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Zhang X, Xiong B, Cheng Y, Huang J, Xue J, Li X, Lu W, Zhu J, Wang L, Yang W, Cheng Z. Berberine inhibits metastasis of ovarian cancer by blocking lipid metabolism, alleviating aging of adipose tissue and increasing tumor infiltrating immune cells. Transl Oncol 2025; 56:102380. [PMID: 40252400 PMCID: PMC12033994 DOI: 10.1016/j.tranon.2025.102380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/20/2025] [Accepted: 03/24/2025] [Indexed: 04/21/2025] Open
Abstract
Extensive peritoneal metastasis and malignant ascites continue to pose substantial challenges in achieving favorable treatment outcomes for ovarian cancer. Berberine (BBR), an active component of numerous traditional Chinese herbs, has demonstrated potent anti - tumor effects across various malignancies, including ovarian cancer. In this study, we comprehensively evaluated the impact of BBR on the growth and metastasis of ovarian cancer both in vitro and in vivo. RNA - sequencing was employed to elucidate the underlying mechanisms. Specifically, we investigated lipid metabolism and mitochondrial function in ovarian cancer cells and mice, comparing BBR - treated and untreated groups. Additionally, CIBERSORT analysis and immunohistochemical (IHC) staining were utilized to confirm BBR's ability to enhance the infiltration of tumor-infiltrating immune cells into adipose tissue and improve the inflammatory tumor microenvironment. Our findings indicate that BBR significantly inhibits the growth and metastasis of ovarian cancer in vitro and in vivo. The effects can be attributed to two key processes. Firstly, BBR suppresses the lipid metabolism by downregulating lipid uptake related receptor CD36, lipid metabolic enzyme and mitochondrial function. Secondly, BBR alleviates the aging of adipose tissue and adipose derived stem cells (ADSCs), thereby decreasing the secretion of senescence-associated secretory phenotype (SASP). These ultimately lead to the increasing the improvement of tumor infiltrating immune cells, such as CD4⁺ helper T cells (CD3⁺CD4⁺) and cytotoxic T lymphocytes (CD3⁺CD8⁺), and inflammation in ovarian cancer tissue. Collectively, these findings suggested a potential therapeutic effect of BBR in the treatment of advanced ovarian cancer, particularly cases complicated by peritoneal metastasis and malignant ascites.
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Affiliation(s)
- Xiaojie Zhang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Department of Gynecology, Jing'an District Hospital of Traditional Chinese Medicine, Shanghai, 200072, PR China; Continuous Education College, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, PR China
| | - Bing Xiong
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Yujie Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Jimei Huang
- Continuous Education College, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, PR China
| | - Jiaying Xue
- Department of Gynecology, Jing'an District Hospital of Traditional Chinese Medicine, Shanghai, 200072, PR China; Continuous Education College, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, PR China
| | - Xiao Li
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Wei Lu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Jihui Zhu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Lian Wang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China.
| | - Weihong Yang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China.
| | - Zhongping Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China.
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You B, Anderson C, Cecere SC, Carrot A, Myers T, Heitz F, Sharma S, Selçukbiricik F, Aghajanian C, Fernebro J, Blank S, Laudani ME, Thaker PH, Yunokawa M, Willmott L, Lisyanskaya A, Hegg R, He Y, Landen C, Lin YG, Alarcón J, Moore KN. Impact of adding the immune checkpoint inhibitor atezolizumab to first-line chemotherapy on progression-free survival in poor-prognosis ovarian cancer: A retrospective analysis from the IMagyn050 trial. Gynecol Oncol 2025; 197:66-73. [PMID: 40286540 DOI: 10.1016/j.ygyno.2025.04.577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 04/11/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Adding the anti-PD-L1 antibody atezolizumab to frontline chemotherapy-bevacizumab regimen did not improve progression-free survival (PFS) in ovarian cancer (OC) patients in IMagyn050 trial. This post-hoc analysis assessed the efficacy of atezolizumab in a subgroup of patients with particularly poor prognosis, as defined by the GCIG meta-analysis-characterized by a poor chemosensitivity and a suboptimal surgical resection. METHODOLOGY This analysis included 1199 evaluable participants with ≥3 available CA-125 concentrations, as required for KELIM score. The prognostic factors were identified through univariable and multivariable analyses. If both the KELIM score (unfavorable <1.0, vs favorable ≥1.0) and surgical outcome (suboptimal, vs optimal resection) demonstrated independent prognostic value, they were to be combined into prognostic subgroups. The PFS benefit of atezolizumab versus placebo was then evaluated within each of these defined subgroups. RESULTS Both the KELIM score and surgical outcome were independent prognostic factors. Combining these two parameters generated three distinct prognostic subgroups. In the poor prognosis subgroup (n = 269), defined by both an unfavorable KELIM score (<1.0) and suboptimal cytoreduction, the addition of atezolizumab was associated with a significantly longer median PFS compared to placebo (14.3 vs 11.3 months; HR 0.75, 95 % CI 0.59-0.95). This benefit was observed in both neoadjuvant and adjuvant settings. No significant PFS benefit was observed in the other prognostic subgroups. CONCLUSION The poor prognostic OC patient subgroup, may have an extension of PFS from treatment intensification with atezolizumab added to frontline chemotherapy-bevacizumab regimen. This hypothesis-generating outcome warrants further understanding on the added role of ICI in the frontline setting.
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Affiliation(s)
- Benoit You
- Lyon University Hospital, IC-HCL, CICLY, EPSILYON, CITOHL, Lyon University, Lyon, France; GINECO, Paris, France.
| | - Charles Anderson
- Willamette valley cancer institute and research center, Eugene, OR, USA
| | - Sabrina Chiara Cecere
- National Cancer Institute of Naples (IRCCS) Fondazione « G. Pascale », Naples, Italy
| | | | | | - Florian Heitz
- AGO Study Group and Ev. Kliniken Essen-Mitte, Essen, Germany; Charité - Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany
| | | | - Fatih Selçukbiricik
- Koç University Hospital, Koç University School of Medicine Department of Medical Oncology, Istanbul, Turkey
| | - Carol Aghajanian
- Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | | | - Stephanie Blank
- Icahn School of Medicine at Mount Sinai, New York, United States
| | | | - Premal H Thaker
- Washington University School of Medicine and Siteman Cancer Center, Saint Louis, MO, United States
| | - Mayu Yunokawa
- Japanese Foundation for Cancer Research, Cancer Institute Hospital of JFCR, Tokyo, Japan
| | | | - Alla Lisyanskaya
- St. Petersburg Oncology & Gynecology, City Clinical Oncology Dispensary, St Petersburg, Russia
| | - Roberto Hegg
- Perola Centro de Pesquisa em Oncologia, São Paulo, Brazil
| | - Yvette He
- Biometrics, Parexel International, Chengdu, China
| | - Charles Landen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, United States
| | | | | | - Kathleen N Moore
- University of Oklahoma Health Sciences Center, Oklahoma City, United States
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Brink GJ, Hami N, Mertens S, Nijman HW, van Lonkhuijzen LRCW, Roes EM, Lok CAR, de Kroon CD, Piek JMJ, Hofhuis W, Snippert HJG, Groeneweg JW, Witteveen PO, Zweemer RP. Response to Systemic Therapies in Patient-Derived Cell Lines from Primary and Recurrent Adult Granulosa Cell Tumors. Mol Cancer Ther 2025; 24:628-638. [PMID: 39600124 DOI: 10.1158/1535-7163.mct-24-0223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/08/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
In patients with the rare adult-type granulosa cell tumor (aGCT), surgery is the primary treatment for both primary and recurrent disease. In cases of inoperable disease, systematic therapy is administered, but variable response rates and drug resistance complicate predicting the most effective therapy. Drug screen testing on patient-derived cell lines may offer a solution. In a national prospective study on aGCT, fresh tissue was cultured into 2D cell lines, testing 27 clinical and experimental drugs. Dose-response curves and synergy were calculated using GraphPad Prism and CompuSyn software. We established 34 patient-derived cell lines from tissue of 20 patients with aGCT. Of these, seven patients had a primary diagnosis of aGCT and 13 patients had recurrent disease. In eight patients, multiple tumor locations were cultured. On each cell line, 10 monotherapies and 17 combinations of drugs were tested. Carboplatin/gemcitabine showed efficacy and synergy in almost all patient-derived cell lines. Synergy could not be detected in the regular carboplatin/paclitaxel and carboplatin/etoposide combinations. Experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Drug screens on patient-derived tumor cell lines reflect the reality of the variable response of systemic therapy in patients with aGCT. In future research, this technique may be used to personalize the systemic treatment of patients with aGCT in a clinical study. The good response to carboplatin/gemcitabine in our patient-derived cell lines can then be confirmed in a clinical setting.
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Affiliation(s)
- Geertruid J Brink
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Nizar Hami
- Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Sander Mertens
- Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hans W Nijman
- Department of Obstetrics and Gynecology, University Medical Center Groningen, Groningen, the Netherlands
| | - Luc R C W van Lonkhuijzen
- Department of Gynecological Oncology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Eva Maria Roes
- Department of Gynecologic Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Christine A R Lok
- Department of Gynecological Oncology, Center Gynaecologic Oncology Amsterdam, Amsterdam, the Netherlands
| | - Cornelis D de Kroon
- Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands
| | - Jurgen M J Piek
- Department of Obstetrics and Gynecology, Catharina Hospital, Eindhoven, the Netherlands
| | - Ward Hofhuis
- Department of Obstetrics and Gynecology, Franciscus Gasthuis en Vlietland, Rotterdam, the Netherlands
| | - Hugo J G Snippert
- Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jolijn W Groeneweg
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Petronella O Witteveen
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ronald P Zweemer
- Department of Gynecologic Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
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Nogueira Rodrigues A, Souto AKDBA, de Andrade DAP, Gomes LM, Koide SS, e Silva RDG, de Souza BB, Massaro JD, de Melo AC, Borges AM, Giro C, de Andrade CAV, da Costa CM, Gimenes DL, de Mello ECB, de Oliveira FC, Lima FMDT, Lopes GL, Bretas GDO, Jacob GG, Silva HLDC, Notaro JF, Alves LL, Moitinho MV, da Silva MC, Abramoff R, Rauber TADC, Dienstmann R, Koyama FC. Homologous recombination deficiency test validation in patients with high-grade advanced ovarian cancer. Front Mol Biosci 2025; 12:1524594. [PMID: 40007558 PMCID: PMC11850238 DOI: 10.3389/fmolb.2025.1524594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/07/2025] [Indexed: 02/27/2025] Open
Abstract
Background Along with BRCA mutation status, homologous recombination deficiency (HRD) testing is a prognostic and predictive biomarker for poly-ADP-ribose polymerase (PARP) inhibitor therapy indication in high-grade epithelial ovarian, fallopian tube, or peritoneal cancer. Approximately 50% of high-grade serous ovarian cancers exhibit HRD, even in the absence of germline or somatic BRCA1/2 loss-of-function mutations. In this scenario, access to a validated diagnostic HRD test can optimize treatment selection and increase the effectiveness of the intervention. Objective To technically validate an in-house next-generation sequencing (NGS)-based HRD test, QIAseq Custom Panel (QIAGEN), by comparing it with the reference assay, MyChoice CDx® Plus HRD (Myriad Genetics), which is used in routine care. Methods This is a prospective cohort study conducted at the Oncoclínicas Precision Medicine (OCPM) laboratory using samples from patients with advanced or relapsed platinum-sensitive ovarian cancer eligible for HRD testing in a diagnostic clinical setting at Oncoclínicas and Co. We assessed the performance of the in-house test (GS Focus HRD) using Cohen's kappa statistic to measure agreement with the gold standard assay (MyChoice® HRD Plus CDx) in HRD status classification, along with other accuracy metrics. Results In total, 41 samples were analyzed (20 HRD-positive, 19 HRD-negative, and 2 inconclusive results with the MyChoice® HRD Plus CDx assay). The GS Focus HRD test demonstrated high concordance for HRD status with the reference test (kappa: 0.8 and 95% CI: 0.60-0.98). Overall accuracy, sensitivity, and specificity were 90%. Six samples had BRCA1/2 mutations identified by the MyChoice® HRD Plus CDx, all of which were detected by the GS Focus HRD test. Conclusion In summary, the results demonstrate substantial agreement and high accuracy of the NGS-based GS Focus HRD test compared to MyChoice® HRD Plus CDx. Our in-house assay is eligible for diagnostic test approval and market access as per Brazilian regulations.
