crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer.

AIMS: With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear. METHODS: An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents. RESULTS: VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model. CONCLUSION: This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

Genetic and clinical landscape of ER + /PR- breast cancer in China.

BACKGROUND: Estrogen receptor-positive and progesterone receptor-negative (ER + /PR-) breast cancer comprise a special type. More than 10% breast cancer patients belonged to ER + /PR-. METHODS: In order to better understand this patient population, we utilized a unique dataset from China, examining the clinicopathological features and genomic profiles of ER + /PR- breast cancers. Our study involved three cohorts: Cohort 1 included 2120 unselected ER-positive female patients with re-evaluated clinicopathological and survival data; Cohort 2 comprised 442 ER-positive females who underwent genetic testing; and Cohort 3 consisted of 77 ER-positive/HER2-negative females tested with MammaPrint and BluePrint. RESULTS: Patients were stratified into four categories based on the PR/ER ratio. Clinically, ER + /PR- tumors (PR/ER ratio = 0) showed the lowest proportion of T1 tumors (10.88%) and highest proportion of HER2-positive tumors (28.36%) than did other ER + /PR + tumors groups. The ER + /PR- group contained a higher number of underweight patients (20.20%). Independently of HER2 status, ER + /PR- patients demonstrated the poorest prognosis. Genomically, the most prevalent mutations were PIK3CA (50%) in ER + /PR + tumors and TP53 (65%) in ER + /PR- tumors. ER + /PR- tumors presented more frequent mutations in TP53, ERBB2, CDK12, SPEN, and NEB, with mutation rates of 65%, 42%, 27%, 13%, and 10%, respectively. Additionally, the Tumor Mutational Burden (TMB) was higher in the ER + /PR- group compared to the ER + /PR + group. The MammaPrint score for the ER + /PR-/HER2- group was significantly lower than that of other groups. In the BluePrint analysis, only four patients were classified as Basal-Type, all of whom were ER + /PR-/HER2-. CONCLUSIONS: In this study, we identified the clinical and genetic characteristics of ER + /PR- breast cancer patients in China. Distinct PR statuses indicated different biological processes of ER + breast cancer and survival outcomes. Future treatment strategies may need to be tailored for ER + /PR- patients.

Oncological outcome of complete response after neoadjuvant chemotherapy for breast conserving surgery: a systematic review and meta-analysis.

BACKGROUND: With limited sample sizes and single-institution designs, how complete response (CR) after neoadjuvant chemotherapy (NAC) influences breast conserving surgery (BCS) and its value in prognosis are not clear. METHODS: A systematic research review was conducted using electronic database. The rate of clinical complete response (cCR) in BCS after NAC and these pathological CR (PCR) and non-pCR BCS patients' local recurrence-free survival (LRFS), distance recurrence-free survival (DRFS), overall survival (OS), and disease-free survival (DFS) rates were collected. A pooled analysis was performed using a fixed or random effects model and a Q test to determine heterogeneity. RESULTS: Sixteen studies with a total of 4639 patients were included. The pooled data revealed that cCR patients compared with non-cCR patients had significantly higher rates of BCS, with a summary estimate odds ratios (OR) of 4.54 (95% CI 2.03-10.17). The pooled data revealed that BCS patients who achieved pCR after NAC had significantly lower rates of LRFS (RR = 0.59, 95% CI 0.38-0.92) and DRFS (RR = 0.27, 95% CI 0.13-0.55). Better DFS (RR = 0.09, 95% CI 0.04-0.25) and OS (RR = 0.36, 95% CI 0.03-3.90) were also seen, but OS was not significantly different. CONCLUSIONS: The rate of successful BCS is higher in the cCR group than in the non-cCR group, means cCR after NAC can encourage patients to receive BCS. The achievement of pCR after NAC in BCS patients was associated with a good prognosis in terms of LRFS and DRFS, but its value in DFS and OS requires further investigation.

Identification of N7-methylguanosine-related miRNAs as potential biomarkers for prognosis and drug response in breast cancer.

