bluuebunny/crossref_metadata_2025_split huggingface dataset:
Commercial next generation sequencing in a real-world cohort of patients with metastatic breast cancer.
Authors: Taneja Kamil , Cohen Jules A. 
Published: June 2023

e13082 Background: Clinicians increasingly order next generation sequencing (NGS) of tissue or liquid (ctDNA) biopsies from patients with metastatic breast cancer. Although some genetic information is clinically actionable, some, particularly non-ERBB2 gene amplifications, is not. We reviewed NGS data from a real-world cohort of metastatic breast cancer patients to evaluate the prevalence of somatic abnormalities using commercial NGS technology. Methods: We evaluated Foundation One NGS data from 44 tissue and 17 liquid biopsies from patients seen in a medical oncology practice between 2016 and 2022. We used KM Plotter to measure overall survival in early-stage patients by relative gene expression. Results: 76% of patients had ductal and 24% had lobular carcinomas. 59% of patients had luminal (ER-positive) and 32% of patients had basal breast cancer (ER-negative). Only 9% of patients had HER2-positive disease. 48% of the tumors had a p53 abnormality, either a point (59%) or frameshift mutation (36%). 50% tumors had a somatic mutation in a tumor suppressor gene such as PTEN, RB or APC. One patient had a germline BRCA1 mutation and 5 patients had germline BRCA2 mutations. 39% of patients carried a somatic mutation in PIK3CA, predominantly H1047R (45%) in the kinase domain or E545X (20%) in the helicase domain. KM plotter showed worse OS in early-stage patients with low p53 gene expression or high PIK3CA expression. 10/11 patients with lobular carcinoma had somatic mutations in CDH1, 70% of which were frameshift mutations. 8/27 patients with luminal cancer had an ESR1 mutation, predominantly Y537 or D538. 9 patients, predominantly luminal, had amplifications of the 11q13 (CCND1). 7 patients had amplifications of 8q24 (MYC). 20q13 (AURKA) amplifications were only seen in luminal cancers. 12p13 (CCND2) amplifications were only seen in basal cancers. 27% of lobular cancers (vs. 6-17% of ductal cancers) demonstrated amplification of the 11q13, 8q24 and/or 8p11 amplicons. 20q13 and 12p13 amplifications were only seen in ductal cancers. Liquid biopsies were more likely to detect point mutations than tissue biopsies. p53 mutations were seen in 65% of liquid vs. 48% of tissue biopsies. 47% of liquid biopsies showed two p53 mutations. PIK3CA mutations were seen in 71% of liquid vs. 39% of tissue biopsies. 18% of liquid biopsies showed two PIK3CA mutations. 93% of basal cancers had at least one p53 mutation. 44% of luminal cancers had a PIK3CA mutation. ESR1, GATA3 and AKT1 mutations were only seen in luminal cancers. While ESR1 mutations were seen in ductal and lobular cancers, GATA3 and AKT1 mutations were only seen in ductal cancers. Conclusions: Commercial NGS testing of a real-world cohort yields actionable mutations that can impact clinical management and outcome of metastatic breast cancer patients. NGS testing demonstrates the range of gene amplifications and corresponds closely with what has been reported in the published literature.
CCT6A and triple-negative breast cancer metastasis: Activating the AKT/MDM2/P53 pathway.
