New insights into HER2-low breast cancer brain metastasis: A retrospective analysis.

BACKGROUND: A considerable number of patients with breast cancer will suffer from brain metastasis in the advanced setting. The HER2 status serves as a significant prognostic factor and the reference of applying treatment for patients with breast cancer brain metastasis (BCBM). METHODS: Between January 2010 and July 2021, patients with BCBM who had available HER2 status were identified. The patients with HER2 1+ in immunohistochemistry (IHC) or IHC 2+ and fluorescence in situ hybridization (FISH) negative were categorized as HER2-low. Comparisons were conducted between the HER2-low and HER2-zero population. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. Survival outcomes were assessed using Kaplan-Meier curves with log-rank test and Cox proportional hazards model. RESULTS: In this study, we analyzed 71 patients with the HER2-low breast cancer subtype and 64 patients with the HER2-zero subtype. Despite the limited sample size, our findings revealed a significantly better OS for patients with HER2-low cancer compared to their HER2-zero counterparts (26 m vs 20 m, p = 0.0017). This trend was particularly notable in the HR-negative group (26 m vs 13 m, p = 0.0078), whereas no significant difference was observed among the HR-positive patients. Furthermore, Cox regression analysis revealed that the HER2-low status was an independent prognostic factor for better survival in the HR-negative patients (p = 0.046 in multivariate analysis). CONCLUSIONS: Patients diagnosed with HER2-low BCBM exhibited a more favorable prognosis than those with HER2-zero BCBM, particularly within the HR-negative subgroup. The low expression of HER2 is supposed to be linked to the prolonged survival of BCBM patients.

Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart (TQB2450) and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer.

In our phase Ib trial (ClinialTrials.gov Identifier: NCT03855358), benmelstobart (TQB2450), a novel humanized IgG1 antibody against PD-L1, plus antiangiogenic multikinase inhibitor, anlotinib, demonstrated promising antitumor activities in pretreated triple negative breast cancer (TNBC) patients. We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes. Targeted next generation sequencing (NGS) was undertaken toward circulating tumor DNA (ctDNA) collected from peripheral blood samples prior to the start of treatment and after disease progression. A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed. The most frequent mutations were TP53 (72%), MLL3 (28%), and PIK3CA (17%). At a blood-based tumor mutational burden (bTMB) cutoff of 6.7 mutations per megabase, patients with low bTMB showed better response to anlotinib plus TQB2450 (50% vs. 7%, P = 0.015) and gained greater PFS benefits (7.3 vs. 4.1 months, P = 0.012) than those with high bTMB. At a maximum somatic allele frequency (MSAF) cutoff of 10%, a low MSAF indicated a better objective response (43% vs. 20%) as well as a significantly longer median PFS (7.9 vs. 2.7 months, P < 0.001). Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs. 11%, P < 0.001) and a significantly longer median PFS (11.0 vs. 2.9 months, P < 0.001) than patients with other scenarios. Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.

A phase Ib study of TQB2450 plus anlotinib in patients with advanced triple-negative breast cancer.

This study explored the safety and preliminary efficacy of the anti-PD-L1 antibody TQB2450 combined with the multi-kinase inhibitor anlotinib in advanced triple-negative breast cancer (TNBC). Patients with advanced TNBC who received at least one line of systemic therapy with anthracyclines and/or taxanes were enrolled in the dose-escalation and dose-expansion cohorts. Between May 29, 2019 and September 28, 2020, 34 patients were enrolled (three in the dose-escalation cohort and 31 in the dose-expansion cohort). The ORR was 26.5% (95% CI, 12.9-44.4) and the DCR was 73.5% (95% CI, 55.6-87.1). The median PFS was 5.6 (95% CI, 2.9-7.5) months, and the median OS was not reached. Seventeen (50.0%) patients had grade ≥3 treatment-related adverse events, with the most common being QT interval prolongation (17.6%) and hypertension (14.7%). No treatment-related deaths occurred. TQB2450 combined with anlotinib as a chemotherapy-free treatment shows promising efficacy with a manageable safety profile for patients with previously treated advanced TNBC.

Cytotoxic Lymphocyte-Related Gene Signature in Triple-Negative Breast Cancer.

