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INTRODUCTION: The aberrant up-regulation of meiotic nuclear division 1 (MND1) in somatic cells is considered as one of the driving factors of oncogenesis, whereas its expression and role in breast invasive cancer (BRCA) remain unclear. Hence, this study embarked on a comprehensive evaluation of MND1 across various cancers and identified its roles in BRCA. METHODS: Based on publicly available databases, including but not limited to UCSC Xena, TCGA, GTEx, GEO, STRING, GeneMANIA, and CancerSEA, we evaluated the expression patterns, genomic features, and biological functions of MND1 from a pan-cancer viewpoint and delved into the implications of MND1 in the prognosis and treatment of BRCA. Further molecular biology experiments were undertaken to identify the role of MND1 in proliferation, migration, and apoptosis in BRCA cells. RESULTS: Elevated levels of MND1 were notably observed in a wide array of tumor types, especially in BRCA, COAD, HNSC, LIHC, LUAD, LUSC, STAD, and UCEC. Elevated MND1 expression was markedly associated with shortened OS in several tumors, including BRCA (HR = 1.52 [95%CI, 1.10-2.09], P = 0.011). The up-regulation of MND1 in BRCA was validated in external cohorts and clinical samples. Survival analyses demonstrated that elevated MND1 expression was associated with decreased survival for patients with BRCA. Co-expressed genes of MND1 were identified, and subsequent pathway analyses based on significantly associated genes indicated that MND1 plays key roles in DNA replication, cell cycle regulation, and DNA damage repair. The observed abnormal elevation and activation of MND1 led to increased proliferation and migration, along with decreased apoptosis in BRCA cells. CONCLUSIONS: MND1 emerges as a promising biomarker for diagnostic and therapeutic targeting in various cancers, including BRCA. The abnormal up-regulation and activation of MND1 are linked to carcinogenesis and poor prognosis among BRCA patients, which may be attributed to its involvement in HR-dependent ALT, warranting further scrutiny.
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The role of neoadjuvant chemotherapy and its benefits in patients with triple-negative breast cancer (TNBC) and small tumors are unclear. This study aims to compare survival differences between clinical T1 TNBC receiving neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC). Data for patients with clinical T1 TNBC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized according to whether they received chemotherapy before or after surgery. Propensity Score Matching (PSM) was used to minimize the influence of confounding factors. OS and BCSS were compared between the two treatment sequences using Kaplan-Meier and univariate and multivariable Cox proportional hazards regression analyses. The study included 6249 women with T1 TNBC. In multivariate analysis, compared with that in the AC group, the hazard ratio for death in the NAC group was 1.54 (95% confidence interval 1.26-1.89, p < 0.001). NAC offers no additional benefits in any age group or T, N subgroups. Our findings suggest that NAC does not provide additional benefit to patients with clinical T1 TNBC, even in the presence of lymph node metastasis, or T1c.
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Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Adulto , Idoso , Quimioterapia Adjuvante/métodos , Programa de SEER , Estadiamento de Neoplasias , Estimativa de Kaplan-Meier , Modelos de Riscos ProporcionaisRESUMO
PURPOSE: Many T1-2N0-1M0 triple-negative breast cancer (TNBC) patients who undergo neoadjuvant chemotherapy (NAC) do not receive breast-conserving therapy (BCT) due to concerns about non-pCR or lymph node metastasis presence. METHODS: T1-2N0-1M0 TNBC patients who underwent NAC between 2010 and 2017 were collected from the SEER database. Factors affecting surgical modalities were analyzed by multinomial logistic regression. The overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated by Kaplan-Meier curves and Cox proportional hazards models. Further stratified subgroup analyses were performed based on the response to NAC and N-stage. Adjusted-hazard ratios were also calculated to exclude potential bias. RESULTS: A total of 1112 patients were enrolled (median follow-up: 81 months), 58.5% received BCT, 23.6% received reconstruction and 17.9% received mastectomy. Response to NAC and N-stage not only influenced the choice of surgical modality but also were independent predictors for OS and BCSS. The surgery-induced survival differences mainly affect OS. Survival analyses demonstrated that the 10-year OS of BCT was superior or equal to that of mastectomy even in patients with partial response (PR) (77.4% vs. 64.1%, P = 0.013), no response (NR) (44.9% vs. 64.2%, P = 0.33), or N1 stage (75.7% vs. 57.4%, P = 0.0021). In the N1-PR cohort, mastectomy may lead to worse OS (P = 0.0012). Besides, between reconstruction and BCT, there was no statistical difference in OS or BCSS (P > 0.05). CONCLUSION: Our study reveals the necessity of breast surgical de-escalation. Besides, physicians should actively recommend reconstruction for individuals who strongly desire mastectomy.