Authors: Yang Mengdi , Cao Jianing , Guo Duancheng , Tao Zhonghua , Hu Xichun 
Published: June 2023

e13087 Background: Triple-negative breast cancer (TNBC) patients are prone to distant recurrence and poorer prognosis. The key molecules and underlying mechanisms of TNBC's aggressive phenotype remain to be further clarified. Methods: First, using the Kaplan-Meier Plotter ( https://kmplot.com/analysis ) and analyzing our collected clinical samples, we established the expression pattern and clinical value of the chaperonin containing TCP1 subunit 6A (CCT6A) in TNBC. We carried out the Cell Counting Kit-8 (CCK8), Transwell, and flow cytometry assay in the TNBC cell lines including MDA-MB-231 and BT549 to assess the effects of knockdown and overexpress of CCT6A. The mechanism of CCT6A in TNBC was identified by using the RNA-seq, KEGG analysis and Co-Immunoprecipitation Mass Spectrometry. Rescue assays verified the role of the AKT Serine/Threonine Kinase 1 (AKT) / Mouse double minute 2 homolog (MDM2)/P53 pathway on CCT6A. Then, the effect of CCT6A on tumor progression and metastasis in vivo was evaluated by the mouse models of tumorigenesis in situ and caudal artery lung metastasis. APG115, a pharmacological p53 activator and immune stimulatory MDM2 inhibitor, combined with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody Ipilimumab was found to prevent TNBC metastasis. Finally, we did a profiling of the tumor immune environment in mice. Results: CCT6A was highly expressed in TNBC ( p<0.0001), and patients with high expression of CCT6A had poor prognosis ( p=0.0053, HR=2.36 [1.27-4.39]). Of note, CCT6A was significantly associated with lymph node metastasis ( p<0.0001). CCT6A promoted cell proliferation, migration, and invasion while inhibiting cell apoptosis and achieving G1/S stage arrest through gain- and loss-of-function approaches. In terms of mechanism, Co-IP and Immunofluorescence assay verified that CCT6A interacted with Keratin 10 (KRT10) which can promote tumor metastasis. Compared with the control group, RNA-seq, and KEGG analysis suggested that AKT/MDM2/P53 signaling was inhibited after knockdown of CCT6A in MDA-MB-231. Furthermore, we found that the tumor volume and the number of lung metastasis sites were significantly reduced in the APG115 combined with Ipilimumab treatment group. Flow cytometry and multiple Immunofluorescence assay showed that TGF-β level from regulatory T cells decreased, while IFN-γ amount from CD8+T cells significantly increased with the combination (both p<0.05). Conclusions: Our research demonstrated that CCT6A can enhance metastasis of triple-negative breast cancer via up-regulating the AKT/MDM2/P53 pathway. These results provide rationales for MDM2 inhibitor combined with anti-CTLA-4 antibody for preventing TNBC metastasis.
Identifying the education, information and support needs of Canadians diagnosed with breast cancer: A Canadian Breast Cancer Network (CBCN) assessment project.
Authors: Ammendolea Cathy , Swiger Kathleen Dickerson , Richter Scott , Adegbembo Bukun 
Published: June 2023

e13088 Background: Assessing the education, information and support needs of Canadians diagnosed with breast cancer involves categorizing and tailoring topics and methods of delivery but, most importantly, it must be rooted in an understating of the patient. In 2022, CBCN initiated a project to identify the needs of the Canadian breast cancer population and develop tailored, focused programs and materials. Methods: CBCN conducted a series of 45-minute key informant interviews (7) with patients and oncologists to determine needs, gaps, programs and materials. Five 90-minute patient focus groups (32 participants) were conducted to enhance the interviews. One group was specifically for metastatic patients. Findings from the interviews and focus groups were used to inform the questions for a survey which was fielded online May1/June 10, 2022. The data analysis began in September 2022 and is on-going. Results: A review of Canadian triple negative breast cancer (TNBC) patients’ responses (n=185 or 18.9% of respondents) showed that only 29.4% had heard the term TNBC before. When asked about educational resources on clinical, practical and support topics TNBC patients preferred them tailored to their breast cancer type (94.3%). TNBC patients reported difficulty locating resources (74.0%) and rated those available satisfactory to poor (44.6%). Sources included websites, social media and printed materials. Specific topics of interest were new treatments and latest research (66.2%), fear of recurrence (63.1%), prevention of illness after breast cancer (60.1%) and long term effects of treatment (57.4%). Conclusions: Public awareness of the types of breast cancer could promote a better understanding of the nature of the disease. Availability of multiple communication channels provides opportunities to disseminate and update resources and deliver them to the patients and providers. While information exists, identifying and increasing the availability of credible, reliable resources tailored to specific types of breast cancer that are easily accessible to both patients and clinicians could enhance the physician-patient dialogue, potentially improve adherence, promote trust and possibly contribute to improved outcomes.
