The prognostic value and its relationship with immune infiltration of ACLY in clear cell renal cell carcinoma.

ATP citrate lyase (ACLY) is activated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Herein, we investigated the prognostic role and potential mechanism of ACLY in ccRCC. The expression profile of ACLY in ccRCC was explored using Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Gene Expression Omnibus (GEO), UALCAN and western blotting assays. The prognosis was investigated using immunohistochemistry (IHC) and Kaplan-Meier plotter assays. The relationship with immune infiltration was further evaluated using Tumor Immune Estimation Resource 2 (TIMER2) and Tumor Immune System Interactions and DrugBank (TISIDB) databases, respectively. Further biological function of ACLY in ccRCC pathogenesis was explored using in vitro experiments. ACLY level was higher in ccRCC than adjacent kidney tissues, and Kaplan-Meier survival analysis showed ACLY mRNA or protein were predictors of poor prognosis in ccRCC patients. Importantly, we reported for the first time that ACLY gene expression was significantly correlated with numerous immune cells and immune inhibitors in ccRCC. ACLY inhibition significantly impaired cell proliferation, induced cell apoptosis, attenuated cell migration, decreased lipid droplets formation, and suppressed epithelial-mesenchymal transition (EMT) of ccRCC. Moreover, these effects might be acted through mammalian target of rapamycin complex 1 (mTORC1) pathway. Collectively, ACLY was not only implicated in ccRCC tumorigenesis and progression, but also potentially interacted with immune infiltration and mTORC1 pathway. Our findings may provide a novel therapeutic strategy by targeting ACLY for ccRCC treatment.

FOXCUT regulates the malignant phenotype of triple-negative breast Cancer via the miR-337-3p/ANP32E Axis.

BACKGROUND: The lack of specific molecular targets and the rapid spread lead to a worse prognosis of triple-negative breast cancer (TNBC). Therefore, identifying new therapeutic and prognostic biomarkers helps to develop effective treatment strategies for TNBC. METHODS: Through preliminary bioinformatics analysis, FOXCUT was found to be significantly overexpressed in breast cancer, especially in TNBC. Tissue samples were collected from 15 TNBC patients, and qRT-PCR was employed to validate the expression of FOXCUT in both TNBC patient tissues and TNBC cell lines. We also carried out the GSEA analysis and KEGG enrichment analysis of FOXCUT. Additionally, the effects of FOXCUT knockdown on TNBC cell malignant behaviors, and aerobic glycolysis were assessed by methods including CCK-8, Transwell, western blot, and Seahorse XF 96 analyses. Moreover, utilizing databases predicting interactions between ceRNAs, corresponding lncRNA-miRNA binding relationships, and miRNA-mRNA interactions were predicted. These predictions were subsequently validated through RNA immunoprecipitation and dual-luciferase reporter assays. RESULTS: FOXCUT exhibited high expression in both TNBC tissues and cell lines, fostering cell malignant behaviors and glycolysis. FOXCUT was found to sponge miR-337-3p, while miR-337-3p negatively regulated the expression of ANP32E. Consequently, FOXCUT ultimately facilitated the malignant phenotype of TNBC by upregulating ANP32E expression. CONCLUSION: This study elucidated the role of FOXCUT in elevating aerobic glycolysis levels in TNBC and driving malignant cancer cell development via the miR-337-3p/ANP32E regulatory axis.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

Characterizing the Efficacy and Safety of Chemotherapy Plus Everolimus in HER2-Negative Metastatic Breast Cancer Harboring Altered PI3K/AKT/mTOR.

