bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tyrosine kinase inhibitors (TKIs) in trastuzumab emtansine (T-DM1) resistant HER2-positive metastatic breast cancer: A real-world study.
Authors: Yin Yongmei , Sun Chunxiao , Hua Yijia , Jiang Mengping , Yang Fan , Wu Xinyu , Zeng Tianyu , Bao Shengnan , Liang Yan , Huang Xiang , Li Wei 
Published: June 2022

e13029 Background: Trastuzumab emtansine (T-DM1) has shown great effectiveness in treating HER2-positive metastatic breast cancer, but therapies subsequent to T-DM1 progression are still controversial. Here, we investigated efficacy and safety of tyrosine kinase inhibitors (TKIs) based therapy in T-DM1 resistant HER2-positive metastatic breast cancer. Methods: From August 2019 to February 2022, 53 HER2-positive metastatic breast cancer patients received TKIs-based therapy after T-DM1 progression in Jiangsu Province Hospital. We reported progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles of TKIs in treating T-DM1 resistant HER2-positive metastatic breast cancer. Results: 53 patients received TKIs-based therapies as a second or later line therapy. 51 (96.2%) patients received a combined therapy, including TKIs plus capecitabine, vinorelbine or trastuzumab. 2 (3.7%) patients received TKIs alone. The median follow-up time was 19.7 months (95%CI 14.829-24.571). The median PFS was 10.6 months (95%CI 5.530-15.670). OS has not reached. ORR was 18.9% and CBR was 72.5%. For patients who had brain metastasis (n = 12), the median PFS was 10.5 months (95%CI 7.406-13.594) and intracranial ORR was 33.3%. Compared with lapatinib (n = 30), pyrotinib (n = 21) provided a better PFS, but no significant difference was observed (8.0 months vs. 19.0 months, P = 0.076). The most common adverse events were thrombocytopenia (12, 22.6%), hand-foot syndrome (11, 20.8%) and diarrhea (6, 11.3%). Conclusions: TKIs-based therapy could improve the survival of T-DM1 resistant HER2-positive metastatic breast cancer patients, including those with brain metastasis. This provides a novel therapeutic option for HER2-positive breast cancer treatments.
Anti-HER2 antibody inetetamab plus camrelizumab and utidelone for pretreated HER2-positive advanced breast cancer: A single-arm, multicenter, phase 2 study.
Authors: Yan Min , Lv Huimin , Niu Limin , Zhang Mengwei , Zeng Huiai , Zhao Shengnan , Wang Jing , Sun Huihui , Chen Shumin 
Published: June 2022

e13030 Background: Treatment options for patients with HER2-positive breast cancer after progression on two or more lines of HER2-directed therapies are scarce. Inetetamab, a novel anti-HER2 antibody, exhibits the same binding affinity to HER2 antigen and antibody-dependent cell-mediated cytotoxicity as trastuzumab. Previous studies have demonstrated the treatment potential of PD-1 inhibitor combined with HER2-targeted therapy in HER2-positive gastric or gastroesophageal junction cancer. Utidelone, a genetically engineered epothilone analogue, has shown promising efficacy in heavily pretreated metastatic breast cancer. This study aimed to investigated inetetamab plus camrelizumab (anti-PD-1 antibody) and utidelone in patients with HER2-positive recurrent or metastatic breast cancer who had progressed after at least two lines of HER2-directed therapies with trastuzumab and tyrosine kinase inhibitors (TKIs). Methods: In this phase 2 study (NCT04681287), patients received intravenous camrelizumab (200 mg once every 3 weeks), inetetamab (8 mg/kg loading dose then 6 mg/kg, day 1), and utidelone (30 mg/m2, days 1-5) until disease progression or intolerable toxicity. The primary endpoint was 3-month progression-free survival (PFS) rate according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Secondary endpoints included objective response rate (ORR), PFS, overall survival, and safety. Simon’s two-stage design was adopted for this study. Results: Between April 2021 and January 2022, a total of 27 patients were enrolled. As of January 2022, 20 patients could be analyzed. The median number of previous systemic therapies for advanced disease was three. Previous HER2-targeted therapies included trastuzumab (20 [100%]), pyrotinib (17 [85%]), lapatinib (7 [35%]), pertuzumab (3 [15%]), and margetuximab (2 [10%]). The first stage required 10 patients, and 8 of them were free from progression at 3 months. The study proceeded to the second stage for another 31 patients, and the accrual is ongoing. The 3-month PFS rate in 20 patients was 75%. The ORR was 30% (6/20); one (5%) patient achieved complete response. The most common treatment-related adverse events (TRAEs) were peripheral neuropathy (19 [98%]), capillary proliferation (19 [98%]), alopecia (18 [90%]), and fatigue (7 [35%]). Grade ≥3 TRAEs included peripheral neuropathy (2 [10%]) and rash (1 [5%]). No treatment-related treatment discontinuation or deaths occurred. Conclusions: Inetetamab plus camrelizumab and utidelone showed promising efficacy and acceptable safety profile in patients with HER2-positive advanced breast cancer after progression on at least two lines of HER2-directed therapies with trastuzumab and TKIs. Clinical trial information: NCT04681287.
Prognostic factors influencing progression-free survival in HER2 positive metastatic breast cancer patients who treated with lapatinib and capecitabine combination.
Authors: Dogan Izzet , Paksoy Nail , Ak Naziye , Vatansever Sezai , Saip Pinar , Aydiner Adnan 
Published: June 2022

