Gastric metastasis from breast cancer: five cases and a single-institutional review.

Gastric metastasis from breast cancer has a high rate of misdiagnosis and missed diagnosis. Data of patients who had gastric metastasis from breast cancer were retrieved from our hospital between 2014 and 2020. The gastric metastasis from breast cancer incidence was 0.04% (5/14,169 cases of breast cancer). Four patients had invasive lobular carcinoma, and the other patient had invasive ductal carcinoma. The time from the initial diagnosis of breast cancer to the appearance of gastric metastasis ranged from 0 to 12 years. One patient's endoscopic presentation was similar to mucosal-associated lymphoid tissue lymphoma and presented with gastric mucosal congestion and edema, widened wrinkles, mixed color fading, and redness. The initial pathological diagnosis of this patient was mucosal-associated lymphoid tissue lymphoma, and breast cancer was finally confirmed by immunohistochemistry. Hormonal receptors were highly expressed in four patients with primary and metastasis lesions and were negative in one patient. Human epidermal growth factor receptor 2 was negative in all patients. Mammaglobin and GATA3 were positive in all patients. In conclusion, the gastric metastasis of breast cancer incidence rate is low, and misdiagnosis can lead to insufficient or excessive treatment. Multiple biopsies and immunohistochemistry should be performed to diagnose gastric metastasis of breast cancer.

Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

Safety of COVID-19 Vaccination in Patients With Breast Cancer: Cross-Sectional Study in China.

BACKGROUND: The widespread use of vaccines against the novel coronavirus disease (COVID-19) has become one of the most effective means to establish a population immune barrier. Patients with cancer are vulnerable to COVID-19 infection, adverse events, and high mortality, and should be the focus of epidemic prevention and treatment. However, real-world data on the safety of vaccines for patients with breast cancer are still scarce. OBJECTIVE: This study aims to compare the safety of COVID-19 vaccines between patients vaccinated before or after being diagnosed with breast cancer. METHODS: Patients with breast cancer who sought medical advice from October 2021 to December 2021 were screened. Those who received COVID-19 vaccines were enrolled in this study to analyze the safety of the vaccines. The primary outcome was patient-reported adverse events (AEs). All events after vaccine injection were retrospectively documented from the patients. RESULTS: A total of 15,455 patients with breast cancer from 41 hospitals in 20 provinces in China were screened, and 5766 patients who received COVID-19 vaccines were enrolled. Of those enrolled, 45.1% (n=2599) of patients received vaccines before breast cancer diagnosis, 41.3% (n=2379) were vaccinated after diagnosis, and 13.6% (n=784) did not known the accurate date of vaccination or cancer diagnosis. Among the patients vaccinated after diagnosis, 85.4% (n=2032) were vaccinated 1 year after cancer diagnosis and 95.4% (n=2270) were vaccinated during early-stage cancer. Of all 5766 vaccinated patients, 93.9% (n=5415) received an inactivated vaccine, 3.7% (n=213) received a recombinant subunit vaccine, and 2.4% (n=138) received other vaccines, including adenovirus and mRNA vaccines. In the first injection of vaccines, 24.4% (n=10, 95% CI 11.2-37.5) of patients who received an adenovirus vaccine reported AEs, compared to only 12.5% (n=677, 95% CI 11.6-13.4) of those who received an inactivated vaccine. Patients with metastatic breast cancer reported the highest incidence of AEs (n=18, 16.5%, 95% CI 9.5-23.5). Following the second injection, patients who received an inactivated vaccine (n=464, 8.7%, 95% CI 8.0-9.5) and those who received a recombinant vaccine (n=25, 8.7%, 95% CI 5.5-12.0) reported the same incidence of AEs. No significant differences in patient-reported AEs were found between the healthy population and patients with breast cancer (16.4% vs 16.9%, respectively); the most common AEs were local pain (11.1% vs 9.1%, respectively), fatigue (5.5% vs 6.3%, respectively), and muscle soreness (2.3% vs 3.6%, respectively). The type of vaccine and time window of vaccination had little impact on patient-reported AEs. CONCLUSIONS: Compared with patients vaccinated before breast cancer diagnosis, there were no significant differences in patient-reported AEs in the patients vaccinated after diagnosis. Thus, it is safe for patients with breast cancer, especially for those in the early stage, to receive COVID-19 vaccines. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200055509; https://tinyurl.com/33zzj882.

