Publications by authors named "Qingyuan Zhang"

201 Publications

A Systematic Review and Meta-Analysis of High-Frequency Prescription of Zhigancao Decoction Combined with Conventional Western Medicine in the Treatment of Chronic Heart Failure.

Evid Based Complement Alternat Med 2021 9;2021:7140044. Epub 2021 Nov 9.

Evidence-Based Medicine Research Center, College of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China.

Background: Chronic heart failure is the main critical illness and cause of death in the later stages of cardiovascular disease, and it is one of the two major challenges in the field of cardiovascular research. The clinical application of traditional Chinese medicine in the prevention and treatment of chronic heart failure has been relatively common in China, and the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine" has been published in China. Combining the literature in this field, the authors found that Zhigancao Decoction has been used in the treatment of chronic heart failure with more clinical research reports and higher frequency (this article refers to it as a high-frequency prescription for short). However, Zhigancao Decoction was not included in the recommended prescriptions in the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine," and there was no relevant systematic review and meta-analysis. For this reason, this article has carried out two parts of work, including systematically organizing the literature in this research field and carrying out systematic review and meta-analysis. This can provide stronger evidence support for Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure and provide a new option for the improvement and update of the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine."

Methods: This article used the bibliometric method to investigate the research articles on the treatment of chronic heart failure with integrated traditional Chinese and Western medicine and analyzed the high-frequency prescriptions which are used and reported frequently. In addition, we also used manual and computer-aided search methods, the search scope includes CNKI, WANFANG, VIP, SinoMed, Web of Science, PubMed, and Cochrane Library, and the search content is the clinical randomized control of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure trials (RCTs). The search period is from the establishment of the database to January 29, 2021. The literature was managed and screened by EndNote software; the quality of the included literature was evaluated according to the modified Jadad scale, and the risk bias was assessed using the Cochrane tool; the results of the included studies were analyzed using the Review Manager 5.3 software; the sources of heterogeneity between the studies were analyzed using Stata16.0 software for sensitivity analysis.

Results: According to the bibliometric analysis, the maximum number of research reports is 553, which are arranged in descending order of 21 prescriptions, including Zhenwu Decoction, Zhigancao, and powder of five drugs containing poria. The second most frequently used prescription is Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure, but its systematic review and meta-analysis still need further research. A total of 17 clinical randomized controlled trials of Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure were included in the search, with a total of 1752 subjects. Meta-analysis results show that Zhigancao combined with conventional Western medicine is more effective than conventional Western medicine in the treatment of chronic heart failure. The advantages are the following 5 outcome indicators: total clinical effective rate, left ventricular ejection fraction, left ventricular end-diastolic diameter, B-type natriuretic peptide, and 6-minute walk test.

Conclusions: There are many prescriptions combined with Western medicine to treat chronic heart failure, among which Zhigancao Decoction is the second most frequently used prescription. There are many original studies on Zhigancao Decoction combined with conventional Western medicine in the treatment of chronic heart failure. The quality of the evaluation research shows that the overall standard is scientific, and a few experimental designs are slightly irregular. Meta-analysis shows that Zhigancao Decoction combined with conventional Western medicine has better therapeutic effects and safety than conventional Western medicine. This shows the characteristics and advantages of integrated Chinese and Western medicine in the treatment of cardiovascular diseases and is worth recommending.
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http://dx.doi.org/10.1155/2021/7140044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595005PMC
November 2021

Computer-assisted quantification of tumor-associated collagen signatures to improve the prognosis prediction of breast cancer.

BMC Med 2021 11 18;19(1):273. Epub 2021 Nov 18.

Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, 350007, China.

Background: Collagen fibers play an important role in tumor initiation, progression, and invasion. Our previous research has already shown that large-scale tumor-associated collagen signatures (TACS) are powerful prognostic biomarkers independent of clinicopathological factors in invasive breast cancer. However, they are observed on a macroscale and are more suitable for identifying high-risk patients. It is necessary to investigate the effect of the corresponding microscopic features of TACS so as to more accurately and comprehensively predict the prognosis of breast cancer patients.

Methods: In this retrospective and multicenter study, we included 942 invasive breast cancer patients in both a training cohort (n = 355) and an internal validation cohort (n = 334) from one clinical center and in an external validation cohort (n = 253) from a different clinical center. TACS corresponding microscopic features (TCMFs) were firstly extracted from multiphoton images for each patient, and then least absolute shrinkage and selection operator (LASSO) regression was applied to select the most robust features to build a TCMF-score. Finally, the Cox proportional hazard regression analysis was used to evaluate the association of TCMF-score with disease-free survival (DFS).