BACKGROUND: The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) have proven to be disappointing. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, a tumor-promoting signaling cascade frequently mutated in breast cancer (BC), has been implicated in chemoresistance. In this study, our objective is to investigate the efficacy and safety of combining everolimus with chemotherapy in mBC patients exhibiting mutations in the PI3K/AKT/mTOR pathway. METHODS: We conducted a retrospective analysis to characterize the efficacy, safety, and their association with clinical and molecular characteristics of metastatic lesions in 14 patients with HER2- mBC. These patients harbored at least one altered member of the PI3K/AKT/mTOR signaling pathway and were treated with a combination of a chemotherapy agent and the mTOR inhibitor everolimus (CT+EVE). RESULTS: The majority of patients belonged to the triple-negative (TN) subtype (9/14, 64.3%), having already undergone 2 lines of chemotherapy (CT) in the metastatic setting (11, 78.6%). These patients carried altered phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and were administered a vinorelbine-containing regimen (10, 71.4%). The objective response rate (ORR) was 42.9%, with a disease control rate of 92.9%. The median progression-free survival (PFS) and overall survival (OS) were 5.9 (95% confidence interval (CI): 4.9-13.6) months and 14.3 (95% CI: 8.5-not reached (NR)) months, respectively. Patients with fewer prior treatment lines tended to exhibit longer PFS. OS, PFS, and ORR were comparable between hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) patients, but numerical improvements were noted in patients with a single PI3K pathway alteration compared to those with more than one alteration. Genomic alterations that surfaced upon progression on CT+EVE included cyclin dependent kinase 4 (CDK4) and epidermal growth factor receptor (EGFR) amplification, as well as neurofibromin 1 (NF1) mutation, suggesting potential mechanisms of acquired resistance. An analysis of adverse events indicated manageable toxicities. CONCLUSIONS: The findings of this study suggest both activity and safety for the combination of chemotherapy and the mTOR inhibitor everolimus (CT+EVE) in patients with HER2- mBC who have alterations in the PI3K pathway, particularly those who have received fewer prior chemotherapy. However, it is crucial to note that large-scale, randomized control studies are warranted to more comprehensively characterize the efficacy and safety of this combination therapy.

Palbociclib sensitizes ER-positive breast cancer cells to fulvestrant by promoting the ubiquitin-mediated degradation of ER-α via SNHG17/Hippo-YAP axis.

PURPOSE: Endocrine therapy is the anti-tumor therapy for human breast cancer but endocrine resistance was a major burden. It has been reported that Palbociclib and fulvestrant can be used in combination for the treatment of patients who are experiencing endocrine resistance. However, the underlying mechanism is unclear. In this study, we aimed to investigate the mechanism by which Palbocicilib affected ER-positive breast cancer, combined with fulvestrant. METHODS: We first detected the effect of palbociclib on cell survival, growth and cycle distribution separately by MTT, colony formation and flow cytometry. Then SNHG17 was screened as palbociclib-targeted LncRNA by LncRNA-seq, and the SNHG17-targeted mRNAs were selected by mRNA-seq for further determination. Subsequently, the underlying mechanism by which palbociclib promoted the cytotoxicity of fulvestrant was confirmed by qRT-PCR, western blot, and immunoprecipitation. Eventually, the xenograft model and immunohistochemistry experiments were used to validate the sensitization effect of palbociclib on fulvestrant and its mechanism in vivo. RESULTS: Palbociclib significantly enhanced the cytotoxicity of fulvestrant in fulvestrant-resistant breast cancer cell lines. Interestingly, this might be related to the lncRNA SNHG17 and the Hippo signaling pathway. And our subsequent western blotting experiments confirmed that overexpressing SNHG17 induced the down-regulation of LATS1 and up-regulated YAP expression. Furthermore, we found that the increased sensitivity of breast cancer cells was closely associated with the LATS1-mediated degradation of ER-α. The following animal experiments also indicated that overexpressing SNHG17 obviously impaired the anti-cancer effect of co-treatment of palbociclib and fulvestrant accompanied by decreased LATS1 and increased ER-α levels. CONCLUSION: Palbociclib might sensitize the cytotoxicity of fulvestrant in ER-positive breast cancer cells by down-regulating SNHG17 expression, and then resulted in the LATS1-inactivated oncogene YAP and LATS1-mediated degradation of ER-α.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial.

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

Use of period analysis to timely assess 5-year relative survival for breast cancer patients from Taizhou, Eastern China.

