Knowledge mapping of immunotherapy for breast cancer: A bibliometric analysis from 2013 to 2022.

Breast cancer is the leading cause of cancer-related death among women globally. Immunotherapy has emerged as a major milestone in contemporary oncology. This study aims to conduct a bibliometric analysis in the field of immunotherapy for breast cancer, providing a comprehensive overview of the current research status, identifying trends and hotspots in research topics. We searched and retrieved data from the Web of Science Core Collection, and performed a bibliometric analysis of publications on immunotherapy for breast cancer from 2013 to 2022. Current status and hotspots were evaluated by co-occurrence analysis using VOSviewer. Evolution and bursts of knowledge base were assessed by co-citation analysis using CiteSpace. Thematic evolution by bibliometrix package was used to discover keywords trends. The attribution and collaboration of countries/regions, institutions and authors were also explored. A total of 7,975 publications were included. In co-occurrence analysis of keywords, 6 major clusters were revealed: tumor microenvironment, prognosis biomarker, immune checkpoints, novel drug delivery methods, immune cells and therapeutic approaches. The top three most frequently mentioned keywords were tumor microenvironment, triple-negative breast cancer, and programmed cell death ligand 1. The most productive country, institution and author were the USA (2926 publications), the University of Texas MD Anderson Cancer Center (219 publications), and Sherene Loi (28 publications), respectively. There has been a rapid growth in studies on immunotherapy for breast cancer worldwide. This research area has gained increasing attention from different countries and institutions. With the rising incidence of breast cancer, immunotherapy represents a research field of significant clinical value and potential.

MAP3K4 kinase action and dual role in cancer.

It is commonly known that the MAPK pathway is involved in translating environmental inputs, regulating downstream reactions, and maintaining the intrinsic dynamic balance. Numerous essential elements and regulatory processes are included in this pathway, which are essential to its functionality. Among these, MAP3K4, a member of the serine/threonine kinases family, plays vital roles throughout the organism's life cycle, including the regulation of apoptosis and autophagy. Moreover, MAP3K4 can interact with key partners like GADD45, which affects organism's growth and development. Notably, MAP3K4 functions as both a tumor promotor and suppressor, being activated by a variety of factors and triggering diverse downstream pathways that differently influence cancer progression. The aim of this study is to provide a brief overview of physiological functions of MAP3K4 and shed light on its contradictory roles in tumorigenesis.

Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that SAM and SH3 domain containing protein 1 (SASH1) expression is negatively correlated with mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) expression in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1 and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Metabolomics assisted by transcriptomics analysis to reveal metabolic characteristics and potential biomarkers associated with treatment response of neoadjuvant therapy with TCbHP regimen in HER2 + breast cancer.

BACKGROUND: This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients. METHODS: A total of 120 plasma samples from 40 patients with HER2 + BrCa were prospectively collected at three treatment times of neoadjuvant therapy (NAT) with TCbHP regimen. Serum metabolites were analyzed based on LC-MS and GC-MS data. Random forest was used to establish predictive models based on pre-therapeutic differentially expressed metabolites. Time series analysis was used to obtain potential monitors for treatment response. Transcriptome analysis was performed in nine available pre­therapeutic specimens of core needle biopsies. Integrated analyses of metabolomics and transcriptomics were also performed in these nine patients. qRT-PCR was used to detect altered genes in trastuzumab-sensitive and trastuzumab-resistant cell lines. RESULTS: Twenty-one patients achieved pCR, and 19 patients achieved non-pCR. There were significant differences in plasma metabolic profiles before and during treatment. A total of 100 differential metabolites were identified between pCR patients and non-pCR patients at baseline; these metabolites were markedly enriched in 40 metabolic pathways. The area under the curve (AUC) values for discriminating the pCR and non-PCR groups from the NAT of the single potential metabolite [sophorose, N-(2-acetamido) iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] or combined panel of these metabolites were greater than 0.910. Eighteen metabolites exhibited potential for monitoring efficacy. Several validated genes might be associated with trastuzumab resistance. Thirty-nine altered pathways were found to be abnormally expressed at both the transcriptional and metabolic levels. CONCLUSION: Serum-metabolomics could be used as a powerful tool for exploring informative biomarkers for predicting or monitoring treatment efficacy. Metabolomics integrated with transcriptomics analysis could assist in obtaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients.