Results: TCMF-score is significantly associated with DFS in univariate Cox proportional hazard regression analysis. After adjusting for clinical variables by multivariate Cox regression analysis, the TCMF-score remains an independent prognostic indicator. Remarkably, the TCMF model performs better than the clinical (CLI) model in the three cohorts and is particularly outstanding in the ER-positive and lower-risk subgroups. By contrast, the TACS model is more suitable for the ER-negative and higher-risk subgroups. When the TACS and TCMF are combined, they could complement each other and perform well in all patients. As expected, the full model (CLI+TCMF+TACS) achieves the best performance (AUC 0.905, [0.873-0.938]; 0.896, [0.860-0.931]; 0.882, [0.840-0.925] in the three cohorts).

Conclusion: These results demonstrate that the TCMF-score is an independent prognostic factor for breast cancer, and the increased prognostic performance (TCMF+TACS-score) may help us develop more appropriate treatment protocols.
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http://dx.doi.org/10.1186/s12916-021-02146-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600902PMC
November 2021

An Immune-Related Gene Prognostic Index for Triple-Negative Breast Cancer Integrates Multiple Aspects of Tumor-Immune Microenvironment.

Cancers (Basel) 2021 Oct 25;13(21). Epub 2021 Oct 25.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, China.

Tumor-immune cell compositions and immune checkpoints comprehensively affect TNBC outcomes. With the significantly improved survival rate of TNBC patients treated with ICI therapies, a biomarker integrating multiple aspects of TIME may have prognostic value for improving the efficacy of ICI therapy. Immune-related hub genes were identified with weighted gene co-expression network analysis and differential gene expression assay using The Cancer Genome Atlas TNBC data set ( = 115). IRGPI was constructed with Cox regression analysis. Immune cell compositions and TIL status were analyzed with CIBERSORT and TIDE. The discovery was validated with the Molecular Taxonomy of Breast Cancer International Consortium data set ( = 196) and a patient cohort from our hospital. Tumor expression or serum concentrations of CCL5, CCL25, or PD-L1 were determined with immunohistochemistry or ELISA. The constructed IRGPI was composed of CCL5 and CCL25 genes and was negatively associated with the patient's survival. IRGPI also predicts the compositions of M0 and M2 macrophages, memory B cells, CD8 T cells, activated memory CD4 T cells, and the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression of TNBC. IRGPI is a promising biomarker for predicting the prognosis and multiple immune characteristics of TNBC.
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http://dx.doi.org/10.3390/cancers13215342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582543PMC
October 2021

Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial.

Nat Med 2021 Nov 4;27(11):1904-1909. Epub 2021 Nov 4.

Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.

Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.
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http://dx.doi.org/10.1038/s41591-021-01562-9DOI Listing
November 2021

High dose and hepatobiliary dysfunction are associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin: a retrospective study.

BMC Pharmacol Toxicol 2021 10 25;22(1):63. Epub 2021 Oct 25.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.

Purpose: In clinical practice, the risk factors for pegylated liposomal doxorubicin-related hand-foot syndrome remain unclear. The purpose of this study was to determine the risk factors associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin.

Methods: This retrospective descriptive analysis included patients with lymphoma who received PLD treatment (≥ 2 cycles of chemotherapy) at our cancer centre and had complete follow-up data from January 2016 to February 2020. Clinical, laboratory data, as well as the occurrence of hand-foot syndrome (incidence, location, severity, impact on follow-up chemotherapy) were obtained. The primary end point was the incidence of hand-foot syndrome, which was classified according to the "Common Terminology Criteria for Adverse Events" (Version 4.0). A multivariate logistic regression analysis was used to identify risk factors for hand-foot syndrome in patients with lymphoma using doxorubicin liposomes.

Findings: A total of 167 patients met the inclusion criteria. 58 developed HFS, of which 45 occurred after the second course of chemotherapy. The multivariate logistic regression analysis revealed that a dose increase of pegylated liposomal doxorubicin and hepatobiliary dysfunction were significantly associated with an increased risk for hand-foot syndrome(dose intensity, OR = 6.479; 95% CI, 1.431-29.331 [P = 0.015]; history of gallstones, OR = 14.144, 95% CI, 1.512-132.346 [P = 0.020]; alanine aminotransferase, OR = 1.194, 95% CI, 1.056-1.350 [P = 0.005]; aspartate aminotransferase, OR = 1.162, 95% CI, 1.010-1.336 [P = 0.035]; and glutamine transpeptidase, OR = 1.092, 95% CI, 1.016-1.174 [P = 0.018]).

Implications: These findings contribute to the risk assessment of patients with lymphoma before using pegylated liposomal doxorubicin. For patients with the above risk factors, preventive measures should be taken in advance to reduce the incidence of HFS.
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http://dx.doi.org/10.1186/s40360-021-00529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543895PMC
October 2021

Camrelizumab for relapsed or refractory classical Hodgkin lymphoma: Extended follow-up of the multicenter, single-arm, Phase 2 study.

Int J Cancer 2021 Oct 21. Epub 2021 Oct 21.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.