The investigation of circRNA profiling reveals the regulatory role of the hsa_circ_0000375/miR-7706 pathway in breast cancer.

BACKGROUND: Circular RNAs (circRNAs) take an effect on tumorigenesis and progression. However, circRNAs have not been systematically identified in breast cancer (BC) as crucial regulators in multitudinous biological processes. This study is conducted to explore novel circRNAs in BC and the corresponding mechanisms of their action. METHODS: The circRNA expression profile and RNA-sequencing data about BC were respectively downloaded from public database. Differentially expressed circRNAs, miRNAs, and mRNAs were identified by fold change filtering. The competing endogenous RNAs (ceRNAs) network was established based on the relationship between circular RNAs, miRNAs and mRNAs. GO and KEGG enrichment analysis of the overlapped genes were carried out to predict the potential functions and mechanisms of circRNAs in BC. The CytoHubba plugin in Cytoscape was applied to identify the hub genes from the PPI regulatory network. Kaplan-Meier plotter was used to perform survival analysis of these hub genes further. Real-time PCR was performed to test the expression of circRNA in BC tissues. Cell function studies including transwell analysis and CCK-8 analysis were used to investigate circRNAs' biological functions. RESULTS: A total of seven circRNAs exhibiting differential expression were identified in this study. After the intersection between the predicted target miRNA and the down-regulated differential miRNAs (DEmiRNAs), circRNA-miRNA interactions involving 3 circRNAs and 4 miRNAs were identified. Venn diagram was utilized to intersect the predicted target genes of the 4 miRNAs and the down-regulated differential genes in BC, and 149 overlapped genes were screened out ulteriorly. Additionally, we built a protein-protein interaction (PPI) network and selected six hub genes. Moreover, the survival data of BC patients suggested that low expression of ADIPOQ, LPL and LEP were significantly correlated with poor prognosis. Results from real-time PCR indicated that hsa_circ_0000375 was significantly down-regulated in breast cancer tissues. Functional in vitro experiments showed that over-expression of hsa_circ_0000375 can restrain proliferation, migration and invasion abilities of breast cancer cells. Further verification indicated that hsa_circ_0000375 exerted its anti-oncogene effect via sponge of miR-7706. CONCLUSIONS: This study constructed and analyzed a circRNA-associated ceRNA regulatory network and uncovered that hsa_circ_0000375 exerted its anti-oncogene effect via sponge of miR-7706.

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.

HER-2 ultra-low breast cancer: exploring the clinicopathological features and prognosis in a retrospective study.

Objective: To explore the clinicopathological features of patients with ultra-low expression of human epidermal growth factor 2 (HER-2) in breast cancer and its impact on prognosis. Methods: Data from 1024 patients with primary breast cancer having HER-2 ultra-low expression from January 01, 2018, to December 31, 2018, were collected and analyzed retrospectively. The clinicopathological features and prognosis were compared using a chi-squared test or Fisher exact probability method. COX regression analysis and log-rank test were used to explore the factors related to the postoperative 5-year survival rate. All analytical data were defined as statistically significant (P < 0.05). Results: Overall survival (OS) was higher in the HER-2 ultra-low group compared to the low expression group (P = 0.022). The tumor diameter, lymph node metastasis (LNM), and Ki67 expression were factors affecting DFS in the HER-2 ultra-low expression group (P < 0.05). The tumor diameter and LNM were risk factors affecting the OS (P < 0.05) in the HER-2 ultra-low expression group. LNM and Ki67 expression were risk factors affecting DFS (P < 0.05) in the HER-2 low expression group. LNM was considered an independent risk factor affecting OS (P < 0.05). Conclusion: Breast cancer with HER-2 ultra-low expression has differences in the clinicopathological features. Breast cancer with HER-2 low expression is more aggressive and has a worse prognosis. This study provides a reference to consider in the treatment of HER-2-low and -ultra-low expression breast cancer.

