, TM is associated with better survival outcomes than BCT.