Camrelizumab (a humanized high-affinity IgG4 mAb against programmed death-l) showed potent antitumor activity, well tolerance and controllable safety in patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL), based on the primary analysis of a Phase 2 study. Here, we present the extended follow-up outcomes. Seventy-five patients who had failed to achieve a remission or experienced progression after autologous stem cell transplantation or had received at least two lines of systemic chemotherapies were enrolled to receive camrelizumab 200 mg every 2 weeks. With a median follow-up of 36.2 months (range, 7.2-38.1), objective response rate per independent central review was 76.0% (95% confidence interval [CI], 64.7-85.1). Among the 57 responders, 31 (54.4%) had ongoing responses. Median duration of response was 31.7 months (95% CI, 16.7-not reached). Median progression-free survival was 22.5 months (95% CI, 14.7-not reached). Thirty-six-month overall survival rate was 82.7% (95% CI, 72.0-89.5). Reactive capillary endothelial proliferation (RCEP) occurred in 97.3% of patients (73/75), but all RCEP were Grade 1 or 2 in severity and 67.1% of these patients (49/73) achieved complete resolution. Occurrence of new RCEP lesions was rare (8/42 [19.0%] at 12 months; 2/32 [6.3%] at 24 months). No treatment-related deaths occurred, and no new toxicities were reported. With extended follow-up, camrelizumab monotherapy continues to provide a robust and durable response, long survival and manageable safety in r/r cHL patients.
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http://dx.doi.org/10.1002/ijc.33852DOI Listing
October 2021

infection disturbs the tumor immune microenvironment and is associated with a discrepant prognosis in gastric de novo diffuse large B-cell lymphoma.

J Immunother Cancer 2021 10;9(10)

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, People's Republic of China

Background: Gastric diffuse large B-cell lymphoma (gDLBCL) related to infection exhibits a wide spectrum of prognosis, and the tumor immune microenvironment (TIME) affects tumor progression. However, there are few studies on the correlation between prognosis and changes of TIME induced by infection in de novo gDLBCL.

Methods: A retrospective study was performed to determine the prognostic value of TIME related to infection in de novo gDLBCL. A total of 252 patients were included and have been treated with standard rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy or other similar regimens in addition to eradication (HPE). All patients were stratified by infection, HPE efficacy, and preliminary TIME evaluation using conventional criteria. Statistical analyses were conducted. To assess the mechanism, 30 subjects were assessed for infection. The components and spatial distributions of TIME were analyzed.

Results: The median follow-up of the 252 patients was 66.6 months (range 0.7-119.2), and the 5-year overall survival (OS) was 78.0%. A total of 109 . positive cases with pathological complete remission and high tumor-infiltrating T lymphocytes (cohort 1) had significantly higher 5-year progression-free survival (88.1% vs 70.5%, p<0.001) and OS (89.2% vs 76.6%, p<0.001) than the other 143 patients (cohort 2). Among 30 patients, 19 were cytotoxin-associated gene A-marked as the cohort 1 subset. Compared with cohort 2, cohort 1 exhibited increased inflammatory factors (tumor necrosis factor-α, interferon γ, etc) and decreased immunosuppressive components (PD-L1, PD-1, IL-10, etc). There was reduced NF-kB activation. Cancer-promoting immune cells (PD-1hiTim-3+ CTL, Tregs, M2-like macrophages, etc) occupied a minor spatial distribution, while the antitumor subtypes increased, corresponding to favorable survival.

Conclusion: evoked inflammatory responses disturb the TIME, causing a differential prognosis in de novo gDLBCL, which can be used to identify patients who could benefit from HPE and immunochemotherapy.
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http://dx.doi.org/10.1136/jitc-2021-002947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515460PMC
October 2021

Tumor-associated macrophages increase COX-2 expression promoting endocrine resistance in breast cancer via the PI3K/Akt/mTOR pathway.

Neoplasma 2021 Sep 17;68(5):938-946. Epub 2021 Jun 17.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

Breast cancer is the most common malignancy in females. The emergence of endocrine resistance is frustrating for estrogen receptor (ER)-positive breast cancer patients even the efficacy of endocrine therapy is acceptable. Our previous study has shown that tumor-associated macrophages (TAMs) are associated with endocrine resistance, yet the mechanism remains unclear. This article is dedicated to discuss the role of TAMs in the endocrine resistance of breast cancer. It was found that tamoxifen-resistant MCF-7 cells induced more macrophages polarized into TAMs. Conversely, TAMs increased the expression of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), which promoted tamoxifen resistance through the activation of the PI3K/Akt/mTOR signaling pathway in MCF-7 cells. Furthermore, clinical analysis supported that five-year progression-free survival (PFS) of breast cancer patients with abundant COX-2 expression in TAMs was shorter (p<0.05). Therefore, these results show a positive feedback loop between TAMs and breast cancer cells, suggesting that TAMs and COX-2 may be new therapeutic targets for breast cancer patients suffering from endocrine resistance.
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http://dx.doi.org/10.4149/neo_2021_201226N1404DOI Listing
September 2021

Platelet lysate functionalized gelatin methacrylate microspheres for improving angiogenesis in endodontic regeneration.