Hsa-miR-497-3p impedes the proliferation and invasion of triple-negative breast cancer cells by controlling epithelial-mesenchymal transition through ZEB1 targeting.

This study aimed to examine the hsa-miR-497-3p effect and mechanism on the behavior of triple-negative breast cancer (TNBC) cells. We evaluated the expression of Hsa-miR-497-3p in tissue samples obtained from patients diagnosed with TNBC or luminal breast cancer (BrCa), utilizing the quantitative fluorescence polymerase chain reaction (PCR) method. We transfected hsa-miR-497-3p mimics and NC into MDA-MB-231 cells, whilehsa-miR-497-3p inhibitor and NC into TNBC cells, respectively. To examine the impact of hsa-miR-497-3p expression level on TNBC cell proliferation, invasion, and migration, we employed MTT, clone formation, Transwell, and wound healing assays. We utilized both q-PCR and western blot to validate the role of hsa-miR-497-3p in the epithelial-mesenchymal transition (EMT) of TNBC cells. To confirm the targeting relationship between hsa-miR-497-3p and ZEB1, we performed luciferase assays, q-PCR, and western blot analysis. We found that the hsa-miR-497-3p expression was down-regulated in both TNBC tissues and cell lines in comparison to luminal BrCa tissues and cell lines. Furthermore, hsa-miR-497-3p overexpression hindered the cell function of TNBC cells MDA-MB-231, while downregulating the mRNA and protein expression of vimentin and N-cadherin, while simultaneously upregulating E-cadherin expression. Our results demonstrate that hsa-miR-497-3p regulates EMT in TNBC cells through ZEB1 targeting, as evidenced by the modulation of the expression of vimentin, N-cadherin, and E-cadherin via ZEB1 inhibition. Overall, our study suggests that hsa-miR-497-3p inhibits the proliferation and invasion of TNBC cells through the modulation of EMT via ZEB1 targeting.

Effect of tumor-infiltrating lymphocytes depending on the presence of postmastectomy radiotherapy on the prognosis in pT1-2N1M0 breast cancer.

Background: Currently, it remains unclear regarding the association between tumor-infiltrating lymphocytes (TILs) and the efficacy of postoperative radiotherapy in primary tumors. Here we attempted to investigate the effect of TILs depending on the presence of postmastectomy radiotherapy (PMRT) on the prognosis in pT1-2N1M0 breast cancer. Methods: The clinical data of pT1-2N1M0 breast cancer patients undergoing mastectomy and axillary lymph node dissection were retrospectively analyzed. The effect of TILs on the prognosis was assessed based on the infiltration degree (low: TILs ≤10%, high: TILs >10%), and then the prognosis of patients with low and high infiltration of TILs was analyzed based on presence or absence of PMRT. Results: Totally 213 patients were eligible for the study, including 162 cases of low infiltration and 51 of high infiltration. High-infiltration patients tended to be ER/PR-negative, HER2-positive, and have high histological grade. The infiltration in triple-negative and HER2-positive subtypes was higher compared with Luminal A subtype. Regarding local-regional recurrence-free survival, recurrence-free survival, and overall survival (OS) rates, the differences were all inapparent whether in high- and low-infiltration patients or in high-infiltration patients with/without PMRT. Compared with those without PMRT, low-infiltration patients with PMRT showed a significantly increased OS rate (92.8% vs. 80.0%, p=0.023). Multivariate analysis further confirmed PMRT as an independent predicator of OS in low-infiltration patients (HR: 0.228, 95%CI: 0.081-0.644, p=0.005). Conclusion: High infiltration of TILs in pT1-2N1M0 breast cancer may be associated with clinicopathological factors. Low-infiltration patients, but not high-infiltration patients, may derive survival benefits from PMRT.

High expression of autophagy-related gene EIF4EBP1 could promote tamoxifen resistance and predict poor prognosis in breast cancer.