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Huang X, Huang Y, Liu K, Zhang F, Zhu Z, Xu K, Li P. Intratumoral and Peritumoral Radiomics for Predicting the Prognosis of High-grade Serous Ovarian Cancer Patients Receiving Platinum-Based Chemotherapy. Acad Radiol 2025; 32:877-887. [PMID: 39289095 DOI: 10.1016/j.acra.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/28/2024] [Accepted: 09/01/2024] [Indexed: 09/19/2024]
Abstract
RATIONALE AND OBJECTIVES This study aimed to develop a deep learning (DL) prognostic model to evaluate the significance of intra- and peritumoral radiomics in predicting outcomes for high-grade serous ovarian cancer (HGSOC) patients receiving platinum-based chemotherapy. MATERIALS AND METHODS A DL model was trained and validated on retrospectively collected unenhanced computed tomography (CT) scans from 474 patients at two institutions, which were divided into a training set (N = 362), an internal test set (N = 86), and an external test set (N = 26). The model incorporated tumor segmentation and peritumoral region analysis, using various input configurations: original tumor regions of interest (ROIs), ROI subregions, and ROIs expanded by 1 and 3 pixels. Model performance was assessed via hazard ratios (HRs) and receiver operating characteristic (ROC) curves. Patients were stratified into high- and low-risk groups on the basis of the training set's optimal cutoff value. RESULTS Among the input configurations, the model using an ROI with a 1-pixel peritumoral expansion achieved the highest predictive accuracy. The DL model exhibited robust performance for predicting progression-free survival, with HRs of 3.41 (95% CI: 2.85, 4.08; P < 0.001) in training set, 1.14 (95% CI: 1.03, 1.26; P = 0.012) in internal test set, and 1.32 (95% CI: 1.07, 1.63; P = 0.011) in external test set. KM survival analysis revealed significant differences between the high-risk and low-risk groups (P < 0.05). CONCLUSION The DL model effectively predicts survival outcomes in HGSOC patients receiving platinum-based chemotherapy, offering valuable insights for prognostic assessment and personalized treatment planning.
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Affiliation(s)
- Xiaoyu Huang
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China (X.H., K.L., F.Z., P.L.)
| | - Yong Huang
- Department of Medical Oncology, The Second People's Hospital of Hefei, Hefei, China (Y.H.)
| | - Kexin Liu
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China (X.H., K.L., F.Z., P.L.)
| | - Fenglin Zhang
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China (X.H., K.L., F.Z., P.L.)
| | - Zhou Zhu
- School of Internet, Anhui University, Hefei, China (Z.Z., K.X.)
| | - Kai Xu
- School of Internet, Anhui University, Hefei, China (Z.Z., K.X.)
| | - Ping Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China (X.H., K.L., F.Z., P.L.); Graduate School of Anhui University of Traditional Chinese Medicine, Hefei, China (P.L.).
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Jiang X, Yang M, Zhang W, Shi D, Li Y, He L, Huang S, Chen B, Chen X, Kong L, Pan Y, Deng P, Wang R, Ouyang Y, Chen X, Li J, Li Z, Zou H, Zhang Y, Song L. Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406688. [PMID: 39488790 DOI: 10.1002/advs.202406688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/29/2024] [Indexed: 11/04/2024]
Abstract
In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.
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Affiliation(s)
- Xingyu Jiang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Muwen Yang
- Department of Radiation Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China
| | - Weijing Zhang
- Department of Radiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Dongni Shi
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Lixin He
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Shumei Huang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Boyu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Xuwei Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Lingzhi Kong
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Yibing Pan
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Pinwei Deng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Rui Wang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Ying Ouyang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Xiangfu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Jun Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Zheng Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan, 650118, China
| | - Hequn Zou
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China
| | - Yanna Zhang
- Department of Gynecology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
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Ghisoni E, Morotti M, Sarivalasis A, Grimm AJ, Kandalaft L, Laniti DD, Coukos G. Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nat Rev Clin Oncol 2024; 21:801-817. [PMID: 39232212 DOI: 10.1038/s41571-024-00937-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 09/06/2024]
Abstract
Despite documented evidence that ovarian cancer cells express immune-checkpoint molecules, such as PD-1 and PD-L1, and of a positive correlation between the presence of tumour-infiltrating lymphocytes and favourable overall survival outcomes in patients with this tumour type, the results of trials testing immune-checkpoint inhibitors (ICIs) in these patients thus far have been disappointing. The lack of response to ICIs can be attributed to tumour heterogeneity as well as inherent or acquired resistance associated with the tumour microenvironment (TME). Understanding tumour immunobiology, discovering biomarkers for patient selection and establishing optimal treatment combinations remains the hope but also a key challenge for the future application of immunotherapy in ovarian cancer. In this Review, we summarize results from trials testing ICIs in patients with ovarian cancer. We propose the implementation of a systematic CD8+ T cell-based immunophenotypic classification of this malignancy, followed by discussions of the preclinical data providing the basis to treat such immunophenotypes with combination immunotherapies. We posit that the integration of an accurate TME immunophenotype characterization with genetic data can enable the design of tailored therapeutic approaches and improve patient recruitment in clinical trials. Lastly, we propose a roadmap incorporating tissue-based profiling to guide future trials testing adoptive cell therapy approaches and assess novel immunotherapy combinations while promoting collaborative research.
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Affiliation(s)
- Eleonora Ghisoni
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Matteo Morotti
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Apostolos Sarivalasis
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Alizée J Grimm
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - Lana Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Denarda Dangaj Laniti
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland
- Agora Cancer Research Center, Lausanne, Switzerland
| | - George Coukos
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL), Lausanne, Switzerland.
- Agora Cancer Research Center, Lausanne, Switzerland.
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Huang X, Huang Y, Liu K, Zhang F, Zhu Z, Xu K, Li P. Predicting prognosis for epithelial ovarian cancer patients receiving bevacizumab treatment with CT-based deep learning. NPJ Precis Oncol 2024; 8:202. [PMID: 39271912 PMCID: PMC11399346 DOI: 10.1038/s41698-024-00688-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model's performance was evaluated using Harrell's C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P < 0.001) and 8.16 in the internal test set (95% CI: 2.5, 26.8; P < 0.001). The multimodal model demonstrated a C-index of 0.76 in the internal test set and a C-index of 0.64 in the external test set. Comparative analysis against FIGO staging revealed an NRI of 0.06 (P < 0.001) for the multimodal model. The model presents opportunities for prognostic assessment, treatment strategizing, and ongoing patient monitoring.
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Affiliation(s)
- Xiaoyu Huang
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong Huang
- Department of Medical Oncology, The Second People's Hospital of Hefei, Hefei, China
| | - Kexin Liu
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fenglin Zhang
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhou Zhu
- Scholl of Internet, Anhui university, Hefei, China
| | - Kai Xu
- Scholl of Internet, Anhui university, Hefei, China.
| | - Ping Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
- Graduate School of Anhui University of Traditional Chinese Medicine, Hefei, China.
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9
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Kacperczyk-Bartnik J, El Hajj H, Bizzarri N, Bilir E, Zwimpfer TA, Strojna AN, Gasimli K, Angeles MA, Ghirardi V, Erfani H, Nikolova T, Theofanakis C, Tóth R, Ponce Sebastià J, Chiva L, Lorusso D. Best original research presented at the 25th European Congress on Gynaecological Oncology: best of ESGO 2024. Int J Gynecol Cancer 2024; 34:1324-1333. [PMID: 39032933 DOI: 10.1136/ijgc-2024-005844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 06/26/2024] [Indexed: 07/23/2024] Open
Abstract
The 'Best of ESGO 2024' article includes a selection of the most highly rated original research presented during the 25th Annual Congress of the European Society of Gynaecologic Oncology (ESGO), held in Barcelona, Spain, March 7-10, 2024. Of 1218 asbtracts submitted, 35 studies presented during the best oral sessions, mini oral sessions, best three minute presentations session, and young investigator session were selected by the ESGO abstract committee and the authors of the European Network of Young Gynae Oncologists (ENYGO). There was a strong focus on the surgical treatment of early stage cervical cancer and the management of advanced or recurrent gynecological cancers using induction therapy, immunotherapy, and maintenance therapy. With this work, ENYGO and ESGO aim to focus the attention of clinicians, scientists, patients, and all stakeholders interested in gynecologic oncology on research advances in the field.