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Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/cirurgia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/mortalidade , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Mastectomia/métodos , Estadiamento de Neoplasias , Programa de SEER , Estudos Retrospectivos , Quimioterapia AdjuvanteRESUMO
PURPOSE: To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. DATA AND METHODS: We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. RESULTS: Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). CONCLUSION: NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.
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Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/mortalidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Idoso , Adulto , Resultado do Tratamento , Antineoplásicos Hormonais/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Mastectomia , Quimioterapia Adjuvante/métodosRESUMO
INTRODUCTION: For HR-positive/HER2-negative patients who can undergo breast-conserving surgery (BCS) but have a tumor size of 2-5 cm or 1-3 lymph node metastases, neoadjuvant chemotherapy (NAC) is still controversial. METHODS: Patients with T2N0-1M0 HR-positive/HER2-negative BC who underwent BCS between 2010 and 2017 were selected from the SEER database. Propensity score matching (PSM) was used to minimize the influence of confounding factors. The overall survival (OS) and breast cancer-specific survival (BCSS) of patients were estimated by KaplanâMeier curves and Cox proportional hazard models. Independent prognostic factors were included to construct a nomogram prediction model. RESULTS: A total of 6475 BC patients were enrolled, of whom 553 received NAC and 5922 received adjuvant chemotherapy (AC). In the T2N0-1M0 population and T2N1M0 subgroup, AC patients before PSM had better OS and BCSS than NAC patients. After PSM, there was no significant difference in OS or BCSS between the two groups. However, in the T2N0M0 subgroup, there was no difference in survival between the AC and NAC groups before and after PSM. Stratified analysis revealed that for complete response (CR) patients, survival was roughly equivalent between the NAC and AC groups. However, the survival of no response (NR) and partial response (PR) patients was significantly worse than that of AC patients. Cox analysis revealed that radiotherapy after BCS was an independent protective factor for OS. NAC is an independent risk factor for NR and PR patients. The nomogram has good prediction efficiency. CONCLUSION: NAC before BCS is not necessary for T2N0-1M0 HR-positive/HER2-negative BC patients.
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Neoplasias da Mama , Mastectomia Segmentar , Terapia Neoadjuvante , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Quimioterapia Adjuvante/métodos , Adulto , Idoso , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Estadiamento de Neoplasias , Prognóstico , Programa de SEERRESUMO
Immunotherapy has shown great potential in cancer treatment. However, even with the intervention of techniques such as immune checkpoint inhibitor therapy, tumors can still achieve immune escape, leading to a low response rate. Abnormal glycosylation is a widely recognized hallmark of cancer. The development of a complex "glyco-code" on the surface of tumor cells can potentially influence the immune system's ability to monitor tumors and can impact the anti-tumor immune response. Therefore, abnormal glycosylation has emerged as a promising target for immunotherapy. Many recent studies have shown that targeted glycosylation can reshape the tumor microenvironment (TME) and promote the immune response, thereby improving the response to immunotherapy. This review summarizes how glycosylation affects anti-tumor immune function in the TME and synthesizes the latest research progress on targeted glycosylation in immunotherapy. It is hoped that by elucidating the basic laws and biological connotations of glycosylation, this review will enable researcher to thoroughly analyze the mechanism of its influence on the immune metabolic regulation network, which will provide a theoretical tool for promoting the clinical application of glycosylation codes.
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Imunoterapia , Neoplasias , Microambiente Tumoral , Glicosilação , Humanos , Imunoterapia/métodos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/metabolismo , Microambiente Tumoral/imunologia , AnimaisRESUMO
INTRODUCTION: Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD: A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS: Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P < 0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION: Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.