e13031 Background: Her2 positivity is detected in about 20% of breast cancer patients. After trastuzumab-based therapy, lapatinib and capecitabine combination is a treatment option in HER2-positive metastatic patients. The study aimed to evaluate the prognostic factors in HER2 positive metastatic breast cancer patients treated lapatinib and capecitabine combination. Methods: We evaluated data of the HER2 positive metastatic breast cancer patients who were treated with lapatinib and capecitabine retrospectively. The patients' clinical, pathological, and treatment features were recorded from the hospital database. Kaplan Meier and Cox regression analysis were used for survival analysis. Results: 102 patients were included in the study. The median age was 47 (range, 24-87), and 99 (97.1%) patients were female. The number of de-novo metastatic patients was 44 (43.1%). The most common metastatic sites were bone (62.4%), brain (58.6%), liver (35.6%), and lung (34.7%), respectively. All patients were previously treated with trastuzumab-based chemotherapy. 44 (44.1%) patients received hormonotherapy (tamoxifen or aromatase inhibitor), and 23 (22.5%) patients palliative radiotherapy. Complete response was 8.2%, partial response 32%, and stable disease 25.8% with lapatinib and capecitabine combinations. At a median follow of 11.6 months, progression-free survival was 8 (95% CI, 5.1-10.8) months. In multivariate analysis, age (p = 0.020), de-novo metastatic disease (p = 0.028), and endocrine therapy (p = 0.020) were statistically significant prognostic factors for progression-free survival. However, history of breast surgery (p = 0.060), number of chemotherapy used with trastuzumab (p = 0.338), number of metastatic sites (p = 0.257), and palliative radiotherapy (p = 0.394) were not significant. Conclusions: We showed real-life outcomes of the lapatinib and capecitabine combination in metastatic HER2-positive breast cancer patients. Also, we detect that being under age 50 years, de-novo metastatic disease, and hormone-negative tumor were poor prognostic factors of progression-free survival.
The role of RARRES2 in regulating lipic metabolic reprogramming in the development of brain metastases in triple negative breast cancer.
Authors: Li Yiqun , Sun Fangzhou , Li Chunxiao , Mo Hongnan , Qian Haili , Ma Fei 
Published: June 2022