Effect of doxorubicin on efficacy of immune checkpoint inhibitors through increasing infiltration of CD8-positive T cells and activating STAT1-IRF1-CXCL10 axis.
Authors: Xiaosu Qiao , Guo Duancheng , Tao Zhonghua , Hu Xichun 
Published: June 2023

e13095 Background: Immune checkpoint inhibitors (ICIs) generate an enduring clinical remission in metastatic cancers. However, the efficacy of ICIs monotherapy for triple negative breast cancer (TNBC) is limited. Strategies are urgently needed to enhance anticancer immune responses in TNBC to prolong survival of patients. Methods: BALB/c mice subcutaneous tumor experiments were done to evaluate the efficacy of doxorubicin combined with PD-1 inhibitor, compared with other chemotherapy including cisplatin and paclitaxel. RNA-seq and single-sample gene set enrichment analysis (ssGSEA) were done with our collected mice tumor tissue to observe changes of tumor immune environment in TNBC after chemotherapy combined with immunotherapy. Then, we performed coculture, Transwell assay and FACs in TNBC cell lines, including MDA-MB-231, BT549 and 4T1, and primary CD8+T cells, to assess effects of doxorubicin on CD8+T cell migration in vitro. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) analysis were enriched from RNA-seq data to seek for a pathway. We analyzed the difference of CD8+T cell infiltration related gene expression, including CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11. Western blot, qPCR and ELISA were utilized to explore possible mechanism in stronger migration of CD8+T cells by doxorubicin. Rescue assays were used to confirm the involved mechanisms. Results: Subcutaneous tumor experiment showed that doxorubicin could enhance the efficacy of immune checkpoint inhibitors (p＜0.05),andthe immune microenvironment in TNBC transferred from "anti-inflammatory" to "proinflammatory" status after doxorubicin combined with immunotherapy, compared with other chemotherapy drugs combined with immunotherapy. Higher CD8+T cells infiltration occurred in TNBC treated with doxorubicin in vivo (p＜0.05). The CD8+T cells migration assay demonstrated a higher CD8+T cell migration with doxorubicin in vitro (p＜0.05). KEGG analysis revealed that the chemokine-related pathway was significantly activated after doxorubicin treatment, in which CXCL10 chemokine was most likely to be responsible for CD8+T cell infiltration based on its expression and secretion (both p<0.01). Further experiments demonstrated that the expression of the whole STAT1-IRF1-CXCL10 axis was up-regulated in TNBC mice treated with doxorubicin (p＜0.01), and the STAT1-IRF1-CXCL10 axis was also activated in doxorubicin-treated TNBC cell lines (p＜0.0001). Conclusions: This research demonstrated that doxorubicin can enhance efficacy of immune checkpoint inhibitors through increasing infiltration of CD8+T cells in triple-negative breast cancer via activating STAT1-IRF1-CXCL10 axis. These results provide rationales of doxorubicin combined with PD-1 inhibitor for extending survival of TNBC patients.
Effect of DUAL pharmacological blockade of AURKA and PD-L1 pathways on plasticity and metastasis for triple negative breast cancer.
Authors: Takchi Andrew , Haddad Tufia C. 