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Neoplasias da Mama , Terapia Neoadjuvante , Nomogramas , Receptor ErbB-2 , Programa de SEER , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Idoso , Prognóstico , Adulto , Estimativa de Kaplan-Meier , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Modelos de Riscos Proporcionais , Estadiamento de NeoplasiasRESUMO
BACKGROUND: The combination of neoadjuvant chemotherapy and anti-angiogenesis therapy for patients with triple-negative breast cancer (TNBC) remains inadequately supported by evidence. We conducted a single-arm, open-label, multicenter, phase II trial to evaluate the efficacy and toxicity of anlotinib plus epirubicin and cyclophosphamide followed by paclitaxel in patients with IIB to IIIA stage TNBC. METHODS: Newly diagnosed patients received epirubicin at 90 mg/m2 and cyclophosphamide at 600 mg/m2 followed by docetaxel at 100 mg/m2 (21 days per cycle; total of 4 cycles), along with oral anlotinib (12 mg qd, d1-14; 21 days per cycle; total of 4 cycles). Subsequently, patients underwent surgery. The primary endpoint of this study was pathologic complete response (pCR). RESULTS: Among the 34 included patients, the median age was 46.5 years (range: 27-72); all were female. Pathological assessment revealed that 17 patients achieved RCB 0 response, which is currently defined as pathologic complete response; 3 patients achieved RCB 1; 12 patients achieved RCB 2; and 1 patient achieved RCB 3. The probability of a grade 3 adverse reaction was 17.6%, and no grade 4 adverse reactions occurred. The most common hematological adverse reaction was leukopenia (13/34, 38.2%), of which 5.9% (2/34) were grade 3. The most common non-hematological adverse reactions were oral mucositis (16/34, 58.8%), fatigue (50.0%), hand-foot syndrome (50.0%), hypertension (44.1%), bleeding (44.1%), and alopecia (32.4%). CONCLUSION: The combination of anlotinib and EC-T chemotherapy demonstrated tolerable side effects in the neoadjuvant treatment of early TNBC. pCR was higher than what has been reported in previous clinical studies of chemotherapy alone. This study provides additional rationale for using anlotinib plus docetaxel-epirubicin-based chemotherapy regimen in patients with early-stage TNBCs.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Docetaxel , Epirubicina , Indóis , Terapia Neoadjuvante , Quinolinas , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Idoso , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
PURPOSE: Gene mutations drive tumor immune microenvironment (TIME) heterogeneity, in turn affecting prognosis and immunotherapy efficacy. PIK3CA is the most frequently mutated gene in breast cancer (BC), yet its relevance to BC prognosis remains controversial. Herein, we sought to determine the impact of PIK3CA mutation-driven immune genes (PDIGs) on BC prognosis in relation to TIME heterogeneity. METHODS: PIK3CA mutation characteristics were compared and verified between the TCGA-BRCA dataset and a patient cohort from our hospital. PIK3CA mutation-driven differentially expressed genes were identified for consensus clustering and weighted gene co-expression network analysis to select the modules most relevant to the immune subtype. Thereafter, the two were intersected to obtain PDIGs. Univariate Cox, LASSO, and multivariate Cox regression analyses were sequentially performed on PDIGs to obtain a PIK3CA mutation-driven immune signature (PDIS), which was then validated using the Gene Expression Omnibus (GEO) database. Differences in functional enrichment, mutation landscape, immune infiltration, checkpoint gene expression, and drug response were compared between different risk groups. RESULTS: PIK3CA mutation frequencies in the TCGA and validation cohorts were 34.49% and 40.83%, respectively. PIK3CA mutants were significantly associated with ER, PR, and molecular BC subtypes in our hospital cohort. The PDIS allowed for effective risk stratification and exhibited prognostic power in TCGA and GEO sets. The low-risk patients exhibited greater immune infiltration, higher expression of common immune checkpoint factors, and lower scores for tumor immune dysfunction and exclusion. CONCLUSION: The PDIS can be used as an effective prognostic model for predicting immunotherapy response to guide clinical decision-making.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Prognóstico , Classe I de Fosfatidilinositol 3-Quinases/genética , Tomada de Decisão Clínica , Análise por Conglomerados , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Currently, research on the prognostic factors of unilateral breast cancer (UBC) patients receiving contralateral prophylactic mastectomy (CPM) is limited. This study aimed to construct a new nomogram to predict these patients' overall survival (OS). METHODS: In this retrospective study, 88,477 patients who underwent CPM or unilateral mastectomy (UM) were selected from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier curves and Cox regression analyses were used to determine the difference in the impact of the 2 surgical methods on the prognosis. Multivariate Cox analysis was used to determine the best prognostic variable and construct a nomogram. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the discrimination capability and clinical effectiveness of the nomogram. RESULTS: The prognosis of patients receiving CPM and UM was significantly different. The DCA curves indicated that the nomogram could provide more excellent clinical net benefits for these patients. The NRI and IDI of the nomogram demonstrated that its performance was better than that of the classical tumor-node-metastasis (TNM) staging system. CONCLUSION: This study developed and validated a practical nomogram to predict the OS of UBC patients undergoing CPM, which provided a beneficial tool for clinical decision-making management.
