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7. Beyond clinical trials: CDK4/6 inhibitor efficacy predictors and nomogram model from real‐world evidence in metastatic breast cancer.

Author

Liu, Binliang, Hu, Zhe‐Yu, Xie, Ning, Liu, Liping, Li, Jing, Yang, Xiaohong, Xiao, Huawu, Zhao, Xuran, Tian, Can, Wu, Hui, Lu, Jun, Gao, Jianxiang, Hu, Xuming, Cao, Min, Shui, Zhengrong, Tang, Yu, and Ouyang, Quchang

Abstract

Background: CDK4/6 inhibitors (CDK4/6i) have shown promising results in the treatment of hormone receptor‐positive (HR+) metastatic breast cancer (MBC) when combined with endocrine therapy (ET). It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice, as well as to analyze the factors that can predict their outcomes. Methods: Patients with HR+ MBC who received CDK4/6i‐based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression‐free survival (PFS). Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria (version 5.0). Results: This study included 344 patients, with a median PFS (mPFS) of 12.8 months (range: 10.4–15.2 months). After adjustment, Cox multivariate regression analysis revealed that visceral metastasis (specifically liver and brain metastases), Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 1, estrogen receptor ≤ 80%, progesterone receptor ≤ 10%, Ki‐67 > 30%, and treatment in later stages were significant factors associated with reduced PFS. Based on this, we created a prognostic nomogram and validated its performance, obtaining a C‐index of 0.714 (95% confidence interval: 0.640–0.787) as well as reliable calibration and clinical impact. The mPFS of CDK4/6i rechallenge was 7.7 months; for patients who initially discontinued CDK4/6i for reasons other than disease progression, CDK4/6i rechallenge still provided a mPFS of 11.4 months. The tolerability and safety of combining CDK4/6is with ET were manageable. Adverse events led to treatment discontinuation in 3.8% of patients. Neutropenia (29.1%), leukopenia (13.7%), and anemia (4.1%) were the primary grade 3/4 adverse reactions. Conclusions: This real‐world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+ MBC. Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Circulating tumor DNA profile and its clinical significance in patients with hormone receptor-positive and HER2-negative mBC

Author

Tang, Yu, Li, Jing, Liu, Binliang, Ran, Jialu, Hu, Zhe-Yu, and Ouyang, Quchang

Subjects
Clinical Relevance, Class I Phosphatidylinositol 3-Kinases, Endocrinology, Diabetes and Metabolism, Biomarkers, Tumor, Humans, Female, Breast Neoplasms, Circulating Tumor DNA
Abstract

BackgroundAfter early-line (first- and second-line) endocrine therapy, hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (mBCs) become resistant to endocrine therapy. Genetic alterations may underlie resistance to endocrine therapies. This study aims to investigate the circulating tumor DNA (ctDNA) alterations and the clinical implication in hormone-receptor-positive, HER2-negative metastatic breast cancer patients with multiline endocrine therapy failure.MethodsThis registered study (NCT05079074, ClinicalTrials.gov) enrolled 104 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who progressed after the early-line endocrine therapy. ctDNA alterations were analyzed by next generation sequencing (NGS). ctDNA alterations were ranked and clustered by using R ‘ComplexHeatmap’ and ‘hclust’ function. ctDNA-guided therapy was administrated. Progression-free survival (PFS) was assessed COX regression analysis, and Kaplan-Meier curves were plotted.FindingsThe top ctDNA altered genes were TP53 (39%), PIK3CA (38%), BRCA1/2 (13%), ESR1 (12%), FGFR (11%), ERBB2 (11%), and GATA3 (9%). Among these genes, TP53, PIK3CA helix domain mutation (PIK3CA-HD), FGFR, ESR1 and GATA3 were related to endocrine therapy resistance. The genetic landscapes changed and tumor mutation burden increased in both TP53-altered and PIK3CA-altered patients. Both BRCA1/2 and ERBB2 alterations correlated with TP53 alterations (P=0.02 and P=0.04, respectively). However, while 93% BRCA1/2 alterations concentrated in PIK3CA-wildtype patients, 82% ERBB2 alterations concentrated in PIK3CA-altered patients. Kaplan–Meier curves showed that patients who received druggable ctDNA alteration-guided treatment (DDAT) had significantly longer PFS than those who received physician-chosen therapy, with median PFS of 6.1 months versus 4.6 months (hazard ratio = 0.53, 95% CI: 0.34-0.85, Logrank P = 0.006).ConclusionMultiple genetic alterations were important reasons for the failure of endocrine therapy for HR-positive and HER2-negative mBC. Targeting these genes might restore the treatment sensitivity and benefit survival.