Objectives: The impact of N7-methylguanosine (m7G) on tumor progression and the regulatory role of microRNAs (miRNAs) in immune function significantly influence breast cancer (BC) prognosis. Investigating the interplay between m7G modification and miRNAs provides novel insights for assessing prognostics and drug responses in BC. Materials and methods: RNA sequences (miRNA and mRNA profiles) and clinical data for BC were acquired from the Cancer Genome Atlas (TCGA) database. A miRNA signature associated with 15 m7G in this cohort was identified using Cox regression and LASSO. The risk score model was evaluated using Kaplan-Meier and time-dependent ROC analysis, categorizing patients into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore potential pathways. The immune system, including scores, cell infiltration, function, and drug sensitivity, was examined and compared between high-risk and low-risk groups. A nomogram that combines risk scores and clinical factors was developed and validated. Single-sample gene set enrichment analysis (ssGSEA) was employed to explore m7G-related miRNA signatures and immune cell relationships in the tumor microenvironment. Additionally, drug susceptibility was compared between risk groups. Results: Fifteen m7G-related miRNAs were independently correlated with overall survival (OS) in BC patients. Time-dependent ROC analysis yielded area under the curve (AUC) values of 0.742, 0.726, and 0.712 for predicting 3-, 5-, and 10-year survival rates, respectively. The Kaplan-Meier analysis revealed a significant disparity in OS between the high-risk and low-risk groups (p = 1.3e-6). Multiple regression identified the risk score as a significant independent prognostic factor. An excellent calibration nomogram with a C-index of 0.785 (95 % CI: 0.728-0.843) was constructed. In immune analysis, low-risk patients exhibited heightened immune function and increased responsiveness to immunotherapy and chemotherapy compared to high-risk patients. Conclusion: This study systematically analyzed m7G-related miRNAs and revealed their regulatory mechanisms concerning the tumor microenvironment (TME), pathology, and the prognosis of BC patient. Based on these miRNAs, a prognostic model and nomogram were developed for BC patients, facilitating prognostic assessments. These findings can also assist in predicting treatment responses and guiding medication selection.

Analysis of Omics Data Reveals Nucleotide Excision Repair-Related Genes Signature in Highly-Grade Serous Ovarian Cancer to Predict Prognosis.

Most of the high-grade serous ovarian cancers (HGSOC) are accompanied by P53 mutations, which are related to the nucleotide excision repair (NER) pathway. This study aims to construct a risk signature based on NER-related genes that could effectively predict the prognosis for advanced patients with HGSOC. In our study, we found that two clusters of HGSOC with significantly different overall survival (OS) were identified by consensus clustering and principal component analysis (PCA). Then, a 7-gene risk signature (DDB2, POLR2D, CCNH, XPC, ERCC2, ERCC4, and RPA2) for OS prediction was developed subsequently based on TCGA cohort, and the risk score-based signature was identified as an independent prognostic indicator for HGSOC. According to the risk score, HGSOC patients were divided into high-risk group and low-risk group, in which the distinct OS and the predictive power were also successfully verified in the GEO validation sets. Then we constructed a nomogram, including the risk signature and clinical-related risk factors (age and treatment response) that predicted an individual's risk of OS, which can be validated by assessing calibration curves. Furthermore, GSEA showed that the genes in the high-risk group were significantly enriched in cancer-related pathways, such as "MAPK signaling pathway", "mTOR signaling pathway", "VEGF signaling pathway" and so on. In conclusion, our study has developed a robust NER-related genes-based molecular signature for prognosis prediction, and the nomogram could be used as a convenient tool for OS evaluation and guidance of therapeutic strategies in advanced patients with HGSOC.

Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC). METHODS: The clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots. RESULTS: Menopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582-0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636-0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659-0.801). CONCLUSION: Menopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.

Impact of nonspecific death on overall survival in early-stage epithelial ovarian cancer patients.