To curate the signature genes of cytotoxic lymphocytes (CLs) and explore the heterogeneity based on the CL-related (CLR) gene signature, we analyzed the gene expression of 592 patients with histologically diagnosed triple-negative breast cancer. Based on the 13-gene panel, CLR signatures were curated and associated with the stage of tumor size. Patients in the CLR-low group exhibited the worse overall survival (OS) (median OS, 75.23 months vs. 292.66 months, p < 0.0001) and were characterized by the upregulation of the NF-κB, Wnt, and p53 pathways, the positive regulation of angiogenesis, and a higher expression of immune checkpoints including CTLA4, LAG3, CD86, ICOS, ICOSLG, and TNFSF9. In cancer immunotherapy cohorts (GSE157284, GSE35640, IMvigor210), a higher CLR signature score was remarkably associated with greater tumor shrinkage and immune characteristics consisting of higher PD-L1 and neoantigen expression, as well as an inflamed tumor microenvironment. In the pan-cancer atlas, the CLR signature was notably associated with patient survival and revealed a profound heterogeneity across the malignancy types. In sum, the CLR signature is a promising indicator for immune characteristics, tumor shrinkage, and survival outcomes following cancer immunotherapy in addition to the prognostic heterogeneity in the pan-cancer atlas.

Prognostic Factors for Triple-Negative Breast Cancer with Residual Disease after Neoadjuvant Chemotherapy.

Valid factors to evaluate the prognosis of triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) are still lacking. We performed this study to explore prognostic factors focusing on genetic alterations and clinicopathology features in non- pathologic complete response (pCR) TNBC patients. Patients initially diagnosed with early-stage TNBC, treated with NAC, and who had residual disease after primary tumor surgery at the China National Cancer Center during 2016 and 2020 were enrolled. Genomic analyses were performed by targeted sequencing for each tumor sample. Univariable and multivariable analyses were conducted to screen prognostic factors for the survival of patients. Fifty-seven patients were included in our study. Genomic analyses showed that TP53 (41/57, 72%), PIK3CA (12/57, 21%), and MET (7/57, 12%), and PTEN (7/57, 12%) alternations commonly occurred. The clinical TNM (cTNM) stage and PIK3CA status were independent prognostic factors of disease-free survival (DFS) (p < 0.001, p = 0.03). A prognostic stratification indicated that patients with clinical stages I &II possessed the best DFS, followed by those with clinical stage III & wild-type PIK3CA. In contrast, patients with clinical stage III & the PIK3CA mutation had the worst DFS. In TNBC patients with residual disease after NAC, prognostic stratification for DFS was observed by combining the cTNM stage and PIK3CA status.

Development and validation of a simple and rapid HILIC-MS/MS method for the quantification of low-abundant lysoglycerophospholipids in human plasma.

Lysoglycerophospholipids (Lyso-GPLs) are an essential class of signaling lipids with potential roles in human diseases, such as cancer, central nervous system diseases, and atherosclerosis. Current methods for the quantification of Lyso-GPLs involve complex sample pretreatment, long analysis times, and insufficient validation, which hinder the research of Lyso-GPLs in human studies, especially for Lyso-GPLs with low abundance in human plasma such as lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylglycerol (LPG), lysophosphatidylserine (LysoPS), lyso-platelet-activating factor (LysoPAF), and cyclic phosphatidic acid (cPA). Herein, we report the development and validation of a simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of Lyso-GPLs with low abundance in plasma. Protein precipitation using MeOH for Lyso-GPL extraction, quick separation (within 18 min) based on hydrophilic interaction liquid chromatography (HILIC), and sensitive MS detection under dynamic multiple reaction monitoring (dMRM) mode enabled efficient quantification of 22 Lyso-GPLs including 2 cPA, 4 LPG, 11 LPA, 2 LysoPS, and 3 LysoPAF in 50 µL of human plasma. The present method showed good linearity (goodness of fit, 0.99823-0.99995), sensitivity (lower limit of quantification, 0.03-14.06 ng/mL), accuracy (73-117%), precision (coefficient of variation ≤ 28%), carryover (≤ 17%), recovery (80-110%), and stability (83-123%). We applied the method in an epidemiological study and report concentrations of 18 Lyso-GPLs in 567 human plasma samples comparable to those of previous studies. Significant negative associations of LysoPAF C18, LysoPAF C18:1, and LysoPAF C16 with homeostatic model assessment for insulin resistance (HOMA-IR) level were observed; this indicates possible roles of LysoPAF in glucose homeostasis. The application of the present method will improve understanding of the roles of circulating low-abundant Lyso-GPLs in health and diseases.

Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (mBC). METHODS: We performed a systematic search with a predefined search strategy in PubMed, Embase and Cochrane CENTRAL databases to perform a network meta-analysis and evaluate the relative efficacies of ET-based treatment regimens in HR+/HER2- mBC patients with different endocrine sensitivity statuses. The study was registered in the PROSPERO database (CRD42021235570). RESULTS: A total of 47 trials (20,267 patients) were included. Analysis of progression-free survival (PFS) in endocrine therapy-sensitive (ETS) patients revealed cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) + fulvestrant 500 mg (Ful 500) (random effect (RE): hazard ratio (HR), 0.46; 95% credibility interval (CrI), 0.27-0.78; surface under the cumulative ranking curve (SUCRA), 0.93; fixed effect (FE): HR, 0.48; 95% CrI, 0.40-0.58; SUCRA, 0.99) to be the best therapy followed by CDK4/6i + aromatase inhibitors (AIs) (RE: HR, 0.53; 95% CrI, 0.40-0.72; SUCRA, 0.86; FE: HR, 0.54; 95% CrI, 0.48-0.61; SUCRA, 0.91). Chemotherapy followed by CDK4/6i + Ful 500 appears to be the most effective option for the endocrine therapy-resistant (ETR) group. Analysis of overall survival revealed CDK4/6i + Ful 500 (SUCRA: 0.99) and AKTi + Ful 500 (SUCRA: 0.87) to be the first-rank regimen for the ETS group and ETR groups, respectively. CONCLUSION: Our comprehensive analysis suggests that CDK4/6i combined with ETs may be the best treatment option in terms of PFS for ETS patients and chemotherapy for ETR patients with HR+/HER2- mBC. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice.

Optimal Choice as First-Line Therapy for Patients with Triple-Negative Breast Cancer: A Bayesian Network Meta-Analysis.

To identify the advantageous therapy as the first-line treatment for patients with triple-negative breast cancer (TNBC). Randomized controlled trials were searched for on Medline, Embase, ClinicalTrials.gov, and the Cochrane Library between January 2001 and December 2021. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and treatment-related adverse events (TRAEs). A Bayesian framework was applied to facilitate indirect comparisons, of which the outcomes were presented using cumulative ranking curve (SUCRA) values, synthesized hazard ratio, risk ratio, and 95% credible interval. A total of 3140 patients were identified. Pooled results of PFS revealed that chemotherapy plus AKT inhibitors (AKTi) was likely the most effective therapy among enrolled therapies (SUCRA = 91.6%), of which the result remained consistent in comparative analysis for OS. In addition, no significant difference was detected between PD-1/PD-L1 antibodies in patients, whereas the PD-1 inhibitors (PD-1i) regimen was advantageous over PD-L1 inhibitor (PD-L1i) therapy for PD-L1 positive TNBC. Concerning TRAEs, an apparent heterogeneity associated with safety profiles were denoted among enrolled agents. Chemotherapy plus AKTi was the most effective therapy with comparable safety profiles. Chemotherapy plus the anti-PD-1 regimen was advantageous over the combination therapy based on the PD-L1 blockade.

Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation.