Objectives: While timely assessment of long-term survival for patients with breast cancer is essential for evaluation on early detection and screening programs, those data are extremely scant in China. We aimed to derive most up-to-date survival estimates and to predict future survival using the cancer registry data from Taizhou city, Eastern China. Methods: Patients diagnosed with breast cancer during 2004-2018 from four cancer registries with high-quality data from Taizhou, Eastern China were included. Period analysis was used to calculate 5-year relative survival (RS) for the overall population and according to the stratification factors sex, age at diagnosis and geographic region. We further predict the upcoming 5-year RS during 2019-2023, using continuous data from three 5-year periods (2004-2008, 2009-2013 and 2014-2018) and a model-based period approach. Results: Overall 6159 patients diagnosed with breast cancer during 2004-2018 were enrolled. The 5-year RS for breast cancer in 2014-2018 reached 88.8%, while women were higher compared to men (90.5% versus 83.7%) and urban areas were higher compared to rural areas (91.9% versus 86.7%). Additionally, we found a clear gradient by age at diagnosis, ranging from 94.8% for age<45 years to 83.3% for age>74 years. Projected overall 5-year RS for the upcoming 2019-2023 could reach 91.5% (84.8% for men and 93.5% for women). Conclusions: We provided, for first time in China, using period analysis, most up-to-date 5-year RS (88.8%) for patients with breast cancer from Taizhou, Eastern China. We also demonstrate the 5-year RS has improved greatly over last 15 years, which has important implications for timely evaluation of early detection and screening programs.

Deep learning-enabled anti-ambient light approach for fringe projection profilometry.

Achieving high-quality surface profiles under strong ambient light is challenging in fringe projection profilometry (FPP) since ambient light inhibits functional illumination from exhibiting sinusoidal stripes with high quantization levels. Conventionally, large-step phase shifting approaches are presented to enhance the anti-interference capability of FPP, but the image acquisition process in these approaches is highly time-consuming. Inspired by the promising performance of deep learning in optical metrology, we propose a deep learning-enabled anti-ambient light (DLAL) approach that can help FPP extract phase distributions from a single fringe image exposed to unbalanced lighting. In this work, the interference imposed by ambient light on FPP is creatively modeled as ambient light-induced phase error (ALPE). Guided by the ALPE model, we generate the dataset by precisely adjusting the stripe contrast before performing active projection, overcoming the challenge of collecting a large sample of fringe images with various illumination conditions. Driven by the novel dataset, the generated deep learning model can effectively suppress outliers among surface profiles in the presence of strong ambient light, thereby implementing high-quality 3D surface imaging. Experimentally, we verify the effectiveness and adaptability of the proposed DLAL approach in both indoor and outdoor scenarios with strong irradiation.

Cardiac Safety in Breast Cancer Patients Receiving Pegylated Liposome Doxorubicin Sequential Anti-HER2 Monoclonal Antibody Therapy.

Background: Cardiotoxicity associated with the sequential use of anthracyclines followed by trastuzumab is common in adjuvant therapy of patients with HER2-positive early breast cancer (eBC). However, the cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) is relatively less studied. Method: Clinical data of patients with HER2-positive eBC treated with PLD and cyclophosphamide (PLD-C) followed by taxanes plus trastuzumab ± pertuzumab (TH or TPH) who then completed standard anti-HER2 treatment for 12 months from June 2012 to August 2021 were retrospectively collected. The primary endpoints were clinical and subclinical cardiotoxicity. Result: In total, 70 eligible patients were enrolled. Among them, 55 patients (78.6%) received PLD-C → TH and 15 patients (21.4%) received PLD-C → TPH. The median follow-up time was 41.8 months. Until August 2021, only two patients had recurrent or metastatic diseases, with 2-year and 5-year disease-free survivals of 98.6% and 96.8%, respectively. Clinical cardiotoxicity occurred in six patients (8.6%), and all of them had an absolute decline of ≥16% from baseline left ventricular ejection fraction (LVEF) but not below the lower limit of normal (LLN = 50%). Subclinical cardiotoxicity events occurred in 17 patients (24.3%), and all of them had absolute declines of ≥10% and <16% from baseline LVEF but not below the LLN. No patients were interrupted from treatment, and all patients completed anti-HER2 treatment for 12 months. The sharpest decrease in LVEF was observed at 18 months after the start of PLD treatment. The cumulative incidences of clinical and subclinical cardiotoxicity were 9.8% and 28.3%, respectively. In the univariate analysis, body mass index, age, left chest wall radiotherapy, and ongoing cardiovascular risk factors were not significantly associated with clinical or subclinical cardiotoxicity (p > 0.05). No patients had congestive heart failure or death caused by PLD or anti-HER2 treatment. Conclusion: The sequential use of PLD and trastuzumab showed a lower incidence of clinical cardiotoxicity, presented as asymptomatic decreased LVEF, compared with the results obtained in previous clinical studies using conventional anthracycline, taxanes and trastuzumab. The study regimen demonstrated good cardiac tolerance and is an alternative strategy for cardioprotection in patients with HER2-positive eBC.