Published: June 2023

e13100 Background: Aurora-A mitotic kinase (AURKA) plays a pivotal role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype (Cancer Stem Cells) characterized by high self-renewal capacity and intrinsic drug resistance. Cancer Stem Cells (CSCs) also shows high PD-L1 expression that plays a critical role in inducing tumor immune escape through CD8+ T-cells exhaustion. For these reasons, molecular characterization of oncogenic pathways that promote stemness and intra-tumoral PD-L1 expression is essential to evaluate whether novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis may impact cancer progression. Methods: (1) TNBC Models: MDA-MB 231 and variant MDA-MB 231/LM cells, and unique TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting assay. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x106 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were randomized into four groups (5 mice per group) and treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. Control groups were treated with saline solution placebo. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Combination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Remarkably, combination of atezolizumab and alisertib also induced a significant reduction of ALDHHigh CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to impair cancer cell plasticity, immune evasion capacity and halt the progression of metastatic TNBCs that currently has limited effective therapeutic options.
Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer: A multi-center, open-label, single-arm, phase II study.
Authors: Peng Peijian , Xu Xiaolu , Zhong Jincai , Lin Hong , Wang Hong , Ye Jin-Hui , Du Caiwen , Wang Zhi-Hui , Yu Gengsheng , Zou Guorong , Ouyang Jie , Wang Yong-Xia , Li Lu-Zhen , Xu Fei , Cui Shi-En 
Published: June 2023

e13102 Background: Eribulin is a non-taxane microtubule inhibitor approved in China for the treatment of patients with advanced breast cancer who progress after ≥2 lines of chemotherapy. Eribulin was shown to improve overall survival (OS) in various subgroups of patients with metastatic breast cancer (MBC) who were pretreated with an anthracycline and taxane. Furthermore, combination chemotherapy with eribulin plus gemcitabine led to a similar progression free-survival (PFS) benefit, with less neurotoxicity, as paclitaxel plus gemcitabine in patients with MBC who had not received prior cytotoxic chemotherapy for metastatic disease. However, the effect of eribulin plus gemcitabine on PFS in second-line or beyond remain unclear. Methods: This phase II, open-label, single-arm study was conducted at 13 institutions in China (NCT05263882). Patients with histologically confirmed HER2-negative MBC who had received at ≥1 prior taxane-containing chemotherapeutic regimen for advanced disease and had received anthracycline-containing regimens in the adjuvant setting, were enrolled between Nov 2021 and Oct 2022. Eligible patients received eribulin 1.4 mg/m2 and gemcitabine 1.0 g/m2 intravenously on days 1 and 8 of a 21-day cycle. Efficacy outcomes included PFS, objective response rate (ORR), and disease control rate (DCR), evaluated using RECIST v1.1. Adverse events (AEs) were graded according to The National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. Results: In total, 54 patients were included; 39 (72.2 %) were HR+/HER2- and 15 (27.8 %) were triple negative, the median age was 49.5 years (range: 31-70) and sites of metastasis were the liver (57.4%), lung (37.0%), bone (59.3%), brain (11.1%) and lymph nodes (53.7%). The median number of previous chemotherapy lines was 3 (range: 2-7): eribulin plus gemcitabine was used in second-line for 15 (27.8%) patients, third-line for 20 (37.0%) patients, fourth-line for 7 (13.0%) patients and ≥fifth-line in 12 (22.2%) patients. The median PFS was 7.7 months. The ORR was 40.7% and the DCR was 66.7%. Best overall responses and PFS rates at 3 and 6 months are shown. The most common grade 3-4 AEs were hematological: Leukopenia (35.2%), anemia (18.6%) and thrombocytopenia (9.4%). No treatment-related death was reported. Conclusions: Eribulin plus gemcitabine is effective in heavily pretreated patients with HER2-negative MBC with a predictable, manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]
Incidence and outcomes of cardiac tamponade in patients with breast cancer.