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Affiliation(s)
| | - Houssein El Hajj
- Cancer Prevention Department, Center de Lutte Contre le Cancer Léon Bérard, Lyon, France
| | - Nicolò Bizzarri
- UOC Ginecologia Oncologica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Esra Bilir
- Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein-Campus Kiel, Kiel, Germany
- Department of Global Health, Koç University Graduate School of Health Sciences, Istanbul, Turkey
| | - Tibor Andrea Zwimpfer
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Gynecological Cancer Center, University Hospital Basel, Basel, Switzerland
| | | | - Khayal Gasimli
- Department of Obstetrics and Gynecology, JW Goethe Frankfurt University, Frankfurt am Main, Germany
| | - Martina Aida Angeles
- Gynecologic Oncology Unit, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Valentina Ghirardi
- UOC Ginecologia Oncologica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Hadi Erfani
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Tanja Nikolova
- Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany
| | - Charalampos Theofanakis
- Division of Gynecologic Oncology, 1st Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens School of Health Sciences, Athens, Greece
| | - Richard Tóth
- Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
| | - Jordi Ponce Sebastià
- Department of Gynecology, University Hospital of Bellvitge (IDIBELL), University of Barcelona, Barcelona, Spain
| | - Luis Chiva
- Gynecology and Obstetrics Department, Clinica Universidad de Navarra, Pamplona, Spain
| | - Domenica Lorusso
- Humanitas San Pio X Milan, Humanitas University Pieve Emanuele, Milan, Italy
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10
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He Q, Wan S, Jiang M, Li W, Zhang Y, Zhang L, Wu M, Lin J, Zou L, Hu Y. Exploring the therapeutic potential of tonic Chinese herbal medicine for gynecological disorders: An updated review. JOURNAL OF ETHNOPHARMACOLOGY 2024; 329:118144. [PMID: 38583732 DOI: 10.1016/j.jep.2024.118144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/19/2024] [Accepted: 04/01/2024] [Indexed: 04/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gynecological disorders have the characteristics of high incidence and recurrence rate, which sorely affects female's health. Since ancient times, traditional Chinese medicine (TCM), especially tonic medicine (TM), has been used to deal with gynecological disorders and has unique advantages in effectiveness and safety. AIM OF THE REVIEW In this article, we aim to summarize the research progress of TMs in-vivo and in-vitro, including their formulas, single herbs, and compounds, for gynecological disorders treatment in recent years, and to offer a reference for further research on the treatment of gynecological disorders and their clinical application in the treatment of TMs. MATERIALS AND METHODS Relevant information on the therapeutic potential of TMs against gynecological disorders was collected from several scientific databases including Web of Science, PubMed, CNKI, Google Scholar and other literature sources. RESULTS So far, there are 46 different formulas, 3 single herbs, and 24 compounds used in the treatment of various gynecological disorders such as premature ovarian failure, endometriosis breast cancer, and so on. Many experimental results have shown that TMs can regulate apoptosis, invasion, migration, oxidative stress, and the immune system. In addition, the effect of TMs in gynecological disorders treatment may be due to the regulation of VEGF, PI3K-AKT, MAPK, NF-κB, and other signaling pathways. Apparently, TMs play an active role in the treatment of gynecological disorders by regulating these signaling pathways. CONCLUSION TMs have a curative effect on the prevention and treatment of gynecological disorders. It could relieve and treat gynecological disorders through a variety of pathways. Therefore, the appropriate TM treatment program makes it more possible to treat gynecological disorders.
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Affiliation(s)
- Qizhi He
- School of Pharmacy, Zunyi Medical University, Guizhou, China; School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Shun Wan
- Hunan University of Chinese Medicine, Changsha, China
| | - Mingli Jiang
- School of Pharmacy, Zunyi Medical University, Guizhou, China
| | - Wei Li
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Yan Zhang
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Lele Zhang
- School of Preclinical Medicine, Chengdu University, Chengdu, China
| | - Mengyao Wu
- Department of Pharmacology, Zhuzhou Qianjin Pharmaceutical Co., Ltd., Zhuzhou, China
| | - Jie Lin
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, China
| | - Liang Zou
- School of Pharmacy, Zunyi Medical University, Guizhou, China; Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China.
| | - Yingfan Hu
- School of Preclinical Medicine, Chengdu University, Chengdu, China.
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11
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Ramachandran R, Nistor S, Gietzmann W, Symons N, Soleymani majd H. Radical total pelvic exenteration with concomitant right nephrectomy in the management of recurrent endometrioid ovarian adenocarcinoma: A case report and literature review. Clin Case Rep 2024; 12:e9148. [PMID: 38962465 PMCID: PMC11220455 DOI: 10.1002/ccr3.9148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/05/2024] [Accepted: 06/13/2024] [Indexed: 07/05/2024] Open
Abstract
Endometrioid ovarian adenocarcinoma is a common subtype of epithelial ovarian cancer that can arise on a background of endometriosis. Maximal cytoreductive effort with an aim to remove all macroscopic disease (achieve R0) is the single independent prognostic factor for survival. Complex multidisciplinary surgeries may be required in order to achieve this.
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Affiliation(s)
| | - Sabina Nistor
- Department of Gynaecology OncologyChurchill Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
| | - William Gietzmann
- Department of UrologyOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Nicholas Symons
- Department of Colorectal SurgeryOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Hooman Soleymani majd
- Department of Gynaecology OncologyChurchill Hospital, Oxford University Hospitals NHS Foundation TrustOxfordUK
- Nuffield Department of Women's and Reproductive HealthUniversity of OxfordOxfordUK
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12
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Tang L, Wang YJ, Wang YY, Li ST, Kong L, Li XT, Ma LL, Liu XX. Construction of ROS-Responsive Hyaluronic Acid Modified Paclitaxel and Diosgenin Liposomes and Study on Synergistic Enhancement of Anti-Ovarian Cancer Efficacy. Int J Nanomedicine 2024; 19:5193-5211. [PMID: 38859958 PMCID: PMC11162966 DOI: 10.2147/ijn.s455942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/23/2024] [Indexed: 06/12/2024] Open
Abstract
Purpose Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG2000-HA and DSPE-PEG2000-TK-PEG5000, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration. Methods and Results PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects. Conclusion The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.
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Affiliation(s)
- Ling Tang
- Department of Obstetrics and Gynecology, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China
| | - Yu-Jia Wang
- Department of Pharmacy, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China
| | - Yuan-Yuan Wang
- Department of Pharmacy, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China
| | - Shu-Tong Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China
| | - Liang Kong
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China
| | - Xue-Tao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China
| | - Ling-Ling Ma
- Department of Obstetrics and Gynecology, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China
| | - Xiu-Xiu Liu
- Department of Obstetrics and Gynecology, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China
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13
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Stiegeler N, Garsed DW, Au-Yeung G, Bowtell DDL, Heinzelmann-Schwarz V, Zwimpfer TA. Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group. Front Oncol 2024; 14:1387281. [PMID: 38894867 PMCID: PMC11183307 DOI: 10.3389/fonc.2024.1387281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 05/15/2024] [Indexed: 06/21/2024] Open
Abstract
Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.
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Affiliation(s)
| | - Dale W. Garsed
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - George Au-Yeung
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - David D. L. Bowtell
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | | | - Tibor A. Zwimpfer
- Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Department of Gynecological Oncology, University Hospital Basel, Basel, Switzerland
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14
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Fusegi A, Nomura H, Ueki A, Abe A, Kamata M, Misaka S, Aoki Y, Tanigawa T, Yunokawa M, Kanao H. Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis. J Obstet Gynaecol Res 2024; 50:1002-1009. [PMID: 38528763 DOI: 10.1111/jog.15935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 03/17/2024] [Indexed: 03/27/2024]
Abstract
AIM Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.
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Affiliation(s)
- Atsushi Fusegi
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hidetaka Nomura
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Arisa Ueki
- Department of Clinical Genetic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akiko Abe
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mayumi Kamata
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoki Misaka
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoichi Aoki
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Terumi Tanigawa
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mayu Yunokawa
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyuki Kanao
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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15
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Leung JH, Leung HWC, Wang SY, Yip Fion HT, Chan ALF. Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis. Medicine (Baltimore) 2024; 103:e38183. [PMID: 38788019 PMCID: PMC11124750 DOI: 10.1097/md.0000000000038183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/18/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. METHODS We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. RESULTS This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. CONCLUSIONS Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.
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Affiliation(s)
- John Hang Leung
- Department of Obstetrics and Gynecology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Henry W. C. Leung
- Department of Radiation Oncology, An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Shyh-Yau Wang
- Department of Radiation, An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Hei-Tung Yip Fion
- Department Management Office for Health Data, Clinical Trial Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Agnes L. F. Chan
- Department of Pharmacy, An-Nan Hospital, China Medical University, Tainan, Taiwan
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16
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Wang L, Xiong B, Lu W, Cheng Y, Zhu J, Ai G, Zhang X, Liu X, Cheng Z. Senolytic drugs dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer. Biomed Pharmacother 2024; 174:116474. [PMID: 38518604 DOI: 10.1016/j.biopha.2024.116474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 03/24/2024] Open
Abstract
Chemotherapy and targeted drugs-induced senescent ovarian cancer cells that accumulate in peritoneal adipose tissue contribute significantly to chronic inflammation, disrupt homeostasis, and may fuel various aspects of cancer progression. However, the pro-senescence effects of chemotherapy and targeted drugs on adipose derived stem cells (ADSCs) within peritoneal adipose tissue remain poorly understood. In this study, we show that the first-line chemotherapy and targeted drugs can induce the cellular senescence of ADSCs in vitro and increase the aging of peritoneal adipose tissue in vivo. These treatments significantly promoted the dysregulation of glucose and lipid metabolism, including insulin resistance and liver lipid accumulation. Our study shows that dasatinib and quercetin, as senolytics, effectively restore glucose homeostasis in mice with ovarian cancer and significantly reduce adipose tissue aging. Importantly, combining these drugs with Carboplatin or Olaparib results in a marked decrease in both peritoneal and adipose tissue metastasis of ovarian cancer cells. Mechanistically, we revealed that there is crosstalk between ovarian cancer cells and senescent ADSCs. The crosstalk increases inflammatory cytokines and chemokines production in ADSCs and notably upregulates chemokine receptors on cancer cells. Collectively, these data indicate that senescent ADSCs induced by chemotherapy and targeted therapy drugs impair adipose tissue function. However, the senolytic drugs dasatinib and quercetin, can significantly ameliorate organ aging and damage induced by these treatments. Notably, dasatinib and quercetin combined with Carboplatin or Olaparib reduced the peritoneal and adipose tissue metastasis of ovarian cancer, ultimately benefiting the mice undergoing chemotherapy and targeted therapy.
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Affiliation(s)
- Lian Wang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Tongji University, School of Medicine, Shanghai, China
| | - Bing Xiong
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Wei Lu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; School of medicine, Anhui University of Science and Technology, Huainan 232001, China
| | - Yujie Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; School of medicine, Anhui University of Science and Technology, Huainan 232001, China
| | - Jihui Zhu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Guihai Ai
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xiaojie Zhang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Gynecology, Jing'an District Hospital of Traditional Chinese Medicine, Shanghai 200072, China.
| | - Xiuni Liu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
| | - Zhongping Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Tongji University, School of Medicine, Shanghai, China; School of medicine, Anhui University of Science and Technology, Huainan 232001, China.