e13047 Background: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastases (BM) and a poor prognosis. As the most lethal form of breast cancer, brain metastases remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastases (BCBM), but the underlying mechanisms are far from been fully elucidated. Methods: Using public datasets and our single-cell transcriptome sequencing data, we identified and verified the specific down-regulation of RARRES2, a multifunctional adipokine and chemokine, in brain metastases of triple negative breast cancer. We investigated the effect of aberrant RARRES2 expression on brain metastases in both in vitro and in vivo studies. Key signaling pathway components were evaluated using qPCR and Western blot analysis. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. Results: We show for the first time that down-regulation of RARRES2 is specifically associated with BCBM, and that RARRES2 promoted BCBM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain-tropic triple negative breast cancer cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols (TAGs) by regulating PTEN-PI3K-SREBP1 signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. Conclusions: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of brain metastases, thereby offering potential therapeutic targets for BCBM in TNBC.
Supporting patients with metastatic breast cancer during therapy with cyclin-dependent kinase 4/6 (CDK) inhibitors: A needs assessment.
Authors: O'Sullivan Ciara Catherine Maria , Jacobs Ginny , Perez Domingo Gregorio , Jackson Katrina , Schowengerdt Bethany , Lazure Patrice , McFadden Pam 
Published: June 2022

e13054 Background: Combination therapy with cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib and abemaciclib) and endocrine therapy (ET) has markedly improved treatment of hormone receptor positive (HR+), HER2-negative (-) advanced or metastatic breast cancer (MBC) worldwide.However, data is limited on why patients may discontinue CDK4/6i based therapy and how healthcare providers (HCPs) see their role in educating patients (Px) about side effects and supporting compliance. Objective: This study identifies reasons for suboptimal compliance and early discontinuation of CDK4/6i in US HR+ HER2- MBC Px, with a focus on HCPs and Px educational needs related to on-treatment monitoring, side effects and symptom management. Methods: A sequential mixed-methods design was used; 45-minute phone interviews (n=25) informed the development of an online survey (n=193). Both phases included HCPs comprising medical oncologists (ONCs), oncology registered nurses (RNs), nurse practitioners, and physician assistants (NPs/PAs) in community-based settings. Results: Identified areas of improvement for HCPs included: suboptimal competencies were identified: educating Px adequately regarding potential side effects and engaging them to monitor, report, and address them. Among HCPs surveyed, 26%-48% reported suboptimal knowledge of side effects of specific CDK4/6i [Table]. Interviewees noted that educating Px and setting expectations on potential side effects was critical, but 52% of ONCs reported suboptimal skill doing so. A majority of HCPs (68%-91%) expect Px to be able to report all side effects, with half of ONCs considering compliance with medication entirely Pxs’ responsibility, compared with NPs/PAs and RNs at 16-17%. Conclusions: This study identified areas where HCPs can improve their ability to counsel Px and address concerns that may influence a Px’s decision to prematurely discontinue therapy and should be used to inform future professional development initiatives. [Table: see text]
Increased lung metastasis with sevoflurane in breast cancer surgery is associated with VEGF and elevated vascular permeability by VEGF in a mouse model of human breast cancer.
Authors: Lin Jun , Li Ru , Huang Yujie , Dilger James P. , Beto Mukherjee Mousumi 
Published: June 2022

e13060 Background: An on-going controversy is whether general anesthetics used in cancer surgery substantially influence the outcome of cancer patients. Thousands of cancer patients undergo surgery with hope of cure. However, postoperative metastasis remains a deadly disease that affects millions of lives, even with all the recent therapeutic advancements. Anesthesia is required for surgical resection of solid tumors and we have shown that general anesthetics substantially influences the process of breast cancer lung metastasis through increasing pulmonary permeability in animal models. Our previous study demonstrates that inhaled anesthetic sevoflurane used during resecting primary breast tumors promotes lung metastasis via IL6 pathway in syngeneic model of murine 4T1 breast cancer cells, compared with an intravenous anesthetic propofol. Methods: Xenograft model of human MDA-MB 231 breast cancer of spontaneous metastasis was utilized in this study to evaluate the effect of commonly used general anesthetics including sevoflurane and propofol on breast cancer lung metastasis and explore the potential mechanism. Results: In this study we show that the metastatic promoting effect of sevoflurane is associated with elevated secretion of VEGF and increased vascular permeability in xenograft model of human MDA-MB 231 breast cancer of spontaneous metastasis. Cytokine array profiling reveals that the mice receiving sevoflurane have increased levels of pro-angiogenic factor VEGF in serum and lung tissues. Sevoflurane enhances the expression level of VEGFR on HUVEC cells. Furthermore, sevoflurane disrupts endothelial monolayer in vitro and elevates pulmonary vascular permeability in vivo. The sevoflurane-promoted breast cancer lung metastasis is reversed by DC101, an antibody targeting mouse VEGFR-2. Conclusions: Our results show that the inhaled anesthetic sevoflurane during surgical removal of primary tumor alter the course of metastasis through regulating secretion of VEGF and associated vascular remodeling. The mechanistic study of general anesthetics on cancer cell metastasis establishes the causal link and could provide the potential therapeutic intervention and guide the clinical trials.
Bacterial community composition in breast cancer subtypes.
Authors: Chan Alfred , Naseem Madiha , Onyshchenko Mykola , Lee Delphine 
Published: June 2022