BACKGROUND: Breast cancer (BC) remains a public health problem. Tamoxifen (TAM) resistance has caused great difficulties for treatment of BC patients. Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) plays critical roles in the tumorigenesis and progression of BC. However, the expression and mechanism of EIF4EBP1 in determining the efficacy of TAM therapy in BC patients are still unclear. AIM: To investigate the expression and functions of EIF4EBP1 in determining the efficacy of TAM therapy in BC patients. METHODS: High-throughput sequencing data of breast tumors were downloaded from the Gene Expression Omnibus database. Differential gene expression analysis identified EIF4EBP1 to be significantly upregulated in cancer tissues. Its prognostic value was analyzed. The biological function and related pathways of EIF4EBP1 was analyzed. Subsequently, the expression of EIF4EBP1 was determined by real-time reverse transcription polymerase chain reaction and western blotting. Cell Counting Kit-8 assays, colony formation assay and wound healing assay were used to understand the phenotypes of function of EIF4EBP1. RESULTS: EIF4EBP1 was upregulated in the TAM-resistant cells, and EIF4EBP1 was related to the prognosis of BC patients. Gene Set Enrichment Analysis showed that EIF4EBP1 might be involved in Hedgehog signaling pathways. Decreasing the expression of EIF4EBP1 could reverse TAM resistance, whereas overexpression of EIF4EBP1 promoted TAM resistance. CONCLUSION: This study indicated that EIF4EBP1 was overexpressed in the BC and TAM-resistant cell line, which increased cell proliferation, invasion, migration and TAM resistance in BC cells.

KIF20A is a Prognostic Marker for Female Patients with Estrogen Receptor-Positive Breast Cancer and Receiving Tamoxifen as Adjuvant Endocrine Therapy.

Purpose: Our aim was to verify whether KIF20A has the potential to serve as a prognostic marker for female patients with estrogen receptor (ER)-positive breast cancer (BC) and treated with tamoxifen (TAM). Patients and Methods: Online tools were used to investigate the potential correlation between KIF20A gene expression and survival of patients with ER-positive BC and TAM treatment. Furthermore, immunohistochemistry (IHC) was conducted to assess the expression levels of KIF20A in patients included from our center. The prognostic value of KIF20A for disease-free survival (DFS) and overall survival (OS) was further evaluated using Cox regression analysis. Results: According to the results obtained from online tools, it was found that patients with low KIF20A expression exhibited significantly better survival outcomes in terms of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and OS compared to those with high KIF20A expression (P < 0.001, P < 0.001, and P = 0.008, respectively). Additionally, significantly lower gene expression of KIF20A was found in patients who responded to TAM than in those who did not respond to TAM (P < 0.001). We further included 203 patients with adjuvant TAM therapy, and IHC for KIF20A was performed on sections from paraffin-embedded blocks. Patients with low KIF20A expression had significantly better DFS and OS (P = 0.001 and 0.002, respectively, log rank test), and the expression of KIF20A was identified as an independent factor for predicting both DFS and OS (P = 0.001 and 0.008, respectively). Conclusion: KIF20A expression is an independent prognostic factor for survival in patients with ER-positive BC who received adjuvant TAM therapy. In clinical practice, IHC evaluation of KIF20A expression in surgical samples before administering tamoxifen may assist in predicting the treatment outcomes of these patients.

An Analysis of Clinical and Pathologic Features, RecurIndex Genomic Profiles, and Survival Outcomes in HER2-Low Breast Cancer.

BACKGROUND: In recent years, breast cancer has become the most common cancer in the world, increasing women's health risks. Approximately 60% of breast cancers are categorized as human epidermal growth factor receptor 2 (HER2)-low tumors. Recently, antibody-drug conjugates have been found to have positive anticancer efficacy in patients with HER2-low breast cancer, but more studies are required to comprehend their clinical and molecular characteristics. METHODS: In this study, we retrospectively analyzed the data of 165 early breast cancer patients with pT1-2N1M0 who had undergone the RecurIndex testing. To better understand HER2-low tumors, we investigated the RecurIndex genomic profiles, clinicopathologic features, and survival outcomes of breast cancers according to HER2 status. RESULTS: First, there were significantly more hormone receptor (HR)-positive tumors, luminal-type tumors, and low Ki67 levels in the HER2-low than in the HER2-zero. Second, RI-LR (P = .0294) and RI-DR (P = .001) scores for HER2-low and HER2-zero were statistically significant. Third, within HER2-negative disease, HR-positive/HER2-low tumors showed highest ESR1, NFATC2IP, PTI1, ERBB2, and OBSL1 expressions. Fourth, results of the survival analysis showed that lower expression of HER2 was associated with improved relapse-free survival for HR-positive tumors, but not for HR-negative tumors. CONCLUSIONS: The present study highlights the unique features of HER2-low tumors in terms of their clinical characteristics as well as their gene expression profiles. HR status may influence the prognosis of patients with HER2-low expression, and patients with HR-positive/HER2-low expression may have a favorable outcome.