Hsa-miR-221-3p promotes proliferation and migration in HER2-positive breast cancer cells by targeting LASS2 and MBD2.

BACKGROUND: Human epidermal growth factor receptor (HER2)-positive breast cancers account for nearly 20% of all breast cancer cases and microRNAs (miRNAs) play crucial roles in disease progression. The study was aimed to explore the role of miR-221-3p in HER2-positive breast cancer. METHODS: Differentially expressed miRNAs were identified by high-throughput sequencing. Quantitative real-time PCR was used to evaluate mRNA levels of corresponding genes. CKK8 and transwell assays were performed to evaluate cell viability and migration. The translation binding was assessed by luciferase assay. RESULTS: Hsa-miR-221-3p was highly upregulated in HER2-positive breast cancer samples, particularly in patients with advanced or metastatic disease, as compared to healthy controls. miR-221-3p upregulation using mimics promoted cell proliferation and migration in HER2-positive cell lines, whereas miR-221-3p suppression had the opposite effect. Additionally, miR-221-3p mimics reduced the expression levels of LASS2 and MBD2 in HER2-positive breast cancer cells; conversely, miR-221-3p inhibition upregulated LASS2 and MBD2. miR-221-3p inhibited the translation of LASS2 and MBD2 by directly binding to their 3'-untranslated regions. Forced expression of LASS2 and MBD2 significantly attenuated the ability of miR-221-3p mimics to enhance cell growth and migration in HER2-positive but not in HER2-negative breast cancer cells. In HER-2-positive breast cancer patients, the levels of miR-221-3p were negatively correlated with the mRNA levels of LASS2 and MBD2. CONCLUSIONS: Upregulation of hsa-miR-221-3 in HER2-positive breast cancer contributes to cancer cell proliferation and migration by directly targeting the tumor suppressors LASS2 and MBD2. Therefore, the hsa-miR-221-3 may serve as a promising and actionable therapeutic target in HER2-positive breast cancer.

Real-World First-Line Treatment Patterns and Outcomes in Hormone Receptor-Positive Advanced Breast Cancer Patients: A Multicenter, Retrospective Study in China.