e13063 Background: Breast cancer is a heterogeneous disease with multiple molecular subtypes and prognostic outcomes. Among these subtypes, Luminal-A is enriched with estrogen receptor and has the best clinical prognosis, whereas triple-negative breast cancer (TNBC) remains an aggressive subtype with poor prognosis. Changes in the diversity of breast microbiome have been associated with breast cancer initiation and progression. We hypothesized that Luminal-A and TNBC subtypes will have differences in both bacterial community composition as well as differences in microbial genomes and pathways. Methods: 6 Luminal-A and 6 TNBC FPPE tissue blocks were processed for both 16S V4 rRNA amplicon sequencing and shotgun metagenomics sequencing. 16S sequencing data was processed using mothur (v1.44.3) and reads were assigned taxonomy against the SILVA 16S rRNA database (v132). Shotgun sequencing was processed using the EBI-Metagenomic (v5) pipeline; bacterial identification was performed using the Kraken pipeline. Results: Shannon alpha-diversity or species enrichment, was significantly higher in Luminal-A compared to TNBC (nonparametric, P = 0.008) and their microbiome composition was significantly different by beta-diversity analysis (bray-curtis dissimilarity, PERMANOVA, P = 0.014). Bacteroides and Sphingomonadaceae species were significantly higher in abundance in Luminal-A, compared to Pseudomonas and Neisseriaceae species abundance in TNBC. Results were validated by shotgun sequencing. Luminal-A and TNBC bacterial metabolic pathways were not statistically different overall (PERMANOVA, P = 0.312). Pathways associated with Luminal-A included Response to Wounding (GO: 0009611), tRNA modification (GO: 0006400), and Cytoplasmic Microtubule Organization (GO: 0031122). Pathways associated with TNBC included troponin complex (GO: 0005861), rRNA processing (GO: 0006364), and CDC73 PAF1 (GO: 0016593). Conclusions: Using both shotgun and amplicon sequencing, this is the first analysis to show that Luminal-A and TNBC subtypes have statistically significant differences in bacterial species composition. Luminal-A had higher species diversity and abundance of Sphingomonadaceae, which are associated with healthy breast tissue and better clinical outcomes. TNBC had lower species diversity and abundance of Pseudomonas and Neisseriaceae, which have been associated with tumor survival and cell growth. Understanding the role of microbiota and its complex interaction with tumor microenvironment could help identify new treatment targets in breast cancer subtypes, and warrants further investigations.
Efficacy of sacituzumab govitecan based regimen in triple-negative breast cancer: A systematic review.
Authors: Khalid Farhan , Kashyap Richi , Singh Vinit , Tayyeb Muhammad , Jaan Ali , Mohan Gaurav , Meghal Trishala 
Published: June 2022