BACKGROUND: Exposure to particulate matter air pollution is associated with an increased risk of cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not yet understood. Enhanced platelet and pro-thrombotic activity in COPD patients may explain their increased cardiovascular risk. We aim to explore whether short-term exposure to ambient particulate matter is associated with pro-thrombotic changes in adults with and without COPD, and investigate the underlying biological mechanisms in a longitudinal panel study. Serum concentration of thromboxane (Tx)B2 was measured to reflect platelet and pro-thrombotic activity. Lipoxygenase-mediated lipid peroxidation products (hydroxyeicosatetraenoic acids [HETEs]) and inflammatory biomarkers (interleukins [ILs], monocyte chemoattractant protein-1 [MCP-1], tumour necrosis factor alpha [TNF-α], and macrophage inflammatory proteins [MIPs]) were measured as potential mediating determinants of particle-associated pro-thrombotic changes. RESULTS: 53 COPD and 82 non-COPD individuals were followed-up on a maximum of four visits conducted from August 2016 to September 2017 in Beijing, China. Compared to non-COPD individuals, the association between exposure to ambient ultrafine particles (UFPs) during the 3-8 days preceding clinical visits and the TxB2 serum concentration was significantly stronger in COPD patients. For example, a 103/cm3 increase in the 6-day average UFP level was associated with a 25.4% increase in the TxB2 level in the COPD group but only an 11.2% increase in the non-COPD group. The association in the COPD group remained robust after adjustment for the levels of fine particulate matter and gaseous pollutants. Compared to the non-COPD group, the COPD group also showed greater increases in the serum concentrations of 12-HETE (16.6% vs. 6.5%) and 15-HETE (9.3% vs. 4.5%) per 103/cm3 increase in the 6-day UFP average. The two lipid peroxidation products mediated 35% and 33% of the UFP-associated increase in the TxB2 level of COPD patients. UFP exposure was also associated with the increased levels of IL-8, MCP-1, MIP-1α, MIP-1ß, TNF-α, and IL-1ß in COPD patients, but these inflammatory biomarkers did not mediate the TxB2 increase. CONCLUSIONS: Short-term exposure to ambient UFPs was associated with a greater pro-thrombotic change among patients with COPD, at least partially driven by lipoxygenase-mediated pathways following exposure. Trial registration ChiCTR1900023692 . Date of registration June 7, 2019, i.e. retrospectively registered.

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials.

Background: Updated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Methods: A systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively. Results: A total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69-0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01-0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions. Conclusions: CDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022321172.

Development and External Validation of a Clinical Nomogram for Individually Predicting Survival of Metaplastic Breast Cancer.

BACKGROUND: Few studies have concerned the prognosis of metaplastic breast cancer (MpBC), a rare and diverse malignancy. A prognostic index estimating the MpBC survival would be attractive in clinical practice. PATIENTS AND METHODS: We retrospectively analyzed MpBC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic factors were identified and the final nomogram was developed to predict the 1-, 3-, or 5-year overall survival (OS). Calibration curves were provided to internally validate the performance of the nomogram and discriminative ability was appraised by concordance index (C-index). RESULTS: A total of 1017 MpBC patients diagnosed between 2010 and 2015 were assigned into 3:1 as training set (n = 763) and SEER validation set (n = 254). An external validation was performed by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018. The nomogram finally consisted of 7 independent prognostic factors and presented a good accuracy for predicting the OS with the C-index of 0.77 (95% CI: 0.751-0.786). Interestingly, the nomogram based on the western (including 92.5% non-Asian) SEER validation population (C-index of nomogram: 0.76, 95% CI: 0.737-0.796) also has an optimal discrimination in Asian population (C-index of nomogram: 0.70). The calibration plots of the nomogram predictions were also accurate and corresponded closely with the actual survival rates. CONCLUSION: This novel nomogram was accurate enough to predict the OS by using readily available clinicopathologic factors in MpBC general population, which could provide individualized recommendations for patients and clinical decisions for physicians.

Clinicopathological Characteristics and Prognosis of HER2-Low Early-Stage Breast Cancer: A Single-Institution Experience.

Background: Human epidermal growth factor 2 (HER2)-low breast cancer, which is defined as HER2 1+ or 2+ in immunohistochemistry without gene amplification, accounts for a considerable part of all breast cancers. However, it remains controversial whether HER2-low breast cancer is a distinct entity. Our aim was to compare the clinicopathological features and survival outcomes between HER2-zero and HER2-low early breast cancer. Methods: The study was a retrospective analysis that enrolled 1,039 patients with available HER2 expression data in a single institute from 2013 to 2014, of whom 262 HER2-positive patients were excluded from the subsequent analysis. The remaining patients were divided into HER2-zero and HER2-low groups. Each group was further categorized into a hormone receptor (HR)-positive and an HR-negative subgroup. Clinicopathological characteristics were collected and compared between HER2-zero and HER2-low groups. The primary endpoint was disease-free survival (DFS) and overall survival (OS), which were analyzed using the Kaplan-Meier method with log-rank test, landmark analysis, and Cox proportional hazards model. Results: A total of 777 non-HER2-positive patients were included in this analysis, of whom 126, 552, 53, and 46 patients were HR-positive/HER2-zero, HR-positive/HER2-low, HR-negative/HER2-zero, and HR-negative/HER2-low, respectively. No significant difference in DFS and OS was detected between the HER2-zero group and the HER2-low group when paired by HR status. Landmark analysis with a time point set at 5 years indicated that HR-positive/HER2-low patients had a better DFS compared with HR-positive/HER2-zero patients after 5 years (p = 0.0047). HER2-low status was an independent prognostic factor for DFS after 5 years [hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.13-0.75, p = 0.01]. Conclusion: The clinicopathological characteristics and prognosis of HER2-zero and HER2-low breast cancer were similar regardless of HR status. Patients with HR-positive/HER2-low tumors tended to have a better DFS than their HR-positive/HER2-zero counterparts after 5 years.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.

HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician's choice of treatment (HR 0.17; 95% CrI 0.03-0.82) or afatinib (HR 0.14; 95% CrI 0.02-1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.

Efficacy and Safety of Bevacizumab in Pretreated Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The use of bevacizumab in patients with previously treated metastatic breast cancer (MBC) is controversial. This meta-analysis was carried out to evaluate the efficacy and safety of the regimen including bevacizumab among patients with pretreated MBC. METHODS: We systematically searched PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials evaluating bevacizumab combined with chemotherapy for previously treated MBC patients. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS) and toxicity. The risk of bias was assessed by the Cochrane Collaboration's tool. The pooled hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CIs) were calculated for the identified studies. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. RESULTS: Four studies involving 1,640 individuals were included. Pooling results showed that the PFS of bevacizumab-containing groups (HR 0.82; 95% CI 0.73-0.93, p = 0.002) was significantly better than that of the control groups, especially when bevacizumab was administered as the second-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-negative MBC (HR 0.77; 95% CI 0.66-0.88, p = 0.0002). The ORR in the bevacizumab-containing group was superior to that in the control group, both in the general (RR 1.45; 95% CI 1.18-1.78, p = 0.0004) and HER2-negative groups (RR 1.30; 95% CI 1.03-1.63, p = 0.03). However, no significant effect on OS was demonstrated for the addition of bevacizumab to the second-line treatment for HER2-negative MBC (HR 0.93; 95% CI 0.79-1.10, p = 0.39). Comparatively, proteinuria was more common in the bevacizumab-containing group. In addition, the application of bevacizumab tended to result in therapy discontinuation due to treatment-related toxicity. CONCLUSIONS: Bevacizumab-containing chemotherapy, in light of its favorable effects on clinical outcomes, could be a preferred therapeutic option for patients with MBC, for whom the disease must be rapidly relieved. Further studies are warranted for exploring the advantageous patients with the receipt of bevacizumab in multiline treatment.

Partitioning indoor-generated and outdoor-generated PM2.5 from real-time residential measurements in urban and peri-urban Beijing.

Limited number of projects have attempted to partition and quantify indoor- and outdoor-generated PM2.5 (PM2.5ig and PM2.5og) where strong indoor sources (e.g., solid fuel, tobacco smoke, or kerosene) exist. This study aimed to apply and refine a previous recursive model used to derive infiltration efficiency (Finf) to additionally partition pollution concentrations into indoor and outdoor origins within residences challenged by elevated ambient and indoor combustion-related sources. During the winter of 2016 and summer of 2017 we collected residential measurements in 72 homes in urban and peri-urban Beijing, 12 of which had additional paired residential outdoor measurements during the summer season. Local ambient measurements were collected throughout. We then compared the calculated PM2.5ig and using (i) outdoor and (ii) ambient measurements as model inputs. The results from outdoor and ambient measurements were not significantly different, which suggests that ambient measurements can be used as a model input for pollution origin partitioning when paired outdoor measurements are not available. From the results calculated using ambient measurements, the mean percentage contribution of indoor-generated PM2.5 was 19 % (σ = 22 %), and 7 % (11 %) of the total indoor PM2.5 for peri-urban and urban homes respectively during the winter; and 18 % (18 %) and 6 % (10 %) of the total indoor PM2.5 during the summer. Partitioning pollution into PM2.5ig and PM2.5og is important to allow investigation of distinct associations between health outcomes and particulate mixes, often with different physiochemical composition and toxicity. It will also inform targeted interventions that impact indoor and outdoor sources of pollution (e.g., domestic fuel switching vs. power generation), which are typically radically different in design and implementation.