Published
2022

16. Eribulin mesylate versus eribulin plus anlotinib in patients with advanced or metastatic breast cancer: Results of a phase II study.

Author

Liu, Liping, primary, Hu, Zhe-Yu, additional, Xie, Ning, additional, Yang, Xiaohong, additional, Xiao, Huawu, additional, Li, Jing, additional, Tian, Can, additional, Wu, Hui, additional, Lu, Jun, additional, Gao, Jianxiang, additional, Hu, Xuming, additional, Cao, Min, additional, Shui, Zhengrong, additional, Liu, Bingliang, additional, and Ouyang, Quchang, additional

Published
2022
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17. Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer

Author

Hu, Zhe-Yu, primary, Zheng, Chanjuan, additional, Yang, Jianbo, additional, Ding, Siyu, additional, Tian, Can, additional, Xie, Ning, additional, Xue, Lian, additional, Wu, Muyao, additional, Fu, Shujun, additional, Rao, Zhouzhou, additional, Price, Matthew A., additional, McCarthy, James B., additional, Ouyang, Quchang, additional, Lin, Jizhen, additional, and Deng, Xiyun, additional

Published
2022
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18. Impact of surgical management of primary tumors in stage IV breast cancer patients: a retrospective observational study based on SEER database

Author

Xie, Ning, primary, Hu, Xiaobo, additional, Tang, Yu, additional, Tian, Can, additional, He, Ying, additional, Hu, Zhe-Yu, additional, Hu, Chongyu, additional, Wang, Xiao, additional, Liu, Xiangyan, additional, Liu, Liping, additional, Xiao, Huawu, additional, Peng, Wei, additional, Zhou, Haoyu, additional, and Ouyang, Quchang, additional

Published
2022
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23. Abstract PS13-17: Capecitabine maintaining treatment improves progression-free survival in metastatic breast cancer: A prospective observational study of 669 cases

Author

Ouyang, Quchang, primary, Hu, Zhe-Yu, additional, Yang, Xiaohong, additional, Liu, Liping, additional, Li, Jing, additional, Xiao, Huawu, additional, Gao, Jianxiang, additional, Lu, Jun, additional, Wu, Hui, additional, Xie, Ning, additional, Hu, Xuming, additional, Tian, Can, additional, Shui, Zhengrong, additional, and Cao, Min, additional

Published
2021
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26. Treatment strategies of hospitalized patients with coronavirus disease-19

Author

Huang, Yaxiong, primary, Cai, Chunlin, additional, Zang, Jinglei, additional, Xie, Jun, additional, Xu, Dan, additional, Zheng, Fang, additional, Zhan, Tao, additional, Huang, Kang, additional, Wang, Yikai, additional, Wang, Xiao, additional, Hu, Zhe-Yu, additional, Deng, Yapeng, additional, and Xie, Yuanlin, additional

Published
2020
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28. PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies

Author

Tang, Yu, primary, Li, Jing, additional, Xie, Ning, additional, Yang, Xiaohong, additional, Liu, Liping, additional, Wu, Hui, additional, Tian, Can, additional, He, Ying, additional, Wang, Xiao, additional, He, Qiongzhi, additional, Hu, Zhe-Yu, additional, and Ouyang, Quchang, additional

Published
2020
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29. FGFR aberrations increase the risk of brain metastases and predict poor prognosis in metastatic breast cancer patients

Author

Xie, Ning, primary, Tian, Can, additional, Wu, Hui, additional, Yang, Xiaohong, additional, liu, Liping, additional, Li, Jing, additional, Xiao, Huawu, additional, Gao, Jianxiang, additional, Lu, Jun, additional, Hu, Xuming, additional, Cao, Min, additional, Shui, Zhengrong, additional, Tang, Yu, additional, Wang, Xiao, additional, Yang, Jianbo, additional, Hu, Zhe-Yu, additional, and Ouyang, Quchang, additional

Published
2020
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35. ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway