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17
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Kim JH, Kim SI, Park EY, Kim ET, Kim H, Kim S, Park SY, Lim MC. Comparison of survival outcomes between olaparib and niraparib maintenance therapy in BRCA-mutated, newly diagnosed advanced ovarian cancer. Gynecol Oncol 2024; 181:33-39. [PMID: 38104527 DOI: 10.1016/j.ygyno.2023.11.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/14/2023] [Accepted: 11/30/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION This multicenter retrospective cohort study aimed to compare survival outcomes and adverse events between maintenance therapy with two poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib and niraparib, in patients with BRCA-mutated, newly diagnosed advanced epithelial ovarian cancer (EOC) who responded to platinum-based chemotherapy. METHODS We enrolled stage III-IV EOC patients with germline and/or somatic BRCA1/2 mutations that had received maintenance therapy with olaparib or niraparib. A 3:1 propensity score matching was conducted using two variables: residual disease size and the presence of germline variants. The primary outcome was progression-free survival (PFS), and the secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and treatment-emergent adverse events (TEAEs). RESULTS In the propensity score-matched analysis, 80 patients who received olaparib and 31 patients who received niraparib were matched (3:1). In the propensity score-matched cohort, median PFS with olaparib vs. niraparib was not reached vs 31.5 months (HR, 1.08; 95% CI, 0.47-2.52; p = 0.854). The median TFST was not reached vs 31.8 months (HR, 1.20; 95% CI, 0.51-2.81; p = 0.682), and neither olaparib nor niraparib reached the median OS (HR, 0.42; 95% CI, 0.01-17.61; p = 0.649). In terms of the incidence rates of any-grade hematologic or non-hematologic TEAEs, higher rates of thrombocytopenia (p = 0.021) and neutropenia (p = 0.011) were observed in the niraparib group. CONCLUSION Advanced EOC patients with BRCA1/2 mutations exhibited no significant difference in OS between olaparib and niraparib, indicating the need to consider individualized strategies for selecting PARP inhibitors based on adverse event profiles.
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Affiliation(s)
- Ji Hyun Kim
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Se Ik Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Young Park
- Biostatistics Collaboration Team, Research Core Center, National Cancer Center, Goyang, South Korea
| | - Eun Taeg Kim
- Department of Obstetrics and Gynecology, Kosin University College of Medicine, Pusan, South Korea
| | - Hyesu Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sangeon Kim
- Rare &Paediatric Cancer Branch and Immuno-Oncology Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, Republic of Korea
| | - Sang-Yoon Park
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Myong Cheol Lim
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea; Rare &Paediatric Cancer Branch and Immuno-Oncology Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, Republic of Korea; Department of Cancer Control and Policy, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
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18
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Huang D, Ke L, Cui H, Li S, Sun F. Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials. BMC Womens Health 2024; 24:34. [PMID: 38218775 PMCID: PMC10788010 DOI: 10.1186/s12905-023-02879-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 12/31/2023] [Indexed: 01/15/2024] Open
Abstract
BACKGROUND Almost all patients with ovarian cancer will experience relapse and eventually develop platinum-resistant. The poor prognosis and limited treatment options have prompted the search for novel approaches in managing platinum-resistant ovarian cancer (PROC). Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of combination therapy with vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors for PROC. METHODS A comprehensive search of online databases was conducted to identify randomized clinical trials published until December 31, 2022. Pooled hazard ratios (HR) was calculated for overall survival (OS) and progression-free survival (PFS), while pooled odds ratio (OR) was calculated for objective response rate (ORR) and treatment-related adverse events (TRAEs). Subgroup analysis was further performed to investigate the source of heterogeneity. RESULTS In total, 1097 patients from eight randomized clinical trials were included in this meta-analysis. The pooled HRs of OS (HR = 0.72; 95% CI: 0.62-0.84, p < 0.0001) and PFS (HR = 0.52; 95% CI: 0.45-0.59, p < 0.0001) demonstrated a significant prolongation in the combination group compared to chemotherapy alone for PROC. In addition, combination therapy demonstrated a superior ORR compared to monotherapy (OR = 2.34; 95%CI: 1.27-4.32, p < 0.0001). Subgroup analysis indicated that the combination treatment of VEGF/VEGFR inhibitors and chemotherapy was significantly more effective than monochemotherapy in terms of OS (HR = 0.71; 95% CI: 0.61-0.84, p < 0.0001), PFS (HR = 0.49; 95% CI: 0.42-0.57, p < 0.0001), and ORR (OR = 2.97; 95% CI: 1.89-4.67, p < 0.0001). Although the combination therapy was associated with higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome compared to monochemotherapy, these toxicities were manageable and well-tolerated. CONCLUSIONS The meta-analysis demonstrated that combination therapy with VEGF/VEGFR inhibitors yielded better clinical outcomes for patients with PROC compared to monochemotherapy, especially when combined with chemotherapy. This analysis provides more treatment options for patients with PROC. SYSTEMATIC REVIEW REGISTRATION [ https://www.crd.york.ac.uk/PROSPERO ], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42023402050.
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Affiliation(s)
- Danxue Huang
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
| | - Liyuan Ke
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Hongxia Cui
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Su Li
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Feilong Sun
- Jiangsu Hengrui Pharmaceuticals Co., LTD, Lianyungang, China
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19
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Guo Y, Chen X, Tang X, Pan S, Zhu T, Zhang Y. Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer. Curr Cancer Drug Targets 2024; 24:733-748. [PMID: 38173064 DOI: 10.2174/0115680096271476231226174810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). METHODS This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). RESULTS Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. CONCLUSION Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.
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Affiliation(s)
- Yanglong Guo
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Xi Chen
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Xuedong Tang
- Department of Gynecologic Oncology, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, 314000, China
| | - Shan Pan
- Department of Gynecologic Oncology, Jiaxing Maternity and Child Health Care Hospital, Jiaxing, Zhejiang, 314000, China
| | - Tao Zhu
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Yingli Zhang
- Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
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20
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Zwimpfer TA, Scherer K, Schötzau A, Heinzelmann‐Schwarz V, Hartmann K, Vetter M, Montavon C. Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers. Cancer Med 2024; 13:e6840. [PMID: 38140783 PMCID: PMC10807606 DOI: 10.1002/cam4.6840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/29/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Exposure to paclitaxel and carboplatin has the risk of developing hypersensitivity reactions (HSRs), which could necessitate using less effective treatments to avoid anaphylaxis. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen; therefore, this study investigated rates and benefits of successful desensitization in patients with gynecologic cancers (GC). METHODS We collected data from 241 patients with GC who had at least one cycle of platinum or taxane chemotherapy. The rate of HSRs and successful desensitization were evaluated, and an outcome analysis was conducted. RESULTS The rate of HSRs to platinum and taxane was 6.39% and 13.07%, respectively. We observed a 100% success rate of desensitization in our cohort. Patients with HSR were significantly younger (57.1 vs. 64.9 years, p = 0.030) in the taxane cohort. Importantly, the overall survival (OS) of patients with platinum and taxane HSRs who underwent desensitization was comparable to that of patients with no HSRs (platinum vs. controls; median OS 60.36 vs. 60.39 months, p = 0.31; taxane vs. controls; OS 80.29 vs. 60.00 months, p = 0.59). CONCLUSION Thus, we show that desensitization for platinum and taxane HSRs is safe and effective, resulting in an outcome that is well comparable to patients without HSR. Based on these observations, desensitization procedures might be considered as standard of care before switching to less effective treatment for patients with GC.
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Affiliation(s)
- Tibor A. Zwimpfer
- Department of Gynecology and Gynecological Oncology, Hospital for WomenUniversity Hospital BaselBaselSwitzerland
- Gynecological Cancer CenterUniversity Hospital BaselBaselSwitzerland
- Peter MacCallum Cancer CenterEast MelbourneVictoriaAustralia
| | - Kathrin Scherer
- Division of Allergy Unit, Department of DermatologyCantonal Hospital AarauAarauSwitzerland
| | - Andreas Schötzau
- Department of Gynecology and Gynecological Oncology, Hospital for WomenUniversity Hospital BaselBaselSwitzerland
| | - Viola Heinzelmann‐Schwarz
- Department of Gynecology and Gynecological Oncology, Hospital for WomenUniversity Hospital BaselBaselSwitzerland
- Gynecological Cancer CenterUniversity Hospital BaselBaselSwitzerland
| | - Karin Hartmann
- Department of DermatologyUniversity Hospital BaselBaselSwitzerland
| | - Marcus Vetter
- Cancer Center, Cantonal Hospital BasellandMedical University ClinicLiestalSwitzerland
| | - Céline Montavon
- Department of Gynecology and Gynecological Oncology, Hospital for WomenUniversity Hospital BaselBaselSwitzerland
- Gynecological Cancer CenterUniversity Hospital BaselBaselSwitzerland
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21
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Kim JH, Kim SI, Park EY, Ha HI, Kim JW, Coleman RL, Bristow RE, Park SY, Fotopoulou C, Lim MC. Impact of postoperative residual disease on survival in epithelial ovarian cancer with consideration of recent frontline treatment advances: A systematic review and meta-analysis. Gynecol Oncol 2023; 179:24-32. [PMID: 39491079 DOI: 10.1016/j.ygyno.2023.10.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 11/05/2024]
Abstract
BACKGROUND Current treatment strategies for primary epithelial ovarian cancer (EOC) have significantly evolved, and the value of complete cytoreduction has not yet been reassessed. The study aimed to investigate the impact of residual disease after cytoreductive surgery for EOC on survival outcomes within the recent paradigm of frontline ovarian cancer treatment. METHODS We searched relevant literature from the MEDLINE, Embase, and Cochrane Library databases to identify randomized controlled trials and prospective clinical trials of primary EOC published between 1 January 2000 and 22 September 2022. To evaluate the impact of postoperative residual tumors on progression-free survival (PFS) and OS, we constructed a linear regression model for log-transformed median PFS and OS. Patients who did or did not receive first-line maintenance therapy were examined. RESULTS A total of 97 trials with 43,260 patients were included:2476 received poly(ADP-ribose) polymerase (PARP) inhibitors and 6587 received bevacizumab. Multivariable analysis of the linear regression model of all studies revealed that the median OS increased by 12.97% for every 10% increase in complete cytoreduction rates, independent of the use of systemic maintenance. In the subgroup analysis of patients receiving maintenance therapies, the effect of complete tumor clearance was potentiated, with a median OS increase of 19.13% for every 10% increase in complete cytoreduction rates. CONCLUSION Total macroscopic tumor clearance at the initial presentation of EOC significantly prolongs OS. Our results establish the importance of complete surgical cytoreduction, even after the introduction of recent advances in frontline treatment for EOC.
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Affiliation(s)
- Ji Hyun Kim
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Se Ik Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Young Park
- Biostatistics Collaboration Team, Research Core Center, National Cancer Center, Goyang, South Korea
| | - Hyeong In Ha
- Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Pusan, South Korea
| | - Jae-Weon Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Robert L Coleman
- Gynecologic Oncology, US Oncology Research, the Woodlands, TX 77380, USA
| | - Robert E Bristow
- Division of Gynecologic Oncology, Obstetrics and Gynecology, Irvine Medical Center, University of California, Orange, CA, USA
| | - Sang-Yoon Park
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea
| | | | - Myong Cheol Lim
- Center for Gynecologic Cancer, National Cancer Center, Goyang, Republic of Korea; Department of Cancer Control and Policy, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea; Rare & Paediatric Cancer Branch and Immuno-oncology Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, Republic of Korea.