Acta Biomater 2021 Dec 20;136:441-455. Epub 2021 Sep 20.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Chengdu Shiliankangjian Biotechnology Co., Ltd.. Electronic address:

Rapid angiogenesis is one of the challenges in endodontic regeneration. Recently, tailored polymeric microsphere system that loaded pro-angiogenic growth factors (GFs) is promising in facilitating vascularization in dental pulp regeneration. In addition, the synergistic effect of multiple GFs is considered more beneficial, but combination usage of them is rather complex and costly. Herein, we aimed to incorporate human platelet lysate (PL), a natural-derived pool of multiple GFs, into gelatin methacrylate (GelMA) microsphere system (GP), which was further modified by Laponite (GPL), a nanoclay with efficient drug delivery ability. These hybrid microspheres were successfully fabricated by electrostatic microdroplet technique with suitable size range (180∼380 µm). After incorporation of the PL and Laponite with GelMA, the Young's modulus of the hybrid hydrogel increased up to about 3-fold and the swelling and degradation rate decreased simultaneously. The PL-derived GFs continued to release up to 28 days from both the GP and GPL microspheres, while the latter released relatively more slowly. What's more, the released GFs could effectively induce tubule formation of human umbilical endothelial cells (HUVECs) and also promote human dental pulp stem cells (hDPSCs) migration. Additionally, the PL component in the GelMA microspheres significantly improved the proliferation, spreading, and odontogenic differentiation of the encapsulated hDPSCs. As further verified by the subcutaneous implantation results, both of the GP and GPL groups enhanced microvascular formation and pulp-like tissue regeneration. This work demonstrated that PL-incorporating GelMA microsphere system was a promising functional vehicle for promoting vascularized endodontic regeneration. STATEMENT OF SIGNIFICANCE: Polymeric microsphere system loaded with pro-angiogenic growth factors (GFs) shows great promise for regeneration of vascularized dental pulp. Herein, we prepared a functional GelMA microsphere system incorporated with human platelet lysates (PL) and nanoclay Laponite by the electrostatic microdroplet method. The results demonstrated that the GelMA/PL/Laponite microspheres significantly improved the spreading, proliferation, and odontogenic differentiation of the encapsulated hDPSCs compared with pure GelMA microspheres. Moreover, they also enhanced microvascular formation and pulp-like tissue regeneration in vivo. This hybrid microsphere system has great potential to accelerate microvessel formation in regenerated dental pulp and other tissues.
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http://dx.doi.org/10.1016/j.actbio.2021.09.024DOI Listing
December 2021

Comparison of combinations of irradiation techniques and jaw conditions in intensity-modulated radiotherapy for lung cancer.

J Appl Clin Med Phys 2021 Oct 10;22(10):178-189. Epub 2021 Sep 10.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Purpose: To assist in the selection of a suitable combination of an irradiation technique and jaw condition in intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc radiotherapy (VMAT) for lung cancer treatment plans.

Materials And Methods: Thirty patients with lung cancer who underwent radiotherapy were enrolled retrospectively. They were categorized as having central lung cancer, peripheral lung cancer with mediastinal lymph node metastasis (peripheral E lung cancer), and peripheral lung cancer without mediastinal lymph node metastasis (peripheral N lung cancer). Four treatment plans were designed for each patient: fixed jaw and adaptive jaw IMRT technique (FJ-IMRT and JA-IMRT), and fixed jaw and jaw tracking VMAT technique (FJ-VMAT and JT-VMAT). The dose parameters of the four group plans were compared and analyzed.

Results: Compared to FJ-IMRT, JA-IMRT significantly reduced the mean dose (D ) and volume percentage of 5 Gy (V ) of the total lung in central and peripheral N lung cancer. Similarly, compared to FJ-VMAT, JT-VMAT provided better protection to most organs at risk (OARs), particularly for total lung and heart. In comparison with IMRT, VMAT significantly improved the conformity index (CI) of the planning target volume for the three lung cancer classifications, and it reduced the dose of almost all OARs except V and D of the total lung. Moreover, the mean monitor units of the VMAT groups were far lower than the IMRT groups.

Conclusion: Based on the dosimetric findings and considering clinical data published on lung and heart side effects, we propose recommendations on the preferred treatment technique based on tumor location and pulmonary function. For central lung cancer with normal pulmonary function, we advise JT-VMAT techniques. Conversely, for central lung cancer with poor pulmonary function, we recommend JA-IMRT techniques. We advocate JA-IMRT for peripheral E lung cancer. For peripheral N lung cancer, JT-VMAT techniques are strongly recommended.
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http://dx.doi.org/10.1002/acm2.13416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504584PMC
October 2021

Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Oct 21;7(10):e213428. Epub 2021 Oct 21.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Importance: The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown.

Objective: To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs.

Design, Setting, And Participants: The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019.

Exposures: Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause.

Results: A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months).

Conclusions And Relevance: In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313051.
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http://dx.doi.org/10.1001/jamaoncol.2021.3428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391779PMC
October 2021

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Eur J Cancer 2021 10 18;156:35-45. Epub 2021 Aug 18.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. Electronic address:

Background: The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN.