Trends in Disparities and Transitions of Treatment in Patients With Early Breast Cancer in China and the US, 2011 to 2021.

Importance: Breast cancer treatment has profoundly improved in China recently. However, trends in disparities and transitions of treatment in early-stage cancer between China and the US are not well known. Objective: To identify changes for patients with early breast cancer by using large databases from China and the US. Design, Setting, and Participants: This multicenter cross-sectional study used the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) database from hospitals in 13 provinces in China and the Flatiron Health (hereinafter referred to as Flatiron) database from more than 280 community oncology clinics in the US. Patients with stage I to III breast cancer diagnosed from January 1, 2011, to December 31, 2021, were included. Data were analyzed from June 10 to December 1, 2022. Main Outcomes and Measures: The distribution of age, clinical stage, and cancer subtypes at diagnosis were examined overall and by year. The mean annual percent change (MAPC) from 2011 to 2021 in systemic therapy and surgery was also analyzed. Results: A total of 57 720 patients with early breast cancer were screened from the CSCO BC (n = 45 970) and Flatiron (n = 11 750) databases. The median age at diagnosis in China among the 41 449 patients included in the age analysis was 47 (IQR, 40-56) years; in the US, the median age was 64 (IQR, 54-73) years. Among patients with clinical stage data in the CSCO BC (n = 22 794) and Flatiron (n = 4413) databases, the proportion of stage I cancer was 7250 (31.8%) vs 2409 (54.6%); stage II cancer, 10 043 (44.1%) vs 1481 (33.6%); and stage III cancer, 5501 (24.1%) vs 523 (11.9%). The proportion of hormone receptor-positive cancer in China was 69.8%, lower than that in the US (87.5%). For patients with ERBB2 (formerly HER2 or HER2/neu)-positive cancer, the proportion in China (30.2%) was higher than that in the US (15.6%). For neoadjuvant therapy, the annual rate increased from 247 of 1553 (15.9%) to 200 of 790 (25.3%) in China, with an MAPC of -4.4% (95% CI, -50.6% to 85.0%; P = .89). For patients with ERBB2-positive cancer, the proportion treated with trastuzumab in early-stage cancer in China increased significantly, with an MAPC of 22.1% (95% CI, 17.4%-26.9%; P < .001), and overtook that in the Flatiron database since 2017 (1684 [68.5%] vs 550 [62.5%]; P < .001). Conclusions and Relevance: The findings of this cross-sectional study suggest that disparities in treatment of early breast cancer narrowed between China and the US during the study period. The rapid growth of trastuzumab treatment in China was suggestive of differential access to targeted ERBB2 therapy.

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.

Methylation detection of circulating tumor cell miR-486-5p/miR-34c-5p in the progression of colorectal cancer