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Nomogramas , Mastectomia Profilática , Programa de SEER , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Mastectomia Profilática/métodos , Mastectomia Profilática/estatística & dados numéricos , Prognóstico , Adulto , Neoplasias da Mama/cirurgia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias Unilaterais da Mama/cirurgia , Neoplasias Unilaterais da Mama/patologia , Idoso , Mastectomia , Estadiamento de Neoplasias , Estimativa de Kaplan-Meier , Curva ROC , Taxa de SobrevidaRESUMO
Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions. In this study, we address these challenges by designing a "on/off" switchable crosslinked paclitaxel (PTX) nanocarrier, BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct "on/off" switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The "off" state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the "on" state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.
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Antineoplásicos , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Microambiente TumoralRESUMO
Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast cancer. In this study, we have explored the aberrantly active kinases in breast cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast cancer (TNBC) progression. We collected 47 pairs of breast cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xl and Vimentin, and decreased levels of Bad, cleaved caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.
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Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Dasatinibe/farmacologia , Camundongos Nus , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Peptídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Quinases da Família srcRESUMO
INTRODUCTION: The survival benefit of axillary lymph node dissection (ALND), sentinel lymph node biopsy (SLNB) combined with radiation, and ALND combined with radiation remains unclear in breast cancer (BC) patients with 1-2 metastatic sentinel lymph nodes (SLNs). This study aims to rigorously evaluate the prognostic impact of these axillary evaluation modalities on BC patients with varying T-stages and to construct a survival prediction nomogram. METHODS: Following screening for inclusion and exclusion criteria, data pertaining to BC patients were extracted from the SEER database. Overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Kaplan-Meier curves and Cox proportional hazards model among patients with different stages who underwent various axillary evaluation modalities. A nomogram was constructed to predict the probability of OS and BCSS. RESULTS: A total of 20,283 patients were included, comprising 9626 who underwent breast-conserving surgery (BCS) and 10,657 who underwent mastectomy. In the T4 stage stratified analysis, both BCS and mastectomy groups exhibited superior OS and BCSS with ALND compared to SLNB combined with radiation. Further, ALND combined with radiation improved OS. However, for T1-3 stages, patients treated with ALND experienced similar or worse survival compared to those treated with SLNB combined with radiation. The calibration curve and C-index (0.746-0.794) of the nomogram demonstrated the efficacy of the survival prediction model. CONCLUSION: In T1-3 BC patients with 1-2 metastatic SLNs, SLNB combined with radiation is a safe alternative to ALND. Conversely, for T4 patients, ALND combined with radiation may offer a preferable choice.
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Axila , Neoplasias da Mama , Excisão de Linfonodo , Metástase Linfática , Estadiamento de Neoplasias , Nomogramas , Programa de SEER , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Feminino , Pessoa de Meia-Idade , Biópsia de Linfonodo Sentinela/métodos , Metástase Linfática/patologia , Idoso , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Adulto , Prognóstico , Mastectomia , Mastectomia Segmentar , Estudos Retrospectivos , Linfonodos/patologia , Linfonodos/cirurgia , Taxa de SobrevidaRESUMO
PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Metilação de DNA , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioma/genética , Metilases de Modificação do DNA/genética , Fenótipo , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Proteínas Supressoras de Tumor/genética , Enzimas Reparadoras do DNA/genéticaRESUMO
Background: Understanding the correlation between female breast cancer (BC) and the prevalence of coronary heart disease (CHD) is important for developing prevention strategies and reducing the burden of female social disease. This study aimed to evaluate the relationship between BC and CHD using data from the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2018. Methods: The study cohort included 16,149 eligible non-pregnant female participants aged 20 years or older. Logistic regression was used to analyze the relationship between BC and CHD, excluding the interaction between covariates and BC through hierarchical subgroup analysis. Results: The study found that participants with BC had a 2.30 times greater risk of developing CHD compared to those without BC [95% confidence interval (CI): 2.29-2.31]. After adjusting for all included covariates, BC was still significantly associated with CHD risk (odds ratio: 1.11, 95% CI: 1.10-1.12). When participants were stratified by age, education level, and prevalence of hypertension, it was evident that participants with BC had a higher risk of developing CHD compared to those without BC, although the effect of BC on CHD varied across stratification. Conclusions: Our study demonstrates the close relationship between CHD and female BC. Therefore, it is necessary to screen patients with CHD for BC and monitor BC survivors for the long-term risk of developing CHD.