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22
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Colombo N, Van Gorp T, Matulonis UA, Oaknin A, Grisham RN, Fleming GF, Olawaiye AB, Nguyen DD, Greenstein AE, Custodio JM, Pashova HI, Tudor IC, Lorusso D. Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study. J Clin Oncol 2023; 41:4779-4789. [PMID: 37364223 PMCID: PMC10602497 DOI: 10.1200/jco.22.02624] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 04/21/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
PURPOSE Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy. METHODS This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points. RESULTS A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 (P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events. CONCLUSION Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance (P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408).
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Affiliation(s)
- Nicoletta Colombo
- Gynecologic Oncology Program, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Medicine and Surgery, University Milan-Bicocca, Milan, Italy
| | - Toon Van Gorp
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium
| | | | - Ana Oaknin
- Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Rachel N. Grisham
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY
| | | | - Alexander B. Olawaiye
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | | | | | | | | | - Domenica Lorusso
- Fondazione Policlinico Universitario Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
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23
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Zhang X, Ding HM, Deng LF, Chen GC, Li J, He ZY, Fu L, Li JF, Jiang F, Zhang ZL, Li BY. Dietary fats and serum lipids in relation to the risk of ovarian cancer: a meta-analysis of observational studies. Front Nutr 2023; 10:1153986. [PMID: 37781114 PMCID: PMC10538548 DOI: 10.3389/fnut.2023.1153986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/24/2023] [Indexed: 10/03/2023] Open
Abstract
Although numerous epidemiological studies investigated the association between dietary fat intakes or serum lipid levels and ovarian cancer risk, a consistent and explicit conclusion for specific dietary fats or serum lipids that increase the risk of ovarian cancer is not available. In this study, a systematic review and meta-analysis were conducted to assess the key dietary fats and serum lipids that increased the risk of ovarian cancer. Databases such as PubMed, Web of Science, and EMBASE were searched for observational studies. A total of 41 studies met the inclusion criteria, including 18 cohort and 23 case-control studies (109,507 patients with ovarian cancer and 2,558,182 control/non-ovarian cancer participants). Higher dietary intakes of total fat (RR = 1.19, 95% CI = 1.06-1.33, I2 = 60.3%), cholesterol (RR = 1.14, 95% CI = 1.03-1.26, I2 = 19.4%), saturated fat (RR = 1.13, 95% CI = 1.04-1.22, I2 = 13.4%), and animal fat (RR = 1.21, 95% CI = 1.01-1.43, I2 = 70.5%) were significantly associated with a higher risk of ovarian cancer. A higher level of serum triglycerides was accompanied by a higher risk of ovarian cancer (RR = 1.33, 95% CI = 1.02-1.72, I2 = 89.3%). This meta-analysis indicated that a higher daily intake of total fat, saturated fat, animal fat, and cholesterol and higher levels of serum triglycerides were significantly associated with an increased risk of ovarian cancer.
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Affiliation(s)
- Xu Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Hong-Mei Ding
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Li-Feng Deng
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guo-Chong Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jie Li
- Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Ze-Yin He
- Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Li Fu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jia-Fu Li
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Fei Jiang
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Zeng-Li Zhang
- Department of Occupational and Environmental Health, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Bing-Yan Li
- Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow University, Suzhou, China
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Castellano G, Corti C, Boldrini L, Gervaso L, Criscitiello C, Curigliano G. Risk of thromboembolic events in patients with metastatic solid tumors treated with PARP inhibitors: A systematic review and meta-analysis of phase 3 randomized controlled trials. Cancer Treat Rev 2023; 119:102601. [PMID: 37473517 DOI: 10.1016/j.ctrv.2023.102601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 07/15/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND AND SCOPE Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized cancer treatment in recent years. These drugs present a favorable safety profile, even though the potential risk of thromboembolic events (TEs) during their use has not been addressed yet. In addition, PARPi have been involved in an active scientific debate regarding non-oncologic indications, particularly during the Coronavirus Disease 2019 pandemic, including potential anti-thromboembolic effect. METHODS To clarify whether patients treated with PARPi for metastatic solid tumors are either at increased or decreased risk of TEs, we conducted a systematic review of the literature and meta-analysis, including all phase 3 randomized controlled trials (RCTs) which investigated PARPi in this setting. Search was conducted through Medline, EMBASE, Pubmed, SCOPUS and Google Scholar in February 2023, including the proceedings of the principal oncology meetings of the last 10 years, with no time restriction. For each included study, frequencies of TEs in experimental and control arm were collected. RESULTS Our search identified 2,369 reports, of which 20 were lastly selected. A total of 4,946 patients were included, across 12 different RCTs. The meta-analysis did not demonstrate either an increased or a reduced risk in TEs in patients treated with PARPi for metastatic disease (OR 1.50, range: 1.00-2.24; 95% CI; P = 0.050), with low heterogeneity and low publication bias. CONCLUSION Although our research did not confirm either increased or decreased risk of TEs for PARPi use, no safety alerts emerged. Thromboembolic risk assessment models should always be integrated in daily clinical routine, to identify high-risk patients.
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Affiliation(s)
- Grazia Castellano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Chiara Corti
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy.
| | - Laura Boldrini
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Lorenzo Gervaso
- Division of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; Molecular Medicine Program, University of Pavia, Pavia, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
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25
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Hockings H, Lakatos E, Huang W, Mossner M, Khan MA, Metcalf S, Nicolini F, Smith K, Baker AM, Graham TA, Lockley M. Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.21.549688. [PMID: 37546942 PMCID: PMC10401956 DOI: 10.1101/2023.07.21.549688] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Drug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re-sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population size in vitro and significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer.
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Affiliation(s)
- Helen Hockings
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Eszter Lakatos
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Weini Huang
- School of Mathematical Sciences, Queen Mary University of London, London, UK
| | - Maximilian Mossner
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Mohammed Ateeb Khan
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Stephen Metcalf
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Francesco Nicolini
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Kane Smith
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Ann-Marie Baker
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Trevor A. Graham
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Michelle Lockley
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Xu K, Wang T, Pan S, He J. The efficacy and toxicity of mirvetuximab soravtansine, a novel antibody-drug conjugate, in the treatment of advanced or recurrent ovarian cancer: a meta-analysis. Expert Rev Clin Pharmacol 2023; 16:1141-1152. [PMID: 37771164 DOI: 10.1080/17512433.2023.2262673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023]
Abstract
INTRODUCTION This meta-analysis aims to systematically analyze the efficacy and toxicity of mirvetuximab soravtansine (MIRV) as second-line and above treatment for advanced or recurrent ovarian cancer. METHODS Candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases up to 1 May 2023. Objective response rate (ORR), progression-free survival (PFS), the incidence of adverse events (AEs), and incidence of grade ≥ 3 AEs were extracted and calculated by meta-analysis of merging ratios or mean to describe the efficacy and toxicity of MIRV. RESULTS Seven eligible prospective studies were included in this meta-analysis, including 605 patients with advanced ovarian cancer who received second-line or higher therapy. ORR of MIRV was 34.2% (95% confidence interval [CI] 25.0-43.5), and PFS was 5.82 months (95%CI 4.47-7.18). The overall incidence of AEs was 87.4% (95%CI 52.9-100.0) and the incidence of grade ≥ 3 AEs was 27.1% (95%CI 18.9-36.1). The most common AEs were vision blurring, nausea, and diarrhea, with incidence of 46.7% (39.6-53.8), 41.8% (34.0-49.9), and 41.3% (30.4-52.5), respectively. CONCLUSIONS MIRV has definite efficacy and good safety as a novel choice for second-line and above treatment of advanced or recurrent FRα positive ovarian cancer. This may have promising application in patients with platinum-resistant diseases. PROSPERO REGISTRATION NUMBER CRD42023428599.
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Affiliation(s)
- Ke Xu
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Oncology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Tianlei Wang
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shenbin Pan
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
| | - Jie He
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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Yoon WH, DeFazio A, Kasherman L. Immune checkpoint inhibitors in ovarian cancer: where do we go from here? CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:358-377. [PMID: 37457131 PMCID: PMC10344730 DOI: 10.20517/cdr.2023.13] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 05/22/2023] [Accepted: 05/31/2023] [Indexed: 07/18/2023]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.
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Affiliation(s)
- Won-Hee Yoon
- Department of Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown Hospital, Blacktown 2148, Australia
- Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
| | - Anna DeFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead 2145, Australia
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
- Department of Gynecological Oncology, Westmead Hospital, Westmead 2145, Australia
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council New South Wales, Sydney 2011, Australia
| | - Lawrence Kasherman
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
- Department of Medical Oncology, Illawarra Cancer Care Centre, Wollongong 2500, Australia
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Xue B, Wang X. Predictive value of PET metabolic parameters for occult lymph node metastases in PET/CT defined node-negative patients with advanced epithelial ovarian cancer. Sci Rep 2023; 13:9439. [PMID: 37296189 PMCID: PMC10256759 DOI: 10.1038/s41598-023-36640-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023] Open
Abstract
Accurate lymph node metastasis (LNM) prediction is crucial for patients with advanced epithelial ovarian cancer (AEOC) since it guides the decisions about lymphadenectomy. Previous studies have shown that occult lymph node metastasis (OLNM) is common in AEOC. The objective of our study is to quantitatively assess the probability of occult lymph node metastasis defined by 18F-Fluorodeoxyglucose PET/CT in AEOC and explore relationship between OLNM and PET metabolic parameters. The patients with pathologically confirmed AEOC who underwent PET/CT for preoperative staging at our institute were reviewed. Univariate and multivariate analysis were performed to evaluate the predictive value of PET/CT-related metabolic parameters for OLNM. The result of our study showed metastatic TLG index had a better diagnostic performance than other PET/CT-related metabolic parameters. Two variables were independently and significantly associated with OLNM in multivariate analysis: metastatic TLG index and primary tumor location. The logistic model combining metastatic TLG index, primary tumor location, and CA125 might be a promising tool to effectively predict the individualized possibility of OLNM for AEOC patients.
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Affiliation(s)
- Bing Xue
- Department of Nuclear Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Xihai Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Jian D, Lianghao Z, Yunge G, Ligang C, Biliang C, Xiaohui L. A Prognostic Model Based on Metabolism-Related Genes for Patients with Ovarian Cancer. DOKL BIOCHEM BIOPHYS 2023; 510:110-122. [PMID: 37582873 DOI: 10.1134/s1607672923600082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/03/2023] [Accepted: 03/09/2023] [Indexed: 08/17/2023]
Abstract
Metabolism-associated genes (MAGs) are important regulators of tumor progression and can affect a variety of physiological processes. In this study, we focused on the relationship between MAGs and Ovarian cancer (OC) prognosis. METHOD Metabolism-related genes were extracted from the Cancer Genome Atlas (TCGA) database. Through univariate COX and lasso regression models, a dynamic risk model based on MAGs was established. Compared with other clinical factors, demonstrated the ability of the model to predict the prognosis of patients with OC. The clinical samples were used to verify the expression of these MAGs. RESULTS A metabolism-associated gene signature was constructed by LASSO Cox regression analysis in OC, which was composed of 3-MAGs (PTGIS, AOC3, and IDO1). The signature was used to classify the OC patients into high-risk and low-risk groups. The overall survival of the low-risk group was significantly better than that of the high-risk group. The analysis of the therapeutic effect of bevacizumab showed that bevacizumab was not conducive to improving the prognosis of the low-risk group. CONCLUSIONS We constructed a prognostic model of MAGs in OC, which can be used to predict the prognosis of OC patients and may have a good guiding significance in the individualized treatment of patients.