Thoracic aorta injury detected by 4D flow MRI predicts subsequent main adverse cardiovascular events in breast cancer patients receiving anthracyclines: A longitudinal study.

PURPOSE: To investigate longitudinal thoracic aorta injury using 3-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) parameters and to evaluate their value for predicting the subsequent main adverse cardiovascular events (MACEs) in breast cancer patients receiving anthracyclines. METHODS: Between July 2020 and July 2021, eighty-eight female participants with breast cancer scheduled to receive anthracyclines with or without trastuzumab prospectively enrolled. Each subjects underwent 4D flow MRI at baseline, 3 and 6 months in relation to baseline. The diameter, peak velocity (Vpeak), wall shear stress (WSS), pulse wave velocity (PWV), energy loss (EL) and pressure gradient (PG) of thoracic aorta were measured. The association between these parameters and subsequent MACEs was performed by Cox proportional hazard models. RESULTS: Ten participants had subsequently MACEs. The Vpeak and PG gradually decreased and the WSS, PWV and EL progressively increased at 3 and 6 months compared with baseline. Adjusted multivariable analysis showed that the WSS of the proximal, mid- and distal ascending aorta [HR, 1.314 (95% confidence interval (CI): 1.003, 1.898)], [HR, 1.320 (95% CI: 1.002, 1.801)] and [HR, 1.322 (95% CI: 1.001, 1.805)] and PWV of ascending aorta [HR, 2.223 (95% CI: 1.010, 4.653)] at 3 months were associated with subsequent MACEs. Combined WSS and PWV of ascending aorta at 3 months yielded the highest AUC (0.912) for predicting subsequent MACEs. CONCLUSION: Combined WSS and PWV of ascending aorta at 3 months is helpful for predicting the subsequent MACEs in breast cancer patients treated by anthracyclines.

The impact of FDI on energy conservation and emission reduction performance: A FDI quality perspective.

According to the climate emission reduction commitment of the Paris Agreement, all countries are actively seeking a new path of energy conservation and emission reduction, and trying to "bend downward" the global greenhouse gas emission curve. For China's carbon peak before 2030 and carbon neutral target before 2060, explore whether FDI can reduce China's energy consumption and carbon emissions. From the new research perspective of FDI quality, this paper explores the potential ways to improve regional energy-carbon emission performance (ECEP), and applied dynamic threshold effect and two-stage least squares for validation. The specific results are as follows: FDI quality improvement can have a significant positive impact on regional ECEP.The development level of renewable energy, the optimization of industrial structure and the enhancement of green innovation ability can positively regulate the impact of FDI on energy-carbon emission performance. At the same time, the results of the dynamic panel threshold model demonstrate that with the economic growth pressure of local governments decreases and the fiscal decentralization increases, the role of FDI quality in promoting the ECEP could be stronger. The influence of FDI quality on ECEP has regional heterogeneity, and the influence of FDI quality on ECEP is regional heterogeneous, and the influence of FDI quality on ECEP is more significant in inland and midwestern regions than in coastal and eastern regions. This study provides experience for FDI to formulate the quality assessment system and formulate foreign investment policy.

Quantification of Hepatic Steatosis on Dual-Energy CT in Comparison With MRI mDIXON-Quant Sequence in Breast Cancer.

OBJECTIVE: The study aimed to evaluate the correlation and diagnostic value of liver fat quantification in unenhanced dual-energy CT (DECT) using quantitative magnetic resonance imaging (MRI) mDIXON-Quant sequence as reference standard in patients with breast cancer. METHODS: Patients with breast cancer were prospectively recruited between June 2018 and April 2020. Each patient underwent liver DECT and MRI mDIXON-Quant examination. The DECT-fat volume fraction (FVF) and liver-spleen attenuation differences were compared with the MRI-proton density fat fraction using scatterplots, Bland-Altman plots, and concordance correlation coefficient. Receiver operating characteristic curves were established to determine the diagnostic accuracy of hepatic steatosis by DECT. RESULTS: A total of 216 patients with breast cancer (mean age, 50.08 ± 9.33 years) were evaluated. The DECT-FVF correlated well with MRI-proton density fat fraction ( r2 = 0.902; P < 0.001), which was higher than the difference in liver-spleen attenuation ( r2 = 0.728; P < 0.001). Bland-Altman analysis revealed slight positive bias; the mean difference was 3.986. The DECT-FVF yielded an average concordance correlation coefficient of 0.677, which was higher than the difference of liver-spleen attenuation (-0.544). The DECT-FVF and the difference in liver-spleen attenuation both lead to mild overestimation of hepatic steatosis. The areas under the curve of DECT-FVF (0.956) were higher than the difference in liver-spleen attenuation (0.807) in identifying hepatic steatosis ( P < 0.001). CONCLUSIONS: Dual-energy CT-FVF may serve as a reliable screening and quantitative tool for hepatic steatosis in patients with breast cancer.

Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.

OBJECTIVE: To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer. DESIGN: Randomised, double blind, placebo controlled, multicentre, phase 3 trial. SETTING: 40 centres in China between 6 May 2019 and 17 January 2022. PARTICIPANTS: 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer. INTERVENTIONS: Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival as assessed by the investigator. RESULTS: Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up. CONCLUSIONS: Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03863223.

Prediction of stock price movement using an improved NSGA-II-RF algorithm with a three-stage feature engineering process.

Prediction of stock price has been a hot topic in artificial intelligence field. Computational intelligent methods such as machine learning or deep learning are explored in the prediction system in recent years. However, making accurate predictions of stock price direction is still a big challenge because stock prices are affected by nonlinear, nonstationary, and high dimensional features. In previous works, feature engineering was overlooked. How to select the optimal feature sets that affect stock price is a prominent solution. Hence, our motivation for this article is to propose an improved many-objective optimization algorithm integrating random forest (I-NSGA-II-RF) algorithm with a three-stage feature engineering process in order to decrease the computational complexity and improve the accuracy of prediction system. Maximizing accuracy and minimizing the optimal solution set are the optimization directions of the model in this study. The integrated information initialization population of two filtered feature selection methods is used to optimize the I-NSGA-II algorithm, using multiple chromosome hybrid coding to synchronously select features and optimize model parameters. Finally, the selected feature subset and parameters are input to the RF for training, prediction, and iterative optimization. Experimental results show that the I-NSGA-II-RF algorithm has the highest average accuracy, the smallest optimal solution set, and the shortest running time compared to the unmodified multi-objective feature selection algorithm and the single target feature selection algorithm. Compared to the deep learning model, this model has interpretability, higher accuracy, and less running time.

Different risk and prognostic factors for liver metastasis of breast cancer patients with de novo and relapsed distant metastasis in a Chinese population.

Purpose: The present study aimed to identify clinicopathological characteristics of breast cancer liver metastasis (BCLM) as well as to characterize the risk and prognostic factors for the liver metastasis (LM) of breast cancer patients with de novo and relapsed distant metastasis in a Chinese population. Materials and methods: Patients with metastatic breast cancer (MBC) who were hospitalized in the Breast Cancer Center at Chongqing University between January 2011 and December 2019 were included in the present study. Logistic regression analyses were conducted to identify risk factors for the presence of BCLM. Cox proportional hazard regression models were performed to determine the prognostic factors for the survival of BCLM patients. The correlation between LM and overall survival was assessed by the Kaplan-Meier method. Results: In total, 1,228 eligible MBC patients, including 325 cases (26.5%) with de novo metastasis (cohort A) and 903 cases (73.5%) with relapsed metastasis (cohort B), were enrolled in the present study. In cohort A and cohort B, 81 (24.9%) and 226 (25.0%) patients had BCLM, respectively. Patients in these two cohorts had different clinicopathological features. Logistic regression analysis identified that the human epidermal growth factor receptor 2 (HER2) status in cohort A as well as the HER2 status and invasive ductal carcinoma histology in cohort B were risk factors for BCLM. The median OS of patients with LM was inferior to that of non-LM patients (17.1 vs. 37.7 months, P = 0.0004 and 47.6 vs. 84.0 months, P < 0.0001, respectively). Cox analysis identified that the primary T stage, Ki67 level, and breast surgery history were independent prognostic factors for cohorts A and B, respectively. Conclusions: De novo and relapsed MBC patients have different risk and prognostic factors for LM. Patients with BCLM have an unfavorable prognosis.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28-75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30-9.11) and 3.72 (95% CI, 1.91-5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58-0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).