OBJECTIVE: To estimate the impacts of nonovarian cancer-specific death (non-OCSD) and ovarian cancer-specific death (OCSD) on early-stage patients, and to determine which statistical method yielded survival results most similar to real-world situations. METHODS: Data of patients with early-stage epithelial ovarian cancer from 1988 to 2015 registered in the Surveillance, Epidemiology, and End Results database were analyzed. The primary outcome events of epithelial ovarian cancer were OCSD, non-OCSD, or alive. Incidences of non-OCSD and OCSD with different clinicopathological factors, cumulative incidences of non-OCSD and OCSD, and overall survival impact of non-OCSD were analyzed. RESULTS: A total of 1606 non-OCSD (8.9%) and 3022 OCSDs (16.8%) were analyzed. Several independent features were associated with non-OCSD, including age (>60 years), radiotherapy, and marital status. In patients with histology (eg, endometrioid or mucinous), well-differentiated cells, stage I disease, or widowed marital status, as well as age older than 60, non-OCSD rates of all causes of death notably distorted overall survival, resulting in inaccurate and biased interpretations. CONCLUSIONS: Overall survival was greatly influenced by non-OCSD in early epithelial ovarian cancer. Future clinical trials should consider non-OCSD as a competing risk event, especially among patients older than 60 years and those with well-differentiated cells, no chemotherapy, and widowed marital status.

PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.

BACKGROUND: PARPBP (PARP1 binding protein) is an important suppressor of homologous recombination during DNA repair, but the expression and function of PARPBP in breast cancer remain unclear. METHODS: PARPBP expression was analyzed in breast cancer patient samples and public datasets for its correlation with clinical outcome. The function of PARPBP in breast cancer cell proliferation and anthracycline treatment response were studied both in vitro and in vivo. RESULTS: PARPBP was upregulated significantly at both mRNA and protein levels in breast cancer tissues compared with normal breast tissues. PARPBP high expression group had poorer overall survival (OS) than the PARPBP low expression group. Knockdown of PARPBP suppressed breast cancer cell proliferation and colony formation while overexpression of PARPBP did the opposite. We found that transcription factor forkhead box M1 (FOXM1) could activate PARPBP expression by directly binding to the promoter of PARPBP. In addition, high expression of PARPBP related with anthracycline resistance in breast cancer. Depletion of PARPBP increased breast cancer cell apoptosis and DNA damage caused by epirubicin. Moreover, tumor xenograft experiments further demonstrated that PARPBP was involved in breast cancer anthracycline resistance. CONCLUSION: Taken together, our results highlight that PARPBP is a prognostic marker and confers anthracycline resistance on breast cancer.

Minimally invasive surgery vs laparotomy for early stage cervical cancer: A propensity score-matched cohort study.

OBJECTIVE: To compare the long-term oncologic outcomes of minimally invasive surgery (MIS) vs laparotomy for patients with stage IB (2018 FIGO) cervical cancer. METHODS: A matched retrospective study of cervical cancer patients who underwent MIS or laparotomy at Sun Yat-sen University Cancer Center from January 2012 to December 2015 was carried out. Patients were restaged according to the 2018 FIGO staging system for cervical cancer, 700 cases with stage IB cervical cancer were enrolled. Propensity score matching (PSM) was performed by software SPSS version 22.0, and a total of 426 patients were enrolled and analyzed. Oncologic outcomes were compared between patients undergoing MIS vs laparotomy. RESULTS: After PSM, there were no statistical differences in other baseline characteristics between MIS and laparotomy, except for age (p = 0.008). In all stage IB patients, MIS group had significantly lower disease-free survival (DFS) rate and overall survival (OS) rate compared with laparotomy group (5-year DFS rate, 87.5% vs 94.1%, hazard ratio for disease recurrence, 2.403; 95% CI, 1.216-4.744; 5-year OS rate, 92.3% vs 98.1%, hazard ratio for death, 3.719; 95% CI, 1.370-10.093). In stage IB1 patients population, MIS was still associated with worse DFS and OS compared to laparotomy (5-year DFS rate: 89.5% vs 100%, p = 0.012; 5-year OS rate: 93.4% vs 100%, p = 0.043). Even in stage IB1 patients without lymph vascular space invasion, worse oncologic outcome could be observed in MIS group (DFS: p = 0.021; OS: p = 0.076). CONCLUSION: Our study suggested that laparotomy resulted in better OS and DFS compared with MIS among patients with stage IB cervical cancer. Even in stage IB1 patients without lymph vascular space invasion (2018 FIGO), laparotomy might be still an oncologically safer approach.