Background: Recent data on first-line treatment patterns administered to hormone receptor-positive (HR+) advanced breast cancer (ABC) patients in the real-world setting are limited. This study aimed to report the first-line treatment patterns and outcomes of HR+ ABC patients in China. Methods: This was a multicenter, noninterventional study. Eligible patients were cytologically or histologically confirmed to have HR+ ABC with ≥2 complete medical records and received first-line therapies between January 2015 and June 2019. Treatment patterns and outcomes were extracted from structured or unstructured electronic medical records. Progression-free survival (PFS) was analyzed with the Kaplan-Meier method. Results: In total, 1072 patients with HR+ ABC were enrolled at 6 treatment sites: 327 human epidermal growth factor receptor 2-positive (HER2+) patients, 696 HER2-negative (HER2-) patients and 49 HER2-unknown patients. Overall, 62.41% of patients received first-line chemotherapy (CT), 21.08% received targeted therapy (TT) and 15.49% received endocrine therapy (ET). For HR+/HER2+ patients, 65.14% received TT, 28.44% received CT, and 5.81% received ET. Compared with patients who received TT, patients who received CT alone, had a significantly worse median PFS (adjusted hazard ratio [HR] =2.59, 95% confidence interval [CI], 1.64-4.10, p<0.001). For HR+/HER2- patients, 77.01% received CT, 20.69% received ET and 1.15% received TT. Compared with patients who received ET, patients who received CT with maintenance therapy had a significantly prolonged median PFS (adjusted HR =0.57, 95% CI, 0.44-0.76, p<0.001). Among HR+/HER2- patients who received CT with maintenance treatment, those with maintenance ET had a longer median PFS than those with maintenance CT, but the difference was not significant (adjusted HR=0.92, 95% CI, 0.64-1.33, p=0.66). Conclusions: This real-world study demonstrates that CT remains the mainstream first-line treatment option for HR+ patients in China. Among patients with HR+/HER2+ ABC, the majority received first-line TT and experienced a PFS benefit. A high percentage of HR+/HER2- patients received CT as first-line therapy in clinical practice. PFS benefit was significantly longer in patients who received CT with maintenance therapy. Moreover, there was no obvious difference in PFS between maintenance ET and CT. Maintenance ET may be a better choice considering its lower toxicity and better quality of life.

Succinate/IL-1ß Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis.

Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by succinate receptor 1 (Sucnr1) and then transferred to effector cells. It is worth exploring whether succinate is capable of facilitating the inflammatory response in atherosclerosis. In this study, we firstly found that arterial serum of Coronary Heart Disease (CHD) patients contained significantly higher succinate and interleukin (IL)-1ß than Health control (HC) subjects, and succinate was positively correlated with IL-1ß. As demonstrated by the in vitro study, succinate/hypoxia-inducible factor 1α (Hif)-1α/IL-1ß signal axis existed and significantly facilitated the inflammatory program in human umbilical vein endothelial cells (HUVECs). Under the coculture, activated macrophages released succinate, which would be transferred to HUVECs via Sucnr1 and then activate Hif-1α to produce a greater amount of IL-1ß. Likewise, the aortic sinus's inflammatory phenotype was found to be more significant within Apoe-/- mice that were injected with succinate. Furthermore, Sucnr1 inhibitor (NF-56-EJ40) could significantly interrupt succinate/IL-1ß signal in HUVECs and macrophages. As revealed by this study, glycolytic metabolism following the release of succinate could be found in atherosclerotic pathology, and succinate would drive succinate/IL-1ß signal dependent on Sucnr1 and then exacerbate inflammatory responses. Sucnr1 might be a novel target for cutting off the transduction of succinate signal to prevent the inflammation of atherosclerosis.

PADI4 promotes epithelial-mesenchymal transition(EMT) in gastric cancer via the upregulation of interleukin 8.

BACKGROUND: Gastric cancer (GC) is one of the deadliest tumours due to its ability to metastasize. The Epithelial-to-mesenchymal transition plays a crucial role in promoting the GC metastasis, which increases the migration and metastasis of tumour cells. Peptidyl arginine deiminase IV (PADI4) is a susceptibility gene for gastric carcinoma. The aim of this study was to evaluate the functional roles of PADI4 in gastric cancer. METHODS: The expression of PADI4 was examined by qRT-PCR, western blot and immunohistochemistry. In addition, the functional roles of PADI4 were explored by over-expression PADI4 plasmids in gastric cancer cells. RESULTS: We found that the expression of PADI4 was up-regulated in GC. PADI4 overexpression in GC cells increased the proliferation, migration, metastasis, clone forming ability, and tumorigenic ability, but reduced the apoptosis ability. The Multi-Analyte ELISArray Kit results showed that interleukin 8 (IL-8) is upregulated in PADI4-overexpressing gastric cells. Using short interfering RNA (siRNA) to silence the expression of IL-8, we demonstrated that IL-8 silencing significantly inhibited the increased migratory capacity in PADI4-overexpressing GC cells. CONCLUSIONS: Our data suggest that PADI4 accelerate metastasis by promoting IL-8 expression in gastric cancer cells, indicating that it is a new PADI4/IL-8 signalling pathway in metastatic GC.