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PURPOSE: This study aimed to assess the actual prognostic significance of different locoregional treatment (LRT) (surgery and radiotherapy) modalities for stage-IV breast cancer (BC) patients and construct a competing risk nomogram to make precise predictions of the breast cancer-specific death (BCSD) risk among LRT recipients. METHODS: A total of 9279 eligible stage-IV BC patients from the Surveillance Epidemiology and End Results (SEER) database were included in this study. Initially, we evaluated the impact of LRT on survival both before and after the propensity score matching (PSM). Then, we used the Cox hazard proportional model and competing risk model to identify the independent prognostic factors for LRT recipients. Based on the screened variables, a comprehensive nomogram was established. RESULTS: Kaplan-Meier curves demonstrated that LRT significantly prolonged overall survival (OS) and breast cancer-specific survival (BCSS) (P < 0.001). In addition, patients treated with surgery combined with postoperative radiotherapy (PORT) possessed the optimal survival (P < 0.001). Regardless of the surgical modalities, primary tumor resection combined with radiotherapy could ameliorate the prognosis (P < 0.05). Subgroup analysis showed that in patients with T2-T4 stage, PORT had a survival benefit compared with those undergoing surgery combined with preoperative radiotherapy (PRRT) and surgery only. Based on the screened independent prognostic factors, we established a comprehensive nomogram to forecast BCSD in 1 year, 2 years and 3 years, which showed robust predictive ability. CONCLUSION: PORT was associated with a lower BCSD in stage-IV BC patients. The practical nomogram could provide a precise prediction of BCSD for LRT recipients, which was meaningful for patients' individualized management.
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Background: Breast cancer (BC) is the most common malignancy among women. Nicotinamide (NAM) metabolism regulates the development of multiple tumors. Herein, we sought to develop a NAM metabolism-related signature (NMRS) to make predictions of survival, tumor microenvironment (TME) and treatment efficacy in BC patients. Methods: Transcriptional profiles and clinical data from The Cancer Genome Atlas (TCGA) were analyzed. NAM metabolism-related genes (NMRGs) were retrieved from the Molecular Signatures Database. Consensus clustering was performed on the NMRGs and the differentially expressed genes between different clusters were identified. Univariate Cox, Lasso, and multivariate Cox regression analyses were sequentially conducted to develop the NAM metabolism-related signature (NMRS), which was then validated in the International Cancer Genome Consortium (ICGC) database and Gene Expression Omnibus (GEO) single-cell RNA-seq data. Further studies, such as gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, SubMap, and Immunophenoscore (IPS) algorithm, cancer-immunity cycle (CIC), tumor mutation burden (TMB), and drug sensitivity were performed to assess the TME and treatment response. Results: We identified a 6-gene NMRS that was significantly associated with BC prognosis as an independent indicator. We performed risk stratification according to the NMRS and the low-risk group showed preferable clinical outcomes (P < 0.001). A comprehensive nomogram was developed and showed excellent predictive value for prognosis. GSEA demonstrated that the low-risk group was predominantly enriched in immune-associated pathways, whereas the high-risk group was enriched in cancer-related pathways. The ESTIMATE and CIBERSORT algorithms revealed that the low-risk group had a higher abundance of anti-tumor immunocyte infiltration (P < 0.05). Results of Submap, IPS, CIC, TMB, and external immunotherapy cohort (iMvigor210) analyses showed that the low-risk group were indicative of better immunotherapy response (P < 0.05). Conclusions: The novel signature offers a promising way to evaluate the prognosis and treatment efficacy in BC patients, which may facilitate clinical practice and management.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Mama , Imunoterapia , Prognóstico , Niacinamida , Microambiente Tumoral/genéticaRESUMO
Low-density lipoprotein (LDL) is a small lipoprotein that plays a vital role in controlling lipid metabolism. LDL has a delicate nanostructure with unique physicochemical properties: superior payload capacity, long residence time in circulation, excellent biocompatibility, smaller size, and natural targeting. In recent decades, the superiority and feasibility of LDL particles as targeted delivery carriers have attracted much attention. In this review, we introduce the structure, composition, advantages, defects, and reconstruction of LDL delivery systems, summarize their research status and progress in targeted diagnosis and therapy, and finally look forward to the clinical application of LDL as an effective delivery vehicle.