Methods: Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC).

Results: Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40-0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50-0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients.

Conclusions: CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN.

Clinical Trial Registration Number: NCT02383966.
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http://dx.doi.org/10.1016/j.ejca.2021.06.039DOI Listing
October 2021

Bisphosphonates and breast cancer survival: a meta-analysis and trial sequential analysis of 81508 participants from 23 prospective epidemiological studies.

Aging (Albany NY) 2021 08 10;13(15):19835-19866. Epub 2021 Aug 10.

Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.

Background: We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment.

Methods: We performed a meta-analysis and trial sequential analysis (TSA) of prospective studies including randomized controlled trials (RCTs) and cohort studies. We performed extensive sensitivity analyses to assess the robustness of the findings.

Results: Seventeen RCTs and eight cohorts with 81508 BCa patients were identified. A significant beneficial effect of BPs on BCa survival was found (RR, 0.725; 95% CI, 0.627-0.839), and the TSA results also suggested firm evidence for this beneficial effect. Both summarized results from RCTs and cohorts provided firm evidence for this effect, although the effect estimates were stronger from cohorts than RCTs (RR, 0.892; 95% CI, 0.829-0.961; 0.570; 95% CI, 0.436-0.745; respectively). This beneficial effect was confirmed for bone-metastases (RR, 0.713; 95% CI, 0.602-0.843) and postmenopausal women (RR, 0.737; 95% CI, 0.640-0.850). Importantly, our results demonstrated that this beneficial effect was retained at least 1-2 years after treatment completion (RR, 0.780; 95% CI, 0.638-0.954) and could persist for up to more than 4 years after treatment completion (RR, 0.906; 95% CI, 0.832-0.987). Extensive sensitivity analyses showed the robustness of our results. The GRADE quality of evidence was generally judged to be moderate to high.

Conclusions: The present study provides firm evidence for a significant beneficial effect of BPs on BCa survival in patients with early-stage BCa, and this effect was retained at least 1-2 years after BP treatment completion.
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http://dx.doi.org/10.18632/aging.203395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386537PMC
August 2021

Caspase-3-mediated GSDME induced Pyroptosis in breast cancer cells through the ROS/JNK signalling pathway.

J Cell Mol Med 2021 09 8;25(17):8159-8168. Epub 2021 Aug 8.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.

Pyroptosis is a new form of programmed cell death generated by some inflammasomes, piloting the cleavage of gasdermin (GSDM) and stimulation of dormant cytokines like IL-18 and IL-1β; these reactions are narrowly linked to certain diseases like diabetic nephropathy and atherosclerosis. Doxorubicin, a typical anthracycline, and famous anticancer drug has emerged as a prominent medication in several cancer chemotherapies, although its application is accompanied with expending of dose-dependent, increasing, irreversible and continuing cardiotoxic side effects. However, the exact path that links the induced pyroptosis to the mechanism by which Doxorubicin (DOX) acts against breast cancer cells is still puzzling. The present study seeks to elucidate the potential link between DOX-induced cell death and pyroptosis in two human breast cancer cell lines (MDA-MB-231 and T47D). We proved that treatment with DOX reduced the cell viability in a dose-dependent way and induced pyroptosis morphology in MDA-MB-231 and T47D cells. Also, protein expression analyses revealed GSDME as a key regulator in DOX-induced pyroptosis and highlighted the related role of Caspase-3 activation. Furthermore, DOX treatments induced intracellular accumulation of ROS, stimulated the phosphorylation of JNK, and Caspase-3 activation, subsequently. In conclusion, the study suggests that GSDME triggered DOX-induced pyroptosis in the caspase-3 dependent reactions through the ROS/JNK signalling pathway. Additionally, it showed that the DOX-induced cardiotoxicity and pyroptosis in breast cancer cells can be minimized by reducing the protein level of GSDME; thus, these outcomes provide a new research target and implications for the anticancer investigations and therapeutic applications.
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http://dx.doi.org/10.1111/jcmm.16574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419174PMC
September 2021

Phase 1 studies comparing safety, tolerability, pharmacokinetics and pharmacodynamics of HLX01 (a rituximab biosimilar) to reference rituximab in Chinese patients with CD20-positive B-cell lymphoma.

Chin J Cancer Res 2021 Jun;33(3):405-416

Shanghai Henlius Biotech, Inc., Shanghai 200233, China.

Objective: This study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01 (a rituximab biosimilar) and reference rituximab sourced from China (MabThera; rituximab-CN).

Methods: Here we report the results of two phase 1 studies. In the phase 1a, open-label, dose-escalation study (NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity (DLT). In the phase 1b, double-blind study (NCT02584920, CTR20140764), eligible patients were given a single dose of 375 mg/m HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1a and the area under the plasma concentration-time curve from time zero to day 91 (AUC) for the phase 1b study. Equivalence was concluded if 90% confidence interval (90% CI) for the geometric least squares mean ratio (GLSMR) fell in the pre-specified equivalence criteria (80%-125%).