Combined everolimus and endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: a retrospective study.

BACKGROUND: Everolimus (EVE) is an inhibitor of the mammalian target of rapamycin (mTOR) pathway, and it is approved for the treatment of advanced breast cancer (ABC). However, there is still little real-world data on using EVE in Chinese breast cancer patients. We retrospectively analyzed real-world data to determine the factors affecting EVE treatment efficacy and patient outcomes. METHODS: We retrospectively collected the treatment information of ABC patients treated with EVE from 2013 to 2020 in Zhejiang Cancer Hospital. Kaplan-Meier analysis and Cox regression methods were used to calculate and compare the progression-free survival (PFS), and identify the factors associated with EVE treatment efficacy. RESULTS: The study finally enrolled 84 patients meeting the requirement; the median PFS in all 84 patients was 6.87 months. Multivariate analysis showed that liver metastasis [hazard ratio, 1.69; 95% confidence interval (CI), 1.00-2.84; P=0.049], and brain metastasis (hazard ratio, 2.65; 95% CI, 1.07-6.58; P=0.036) were independent risk factors. Subgroup analyses demonstrated EVE + fulvestrant (FUL) was not superior to EVE + aromatase inhibitors (AIs) for PFS (5.77 vs. 7.97 months, P=0.0735). Furthermore, it showed EVE + AI was superior to EVE + FUL in some subgroups: postmenopausal group (hazard ratio, 0.50; 95% CI, 0.26-0.98); without bone metastasis group (hazard ratio, 0.22; 95% CI, 0.06-0.80); visceral disease group (hazard ratio, 0.37; 95% CI, 0.20-0.69). CONCLUSIONS: EVE combined with endocrine therapy is an effective treatment option for Chinese patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) breast cancer, although EVE + FUL was not superior to EVE + AI. Liver metastasis and brain metastasis were independent risk factors for successful EVE + endocrine therapy.

Preoperative Systemic Therapy Versus Upfront Surgery in HER2-Positive Breast Cancer in the Real World.

PURPOSE: To compare survival in different strategies, preoperative systemic treatment versus upfront surgery, in HER2-positive early breast cancer patients in the real world. METHODS: According to the actual upfront treatment, eligible patients from 2012 to 2015 were classified as preoperative systemic treatment or upfront surgery group prospectively. The primary endpoint is disease-free survival; the second endpoint is overall survival. All the outcomes were examined in the propensity score matching model and inverse probability of treatment weighting model. RESULTS: Included in the analysis were 1,067 patients (215 in the preoperative systemic treatment group, 852 in the upfront surgery group). In the propensity score matching model (matching at 1:1 ratio), the disease-free survival of the preoperative systemic treatment group was significantly higher than that of the upfront surgery group (hazard ratio, 0.572, 95%CI, 0.371-0.881, P, 0.012). In the inverse probability of treatment weighting model, there was no significant difference in disease-free survival between the two groups (hazard ratio, 0.946, 95%CI, 0.763-1.172, P, 0.609). For overall survival, there was no significant difference between the two groups. CONCLUSION: The HER2-positive patients who accepted preoperative systemic treatment had better disease-free survival than those who underwent upfront surgery by real-world statistic methods. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT04249440.

Real-world effectiveness of eribulin in heavily pretreated patients with metastatic breast cancer in China: a multicenter retrospective study.