Comparison of effects of different anesthesia methods on immune function and liver function of liver cancer patients after operation.

Liver cancer, one of the most common malignant tumors, has seriously threatened people's physical and mental health. The paper was conducted to investigate the functions of two different anesthesia methods on Tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and T lymphocyte subsets in patients undergoing liver cancer resection, and to explore the liver function impact of patients undergoing liver cancer surgery. 80 liver cancer patients were split into propofol intravenous anesthesia group and sevoflurane inhalation anesthesia group. The patient's operation-related indicators and changes in TNF-α, CRP and T lymphocyte subsets before anesthesia, after anesthesia, 1 day after anesthesia, and 3 days after anesthesia were calculated. The levels of TNF-α and CRP in the two groups after operation were clearly higher than those before anesthesia, but there was no obvious difference between the two groups. After operation, the TNF-α of the propofol intravenous anesthesia group was lower than the sevoflurane inhalation anesthesia group. The CD3+, CD4+ and CD4+/CD8+ levels in both groups recovered to the pre-anaesthesia level 3 days after the operation. The levels of ALT, AST, ALB and TBIL returned to normal at d4 in both propofol intravenous anesthesia and sevoflurane inhalation anesthesia groups. Compared with evoflurane inhalation anesthesia for patients with liver cancer, intravenous anesthesia with propofol can reduce the body's inflammatory response to a certain extent, has weak inhibitory effect on T lymphocyte immune function, and a smaller effect on liver function.

Neutrophil-to-lymphocyte ratio is a negative prognostic biomarker for luminal A breast cancer.

Background: Inflammation plays an important role in the occurrence, development, and metastasis of tumors. However, the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in patients with luminal A breast cancer has rarely been reported in the literature. The purpose of this study was to investigate the relationship between preoperative peripheral blood NLR and the survival rate of patients with luminal A breast cancer. Methods: Data from 226 eligible patients with luminal A breast cancer at the Chongqing University Cancer Hospital between 2011 and 2016 were obtained. The cut-off value for NLR for predicting overall survival (OS) rate was obtained from the receiver operating characteristic (ROC) curve. The baseline characteristics of 2 groups were compared using the Chi-square test or Fisher's exact test, and OS was estimated using the Kaplan-Meier method. Cox analysis was performed to determine the correlation between clinicopathological parameters and prognosis. Results: ROC curve analysis showed that the cutoff value for NLR to predict OS was 2.0. Kaplan-Meier analysis revealed that the OS of patients with a NLR <2.0 was significantly longer than that of patients with a higher NLR >2 (P<0.0001). The area under the curve (AUC) for NLR to predict OS was 0.781 [95% confidence interval (CI): 0.712-0.851], sensitivity was 54.17%, and specificity was 97.06%. In univariate Cox regression analysis, NLR, tumor (T) stage (T3-T4 vs. T1-T2), and histological grade (II-III vs. I) were all significantly associated with OS. In multivariate Cox regression analysis, NLR and histology grade (II-III vs. I) were independent prognostic factors for OS. Conclusions: The results suggested that higher preoperative NLR was associated with worse prognosis in luminal A breast cancer.

The effects of neoadjuvant zoledronic acid in breast cancer patients: A meta-analysis of randomized controlled trials.

To explore the effects of Zoledronic acid (ZA) in the neoadjuvant setting, we conducted a meta-analysis of randomized controlled trials (RCTs) of neoadjuvant therapy with or without ZA in breast cancer (BC). A systematic literature search was carried out by two reviewers independently on the basis of three electronic databases up to February 2022. Six RCTs with a total of 949 patients, comparing neoadjuvant therapy with or without ZA in BC were included. In the total population, adding ZA to the neoadjuvant setting didn't improved the pathological complete response (pCR) rates (Risk Ratio (RR) = 1.38, 95% CI 0.94-2.03, p = 0.10). However, subgroup analysis revealed that the addition of ZA resulted in an increased pCR rate in postmenopausal women (RR = 2.30, 95% CI 0.93-5.71, p = 0.07) and in patients with triple-negative BC (RR = 2.85, 95% CI 1.01-8.03, p = 0.05), although these results were not statistically significant. Furthermore, the additional ZA did not show benefits on objective response rate, breast-conserving surgery rate or recurrence rate. For mortality, however, the additional ZA resulting in worse outcome compared to the control group (RR = 1.48, 95% CI 1.04-2.10, p = 0.03). Our study suggested that addition of ZA to neoadjuvant therapy didn't improved the pCR rate. Further investigations are warranted in postmenopausal women and patients with triple-negative BC, since these subgroups might benefit from ZA treatment.