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Affiliation(s)
- Dong Jian
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Zhai Lianghao
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Gao Yunge
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Chen Ligang
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Chen Biliang
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China
| | - Lv Xiaohui
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 710032, Shaanxi Xi'an, China.
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Liu X, Jin S, Zi D. Overall survival prediction models for gynecological endometrioid adenocarcinoma with squamous differentiation (GE-ASqD) using machine-learning algorithms. Sci Rep 2023; 13:8395. [PMID: 37225749 DOI: 10.1038/s41598-023-33748-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 04/18/2023] [Indexed: 05/26/2023] Open
Abstract
The actual 5-year survival rates for Gynecological Endometrioid Adenocarcinoma with Squamous Differentiation (GE-ASqD) are rarely reported. The purpose of this study was to evaluate how histological subtypes affected long-term survivors of GE-ASqD (> 5 years). We conducted a retrospective analysis of patients diagnosed GE-ASqD from the Surveillance, Epidemiology, and End Results database (2004-2015). In order to conduct the studies, we employed the chi-square test, univariate cox regression, and multivariate cox proportional hazards model. A total of 1131 patients with GE-ASqD were included in the survival study from 2004 to 2015 after applying the inclusion and exclusion criteria and the sample randomly split into a training set and a test set at a ratio of 7:3. Five machine learning algorithms were trained based on nine clinical variables to predict the 5-year overall survival. The AUC of the training group for the LR, Decision Tree, forest, Gbdt, and gbm algorithms were 0.809, 0.336, 0.841, 0.823, and 0.856 respectively. The AUC of the testing group was 0.779, 0.738, 0.753, 0.767 and 0.734, respectively. The calibration curves confirmed good performance of the five machine learning algorithms. Finally, five algorithms were combined to create a machine learning model that forecasts the 5-year overall survival rate of patients with GE-ASqD.
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Affiliation(s)
- Xiangmei Liu
- Guizhou Medical University, Guiyang, China
- Department of Gynecology and Obstetrics, Guizhou Provincial People's Hospital, Guiyang, China
| | - Shuai Jin
- School of Big Health, Guizhou Medical University, Guiyang, China
| | - Dan Zi
- Department of Gynecology and Obstetrics, Guizhou Provincial People's Hospital, Guiyang, China.
- Department of Gynecology and Obstetrics, The Affiliated People's Hospital of Guizhou Medical University, Guiyang, China.
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Sohn EJ, Kim JH, Oh SO, Kim JY. Regulation of self-renewal in ovarian cancer stem cells by fructose via chaperone-mediated autophagy. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166723. [PMID: 37087023 DOI: 10.1016/j.bbadis.2023.166723] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/24/2023]
Abstract
The chaperone-mediated autophagy (CMA) pathway is deregulated in different types of cancers; however, its role in cancer stem cells (CSCs) is unknown yet. Development of ovarian cancer, the most lethal gynecological type of cancer, involves the metastasis of CSCs to the abdominal cavity. This study aims to determine the role of CMA in ovarian CSCs. We found that the transcription factor EB (TFEB) and trehalose, a disaccharide that induces TFEB activation, enhance the expression of octamer-binding transcription factor 4 (OCT4) stem cell and lysosomal-associated membrane protein 2A (LAMP2A) CMA markers. However, trehalose did not increase the level of the LC3II macroautophagy marker in ovarian CSCs. In A2780 and SKOV3 ovarian CSCs, LAMP2A and heat shock protein 70 (HSC70) exhibited higher expression levels than in normal adherent cells. Our results showed that the silencing of the LAMP2A gene resulted in reduced sphere formation and enhanced GLUT5 expression in ovarian CSCs. Moreover, the treatment with fructose reduced sphere formation and enhanced the expression levels of LAMP2A, SOX2, and OCT4 in ovarian CSCs. The KEGG functional analysis revealed that differentially expressed genes were enriched in the ferroptosis pathway in A2780-spheroid (SP) cells after treatment with fructose. In A2780-SP and SKOV3-SP cells, the level of SLC7A11 decreased whereas FTH increased after treatment with fructose. Taken together, our results suggest that CMA is mediated in CSCs via fructose metabolism.
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Affiliation(s)
- Eun Jung Sohn
- College of Medicine, Pusan National University, Yangsan, Republic of Korea.; Inje University, 197 Injero, Gimhae 50834, Republic of Korea.
| | - Jae Ho Kim
- Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Sec-Ok Oh
- Department of Anatomy, School of Medicine, Yangsan, Republic of Korea; Korea School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Jin-Young Kim
- The School of Korean Medicine Pusan National University, Yangsan 50612, Republic of Korea; Korea Pusan National University, Yangsan, Republic of Korea
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Huang X, Huang Y, Li P. How do serum lipid levels change and influence progression-free survival in epithelial ovarian cancer patients receiving bevacizumab treatment? Front Oncol 2023; 13:1168996. [PMID: 37064140 PMCID: PMC10090393 DOI: 10.3389/fonc.2023.1168996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
BackgroundThis study aimed to investigate how serum lipid levels affect epithelial ovarian cancer (EOC) patients receiving bevacizumab treatment and to develop a model for predicting the patients’ prognosis.MethodsA total of 139 EOC patients receiving bevacizumab treatment were involved in this study. Statistical analysis was used to compare the median and average values of serum lipid level variables between the baseline and final follow-up. Additionally, a method based on machine learning was proposed to identify independent risk factors for estimating progression-free survival (PFS) in EOC patients receiving bevacizumab treatment. A PFS nomogram dividing the patients into low- and high-risk categories was created based on these independent prognostic variables. Finally, Kaplan–Meier curves and log-rank tests were utilized to perform survival analysis.ResultsAmong EOC patients involved in this study, statistical analysis of serum lipid level variables revealed a substantial increase in total cholesterol, triglycerides, apolipoprotein A1, and free fatty acids, and a significant decrease in apolipoprotein B from baseline to final follow-up. Our method identified FIGO stage, combined chemotherapy regimen, activated partial thromboplastin time, globulin, direct bilirubin, free fatty acids, blood urea nitrogen, high-density lipoprotein cholesterol, and triglycerides as risk factors. These risk factors were then included in our nomogram as independent predictors for EOC patients. PFS was substantially different between the low-risk group (total score < 298) and the high-risk group (total score ≥ 298) according to Kaplan–Meier curves (P < 0.05).ConclusionSerum lipid levels changed variously in EOC patients receiving bevacizumab treatment. A prediction model for PFS of EOC patients receiving bevacizumab treatment was constructed, and it can be beneficial in determining the prognosis, selecting a treatment plan, and monitoring these patients’ long-term care.
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Affiliation(s)
- Xiaoyu Huang
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Yong Huang
- Department of Medical Oncology, The Second People’s Hospital of Hefei, Hefei, China
| | - Ping Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Ping Li,
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Wang DF, Shi XW, Zhang C, Zhang J, Liu H, Huang JM, Zhang GN, Wen QL. Real-world applications of PARPi maintenance therapy for recurrent ovarian cancer: A single-center study in China. Gynecol Oncol 2023; 170:25-31. [PMID: 36608384 DOI: 10.1016/j.ygyno.2022.12.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/04/2022] [Accepted: 12/24/2022] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To assess the actual clinical application of poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) maintenance therapy in Chinese patients with recurrent ovarian cancer, and to explore prognostic factors associated with progression-free survival (PFS). METHODS We retrospectively assessed real-world clinical data from our hospital using the inclusion and exclusion criteria of representative randomized controlled trials, analyzed the prognosis, and performed univariate and multivariate analyses of prognostic factors. RESULTS Between 2019 and 2022, the proportion of platinum-sensitive recurrence ovarian cancer patients who received PARPi maintenance therapy increased to 29.6%, 53.3%, 43.8% and 62.2%, respectively, each year. A total of 48 patients were included in the prognostic analysis, of which 32 and 16 received olaparib and niraparib, respectively. Using the criteria of the Study19 and SOLO2 studies, the olaparib group in our patients had coincidence rates of 56.3% and 18.8%, respectively. Using the criteria of the NOVA and NORA studies, the niraparib group had coincidence rates of 31.3% and 37.5%, respectively. Median PFS was 26.1 months (95% CI 20.2-32.1). Response to primary therapy was an independent prognostic factor for PFS (relative risk, 3.248; 95% CI 1.081-9.757, P = 0.036). CONCLUSIONS PARPi maintenance therapy was also effective in real world applications. Complete response (CR) to primary therapy was an independent factor favorably affecting PFS. Therefore, primary treatment choices aimed at optimal cytoreduction during primary surgery and improving the CR rate should still be considered, which positively affects the long-term prognosis of patients in the new treatment mode.
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Affiliation(s)
- Deng-Feng Wang
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China; Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xun-Wei Shi
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China
| | - Can Zhang
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China
| | - Jie Zhang
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China
| | - Hong Liu
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China
| | - Jian-Ming Huang
- Department of Biochemistry & Molecular Biology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Chengdu 610041, China
| | - Guo-Nan Zhang
- Department of Gynecologic Oncology, the Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Cancer Hospital & Institute, Sichuan, Cancer Center, Chengdu 610041, China.
| | - Qing-Lian Wen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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Immunotherapeutic Approaches in Ovarian Cancer. Curr Issues Mol Biol 2023; 45:1233-1249. [PMID: 36826026 PMCID: PMC9955550 DOI: 10.3390/cimb45020081] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Ovarian cancer (OC) is gynecological cancer, and diagnosis and treatment are continuously advancing. Next-generation sequencing (NGS)-based diagnoses have emerged as novel methods for identifying molecules and pathways in cancer research. The NGS-based applications have expanded in OC research for early detection and identification of aberrant genes and dysregulation pathways, demonstrating comprehensive views of the entire transcriptome, such as fusion genes, genetic mutations, and gene expression profiling. Coinciding with advances in NGS-based diagnosis, treatment strategies for OC, such as molecular targeted therapy and immunotherapy, have also advanced. Immunotherapy is effective against many other cancers, and its efficacy against OC has also been demonstrated at the clinical phase. In this review, we describe several NGS-based applications for therapeutic targets of OC, and introduce current immunotherapeutic strategies, including vaccines, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cell transplantation, for effective diagnosis and treatment of OC.