BACKGROUND: Eribulin is a nontaxane microtubule inhibitor approved in China for patients with advanced breast cancer who show progression after ⩾2 lines of chemotherapy. The aim of this study was to determine the efficacy and safety profile of eribulin and explore potential predictive factors for the efficacy of eribulin among Chinese women with metastatic breast cancer (MBC) in real-world practice. PATIENTS AND METHODS: A total of 272 consecutive MBC patients who were treated with eribulin between November 2019 and October 2020 in 9 institutions nationwide were included in this study. Eribulin was administered intravenously at a dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Adverse events (AEs) were graded according to The National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. RESULTS: Eribulin showed a median PFS of 4.1 months (95% confidence interval [CI] 3.6-4.6); however, the OS data were immature. The ORR was 17.6% and the CBR was 24.6%. A total of 51.8% of patients received eribulin monotherapy, while 48.2% of patients were treated with eribulin plus targeted therapy or other chemotherapy. The number of metastatic sites, duration of previous taxane treatment for MBC, and combination with bevacizumab were significant in Cox multivariate analysis (p = 0.023, p = 0.048, and p = 0.046, respectively) and were significantly associated with PFS of eribulin. The most common AEs with eribulin treatment were hematological toxicities, including neutropenia, leukopenia, and anemia. CONCLUSION: Eribulin was effective with a manageable toxicity profile in clinical practice. Furthermore, when prescribed in combination with other agents, eribulin did not increase the toxic effects of each agent. Eribulin monotherapy or plus other agents is an alternative for the heavily pretreated patients with MBC.

Ki67 and progesterone receptor status predicts sensitivity to palbociclib: a real-world study.

BACKGROUND: Palbociclib combined with endocrine therapy has been approved as a front-line treatment for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC). A key challenge remains to uncover biomarkers to identify those patients who may benefit from palbociclib treatment. METHODS: We retrospectively analyzed the values of Ki67 and progesterone receptor (PR) as detected by immunohistochemistry in 81 ABC patients with palbociclib and hormone therapy treatment, and evaluated the impact on progression-free survival (PFS). RESULTS: In the total population, women with Ki67 ≥14% had marginally significantly shorter PFS than those with Ki67 <14% (P=0.062). Patients with Ki67 ≥30% had significantly shorter PFS than those with Ki67 <30% (P=0.048). Meanwhile, PR ≥20% was associated with longer PFS. Moreover, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. As for the hormone therapy subgroup, there were significant associations between Ki67 and PR levels and PFS in the aromatase inhibitors (AIs) subgroup. Patients with Ki67 ≥14% or Ki67 ≥30% had shorter PFS than those with Ki67 <14% or Ki67 <30%, respectively (P=0.024, P<0.001). Additionally, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. When both Ki67 and PR were considered, there were significant differences between the different cohorts. Compared with patients with Ki67 ≥14% and PR <20%, those with Ki67 <14% and PR ≥20% had significantly longer PFS. In addition, patients with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. Furthermore, in the AI cohort, patients with Ki67 <14% and PR ≥20% had significantly longer PFS than those with Ki67 ≥14% and PR <20%. Women with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. CONCLUSIONS: The present study indicates that both Ki67 and PR have great impacts on palbociclib and hormone therapy and may contribute to selecting more effective partners for palbociclib.

Exploring the concepts and practices of advanced breast cancer treatment: a narrative review.

OBJECTIVE: To explore the concepts and practices of advanced breast cancer treatment. BACKGROUND: Metastatic breast cancer (MBC) has become a chronic disease, with a median overall survival (OS) of around 3 years and a 5-year survival rate of about 25%. OS are strongly associated with the best available care, which consists of not only application of guidelines, but also multidisciplinary specialized care, the most efficacious medicines, and so on. Advanced breast cancer (ABC) Guidelines are the most important and authoritative guidelines for MBC. METHODS: In this review, we demonstrate the history and evolution of the global ABC Guidelines. Since 2015, Chinese multidisciplinary experts have drafted guidelines for clinical diagnosis and treatment of MBC. All of these ABC guidelines describe specialized therapeutic principles for different subtypes MBC in detail. Encouragingly, we have found that some special subtypes are hopeful of being cured, such as HER-2 positive patients with low tumor burden or HR-positive (HR+) MBC with non-visceral metastasis. In our opinion, the definition of cure of MBC is that MBC patients achieve CR and remain for more than five years after systemic treatment, including those with local therapy. Consequently, we also have conducted some researches and meaningful explorations in different subtypes of MBC. In HER2 positive MBC, our study revealed that regular HER2 circulating extracellular domain (ECD) assay can provide the real-time monitoring of tumor burden and prediction of poor outcome, and may present an important opportunity to reassess HER2 status. In HR+ MBC, we suggested that hormone therapy (HT) maintenance is the priority choice for HR+/HER2- MBC after first-line combined chemotherapy. Besides, our real-world study revealed that fulvestrant combined with ovarian suppression was an active option for premenopausal HR+/HER2- MBC. And also, we observed that everolimus (low-dose) combined with hormone therapy was still effective for HR+/HER2- MBC. For mTNBC patients, we found that THA and endostatin exhibited potential efficacy and was well tolerated in pretreated patients. CONCLUSIONS: Our concepts and practices will contribute to the design of relevant clinical research and accumulation of evidence, and cure of MBC is promising.