Results: Between June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events (AEs), discontinuations or DLTs. Between November 8, 2014 and August 13, 2015, 87 eligible patients were enrolled in the phase 1b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC being 89.6% (90% CI: 80.4%-99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups.

Conclusions: Treatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma. HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.03.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286892PMC
June 2021

Phase I Study and Pilot Efficacy Analysis of Entinostat, a Novel Histone Deacetylase Inhibitor, in Chinese Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer.

Target Oncol 2021 09 1;16(5):591-599. Epub 2021 Jul 1.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China.

Background: Previous clinical trials have demonstrated that entinostat in combination with exemestane had good tolerability and significant clinical efficacy in patients with advanced hormone receptor positive (HR+) and HER2 negative (HER2-) metastatic breast cancer (MBC) in the USA. However, no clinical trials have been conducted in Chinese populations.

Objective: To investigate the safety, pharmacokinetics, and pilot efficacy of entinostat with or without exemestane in Chinese postmenopausal patients with locally advanced or metastatic HR+ /HER2- MBC.

Patients And Methods: Nineteen patients received entinostat for 4 weeks (dose-limiting toxicity (DLT) observation stage) at 3, 5, or 7 mg/week, with a "3+3" dose-escalation design and in combination with exemestane thereafter (extended treatment stage: entinostat, 3 or 5 mg/week; exemestane, 25 mg/day). An additional 21 patients were enrolled to assess the entinostat (5 mg) plus exemestane (25 mg) pharmacokinetic profile and potential efficacy.

Results: The peak entinostat serum concentration and area under the curve increased dose proportionally, without significant interaction between entinostat and exemestane. Entinostat was well tolerated at all doses. The most common grade 3/4 adverse effects (AEs) included neutropenia (31.6%) and thrombocytopenia (15.8%). In the DLT observation stage, grade 3/4 AEs accounted for 16.7% in the 5 mg group with one suspicious DLT (G3 ventricular tachycardia) and 33.3% in the 7 mg group. In the extended treatment stage, 2/16 patients achieved partial response and three patients experienced stable disease (> 12 weeks). The median progression-free survival was 9.41 months for the additional 21 patients, who experienced grade 3/4 AEs of neutropenia (38%), thrombocytopenia (9.5%), anemia (9.5%), and fatigue (9.5%).

Conclusion: Entinostat with exemestane showed reasonable safety, tolerability, and encouraging efficacy in Chinese patients with HR+/HER2- MBC. These results support further evaluation in a randomized, double-blind Phase III study with a weekly 5 mg entinostat dose in a Chinese population.

Trial Registration: NCT02833155.
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http://dx.doi.org/10.1007/s11523-021-00823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484140PMC
September 2021

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

Adv Sci (Weinh) 2021 06 27;8(11):e2003732. Epub 2021 Mar 27.

Heifei National Laboratory for Physical Sciences at the Microscale of USTC, CAS Centre for Excellence in Molecular Cell Science, the First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, 230027, China.

Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1-mediated down-regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.
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http://dx.doi.org/10.1002/advs.202003732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188220PMC
June 2021

Sodium/glucose cotransporter 1-dependent metabolic alterations induce tamoxifen resistance in breast cancer by promoting macrophage M2 polarization.

Cell Death Dis 2021 05 18;12(6):509. Epub 2021 May 18.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, 150081, Heilongjiang, China.

Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive breast cancer, but tumors eventually develop resistance. However, endocrine therapy resistance mechanisms mediated through interactions between breast cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1α/signal transducer and activator of transcription-3 pathway. In turn, M2-like TAMs activate breast cancer cells through EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher expression of SGLT1 and CD163 TAMs was associated with endocrine-resistant ER-positive breast cancers. Our study identifies a novel vicious cycle of metabolic reprogramming, M2-like TAM polarization, and endocrine therapy resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to overcome endocrine therapy resistance in breast cancer.
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http://dx.doi.org/10.1038/s41419-021-03781-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131586PMC
May 2021

FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect.

Mol Ther 2021 09 1;29(9):2737-2753. Epub 2021 May 1.

Department of Cellular Engineering Lab, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address:

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.
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http://dx.doi.org/10.1016/j.ymthe.2021.04.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417517PMC
September 2021

Enhancing Fatty Acid Catabolism of Macrophages Within Aberrant Breast Cancer Tumor Microenvironment Can Re-establish Antitumor Function.

Front Cell Dev Biol 2021 15;9:665869. Epub 2021 Apr 15.

Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, China.