Author

Yang Dajun, Zhu Xiao-Feng, Sun Jian, Hu Zhe-Yu, and Zeng Yi-Xin

Subjects
Medicine
Abstract

Abstract Background apogossypolone (ApoG2) is a novel derivate of gossypol. We previously have reported that ApoG2 is a promising compound that kills nasopharyngeal carcinoma (NPC) cells by inhibiting the antiapoptotic function of Bcl-2 proteins. However, some researchers demonstrate that the antiproliferative effect of gossypol on breast cancer cells is mediated by induction of cell cycle arrest. So this study was aimed to investigate the effect of ApoG2 on cell cycle proliferation in NPC cells. Results We found that ApoG2 significantly suppressed the expression of c-Myc in NPC cells and induced arrest at the DNA synthesis (S) phase in a large percentage of NPC cells. Immunoblot analysis showed that expression of c-Myc protein was significantly downregulated by ApoG2 and that the expression of c-Myc's downstream molecules cyclin D1 and cyclin E were inhibited whereas p21 was induced. To further identify the cause-effect relationship between the suppression of c-Myc signaling pathway and induction of cell cycle arrest, the expression of c-Myc was interfered by siRNA. The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle. In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo. Conclusion Our findings indicated that ApoG2 could potently disturb the proliferation of NPC cells by suppressing c-Myc signaling pathway. This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy.

Published
2009
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37. The expression of p63 is associated with the differential stage in nasopharyngeal carcinoma and EBV infection

Author

Li Da-Jiang, Pan Zhi-Gang, Guo Can, Yun Jing-Ping, Zheng Mei-Zhen, Hu Zhe-Yu, Cheng Li-Zhen, and Zeng Yi-Xin

Subjects
Medicine
Abstract

Abstract Background Nasopharyngeal carcinoma (NPC) is common among Southern Chinese and the main histology is the undifferentiated carcinoma associated with Epstein-Barr virus (EBV) infection. p63 is a recently proved member of the p53 family based on the structural similarity to p53, but its function in NPC is still unknown. This study was aimed to investigate the association between p63 and NPC. Results p63 was expressed in 100%(202/202) of nasopharyngeal carcinoma (NPC) tissues but not in 29 nasopharynx inflammation and 17 non-cancerous nasopharyngeal epidermises on a tissue microarray by immunohistostaining. Further investigation suggested that the p63 expression was associated with the differential stage of NPC: p63 strong staining in Keratinizing squamous cell carcinoma, differentiated non-keratinizing NPC and undifferentiated non-keratinizing NPC presented the percentage of 5/8 (62.5%), 43/48 (92.5%) and 50/50 (100%), respectively. A significant difference (p = 0.001) existed between the keratinizing and non-keratinizing groups. No pathogenic mutations were detected in p63 gene in 12 primary NPC tissues and matched peripheral blood lymphocytes (PBL). Half-life measurement study revealed distinct stability of p63 protein in the different cell lines, especially between the carcinoma cell lines with EBV infection and the non-cancerous cell lines. The results of immunoprecipitation suggested a direct interaction between Epstein-Barr virus nuclear antigen 5 (EBNA-5) and p63 protein in NPC, and this binding would increase the stability of p63. Conclusion Our data suggested p63 might be used as an adjunct diagnostic marker of NPC and contributed a new way to understand the contribution of the EBV in the pathogenesis of NPC.

Published
2006
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38. Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast Cancer Patients with Multiline Resistance

Author

Hu, Zhe-Yu, primary, Xie, Ning, additional, Tian, Can, additional, Yang, Xiaohong, additional, Liu, Liping, additional, Li, Jing, additional, Xiao, Huawu, additional, Wu, Hui, additional, Lu, Jun, additional, Gao, Jianxiang, additional, Hu, Xuming, additional, Cao, Min, additional, Shui, Zhengrong, additional, Xiao, Mengjia, additional, Tang, Yu, additional, He, Qiongzhi, additional, Chang, Lianpeng, additional, Xia, Xuefeng, additional, Yi, Xin, additional, Liao, Qianjin, additional, and Ouyang, Quchang, additional

Published
2018
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42. ApoG2, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts

Author

Comprehensive Cancer Center and Departments of Internal Medicine, University of Michigan, Ann Arbor, MI ; Ascenta Therapeutics Incorporation, Malvern, PA ; Fax: +858-436-1201 ; Ascenta Therapeutics Incorporation, Malvern, PA, 19355, USA, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China ; Zhe-Yu Hu, Xiao-Feng Zhu and Zhen-Dong Zhong contributed equally to this work., State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China ; Fax: +86-20-8734-3295 ; Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China, Hu, Zhe-Yu, Zhu, Xiao-Feng, Zhong, Zhen-Dong, Sun, Jian, Wang, Jing, Yang, Dajun, Zeng, Yi-Xin, Comprehensive Cancer Center and Departments of Internal Medicine, University of Michigan, Ann Arbor, MI ; Ascenta Therapeutics Incorporation, Malvern, PA ; Fax: +858-436-1201 ; Ascenta Therapeutics Incorporation, Malvern, PA, 19355, USA, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China ; Zhe-Yu Hu, Xiao-Feng Zhu and Zhen-Dong Zhong contributed equally to this work., State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China ; Fax: +86-20-8734-3295 ; Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China, Hu, Zhe-Yu, Zhu, Xiao-Feng, Zhong, Zhen-Dong, Sun, Jian, Wang, Jing, Yang, Dajun, and Zeng, Yi-Xin

Abstract

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. It has been reported that overexpression of antiapoptotic Bcl-2 family proteins in NPC has caused the lack of long-term efficacy of conventional therapies. Apogossypolone (ApoG2), a novel small-molecule inhibitor of antiapoptotic Bcl-2 family proteins, has been discovered as the optimized derivative of gossypol. In this study, we found that in NPC cells, ApoG2 totally blocked the antiapoptotic function of Bcl-2 family proteins without affecting the expression levels of these proteins. ApoG2 selectively inhibited proliferation of 3 NPC cell lines (C666-1, CNE-1 and CNE-2) that highly expressed the antiapoptotic Bcl-2 proteins. This inhibitory activity was associated with release of cytochrome c, activation of caspase-9 and caspase-3 and apoptosis of sensitive NPC cells. However, ApoG2 had no obvious inhibitory effect on NPC cell line HONE-1, which expressed antiapoptotic Bcl-2 and Bcl-xL at a low level. We further found that ApoG2 effectively suppressed tumor growth of NPC xenografts in nude mice and enhanced the antitumor effect of CDDP (cisplatin) on NPC cells in vitro and in vivo . Immunohistochemical results showed that the expression of CD31 decreased after ApoG2 treatment, which suggested inhibition of angiogenesis in NPC xenografts. Our findings strongly suggest that ApoG2 may serve as a novel inhibitor of Bcl-2 family proteins and, by targeting these proteins, may become a promising drug for the treatment of NPC. ?? 2008 Wiley-Liss, Inc.

Published
2008

50. Apogossypolone inhibits cell growth by inducing cell cycle arrest in U937 cells.

Author

Sun J, Li ZM, Hu ZY, Zeng ZL, Yang DJ, and Jiang WQ

Subjects
Apoptosis drug effects, Caspase 3 metabolism, Cell Survival drug effects, Cyclin D1 metabolism, Cyclin E metabolism, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cytochromes c metabolism, Dose-Response Relationship, Drug, Gossypol pharmacology, Humans, Lymphoma metabolism, Mitochondria drug effects, Mitochondria metabolism, Proto-Oncogene Proteins c-myc metabolism, Time Factors, U937 Cells, Antineoplastic Agents pharmacology, Cell Cycle drug effects, Cell Proliferation drug effects, Gossypol analogs & derivatives, Lymphoma pathology
Abstract

We examined the effect of apogossypolone (ApoG2), a new derivative from gossypol on cell cycle regulation in U937 human leukemic monocyte lymphoma cells in vitro. ApoG2 decreased the viability of U937 cells by inducing G1 arrest followed by apoptosis in a dose-dependent manner. The G0/G1 phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the ApoG2-induced G1 arrest was mediated through the increased expression of Cdki proteins (p21cip1/waf1) with a simultaneous decrease in cdk2, cdk4, cyclin D1 and cyclin E expression. The induction of apoptosis after treatment with ApoG2 for 12, 24 and 48 h was demonstrated by flow cytometry analysis. ApoG2 also induced cytochrome c release and activation of caspase-3. To our knowledge, this is the first time that ApoG2 has been reported to potently inhibit the proliferation of human monocytic lymphoma U937 cells through G1 arrest. These findings suggest that ApoG2 may be a potential chemotherapeutic agent for the treatment of cancer.

Published
2009
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