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Guo L, Wang J, Li N, Cui J, Su Y. Peptides for diagnosis and treatment of ovarian cancer. Front Oncol 2023; 13:1135523. [PMID: 37213272 PMCID: PMC10196167 DOI: 10.3389/fonc.2023.1135523] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 04/24/2023] [Indexed: 05/23/2023] Open
Abstract
Ovarian cancer is the most deadly gynecologic malignancy, and its incidence is gradually increasing. Despite improvements after treatment, the results are unsatisfactory and survival rates are relatively low. Therefore, early diagnosis and effective treatment remain two major challenges. Peptides have received significant attention in the search for new diagnostic and therapeutic approaches. Radiolabeled peptides specifically bind to cancer cell surface receptors for diagnostic purposes, while differential peptides in bodily fluids can also be used as new diagnostic markers. In terms of treatment, peptides can exert cytotoxic effects directly or act as ligands for targeted drug delivery. Peptide-based vaccines are an effective approach for tumor immunotherapy and have achieved clinical benefit. In addition, several advantages of peptides, such as specific targeting, low immunogenicity, ease of synthesis and high biosafety, make peptides attractive alternative tools for the diagnosis and treatment of cancer, particularly ovarian cancer. In this review, we focus on the recent research progress regarding peptides in the diagnosis and treatment of ovarian cancer, and their potential applications in the clinical setting.
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Unresectable Ovarian Cancer Requires a Structured Plan of Action: A Prospective Cohort Study. Cancers (Basel) 2022; 15:cancers15010072. [PMID: 36612068 PMCID: PMC9817808 DOI: 10.3390/cancers15010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Patients with unresectable disease during cytoreductive surgery (CRS) for advanced-stage ovarian cancer are underreported. Knowledge of treatment and survival after surgery is limited. The aim of this study is to address the knowledge gap about postoperative treatment and survival of patients whose surgery was abandoned due to unresectability after abdominal exploration. METHODS Women with FIGO stage IIIB-IV epithelial ovarian cancer whose disease was considered to be unresectable during surgery were included in this prospective study, a post hoc analysis of the PlaComOv study. The unresectable disease was defined as the inability to achieve at least suboptimal CRS without attempted CRS after careful inspection of the entire abdomen. Preoperative clinical data, perioperative findings, postoperative treatment and survival data were analyzed. RESULTS From 2018 to 2020, 27 patients were included in this analysis. Treatment ranged from the cessation of treatment to one or several lines of chemotherapy with or without maintenance therapy. The median overall survival was 16 (IQR 5-21) months (95%CI 14-18). At 24 months of follow-up, four patients (15%) were alive. CONCLUSIONS This study indicated a two-year survival of 15%. Optimal treatment strategies in terms of survival benefits are still ill-defined. Further study of this specific group of patients is warranted. We advocate an (inter)national registry of patients with unresectable cancer and comprehensive follow-up.
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Grisham RN, Chui MH. Advancements in Low-Grade Serous Carcinoma of the Ovary and Peritoneum. Curr Oncol Rep 2022; 24:1549-1555. [PMID: 35962920 PMCID: PMC9613594 DOI: 10.1007/s11912-022-01315-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Low-grade serous ovarian cancer (LGSOC) is a rare form of epithelial ovarian cancer that generally exhibits a protracted course and is less sensitive to chemotherapy than high-grade serous ovarian cancer. Over the past decade, it has become clear that patients with LGSOC have a clinically distinct course and are molecularly and histologically unique from patients with high-grade serous ovarian cancer. RECENT FINDINGS Endocrine therapy is frequently used for the treatment of patients with recurrent LGSOC and is now also part of the standard upfront treatment of this disease, with an ongoing phase III clinical trial seeking to determine if chemotherapy can be eliminated altogether from the initial treatment of LGSOC. Tumors are frequently found to exhibit alterations affecting the mitogen-activated protein kinase (MAPK) pathway, recently leading to developments in the use of targeted treatments for those patients with recurrent disease. LGSOC is a clinically, histologically, and molecularly unique form of epithelial ovarian cancer. Recent advances in the understanding of endocrine and molecular drivers of this disease have led to changes in both the treatment of newly diagnosed and recurrent disease, with ongoing studies focused on refining upfront therapy and seeking novel targeted combinations for those patients with recurrent disease.
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Affiliation(s)
- Rachel N Grisham
- Gynecologic Medical Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
| | - M Herman Chui
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Manning-Geist B, Gordhandas S, Liu YL, Zhou Q, Iasonos A, Da Cruz Paula A, Mandelker D, Roche KL, Zivanovic O, Maio A, Kemel Y, Chi DS, O’Cearbhaill RE, Aghajanian C, Weigelt B, Chui MH, Grisham RN. MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma. Clin Cancer Res 2022; 28:4456-4465. [PMID: 35443055 PMCID: PMC9582036 DOI: 10.1158/1078-0432.ccr-21-4183] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/18/2022] [Accepted: 04/14/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). EXPERIMENTAL DESIGN Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. RESULTS Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. CONCLUSIONS This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357.
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Affiliation(s)
- Beryl Manning-Geist
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sushmita Gordhandas
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ying L. Liu
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qin Zhou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexia Iasonos
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arnaud Da Cruz Paula
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Diana Mandelker
- Diagnostic Molecular Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kara Long Roche
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Oliver Zivanovic
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Anna Maio
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Yelena Kemel
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Dennis S. Chi
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Roisin E. O’Cearbhaill
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Carol Aghajanian
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Britta Weigelt
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Herman Chui
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rachel N. Grisham
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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Wang N, Yang Y, Jin D, Zhang Z, Shen K, Yang J, Chen H, Zhao X, Yang L, Lu H. PARP inhibitor resistance in breast and gynecological cancer: Resistance mechanisms and combination therapy strategies. Front Pharmacol 2022; 13:967633. [PMID: 36091750 PMCID: PMC9455597 DOI: 10.3389/fphar.2022.967633] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/04/2022] [Indexed: 12/02/2022] Open
Abstract
Breast cancer and gynecological tumors seriously endanger women’s physical and mental health, fertility, and quality of life. Due to standardized surgical treatment, chemotherapy, and radiotherapy, the prognosis and overall survival of cancer patients have improved compared to earlier, but the management of advanced disease still faces great challenges. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been clinically approved for breast and gynecological cancer patients, significantly improving their quality of life, especially of patients with BRCA1/2 mutations. However, drug resistance faced by PARPi therapy has hindered its clinical promotion. Therefore, developing new drug strategies to resensitize cancers affecting women to PARPi therapy is the direction of our future research. Currently, the effects of PARPi in combination with other drugs to overcome drug resistance are being studied. In this article, we review the mechanisms of PARPi resistance and summarize the current combination of clinical trials that can improve its resistance, with a view to identify the best clinical treatment to save the lives of patients.
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Affiliation(s)
- Nannan Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Dongdong Jin
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou, China
| | - Zhenan Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Shen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanhuan Chen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyue Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Endometrial Disease Prevention and Treatment, Zhengzhou, China
- *Correspondence: Li Yang, ; Huaiwu Lu,
| | - Huaiwu Lu
- Department of Gynaecological Oncology, Sun Yat Sen Memorial Hospital, Guangzhou, China
- *Correspondence: Li Yang, ; Huaiwu Lu,
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Shu Y, Liu Y, He X, Ding Y, Zhang Q. Cost-effectiveness analysis of olaparib as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in china. Front Pharmacol 2022; 13:818579. [PMID: 36034834 PMCID: PMC9411944 DOI: 10.3389/fphar.2022.818579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 07/11/2022] [Indexed: 11/24/2022] Open
Abstract
Objective: The aim of this study was to investigate the cost-effectiveness of olaparib as the maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China. Methods: A Markov model was developed to simulate the clinical course of typical patients with ovarian cancer in the SOLO2 trial. The Weibull survival model was employed to fit the Kaplan–Meier progression-free survival and overall survival probabilities of the olaparib and placebo strategies, respectively. The clinical and direct costs data were derived from randomized clinical trials and published reports. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were estimated over a 10-year lifetime horizon. Meanwhile, one-way and probabilistic sensitivity analyses were used to explore the impact of uncertainty on the model’s outcomes. Results: Overall, the incremental effectiveness and cost of olaparib versus placebo were 0.56 QALYs and $43,292.92, respectively, resulting in an ICER of $77,620.56/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The results were sensitive to the cost of olaparib and utility of PFS. Scenario analyses suggested that when the cost of olaparib was reduced by 60%, ICER decreased to $30,611.52/QALY, lower than the WTP threshold of China. Conclusion: The findings from the present analysis suggest that olaparib with a 60% discount as maintenance therapy might be cost effective in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China.
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Affiliation(s)
- Yamin Shu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanxin Liu
- Department of Pharmacy, Pengzhou People’s Hospital, Pengzhou, China
| | - Xucheng He
- Department of Pharmacy, Pengzhou Second People’s Hospital, Pengzhou, China
| | - Yufeng Ding
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qilin Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Qilin Zhang,
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Xie W, Yu J, Yin Y, Zhang X, Zheng X, Wang X. OCT4 induces EMT and promotes ovarian cancer progression by regulating the PI3K/AKT/mTOR pathway. Front Oncol 2022; 12:876257. [PMID: 36033461 PMCID: PMC9399417 DOI: 10.3389/fonc.2022.876257] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022] Open
Abstract
Background Octamer-binding transcription factor 4 (OCT4) is a key stem cell transcription factor involved in the development of various cancers. The role of OCT4 in ovarian cancer (OC) progression and its molecular mechanism are not fully understood. Methods First, immunohistochemistry (IHC) assays of ovarian benign cyst tissues, OC tissues, and omental metastatic tissues were performed to reveal OCT4 expression profiles. We knocked down OCT4 in two OC cell lines (SKOV3 and A2780) using a lentiviral vector and performed in vitro and in vivo experiments. OCT4 was knocked down to assess the proliferation, migration, and invasion of OC cells using CCK-8, colony formation, wound healing, and Transwell assays. In addition, the nude tumor mouse model was used for in vivo study. Mechanistically, we demonstrated that OCT4 influenced protein expression in the phosphoinositol 3-kinase (PI3K)/AKT/mTOR pathway and epithelial-mesenchymal transition (EMT)-related proteins by Western blotting and immunofluorescence (IF) assays. The interaction between OCT4 and p-AKT was further confirmed by coimmunoprecipitation (CoIP) assays. Importantly, AKT activation by its activator SC79 reversed the biological functions of OCT4 knockdown. Results OCT4 expression was significantly upregulated in OC samples and metastatic tissues. OCT4 knockdown notably inhibited the proliferation, migration, and invasion of OC cells in vitro and in vivo. Moreover, the expression of p-PI3K, p-AKT, and p-mTOR was downregulated after OCT4 knockdown. An AKT agonist reversed the effect of OCT4 knockdown on OC cells. EMT in OC samples was enhanced by OCT4. Conclusions Our study shows that OCT4 promotes the proliferation, migration, and invasion of OC cells by participating in the PI3K/AKT/mTOR signaling axis, suggesting that it could serve as a potential therapeutic target for OC patients.