Adverse effects of being underweight on young female breast cancer patients with lymph node metastases.

Background: This study aimed to examine the effect of underweight in breast cancer. Methods: We performed a retrospective analysis of 3891 female patients diagnosed with primary breast cancer (I-IV stages). Body mass index (BMI) defined by World Health Organization criteria as follow: Underweight (UW; BMI<18.5 kg/m2), normal weight (NW; BMI =18.5-24.9 kg/m2) and overweight or obese (OW; BMI≥25 kg/m2). We performed to evaluate the association between low BMI and clinical outcome in different age (18-40 years and over 40 years) breast cancer. Results: In our study, about 7% patients suffer from being underweight and 25% patients suffer from being overweight. Underweight is more prominent in young age group. Although no relationship was found between the recurrence rate and being underweight (HR 1.467(95 % CI 0.940-2.291), P=0.092 for disease-free survival), multivariate regression analysis confirmed that low BMI was an independent overall survival (OS) prognostic factor in young patients (HR 1.610(95 % CI 1.028-2.523), P=0.037 for OS). Further analysis showed the prognostic significance of underweight only seen in young patients with axillary lymph node metastasis or III-IV stage patients. Conclusions: Our results demonstrate the prognostic importance of low BMI in young breast cancer patients (under 40 years old) with lymph node metastases. The role of low BMI in breast cancer might depend on patients' age and clinical stage.

Prognostic value of prostaglandin I2 synthase and its correlation with tumor-infiltrating immune cells in lung cancer, ovarian cancer, and gastric cancer.

BACKGROUND: Prostaglandin I2 synthase (PTGIS) is a crucial gene for the synthesis of prostaglandin I2, which has multiple roles in inflammation and immune modulation. However, studies on the prognostic value of PTGIS and its correlation with tumor-infiltrating immune cells in multiple cancers are still rare. RESULTS: Multiple datasets of the Oncomine database showed that PTGIS was expressed at low levels in lung cancer and ovarian cancer compared to the levels in normal tissues. Kaplan-Meier plotter showed that high PTGIS was associated with poor overall survival and progression-free survival in lung, ovarian, and gastric cancers. Moreover, PTGIS expression was significantly positively correlated with infiltrating levels of macrophages and was strongly associated with a variety of immune markers, especially tumor-associated macrophages (TAMs) and T-regulatory cells (Tregs). CONCLUSIONS: High expression of PTGIS could promote the infiltration of TAMs and Tregs in the tumor microenvironment and deteriorate outcomes of patients with lung, ovarian, and gastric cancers. These findings suggest that PTGIS could be taken as a potential biomarker of prognosis and tumor-infiltrating immune cells. METHODS: PTGIS expression was investigated in different datasets of the Oncomine database, and its expression levels in various tumors and corresponding normal tissues were analyzed by the Tumor Immune Estimation Resource (TIMER). Then, the clinical prognostic value of PTGIS was assessed with online public databases. In addition, we initially explored the correlation between PTGIS and tumor-infiltrating immune cells by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA).

Prognostic Values Of Preoperative Serum CEA And CA125 Levels And Nomograms For Young Breast Cancer Patients.