Clinicopathological characteristics and prognosis of microinvasive breast cancer: A population-based analysis.

OBJECTIVES: Microinvasive breast cancer (MIBC) is a special type of breast cancer with a relatively low prevalence, of which the understanding remains controversial. In this article, we aimed to clarify the clinicopathological characteristics and prognosis of MIBC in the setting of different molecular subtypes and give feasible suggestions on clinical practice in MIBC. METHODS: This study utilized the data from Surveillance, Epidemiology, and End Results (SEER) database. Patients were divided into subgroups based on the molecular subtypes, of which the clinicopathological characteristics were further undergone comparative analyses. Kaplan-Meier method and Cox proportional hazard regression analysis were employed to determine the prognosis of the subtypes, and to explore the prognostic factors. Patients were randomly assigned in a 7:3 ratio to the training and validation cohorts. The independent risk variables were then adopted to generate a nomogram to predict the 3- and 5-year survival probability. RESULTS: A total of 4301 MIBC patients between 2010 and 2016 were obtained from the SEER database, which were subsequently separated into HR+/HER2- (n = 2598), HR+/HER2+ (n = 723), HR-/HER2+ (n = 633), and HR-/HER2- (n = 347) groups. The HR+/HER2+ group showed the best overall survival (OS) (81.28 months, 95% CI 80.45-82.11) compared with other groups (p = 0.0089). The application of radiotherapy in HR+/HER2- and HR+/HER2+ MIBC patients brought out additional survival benefit compared with those without radiotherapy (p < 0.0001 and p = 0.024, respectively). The prognosis among four subgroups with or without chemotherapy showed no statistical difference. Based on the curated nomogram, the high-score group exhibited a better OS compared with patients from the low-score group. CONCLUSIONS: Profound heterogeneity was detected among different molecular subtypes in MIBC patients, of which HR+/HER2+ subtype presented the best prognosis. For HR-positive MIBC patients, increasing survival benefits could be retrieved from radiotherapy. Chemotherapy was not recommended for patients with MIBC. Individual-based protocols were introduced based on the nomogram which warranted further validation.

Clinical outcomes and a nomogram for de novo metastatic breast cancer with lung metastasis: a population-based study.

To better understand the clinical characteristics of newly diagnosed lung metastatic breast cancer (LMBC) and quantify its prognosis, we retrieved data on patients with LMBC from the Surveillance, Epidemiology, and End Results database. Eligible patients were randomly assigned to training and validation cohorts (ratio 7:3) to establish a nomogram using the Cox proportional hazards regression model. In total, 4310 patients with LMBC were enrolled, including 52.4% (2259/4310) HR+/HER2-, 17.6% (757/4310) HR+/HER2+, 10.8% (467/4310) HR-/HER2+, and 19.2% (827/4310) HR-/HER2- subtype patients. Inclinations of lung and brain involvement in HR-/HER2+ and HR-/HER2- subgroups, liver involvement in the HER2 overexpressing subgroup, and bone involvement in the HR-positive subgroup were detected in the LMBC population. Regarding prognosis, HR+/HER2+ subtype patients presented the most favorable profile (mOS 35.0 months, 95% CI 30.1-39.9), while HR-/HER2- patients exhibited the worst (mOS 11.0 months, 95% CI, 10.0-11.9). A nomogram was developed in the training cohort and validated internally (C-index 0.70) and externally (C-index 0.71), suggestive of decent performance. This study assessed the clinical outcomes associated with molecular subtypes, metastatic patterns, and surgical intervention and provided a robust nomogram for the estimation of survival probabilities, which are promising for the management of LMBC in clinical practice.

Ceramide metabolism mediates the impaired glucose homeostasis following short-term black carbon exposure: A targeted lipidomic analysis.