Aims This study set out to examine the expression and methylation levels of miR-486-5p/miR-34c-5p and its mechanism of action based on the microRNA methylation level of circulating tumor cells (CTCs) in colorectal cancer (CRC) through clinical data and tissue detection. Methods EGFR and EpCAM immunophospholipid magnetic spheres (EpCAM-IML/EGFR-IML) were synthesized by the thin film method to capture CTCs in peripheral blood. The expression of miR-486-5p/miR-34c-5p was detected via real-time fluorescent quantitative PCR (RT-PCR). Methylation-specific PCR was implemented to detect the methylation level of miR-486-5p/miR-34c-5p, and 5-Aza-dC was used for demethylation treatment to detect the effect of changes in methylation levels on the tumor cells development. Cell Counting Kit-8 (CCK-8) analysis, transwell assay, and flow cytometry were used to determine the effects of demethylation and overexpression on the proliferation, invasion, migration, and apoptosis of CRC cells. Results The results showed that the expression and methylation levels of the miR-486-5p/miR-34c-5p isolated from CTCs were low and the methylation level was high in tumor cells and tissues. In CRC cell lines, demethylation and overexpression of miR-486-5p/miR-34c-5p could effectively inhibit the proliferation, invasion and migration of tumor cells, and facilitate tumor apoptosis (p < 0.05). Conclusion The constructed CTCs sorting system has characteristics of high specificity and high sensitivity, is a supplement to tissue samples, and has guiding significance for the clinical rational use of drugs and personalized therapy (AU)

GLIS Family Zinc Finger 3 Promotes Triple-Negative Breast Cancer Progression by Inducing Cell Proliferation, Migration and Invasion, and Activating the NF-κB Signaling Pathway.

Triple-negative breast cancer (TNBC) puts a great threat to women's health. GLIS family zinc finger 3 (GLIS3) belongs to the GLI transcription factor family and acts as a critical factor in cancer progression. Nevertheless, the part of GLIS3 played in TNBC is not known. Immunohistochemical (IHC) staining analysis displayed that GLIS3 was highly expressed in TNBC tissues. The effect of GLIS3 on the malignant phenotype of TNBC was tested in two different cell lines according to GLIS3 regulation. Upregulation of GLIS3 promoted the proliferation, migration, and invasion of TNBC cell lines, whereas the knockdown of GLIS3 suppressed these tumor activities. Inhibition of GLIS3 induced TNBC cell apoptosis. Furthermore, study as immunofluorescence and electrophoretic mobility shift assay confirmed that the nuclear factor-κB (NF-κB) signaling pathway activated by GLIS3 played an important role in TNBC cells' malignant phenotype. In conclusion, the present work demonstrated that GLIS3 acts as a crucial element in TNBC progression via activating the NF-κB signaling pathway. Accordingly, above mentioned findings indicated that modulation of GLIS3 expression is a potential tactic to interfere with the progression of TNBC.

Role of PAX2 in breast cancer verified by bioinformatics analysis and in vitro validation.

Background: Breast cancer (BC) is the most frequently diagnosed cancer in women and the second most common cancer among newly diagnosed cancers worldwide. Studies have shown that paired box 2 (PAX2) participates in the tumorigenesis of some cancer cells, but its role in BC is still unclear. Methods: Transcriptome expression profiles and clinicopathological information of BC were downloaded from The Cancer Genome Atlas (TCGA) database to explore the expression level and prognostic value of PAX2. Gene set enrichment analysis (GSEA) and functional enrichment analysis were performed to investigate the functions and pathways of PAX2. Moreover, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to determine the expression of PAX2 in BC tissues, and the predictive value of PAX2 in clinical samples was assessed. Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell growth. The migration and invasive capacities of cells were assessed by wound healing assay and Transwell assay. Results: PAX2 was upregulated in the TCGA-BC datasets. GSEA suggested that PAX2 may be involved in the regulation of signaling pathways such as MAPK. Moreover, PAX2 was overexpressed in BC tissues, and PAX2 expression was associated with tumor size and lymph node metastasis. PAX2 deficiency could promote the growth, migration, and invasion of BC cells. Conclusions: Upregulation of PAX2 inhibited BC cell growth, migration, and invasion, making PAX2 a potential therapeutic target for BC.

Has_circ_0048764 promotes breast cancer progression by sponging miR-578 and regulating HMGA2 expression.