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INTRODUCTION: Immediate postmastectomy reconstruction for breast cancer has been widely used due to its unique esthetic and psychological effects. However, no other population-based study has investigated the effects of different reconstruction types on the survival in patients with triple negative breast cancer (TNBC). METHODS: We selected patients who met the eligibility criteria from the Surveillance, Epidemiology, and End Results cancer registry (N = 9760). We then assessed the effect of different reconstructive surgical approaches (implant, autologous, implant and autologous combined reconstruction) on the overall survival (OS) and breast cancer-specific survival (BCSS) by using the Kaplan-Meier survival curve and Cox proportional hazard regression analyses. The nomograms were used to predict OS and BCSS. And the competitive risk model was used to assess breast cancer-specific death (BCSD) and non-breast cancer-specific death (NBCSD). RESULTS: Statistical analysis suggested that the three reconstruction methods had better OS and BCSS with lower hazard than mastectomy alone (log-rank test, p < 0.05). Multivariate stratified analysis showed that patients aged 40-60 years had the greatest improvement in OS (Adjusted hazard ratio [AHR], 0.646; 95% Confidence Interval [CI], 0.439-0.950; p = 0.026) with combined reconstruction. BCSS could be improved only by implant reconstruction (AHR, 0.672; 95% CI, 0.514-0.878; p = 0.004). In addition, autologous reconstruction (AHR, 0.570; 95% CI, 0.350-0.929; p = 0.024) and implant reconstruction (AHR, 0.538; 95% CI, 0.339-0.853; p = 0.008) improved OS in patients >60 years of age. The survival prediction model quantified the survival benefits of TNBC patients undergoing different surgeries. Moreover, the C-indexes showed the good predictive ability of the nomograms. CONCLUSIONS: Our results suggest that for TNBC patients, there is a survival benefit of immediate postmastectomy reconstruction compared with mastectomy alone. Among them, implant reconstruction has the most obvious advantage.
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Neoplasias da Mama , Mamoplastia , Neoplasias de Mama Triplo Negativas , Humanos , Pessoa de Meia-Idade , Feminino , Mastectomia , Programa de SEER , Mama/cirurgiaRESUMO
Introduction: It is still unclear whether radiotherapy affects the long-term survival of breast cancer (BC) patients after immediate breast reconstruction (IBR). This study aims to evaluate the actual prognostic impact of radiotherapy on BC patients undergoing IBR, and to construct survival prediction models to predict the survival benefit of radiotherapy. Methods: Data on eligible BC patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Competing risk models were used to assess breast cause-specific death (BCSD) and non-breast cancer cause-specific death (NBCSD). Kaplan-Meier curve, Cox risk regression model and forest map were used to evaluate and demonstrate overall survival (OS) and breast cancer-specific survival (BCSS). Survival prediction nomograms were used to predict OS and BCSS probabilities. Results: A total of 22,218 patients were selected, 24.9% received radiotherapy and 75.1% were without radiotherapy. Competing risk models showed that whether BCSD or NBCSD, the cumulative long-term risk of death in the radiotherapy group was higher than that in the non-radiotherapy group. The Kaplan-Meier curve showed that patients with different lymph node metastasis had different radiotherapy benefits. Multivariate stratified analysis showed that radiotherapy after autologous reconstruction was associated with poor BCSS in patients with stage N0, and radiotherapy after autologous reconstruction and combined reconstruction improved OS and BCSS in patients with stage N3. The C-indexes of nomogram (between 0.778 and 0.847) and calibration curves showed the good prediction ability of survival prediction model. Conclusions: Radiotherapy can improve OS and BCSS in N3 stage BC patients undergoing immediate autologous reconstruction after mastectomy. The practical nomograms can be used to predict OS and BCSS of patients with or without radiotherapy, which is helpful for individualized treatment.