BACKGROUND: Young breast cancer patients have poor prognosis compared to older patients in both overall survival (OS) and loco-regional failure-free survival. Carcinoembryonic antigen (CEA) and Cancer antigen 125 (CA125) have been widely used, but their prognostic value in young breast cancer patients remains unknown. The objectives of this study were to evaluate the prognostic value of preoperative CEA and CA125 serum levels and to build nomograms for better prognostic prediction of young Chinese breast cancer patients using both tumor markers. METHODS: We included 576 young breast cancer patients (≤40 years at diagnosis) and collected their preoperative information. The best cut-off values of the CEA and CA125 were identified with receiver operating characteristic (ROC) curves. Univariate and multivariate analyses were used to identify the relative risks of factors for the overall survival (OS), and disease-free survival (DFS), and nomograms were constructed based on these identified factors. RESULTS: The best cut-off values for CEA and CA125 in young breast cancer patients was 3.38 ng/mL and 19.38 U/mL, respectively. Kaplan-Meier analysis showed that young patients with low levels of CEA and/or CA125, had longer OS and DFS. Multivariate analysis suggested that both CEA and CA125 levels were independent predictive elements for OS. Nomograms were built and showed a better predictive ability for OS (AUC = 0.856) and DFS (AUC = 0.702) in young breast cancer patients. CONCLUSION: Preoperative serum CEA and CA125 levels could be the independent prognostic factors for OS, and the nomograms including these two variables provide more personal forecasts information to help physicians optimize treatment for young breast cancer patients better.

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer.

Clinical trials testing Janus kinase-1 (JAK1) inhibitors in cancers are under way. Whether the JAK1 mRNA levels in breast tumors correlates with outcome has not been evaluated. JAK1 expression was analyzed via the Oncomine database and Tumor IMmune Estimation Resource site. Tumor tissues from 57 breast cancer patients were used for qRT-PCR and immune infiltration assessment. JAK1 expression was significantly lower in breast invasive carcinoma compared with adjacent normal tissues. Public databases (Kaplan-Meier plotter and PrognoScan) showed that low JAK1 expression was associated with poorer survival. Data from The Cancer Genome Atlas (TCGA) showed that high JAK1 expression was associated with increased survival in both TNM I-II and TNM III-IV patients. JAK1 was inversely correlated with tumor size status, lymph node status, and TNM of breast cancer patients. JAK1 levels were correlated with the T cell transcript-enriched LYM metagene signature and was significantly lower in the low tumor infiltrating lymphocytes (TILs) group. JAK1 expression levels had significant positive correlations with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in breast cancer and not with other B cells. In conclusion, JAK1 mRNA levels were correlated with prognosis and immune infiltrating levels in breast cancer.

Correction to: Elevated expression of CST1 promotes breast cancer progression and predicts a poor prognosis.

In Figure 7f the panel for c-myc of MDA-MB-468 was erroneously duplicated. The corrected version of the figure is shown in this paper. This correction does not influence the conclusion of the study and we sincerely apologize for this oversight.

The value of neutrophil-to-lymphocyte ratio for response and prognostic effect of neoadjuvant chemotherapy in solid tumors: A systematic review and meta-analysis.

Introduction: The neutrophil-to-lymphocyte ratio (NLR) has been found to be an indicator of poor prognosis in many tumour types. However, little is known about the relationship between the NLR and patients with tumours who receive neoadjuvant chemotherapy (NAC) in terms of response rate and prognostic ability. We thus performed this meta-analysis to further investigate this relationship. Methods: An electronic systematic literature search for articles published before September 2017 was performed to explore the association between the pretreatment NLR and outcome in patients treated with NAC. Data were extracted by the reported odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) for the response rate and the survival outcome, respectively. The results were pooled using the random-effect or fixed-effect model. Results: Thirty-three studies were eventually included in our study, and all were published no earlier than 2011. An NLR that was higher than the cut-off was associated with a lower pathological complete response (pCR) rate in patients with cancer (OR = 1.72, 95% CI, 1.26-2.33). A lower NLR was associated with better overall survival (OS) (HR = 1.58, 95% CI, 1.34-1.86), cancer-specific survival (CSS) (HR = 2.22, 95% CI, 1.32-3.74), disease-free survival (DFS) (HR = 1.32, 95% CI, 1.10-1.59) and recurrence-free survival (RFS) (HR = 1.90, 95% CI, 1.50-2.40). Conclusion: Overall, an NLR lower than the cut-off value indicated a greater chance for pCR and may predict good survival outcomes after NAC for patients with solid tumours. The use of the NLR for risk stratification before NAC should be further demonstrated by future large-scale prospective studies.