Optimal radiotherapy modality sparing for cardiac valves in left-sided breast cancer.

Background: The cardiotoxicity caused by radiotherapy is a critical problem in the treatment of patients with breast cancer. The appropriate radiotherapy modality sparing for cardiac valves in left-sided breast cancer has not been well defined. The aim of this study was thus to compare the dosimetric differences in heart and cardiac valves of 3-dimensional conformal radiotherapy (3D-CRT), fixed-field intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) to find the optimal radiotherapy modality sparing for cardiac valves in patients with left breast cancer. Methods: From January 5, 2021, to March 15, 2021, 21 patients with left-sided breast cancer postmastectomy were included in this study, and 3 different plans for adjuvant radiation were created using 3D-CRT, IMRT, and VMAT for each patient. All patients received 50 Gy in 25 fractions. The mean dose (Dmean) of the heart; percentage volume of the heart receiving ≥5 Gy (V5), ≥30 Gy (V30), and ≥40 Gy (V40); and the Dmean and the near-maximum dose (D0.03cc) of cardiac valves were extracted from dose-volume histograms (DVHs) and compared. The correlations in dosimetric factors between cardiac valves and the whole heart were analyzed. Results: IMRT significantly decreased the values of V5, V30, V40, and Dmean in the whole heart compared to 3D-CRT and VMAT (P<0.001). Among the 3 different plans, IMRT had the lowest radiation dose to the Dmean and the D0.03cc of the aortic valve (1.27 Gy/1.75 Gy), pulmonary valve (3.44 Gy/6.89 Gy), tricuspid valve (1.02 Gy/1.14 Gy), and mitral valve (0.93 Gy/1.00 Gy). Pearson correlation analysis found that local parameters (Dmean and D0.03cc) within valves were strongly correlated to the global parameters (V5, V30, V40, and Dmean) of the heart. Conclusions: This study revealed that IMRT showed the lowest cardiac valves dose compared with 3D-CRT and VMAT in left-sided breast cancer radiotherapy. IMRT might be the optimal modality sparing for cardiac valves in this group of patients. Further studies need to be carried out in order to validate the protective role of IMRT on the cardiac valves.

The PER3rs772027021 SNP induces pigmentation phenotypes of dyschromatosis universalis hereditaria.

Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM_001289861) was detected in each affected individual of the DUH family; the c. 517C > T SNP of PER3 (PER3rs772027021 SNP) and a novel mutation in exon 14 of SASH1 (c. 1574C > G (p.T525R)) were both found in the proband. The affected individuals carrying PER3rs772027021 SNP in this family demonstrated mild-pigmented phenotypes compared to those of the proband carrying PER3rs772027021 SNP and SASH1 T525R mutation. Increased melanin synthesis was induced by PER3rs772027021 SNP in the melanocytes of affected epithelial tissues. Mutated SASH1 or PER3rs772027021 SNP alone or cooperation of mutation of SASH1 and PER3rs772027021 SNP synergistically led to increased melanin synthesis and enhanced proliferation of melanoma cells in vitro. We also phenotypically characterized a commercially available zebrafish mutant line harboring the PER3rs772027021 SNP to induce melanocyte proliferation in vivo. Our results are the first to reveal that this PER3 SNP may be pathogenic for a novel DUH subtype with mild hyperpigmented and/or hypopigmented phenotypes and that mutation of SASH1 and PER3 cooperatively promotes hyperpigmentation phenotypes. KEY MESSAGES: PER3 rs772027021 SNP is identified to be associated with hyperpigmentation and/or hypopigmentation phenotype and the novel pathogenic variant of PER3 rs772027021 SNP probably contributed the pathogenesis of DUH. SASH1T525R mutation is confirmed to associate with DUH. A novel autosomal dominant inheritance DUH subtype with mild pigmentated phenotypes is caused by the PER3rs772027021 SNP.