Triple-negative breast cancer (TNBC) remains an intractable challenge owing to its aggressive nature and lack of any known therapeutic targets. Macrophages play a crucial role in cancer promotion and poor prognosis within the tumor microenvironment (TME). The phagocytosis checkpoint in macrophages has broader implications for current cancer immunotherapeutic strategies. Here, we demonstrate the modulation in the antitumor activity of macrophages within the aberrant metabolic microenvironment of TNBC by metabolic intervention. The co-culture of macrophages with TNBC cell lines led to a decrease in both their phagocytic function and expression of interleukin (IL)-1β and inducible nitric oxide synthase (iNOS). The transcription of glycolysis and fatty acid (FA) catabolism-related factors was inhibited within the dysregulated tumor metabolic microenvironment. Enhancement of FA catabolism by treatment with the peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, fenofibrate (FF), could re-establish macrophages to gain their antineoplastic activity by activating the signal transducer and activator of transcription 1 (STAT1) signaling pathway and increasing ATP production by FA oxidation. The combination of fenofibrate and anti-CD47 therapy significantly inhibited tumor growth in a 4T1 tumor-bearing mouse model. In conclusion, the enhancement of FA catabolism of macrophages could re-establish them to resume antitumor activity in the TME. Anti-CD47 therapy combined with fenofibrate may serve as a novel and potential immunotherapeutic approach for the treatment of TNBC.
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http://dx.doi.org/10.3389/fcell.2021.665869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081981PMC
April 2021

LncRNA ST7-AS1 is a Potential Novel Biomarker and Correlated With Immune Infiltrates for Breast Cancer.

Front Mol Biosci 2021 12;8:604261. Epub 2021 Apr 12.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China.

Long noncoding RNA (lncRNA) ST7-AS1 can be observed in various cancers, but its role in breast cancer (BRC) remains unclear. Our aim is to, on the basis of The Cancer Genome Atlas (TCGA) database, prove the correlation between lncRNA ST7-AS1 and BRC. The lncRNA ST7-AS1 expression and its roles in the prognosis of BRC were explored using data from the TCGA database. The expression level of lncRNA ST7-AS1 in BRC samples was detected using RT-PCR. The 1-, 3-, or 5-year survival rate was predicted using a nomogram established through Cox proportional hazard regression. At last, the biological function was explored through gene ontology (GO) analysis and gene set enrichment analysis (GSEA). The hallmark pathways significantly involved in hub genes were described through functional enrichment analysis. The correlation between lncRNA ST7-AS1 expression and immune infiltration was analyzed through single-sample GSEA (ssGSEA). LncRNA ST7-AS1 expression was downregulated in BRC. Decreased lncRNA ST7-AS1 expression in BRC was correlated with advanced clinical pathologic characteristics (high grade, histological type, age, menopause status, and HER2 status), survival time, and poor prognosis. The nomogram was established for using lncRNA ST7-AS1 to predict 1-, 3-, or 5-year survival in patients with BRC. In addition, GO and pathway analyses suggested the involvement of lncRNA ST7-AS1 in cell cycle, DNA repair, and immune cell infiltration in the BRC immune microenvironment. We found the correlation of lncRNA ST7-AS1 with T helper cells and DC cells. Low expression of lncRNA ST7-AS1 indicates poor prognosis and has an impact on cell cycle, DNA repair, and proportion of infiltrating immune cells in the BRC microenvironment. Therefore, lncRNA ST7-AS1 can be used as a protective prognostic marker and a potential treatment target for BRC.
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http://dx.doi.org/10.3389/fmolb.2021.604261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075053PMC
April 2021

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 05 10;22(5):678-689. Epub 2021 Apr 10.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.

Background: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Methods: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing.

Findings: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.

Interpretation: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Funding: Bayer.
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http://dx.doi.org/10.1016/S1470-2045(21)00145-5DOI Listing
May 2021

Pharmacokinetics, safety, activity, and biomarker analysis of palbociclib plus letrozole as first-line treatment for ER+/HER2- advanced breast cancer in Chinese women.

Cancer Chemother Pharmacol 2021 07 9;88(1):131-141. Epub 2021 Apr 9.

Pfizer Inc, San Diego, CA, USA.

Purpose: This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China.

Methods: Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments.

Results: By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUC was 1217 and 2501 ng∙h/mL, and t was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed.

Conclusions: Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile.

Clinical Trial Registration: NCT02499146.
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http://dx.doi.org/10.1007/s00280-021-04263-9DOI Listing
July 2021

Risk factors for pegylated liposomal doxorubicin-induced moderate to severe hand-foot syndrome in breast cancer patients: assessment of baseline clinical parameters.

BMC Cancer 2021 Apr 7;21(1):362. Epub 2021 Apr 7.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.

Background: Hand-foot syndrome (HFS) is a side effect of skin related to pegylated liposomal doxorubicin (PLD) application. Moderate to severe hand-foot syndrome (MSHFS) might have a serious impact on patients' quality of life and treatment. However, information on risk factors for the development of MSHFS is still limited. To analyze the risk factors for PLD-induced MSHFS in breast cancer patients and constructed a logistic regression prediction model.

Methods: We conducted a retrospective analysis of breast cancer patients who were treated with a PLD regimen in the Tumor Hospital of Harbin Medical University from January 2017 to August 2019. A total of 26 factors were collected from electronic medical records. Patients were divided into MSHFS (HFS > grade 1) and NMHFS (HFS ≤ grade 1) groups according to the NCI classification. Statistical analysis of these factors and the construction of a logistic regression prediction model based on risk factors.