Clinicopathological and Prognostic Significance of Cancer Antigen 15-3 and Carcinoembryonic Antigen in Breast Cancer: A Meta-Analysis including 12,993 Patients.

PURPOSE: The prognostic role of serum cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) in breast cancer remains controversial. In this study, we conducted a meta-analysis to investigate the prognostic value of these two markers in breast cancer patients. METHODS: After electronic databases were searched, 36 studies (31 including information regarding CA15-3 and 23 including information regarding CEA) with 12,993 subjects were included. Based on the data directly or indirectly from the available studies, the hazard ratios (HRs) and odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled according to higher or lower marker levels. RESULTS: Elevated CA15-3 or CEA was statistically significant with poorer DFS and OS in breast cancer (multivariate analysis of OS: HR = 2.03, 95% CI 1.76-2.33 for CA15-3; HR = 1.79, 95% CI 1.46-2.20 for CEA; multivariate analysis of DFS: HR = 1.56, 95% CI 1.06-1.55 for CA15-3; HR = 1.77, 95% CI 1.53-2.04 for CEA). Subgroup analysis showed that CA15-3 or CEA had significant predictive values in primary or metastasis types and different cut-offs and included sample sizes and even the study publication year. Furthermore, elevated CA15-3 was associated with advanced histological grade and younger age, while elevated CEA was related to the non-triple-negative tumor type and older age. These two elevated markers were all associated with a higher tumor burden. CONCLUSIONS: This meta-analysis showed that elevated serum CA15-3 or CEA was associated with poor DFS and OS in patients with breast cancer, and they should be tested anytime if possible.

Determination of the prognostic value of preoperative CA15-3 and CEA in predicting the prognosis of young patients with breast cancer.

To the best of our knowledge, no previous study has investigated the association of carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) with the prognosis for young patients (≤40 years) with breast cancer. In the present study, preoperative CEA and CA15-3 serum levels were evaluated in the prediction of the prognosis for young patients with breast cancer. In total, 699 patients were recruited, for which the CEA and CA15-3 serum levels had been measured prior to surgery via a blood sample. The optimal cut-off high and low values were determined using receiver operating characteristic curve analysis and Youden's index. The value of CEA and CA15-3 in predicting overall survival (OS) and disease-free survival (DFS) were measured using univariate and multivariate Cox's regression analyses. The cut-off values were 3.38 ng/ml and 12.32 U/ml for CEA and CA15-3, respectively. It was identified that CEA, but not CA15-3, was a predictor for the prognosis of the young patients with breast cancer. Multivariate analysis confirmed that CEA, but not CA15-3, was an independent prognostic marker for all young patients with breast cancer. In total, 623 young patients exhibited decreased levels of CEA; in these patients, CA15-3 with a cut-off value of 12.48 U/ml was an independent prognostic factor for OS and DFS. Preoperative serum CEA may thus serve as an independent predictor of poor prognosis for young patients with breast cancer. However, for low-risk patients with decreased CEA levels, serum CA15-3 may supplement the prediction of overall prognosis.

Efficacy of PI3K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: A literature-based meta-analysis of 46 randomised control trials.