Authors: Ilerhunmwuwa Nosakhare Paul , Wasifuddin Mustafa , Hakobyan Narek , Tahir Muhammad , Avezbakiyev Boris 
Published: June 2023

e13108 Background: Cardiac tamponade (CT) is a cardio-oncological emergency reported to be associated with poor outcomes in some solid tumors, such as lung cancers. There is a paucity of literary evidence on CT in patients with breast cancer. We sought to examine the Nationwide Inpatient Sample (NIS) -the largest inpatient database in the United States- to determine the incidence and factors associated with CT, and the in-hospital outcomes in patients with breast cancer. Methods: We retrospectively explored the NIS database collected from 2016 to 2020. Patients aged ≥ 18 with breast cancer and CT were selected using ICD-10 diagnostic codes. Univariate, multivariate logistic, and negative binomial regression models were used to assess the annual incidence trends, determine factors associated with cardiac tamponade and in-hospital outcomes among patients with breast cancer. Results: A total of 144,405 breast cancer patients (weighted n= 722,025) were examined, of which 345 (0.24%) had CT. The incidence of CT rose from 25 per 10 000 in 2016 to 27.3 per 10 000 cases of breast cancer in 2020 though this was not statistically significant (p=0.409). Patients with CT were more likely to be younger (60 ± 13 vs 66 ± 14, p<0.001), with comorbidity index ≥ 5 (90.72% vs 9.28%, p<0.0001), history of chemotherapy (18.84% vs 12.46%, p=0.0004), history of radiation therapy (17.97% vs 10.80%, p<0.0001), and had Medicare (50.43% vs 49.57%, p<0.001). After multivariate adjustment, comorbidity index ≥ 5 (aOR=5.16, 95% CI: 3.03 - 8.78; p<0.001), and history of irradiation (aOR=1.45, 95% CI: 1.08 - 1.96; p=0.014), were found to be independent predictors of CT. However, the risk of CT was less with age > 65 years (aOR=0.64, 95% CI: 0.47 - 0.87; p=0.004). Regarding in-hospital outcomes, after controlling for other covariates, CT was associated with an increased risk of mortality (aOR=1.71, 95% CI: 1.16 - 2.52; p=0.07) and longer hospital stay (7.25 ± 5.77 vs 4.78 ± 5.45; incidence risk ratio [IRR]:1.49, 95% CI: 1.36 - 1.63; p <0.001). Conclusions: Cardiac tamponade is rare in breast cancer and tends to occur more in patients who are younger, have comorbidities, and prior radiation therapy. It is associated with increased risk of in-hospital mortality and longer stay. Risk stratification of patients with breast cancer when deciding treatment is relevant to reduce the likelihood of CT and improve outcomes. Further studies are needed to establish the optimal management of CT in patients with breast cancer.
A prospective, single-arm, single-center, exploratory clinical study of anlotinib combined with irinotecan in second-line and above treatment of HER-2–negative advanced breast cancer.
Authors: Zhang Ying , Xu Wenhuan , Zhao Yutian , Guo Xuedan , Hong Tingting , Yan Yidan , Wu Xiaohong 
Published: June 2023

e13114 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Irinotecan is a semi-synthetic water-soluble camptothecin derivative which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of irinotecan combined with anlotinib in second-line and above treatment of HER-2 negative advanced breast cancer. (ChiCTR2000037448) Methods: This open-label, single-arm, phase II study enrolled women aged 18 years and older with HER2-negative breast cancer who underwent ≥1 line chemotherapy, All patients were treated with irinotecan (60mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to November 2022, 14 patients were enrolled in this study. Median follow-up was 10.8 months (95% CI 4.3-17.3). Median PFS was 5.9 months (95% CI 2.0-9.8). Of all the patients whose efficacy could be evaluated (13/14), no patient achieved complete response (CR); 3(23.07%) and 8(61.54%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 23.1% (95% CI 5.0-53.8) and DCR was 84.6% (95% CI 54.6-98.1). OS has not reached. The major treatment-related adverse events (incidence≥10%) were fatigue (42.86%), hypertension (42.86%), neutropenia (28.57%), hand foot syndrome (21.43%) and myelosuppression (14.29%). There is no grade 3/4 adverse events occurred.28.57% (4/14) of patients had dose reductions. Conclusions: The combination of irinotecan and anlotinib showed better treatment response and tolerable toxicity in the treatment of second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed. Clinical trial information: ChiCTR2000037448 .