Results: A total of 44.7% (206/461) of patients developed MSHFS. The BMI, dose intensity, and baseline Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) levels in the MSHFS group, as well as good peripheral blood circulation, excessive sweat excretion, history of gallstones, and tumour- and HER2-positive percentages, were all higher than those in the NMHFS group (P < 0.05). The model for predicting the occurrence of MSHFS was P = 1/1 + exp. (11.138-0.110*BMI-0.234*dose intensity-0.018*baseline ALT+ 0.025*baseline AST-1.225*gallstone history-0.681* peripheral blood circulation-1.073*sweat excretion-0.364*with or without tumor-0.680*HER-2). The accuracy of the model was 72.5%, AUC = 0.791, and Hosmer-Lemeshow fit test P = 0.114 > 0.05.

Conclusions: Nearly half of the patients developed MSHFS. The constructed prediction model may be valuable for predicting the occurrence of MSHFS in patients.
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http://dx.doi.org/10.1186/s12885-021-08028-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025507PMC
April 2021

Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial.

BioDrugs 2021 May 7;35(3):337-350. Epub 2021 Apr 7.

Shanghai Henlius Biotech, Inc., Shanghai, China.

Background: HLX02 is an approved biosimilar of trastuzumab.

Objective: This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer.

Patients And Methods: This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication.

Results: Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of - 0.1% (95% CI - 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies.

Conclusions: Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab.

Clinical Trial Registration: Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017).
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http://dx.doi.org/10.1007/s40259-021-00475-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084805PMC
May 2021

Body Composition as a Predictor of Toxicity and Prognosis in Patients with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

Curr Oncol 2021 03 23;28(2):1325-1337. Epub 2021 Mar 23.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China.

Background: Our study measured the body composition of Diffuse large B-cell lymphoma (DLBCL) patients receiving rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen by computed tomographic (CT) and assessed their correlation with treatment-related toxicity and other adverse outcomes.

Methods: We retrospectively analyzed 201 DLBCL patients who underwent pre-treatment abdominal CT examination. CT images were used to assess body composition metrics at the third lumbar vertebrae including fat tissues and muscle. Based on the skeletal muscle area (SMA) and density (SMD), skeletal muscle index (SMI), skeletal muscle gauge (SMG = SMI × SMD) and lean body mass (LBM) were calculated. Also analyzed were the toxicity, adverse events and survival.

Results: We found that SMG, SMD, SMI and LBM were correlated with any grade 3-4 toxicity, dose reduction, hospitalization or termination of the treatment due to immunochemotherapy and worse survival. However, multivariate analysis demonstrated SMG [progression-free survival (PFS): hazard ratio (HR), 2.889; 95% CI, 1.401-5.959; = 0.004; overall survival (OS): HR, 2.655; 95% CI, 1.218-5.787; = 0.014] was the best predictor of poor prognosis.

Conclusions: SMG, SMD, SMI and LBM were identified as predictors of adverse reactions and poor survival. SMG was an innovative and valuable indicator of immunochemotherapy toxicity and other adverse outcomes. Additionally, it can be used to individualize antineoplastic drug dosing.
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http://dx.doi.org/10.3390/curroncol28020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025815PMC
March 2021

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy.

BMC Cancer 2021 Mar 31;21(1):341. Epub 2021 Mar 31.

Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

Background: To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents.

Methods: The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg.

Results: Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF.

Conclusion: The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial.

Trial Registration: ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).
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http://dx.doi.org/10.1186/s12885-021-08093-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010964PMC
March 2021

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

Adv Ther 2021 04 9;38(4):1889-1903. Epub 2021 Mar 9.

Hematology Department, Qilu Hospital of Shandong University, Jinan, China.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL).

Methods: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20) DLBCL randomly received IBI301 (375 mg/m) plus the standard CHOP or rituximab (375 mg/m) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin.

Results: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05).

Conclusions: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20 DLBCL.

Trial Registration: This trial is registered on ClinicalTrials.gov (NCT02867566).
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http://dx.doi.org/10.1007/s12325-020-01603-8DOI Listing
April 2021

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte.

Cancer Immunol Immunother 2021 Oct 10;70(10):2893-2909. Epub 2021 Mar 10.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, People's Republic of China.

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.
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http://dx.doi.org/10.1007/s00262-021-02898-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423647PMC
October 2021

ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2021 04 23;39(12):1317-1328. Epub 2021 Feb 23.

Division of Hematology, A.O.U. Città della Salute e della Scienza Hospital and University, Torino, Italy.

Purpose: Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.

Methods: Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.

Results: A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% 48%), anemia (22% 14%), thrombocytopenia (17% 11%), and leukopenia (14% 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.

Conclusion: ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
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http://dx.doi.org/10.1200/JCO.20.01366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078325PMC
April 2021
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