BACKGROUND: The phosphatidylinositol-3- kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) plays a key role in cancer. We performed this meta-analysis to assess the clinical effect of using PI3K/AKT/mTOR pathway inhibitors on advanced solid tumours. METHODS: All the randomised controlled trials (RCT) that compared the therapy with PI3K/AKT/mTOR pathway inhibitors with other therapies were included. The main end-point was progression-free survival (PFS); other end-points included overall survival (OS) and objective response rate (ORR). A subgroup analysis was performed mainly for PFS. RESULTS: In total, 46 eligible RCT were included. The pooled results showed that PI3K/AKT/mTOR pathway inhibitor-based regimens significantly improved the PFS of patients with advanced solid tumours (hazard ratios (HR) = 0.79; 95% confidence intervals (CI): 0.71-0.88) and PI3K pathway mutations (HR = 0.69; 95% CI: 0.56-0.85). All single PI3K/AKT/mTOR pathway inhibitor therapies were compared with other targeted therapies (HR = 0.99; 95% CI: 0.93-1.06) and dual targeted therapies, including PI3K/AKT/mTOR pathway inhibitors and other targeted therapies (HR = 1.04; 95% CI: 0.62-1.74), which showed no significant differences in the PFS. Additional PI3K/AKT/mTOR pathway inhibitors showed no advantage with respect to the OS (HR = 0.98; 95% CI: 0.90-1.07) or ORR (risk ratio (RR) = 1.02; 95% CI: 0.87-1.20). CONCLUSION: Our meta-analysis results suggest that the addition of the PI3K pathway inhibitors to the therapy regiment for advanced solid tumours significantly improves PFS. The way that patients are selected to receive the PI3K pathway inhibitors might be more meaningful in the future.

High expression of TACC2 in hepatocellular carcinoma is associated with poor prognosis.

BACKGROUND: Transforming acidic coiled-coil protein 2 (TACC2) is a member of TACC family proteins which is mainly involved in the stabilization of spindles and regulation of microtubule dynamics through interactions with molecules involved in centrosomes/microtubules. TACC2 is involved in tumorigenesis of variety of cancers but the clinical significance of TACC2 protein in hepatocellular carcinoma (HCC) is still unclear. OBJECTIVE: This study aims to investigate the expression of TACC2 in HCC and determine if clinical significance and prognostic relevance exists. METHODS: We performed quantitative PCR (qPCR) and western blot to examine TACC2 mRNA and protein expression in paired HCC tissues and matched adjacent non-cancerous tissues. Immunohistochemistry was performed in 106 postoperative HCC samples. RESULTS: There was higher expression of TACC2 protein and mRNA in HCC tissue. Immunohistochemistry analysis showed high expression of TACC2 in HCC tissue and was significantly associated with the capsular extension, tumor recurrence and shortened overall and disease free survival. The Cox regression analysis suggested that a high expression of TACC2 was an independent prognostic factor for HCC patients. CONCLUSION: This finding suggests that TACC2 may be a useful tool as a candidate biomarker to predict the recurrence and prognosis of HCC.

circEPSTI1 as a Prognostic Marker and Mediator of Triple-Negative Breast Cancer Progression.

Circular RNAs (circRNAs) represent a class of non-coding RNAs that play a vital role in modulating gene expression and several pathological responses. However, the expression profile and function of circRNAs in triple-negative breast cancer (TNBC) remain unknown. In the current study, we investigated the expression profile of human circRNAs in TNBC tissues and identified circEPSTI1 (hsa_ circRNA_000479) as a significantly upregulated circRNA. Methods: We performed circular RNA microarray assays to screen circular RNA expression profiles of TNBC and further investigated circEPSTI1. We observed the effect of circEPSTI1 on proliferation, clonal formation and apoptosis in TNBC by knocking downcircEPSTI1 in three TNBC cell lines. Based on the MRE analysis and luciferase reporter assay, we found that circEPSTI1 binds to miRNAs as a miRNA sponge and the co-target genes of miRNAs. We performed xenograft experiments in mice to confirm our findings. We evaluated circEPSTI1 levels in 240 TNBC patients by ISH. Results: Knockdown of circEPSTI1 inhibits TNBC cell proliferation and induces apoptosis. In vitro and in vivo experiments indicated that circEPSTI1 binds to miR-4753 and miR-6809 as a miRNA sponge to regulate BCL11A expression and affect TNBC proliferation and apoptosis. High levels of circEPSTI1 correlate with reduced survival in TNBC patients. Conclusions: The circEPSTI1-miR-4753/6809-BCL11A axis affect the proliferation and apoptosis of triple-negative breast cancer through the mechanism of competing endogenous RNAs (ceRNA). In addition, our results identify circEPSTI1 as an independent prognostic marker for survival in patients with TNBC.