e13068 Background: Sacituzumab govitecan (SG) is an drug-antibody conjugate composed of anti-trophoblast cell-surface antigen 2 (Trop-2) IgG1 Kappa antibody with SN-38 through a hydrolysable linker. SG has a promising efficacy safety profile in triple negative breast cancer (TNBC) and was given regular approval for nonresectable locally advanced or metastatic disease with 2 or more previous line of therapies. This review aims to explore the efficacy and safety of SG-regimens for the treatment of TNBC. Methods: We conducted a literature search using three databases (PubMed, Embase, and ClinicalTrials.gov). Our search strategy included MeSH and keywords for breast cancer and SG including trade and generic names from the date of inception to January 15, 2022. Initial databases yielded 275 articles. After exclusion, two clinical trials on the use of SG in pretreated TNBC were included. Results: Among a total of 963 enrolled patients, 379 patients were evaluated. Majority of the patients received SG dose of 10 mg/kg. Bardia et al. studied the efficacy of SG in TNBC pts (n = 235) in phase III (ASCENT) trial achieved an overall response rate (ORR) of 31%. The median overall survival (OS) was 11.8 months (95% CI 10.5-13.8) and a median progression-free survival (PFS) was 4.8 months (95% CI, 4.1-5.8).Similarly, in another study Bardia et al. studied SG in TNBC pts (n = 144) in phase I/II (basket) trial and observed ORR of 33.3%. The median overall survival (OS) was 13 months (95% CI, 11.2 to 14) and a median progression-free survival (PFS) was 5.6 months (95% CI, 4.8 to 6.6). (Table) Diarrhea and Nausea was the most common adverse effect reported by the patient whereas neutropenia was the most common grade 3 adverse effect. Conclusions: SC showed promising outcomes in terms of ORR for the treatment of TNBC. [Table: see text] [Table: see text]
Humoral and cell-mediated immune response to the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with cancer on active treatment: Focus on wild type, Delta and Omicron strains.
Authors: Lasagna Angioletta , Cassaniti Irene , Bergami Federica , Lilleri Daniele , Percivalle Elena , Quaccini Mattia , Alessio Niccolò , Comolli Giuditta , Sarasini Antonella , Camilla Josè , Ferrari Alessandro , Arena Francesca , Secondino Simona , Cicognini Daniela , Schiavo Roberta , Lo Cascio Giuliana , Cavanna Luigi , Baldanti Fausto , Pedrazzoli Paolo 
Published: June 2022

e13505 Background: Although a full course of COVID-19 vaccine is effective in cancer patients, the duration of the protection and the efficacy of a booster dose against the new variants remain unknown. We prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 mRNA vaccine in cancer patients undergoing active treatment. Methods: Patients with solid cancer, vaccinated with a booster dose during active treatment, were prospectively enrolled in this study. Patients were classified in SARS-CoV-2 naïve (without previous COVID-19 infection) and SARS-CoV-2 experienced (with previous COVID-19 infection). Neutralizing antibody (NT Abs) titer and total anti-Spike IgG concentration were quantified in serum. Heparinized whole blood samples were used for SARS-CoV-2 Interferon Gamma Release Assay (IGRA). The primary endpoint was to assess the increase of IgG antibody level between baseline (T0) and 3 weeks after the booster (T1). Results: 142 consecutive patients were recruited. In SARS-CoV-2 naïve subjects, median level of IgG was 157 BAU/mL (interquartile range (IQR) 62-423) at T0 and reached median of 2080 (IQR 2080-2080) at three weeks after booster administration (T1; p < 0.0001). A median 16-fold increase of SARS-CoV-2 NT Abs titre (IQR 4-32) was observed in naïve subjects (from median 20 IQR 10-40 to median 640 IQR 160-640; p < 0.0001). Median IFN-γ level at T1 was significantly higher than that measured at T0 in SARS-CoV-2 naïve subjects (p = 0.0049) but not in SARS-CoV-2 experienced patients. No difference was observed in terms of median response between patients treated with immunotherapy and chemotherapy (p > 0.05). A stronger correlation between SARS-CoV-2 NT Abs and total IgG level was observed at T0 (r = 0.76; p < 0.0001) compared to T1 (r = 0.27, p = 0.0081). No correlation as regards the number of days was observed from the first to the third vaccination and SARS-CoV-2 NT Abs/total IgG. The median level of SARS-CoV-2 NT Abs was 32-fold lower against Omicron compared to wild type strain (p = 0.0004) and 12-fold lower compared to Delta strain (p = 0.0110). Conclusions: The third dose is able to trigger both the humoral and the cell-mediated immune response in cancer patients on active treatment. Our preliminary data about the neutralization of the SARS-CoV-2 vaccine against variants of concern (VOCs) seem to confirm the vaccine lower activity.