BACKGROUND: Ambient particulate matter (PM), especially its carbonaceous composition black carbon (BC) increases cardiometabolic risks, yet the underlying mechanisms are incompletely understood. Ceramides (Cer; a class of sphingolipids) are biological intermediates in glucose metabolism. OBJECTIVES: To explore whether Cer metabolism mediates impaired glucose homeostasis following short-term PM exposure. METHODS: In a panel study in Beijing, China, 112 participants were followed-up between 2016 and 2017. Targeted lipidomic analyses quantified 26 sphingolipids in 387 plasma samples. Ambient BC and PM with aerodynamic diameter ≤ 2.5 µm (PM2.5) were continuously monitored in a station. We examined the associations of sphingolipid levels with average BC and PM2.5 concentrations 1-14 days before clinical visits using linear mixed-effects models, and explored the mediation effects of sphingolipids on PM-associated fasting blood glucose (FBG) difference using mediation analyses. RESULTS: Increased levels of FBG and multiple sphingolipids in Cer metabolic pathways were associated with BC exposure in 1-14-day time window, but not with PM2.5 exposure. For each 10 µg/m3 increase in the average BC concentration 1-14 days before the clinical visits, species in the Cer C24:1 pathway (Cer, dihydroceramide, hexosylceramide, lactosylceramide, and sphingomyelin C24:1) increased in levels ranging from 11.8% (95% confidence interval [CI]: -6.2-33.2) to 48.7% (95% CI: 8.8-103.4), as did the Cer C16:0, C18:0, and C20:0 metabolic pathway species, ranging from 3.2% (95% CI: -5.6-12.9) to 32.4% (95% CI: 7.0-63.8), respectively. The Cer C24:1 metabolic pathway species mediated 6.5-25.5% of the FBG increase associated with BC exposure in 9-day time window. The Cer C16:0, C18:0, and C20:0 metabolic pathway species mediated 5.4-26.2% of the BC-associated FBG difference. CONCLUSIONS: In conclusion, Cer metabolism may mediate impaired glucose homeostasis following short-term BC exposure. The current findings are preliminary, which need to be corroborated by further studies.

Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.

PURPOSE: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early stage breast cancer in China. METHODS: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman's correlation analysis, while the impact of TOP2A expression on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. RESULTS: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low expression. TOP2A over-expression was in positive associations with a higher Ki67 index (r = 0.83, P < 0.001), HER2 positive (r = 0.26, P < 0.001), a larger tumor size (r = 0.14, P < 0.001), and a higher histologic grade (r = 0.59, P < 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression (r = - 0.40, P < 0.001) in early breast cancer. TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P < 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 2.04; 95% confidence interval [95% CI] 1.30-3.18, P = 0.0018) and OS (HR = 3.54; 95%CI 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. CONCLUSION: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, Ki67 index, tumor size, histologic grade and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.

The impact of hormone receptor on the clinical outcomes of HER2-positive breast cancer: a population-based study.

BACKGROUND: To investigate the impact of hormone receptor (HR) on the clinicopathological characteristics and prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: Using the Surveillance, Epidemiology, and End Results database, we enrolled patients diagnosed with HER2-positive breast cancer between 2010 and 2016, which were successively assessed for eligibility and categorized into HR + /HER2 + and HR-/HER2 + subgroups. Clinicopathological characteristics were undergone comparative analyses with the baseline distinctions calibrated by propensity score matching, while the survival outcomes were compared using Kaplan-Meier method with log-rank tests. RESULTS: A total of 46,803 HER2-positive breast cancer patients were identified, of which 32,919 individuals were HR + /HER2 + subtype and 13,884 individuals were HR-/HER2 + subtype, respectively. Comparatively, HR + /HER2 + breast cancer presented a lower histological grade, a smaller tumor size, a lower nodal involvement, and a lower rate of de novo stage IV disease. Substantial heterogeneity was detected in the metastatic patterns of organ-specific involvement between the two subgroups with initial metastasis. Overall, patients with HR + /HER2 + tumors had increasingly favorable prognosis in terms of overall survival and breast cancer-specific survival than patients with the HR-/HER2 + subtype. However, this kind of tendency exhibited disparities associated with HR-specific subtypes based on estrogen receptor (ER) and progesterone receptor (PgR) status, in which ER-/PgR + tended to present the worst prognosis. CONCLUSION: This study revealed profound heterogeneity associated with HR status in the clinical outcomes of HER2-positive breast cancer regarding clinicopathological features, metastatic patterns, and prognosis. Prospective studies to optimize therapeutic strategies for HER2-positive subgroups are warranted.