BACKGROUND: Circular RNAs (circRNAs) function as important regulators in the progression of cancers. The role of circRNA_0048764 (circ_0048764) in the development of breast cancer (BC) remains inconclusive. This work investigates the biological function and molecular mechanism of circ_0048764 in BC. METHODS: Quantitative real-time PCR (qRT-PCR) was conducted to measure the expression levels of circ_0048764, microRNA-578 (miR-578) and high mobility group AT-hook 2 (HMGA2) mRNA. The viability of BC cells was examined by cell counting kit 8 (CCK-8) assay. Besides, cyclin D1, proliferating cell nuclear antigen (PCNA) and HMGA2 expression levels were detected by western blot. The migrative and invasive capability of BC cells were probed by transwell assay. The relationships between miR-578 and circ_0048764 or HMGA2 3'-UTR were validated by dual-luciferase reporter gene assay. RESULTS: Circ_0048764 was highly expressed in BC tissues and cells, which was significantly associated with tumor size (≥2 cm), lymph node status (positive), and higher TNM stage of BC patients. Circ_0048764 depletion suppressed the proliferative, migrative, and invasive abilities of BC cells, which was rescued by transfection of miR-578 inhibitors. The binding sites were verified between circ_0048764 and miR-578. HMGA2 was identified to be a target of miR-578 in BC cells, and circ_0048764 positively regulated HMGA2 expression in BC cells via repressing miR-578. CONCLUSION: Circ_0048764 promotes BC cell growth, migration and invasion via absorbing miR-578 and up-regulating HMGA2.

Methylation detection of circulating tumor cell miR-486-5p/miR-34c-5p in the progression of colorectal cancer.

AIMS: This study set out to examine the expression and methylation levels of miR-486-5p/miR-34c-5p and its mechanism of action based on the microRNA methylation level of circulating tumor cells (CTCs) in colorectal cancer (CRC) through clinical data and tissue detection. METHODS: EGFR and EpCAM immunophospholipid magnetic spheres (EpCAM-IML/EGFR-IML) were synthesized by the thin film method to capture CTCs in peripheral blood. The expression of miR-486-5p/miR-34c-5p was detected via real-time fluorescent quantitative PCR (RT-PCR). Methylation-specific PCR was implemented to detect the methylation level of miR-486-5p/miR-34c-5p, and 5-Aza-dC was used for demethylation treatment to detect the effect of changes in methylation levels on the tumor cells development. Cell Counting Kit-8 (CCK-8) analysis, transwell assay, and flow cytometry were used to determine the effects of demethylation and overexpression on the proliferation, invasion, migration, and apoptosis of CRC cells. RESULTS: The results showed that the expression and methylation levels of the miR-486-5p/miR-34c-5p isolated from CTCs were low and the methylation level was high in tumor cells and tissues. In CRC cell lines, demethylation and overexpression of miR-486-5p/miR-34c-5p could effectively inhibit the proliferation, invasion and migration of tumor cells, and facilitate tumor apoptosis (p < 0.05). CONCLUSION: The constructed CTCs sorting system has characteristics of high specificity and high sensitivity, is a supplement to tissue samples, and has guiding significance for the clinical rational use of drugs and personalized therapy.

circRNF10 Regulates Tumorigenic Properties and Natural Killer Cell-Mediated Cytotoxicity against Breast Cancer through the miR-934/PTEN/PI3k-Akt Axis.

Circular RNA (circRNA), a type of non-coding RNA, has received a great deal of attention with regard to the initiation and progression of tumors. However, the molecular mechanism and function of circRNAs in breast cancer (BC) remain unclear. In the current study, we discovered that hsa_circ_0028899 (also called circRNF10) was significantly reduced in BC tissues, and a higher level of circRNF10 was markedly related to a favorable prognosis. The results of CCK8, colony formation, Transwell, ELISA, and NK cell-mediated cytotoxicity assays indicated that increased circRNF10 expression could significantly repress the proliferation, invasion, and migration of BC cells and enhance the killing efficiency of NK cells against BC cells. According to these biological functions, the possible role and molecular mechanism of circRNF10 in BC cells were further investigated. We used bioinformatics prediction tools to predict circRNF10-bound miRNAs, which were verified by many experimental studies, including FISH, luciferase reporter assays, RIP, and Western blots. These data suggest that circRNF10 serves as a molecular sponge for miR-934 to further regulate PTEN expression and PI3k/Akt/MICA signaling in vitro and tumor growth in vivo. Altogether, these findings reveal that circRNF10 functions as a novel anti-oncogene in BC via sponging miR-934 and suppressing the PI3K/Akt/MICA pathway.