Long non-coding RNA TPT1-AS1 sensitizes breast cancer cell to paclitaxel and inhibits cell proliferation by miR-3156-5p/caspase 2 axis.

Long non-coding RNAs (lncRNAs) are key modulators during cancer progression. Application of using lncRNA expression to evaluate patient prognosis and sensitivity to treatment is highly anticipated, yet the expression and mechanism of many lncRNAs remain unknown. Herein, we projected for the investigation of TPT1-AS1 function in breast cancer. TPT1-AS1 was assessed by bioinformatic analysis of publicly available datasets and quantitative real-time PCR (qRT-PCR). Cell sensitivity to paclitaxel and cell proliferation was measured by flow cytometry and CCK-8. Interaction among TPT1-AS1, microRNA (miRNA, miR)-3156-5p and Caspase 2 (CASP2) was studied by bioinformatic analysis, qRT-PCR, western blot as well as dual luciferase reporter assay. Herein, TPT1-AS1 was significantly diminished in breast cancer from publicly available datasets and our collected samples. In breast cancer cells, TPT1-AS1 overexpression repressed cell proliferation and sensitized breast cancer cells to paclitaxel. RegRNA 2.0 predicted a potential interaction between TPT1-AS1 and miR-3156-5p which was confirmed by qRT-PCR as well as dual luciferase reporter assay. CASP2, a proapoptotic gene, was corroborated to be targeted by miR-3156-5p. Meanwhile, TPT1-AS1 upregulated CASP2 in breast cancer cells, and its biological function was reversed by CASP2 knockdown. Collectively, TPT1-AS1 diminished cell proliferation and sensitized cells to chemotherapy by sponging miR-3156-5p and upregulating CASP2, acting as a biomarker for patients with breast cancer.

Differences in the clinicopathological characteristics of pure and mixed invasive micropapillary breast carcinomas from eastern China.

BACKGROUND: Invasive micropapillary carcinoma of the breast (IMPC) is a rare pathologic subtype of breast cancer. Since the differences in the pathological features of pure and mixed IMPCs are not fully understood, we aimed to investigate the difference in clinicopathological characteristics between localized pure and mixed IMPCs. METHODS: A total of 121 localized IMPC cases were included. The clinicopathological features and survival estimates of the pure IMPC and mixed IMPC groups were compared. Targeted sequencing was performed to investigate the genomic profile of paired primary breast cancer and metastatic tissue samples from two pure IMPCs and four mixed IMPCs. RESULTS: Overall, 48 cases were pure IMPC and 73 were mixed IMPC. The pure group had a significantly higher proportion of Luminal B compared to the mixed group (37.5% vs. 15.1%). The pure group had a similar HER2 overexpression rate (31.2% vs. 32.9%) and mean age at diagnosis (51.0 vs. 50.2 years), compared with the mixed group. The pure group had a significantly higher proportion of stage IIIC cases compared with the mixed group (38.3% vs. 17.8%). We found no significant difference in the 3-year disease-free survival (DFS) between the two groups (83.7% vs. 80.0%), but the mixed group had a better overall survival (OS) compared with the pure group [HR =0.28 (0.091-0.868), P=0.047]. CONCLUSIONS: We found that pure IMPC had a more aggressive behavior with locally advanced disease and a higher proportion of Luminal B than mixed IMPC. Mixed IMPC had a longer OS compared to pure IMPC, but there was no significant difference in the 3-year DFS between the two groups.