Recurrent Metaplastic Breast Cancer with Subtype Converted from Triple-Negative to HER2-Positive: A Case Report and Literature Review.

Background: Metaplastic breast cancer (MBC) is an extremely rare malignant breast disease that has rarely been reported. The molecular subtype of MBC is mostly triple-negative, with a high recurrence rate and a worse prognosis. Due to its low HR- and HER2-positive rate, reports on endocrine and targeted therapy are very limited. Case report: We report a case of infrequent triple-negative MBC, which, although at an early stage, quickly developed multiple recurrent lesions in the chest wall. The tumor relapsed repeatedly after comprehensive treatment, including surgery, chemotherapy and radiotherapy. However, pathological results after the third surgery suggested that the molecular subtype had changed from triple-negative to HER2-positive. The previous comprehensive treatment had not been able to effectively control the disease, but the patient achieved a long progression-free survival time through chemotherapy and trastuzumab targeted therapy after the subtype change. To date, there has been no recurrence for over eight years. Conclusion: Among repeatedly relapsed MBC patients, further investigation should be taken into consideration. As in the case presented in our study, it is possible that the HER2 status can convert from negative to overexpression. Moreover, for HER2-positive MBC patients, anti-HER2 therapy is recommended. The decision-making process requires multidisciplinary involvement.

A Phase IIb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments.

Refractory or relapsing metastatic triple-negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate, targeting human trophoblast cell-surface antigen 2 (Trop-2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed ≥2 prior chemotherapy regimens. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the Independent Review Committee. Secondary endpoints included: duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and safety. Eighty female Chinese patients (median age 47.6 years; range 24-69.9 years) received ≥1 SG dose with a median of 8 treatment cycles by the cutoff date (August 6, 2021). Median number of prior systemic cancer treatments was 4.0 (range 2.0-8.0). ORR and CBR were reported 38.8% (95% confidence interval [CI]: 28.06-50.30) and 43.8% (95% CI, 32.68-55.30) of patients, respectively. The median PFS was 5.55 months (95% CI, 4.14-N/A). SG-related Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable.

Construction and validation of a prognostic nutritional index-based nomogram for predicting pathological complete response in breast cancer: a two-center study of 1,170 patients.

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) is associated with favorable outcomes in breast cancer patients. Identifying reliable predictors for pCR can assist in selecting patients who will derive the most benefit from NAC. The prognostic nutritional index (PNI) serves as an indicator of nutritional status and systemic immune competence. It has emerged as a prognostic biomarker in several malignancies; however, its predictive value for pCR in breast cancer remains uncertain. The objective of this study is to assess the predictive value of pretreatment PNI for pCR in breast cancer patients. Methods: A total of 1170 patients who received NAC in two centers were retrospectively analyzed. The patients were divided into three cohorts: a training cohort (n=545), an internal validation cohort (n=233), and an external validation cohort (n=392). Univariate and multivariate analyses were performed to assess the predictive value of PNI and other clinicopathological factors. A stepwise logistic regression model for pCR based on the smallest Akaike information criterion was utilized to develop a nomogram. The C-index, calibration plots and decision curve analysis (DCA) were used to evaluate the discrimination, calibration and clinical value of the model. Results: Patients with a high PNI (≥53) had a significantly increased pCR rate (OR 2.217, 95% CI 1.215-4.043, p=0.009). Tumor size, clinical nodal status, histological grade, ER, Ki67 and PNI were identified as independent predictors and included in the final model. A nomogram was developed as a graphical representation of the model, which incorporated the PNI and five other factors (AIC=356.13). The nomogram demonstrated satisfactory calibration and discrimination in the training cohort (C-index: 0.816, 95% CI 0.765-0.866), the internal validation cohort (C-index: 0.780, 95% CI 0.697-0.864) and external validation cohort (C-index: 0.714, 95% CI 0.660-0.769). Furthermore, DCA indicated a clinical net benefit from the nomogram. Conclusion: The pretreatment PNI is a reliable predictor for pCR in breast cancer patients. The PNI-based nomogram is a low-cost, noninvasive tool with favorable predictive accuracy for pCR, which can assist in determining individualized treatment strategies for breast cancer patients.