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Zhang J, He T, Yin Z, Shang C, Xue L, Guo H. Ascitic Senescent T Cells Are Linked to Chemoresistance in Patients With Advanced High-Grade Serous Ovarian Cancer. Front Oncol 2022; 12:864021. [PMID: 35875098 PMCID: PMC9301961 DOI: 10.3389/fonc.2022.864021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Senescent T cells are reported to be increased in patients with cancer and are poor prognostic indicators. However, the distribution of senescent T cells and their correlation with clinical features in high-grade serous ovarian cancer (HGSOC) is unknown. We detected the percentage of senescent T cells in the peripheral blood and ascites of patients with advanced HGSOC (n = 86) at diagnosis by flow cytometry. Compared with healthy donors, patients with HGSOC exhibited an accumulation of CD28−CD57+ (Tsen) CD8+ T cells in the peripheral blood and ascites. The frequency of Tsen CD8+ T cells in the peripheral blood was positively correlated with age and pretreatment serum CA125 and increased in patients with large volume ascites, whereas the frequency of Tsen CD8+ T cells in ascites was elevated in patients with lymph node metastasis. Patients with Tsen-high in ascites (>19.92%), but not in the peripheral blood, were more likely to be resistant to chemotherapy and had shorter progression-free survival. Tsen CD8+ T cells exhibited common senescence features including increased SA-β-gal activity, declines in proliferation, loss of CD27 and gain of KLRG-1, and the production of cytokines. In ascites, the percentage of Tsen CD8+ T cells was positively correlated with levels of interleukin-10 and granzyme B. This study suggests the potential of ascitic Tsen CD8+ T cells at diagnosis as a prognostic biomarker in HGSOC.
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Affiliation(s)
- Jie Zhang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Tianhui He
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Zhongnan Yin
- Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Chunliang Shang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Lixiang Xue
- Cancer Center, Peking University Third Hospital, Beijing, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- *Correspondence: Hongyan Guo, ; Lixiang Xue,
| | - Hongyan Guo
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- *Correspondence: Hongyan Guo, ; Lixiang Xue,
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Gao Q, Zhu J, Zhao W, Huang Y, An R, Zheng H, Qu P, Wang L, Zhou Q, Wang D, Lou G, Wang J, Wang K, Low J, Kong B, Rozita AM, Sen LC, Yin R, Xie X, Liu J, Sun W, Su J, Zhang C, Zang R, Ma D. Olaparib Maintenance Monotherapy in Asian Patients with Platinum-Sensitive Relapsed Ovarian Cancer: Phase III Trial (L-MOCA). Clin Cancer Res 2022; 28:2278-2285. [PMID: 35131903 PMCID: PMC9359747 DOI: 10.1158/1078-0432.ccr-21-3023] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/27/2021] [Accepted: 02/02/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE In patients with platinum-sensitive relapsed (PSR) ovarian cancer, olaparib maintenance monotherapy significantly improves progression-free survival (PFS) versus placebo. However, evidence in the Asian population is lacking. This is the first study to evaluate olaparib efficacy and tolerability exclusively in Asian patients with PSR ovarian cancer. PATIENTS AND METHODS Considering the limited placebo effect and significant clinical benefit of olaparib in previous trials, and the rapid approval of olaparib in China, this phase III study was designed as an open-label, single-arm trial. Patients with high-grade epithelial PSR ovarian cancer were enrolled from country-wide clinical centers across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. Primary endpoint was median PFS (mPFS). Primary analysis of PFS using the Kaplan-Meier method was performed when data reached 60% maturity (clinicaltrials.gov NCT03534453). RESULTS Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received ≥3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval ≤12 months. At primary data cut-off (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively. Adverse events (AE) occurred in 99.1% of patients (grade ≥3, 48.7%); 9.4% discontinued therapy due to treatment-related AEs. CONCLUSIONS Olaparib maintenance therapy was highly effective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. This study highlights the promising efficacy of olaparib in this Asian population. See related commentary by Nicum and Blagden, p. 2201.
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Affiliation(s)
- Qinglei Gao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Jianqing Zhu
- Department of Gynecologic Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Weidong Zhao
- Department of Gynecologic Oncology, Anhui Provincial Cancer Hospital, Hefei, China
| | - Yi Huang
- Department of Gynecologic Oncology, Hubei Cancer Hospital, Wuhan, China
| | - Ruifang An
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hong Zheng
- Department of Gynecology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital, Beijing, China
| | - Pengpeng Qu
- Department of Gynecology Oncology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Li Wang
- Department of Gynecologic Oncology, Affiliated Cancer Hospital of Zhengzhou University, (Henan Cancer Hospital), Zhengzhou, China
| | - Qi Zhou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Danbo Wang
- Department of Gynecologic Oncology, Liaoning Cancer Hospital, Shenyang, China
| | - Ge Lou
- Department of Gynecologic Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jing Wang
- Department of Gynecologic Oncology, Hunan Cancer Hospital, Changsha, China
| | - Ke Wang
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - John Low
- Cancer Centre @ PHKL, Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Abdul Malik Rozita
- Clinical Oncology Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Lim Chun Sen
- Oncology Department, Hospital Sultan Ismail, Johor Bahru, Malaysia
| | - Rutie Yin
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China
| | - Xing Xie
- Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jihong Liu
- Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wei Sun
- Department of Gynecologic Oncology, Anhui Provincial Cancer Hospital, Hefei, China
| | - Jingya Su
- Department of Medical Affairs, AstraZeneca, Shanghai, China
| | - Chunyi Zhang
- Department of Medical Affairs, AstraZeneca, Shanghai, China
| | - Rongyu Zang
- Department of Gynaecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ding Ma
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
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Wu W, Zhou S, Liu T, Liang D. Mitochondrial transcription factor B2 overexpression increases M2 macrophage infiltration via cytosolic mitochondrial DNA-stimulated Interleukin-6 secretion in ovarian cancer. Bioengineered 2022; 13:12211-12223. [PMID: 35577351 PMCID: PMC9275939 DOI: 10.1080/21655979.2022.2074615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Mitochondrial transcription factor B2 (TFB2M) is a protein modulating both mitochondrial DNA (mtDNA) transcription and compacting. In this study, we explored the expression profile of TFB2M in ovarian cancer, its association with infiltration of tumor-associated macrophages (TAMs), and its influence on macrophage polarization. Serial sections of ovarian cancer tissue arrays were stained to detect TFB2M and CD163 expression. Epithelial ovarian cancer cell line OVISE and CAOV4 were used to assess the influence of TFB2M on IL-6 expression. THP-1 cells were utilized as an in vitro model for macrophage migration and polarization. Results showed that higher TFB2M expression is associated with poor survival in ovarian cancer patients. IHC staining confirmed a moderately positive correlation between TFB2M expression and the infiltration of CD163-positive cells in 68 primary ovarian cancer cases. TFB2M overexpression was associated with increased mtDNA outside the mitochondria and elevated IL-6 expression in ovarian cancer cells. When cytosolic mtDNA was selectively inhibited by DNase I, TFB2M-induced IL-6 upregulation was canceled. TFB2M overexpression could activate the nuclear factor kappa-B (NF-κB) signaling pathway via promoting nucleus entry of p65 and p-p65, which was abrogated by inhibiting cytosolic mtDNA, TLR9, or NF-κB signaling pathway. Conditioned medium from OIVSE cells with TFB2M overexpression could induce macrophage migration and M2 polarization. However, these inducing effects were abrogated by DNase I, TLR9 inhibitor, and anti-IL-6 R pretreatment. In conclusion, this study showed a novel role of TFB2M in the immunosuppressive tumor microenvironment. It promotes M2 macrophage infiltration via a cytosolic mtDNA/TLR9/NF-κB/IL-6 pathway in ovarian cancer.
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Affiliation(s)
- Weilu Wu
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Shijie Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tianmin Liu
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Dongni Liang
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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Wang W, Cho U, Yoo A, Jung CL, Kim B, Kim H, Lee J, Jo H, Han Y, Song MH, Lee JO, Kim SI, Lee M, Ku JL, Lee C, Song YS. Wnt/β-Catenin Inhibition by CWP232291 as a Novel Therapeutic Strategy in Ovarian Cancer. Front Oncol 2022; 12:852260. [PMID: 35646632 PMCID: PMC9134752 DOI: 10.3389/fonc.2022.852260] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/08/2022] [Indexed: 11/30/2022] Open
Abstract
The poor prognosis of ovarian cancer patients mainly results from a lack of early diagnosis approaches and a high rate of relapse. Only a very modest improvement has been made in ovarian cancer patient survival with traditional treatments. More targeted therapies precisely matching each patient are strongly needed. The aberrant activation of Wnt/β-catenin signaling pathway plays a fundamental role in cancer development and progression in various types of cancer including ovarian cancer. Recent insight into this pathway has revealed the potential of targeting Wnt/β-catenin in ovarian cancer treatment. This study aims to investigate the effect of CWP232291, a small molecular Wnt/β-catenin inhibitor on ovarian cancer progression. Various in vitro, in vivo and ex vivo models are established for CWP232291 testing. Results show that CWP232291 could significantly attenuate ovarian cancer growth through inhibition of β-catenin. Noticeably, CWP232291 could also s suppress the growth of cisplatin-resistant cell lines and ovarian cancer patient-derived organoids. Overall, this study has firstly demonstrated the anti-tumor effect of CWP232291 in ovarian cancer and proposed Wnt/β-catenin pathway inhibition as a novel therapeutic strategy against ovarian cancer.
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Affiliation(s)
- Wenyu Wang
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Untack Cho
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Anna Yoo
- Drug Discovery Center, JW Pharmaceutical Corporation, Seoul, South Korea
| | - Chae-Lim Jung
- Drug Discovery Center, JW Pharmaceutical Corporation, Seoul, South Korea
| | - Boyun Kim
- Department of Biosafety, College of Life and Health Science, Kyungsung University, Busan, South Korea
| | - Heeyeon Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - Juwon Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - HyunA Jo
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - Youngjin Han
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Myoung-Hyun Song
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Ja-Oh Lee
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Se Ik Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
| | - Maria Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
| | - Ja-Lok Ku
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Cheol Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Yong Sang Song
- Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
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Maintenance Therapy with Aromatase Inhibitor in epithelial Ovarian Cancer (MATAO): study protocol of a randomized double-blinded placebo-controlled multi-center phase III Trial. BMC Cancer 2022; 22:508. [PMID: 35524184 PMCID: PMC9074273 DOI: 10.1186/s12885-022-09555-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/17/2022] [Indexed: 11/24/2022] Open
Abstract
Background A high percentage of epithelial ovarian cancers (EOC) express the estrogen receptor (ER), which is an ideal target for endocrine therapy. Letrozole is a proven, potent aromatase inhibitor, extensively tested and used in the treatment of ER positive breast cancer. In addition, it seems a potent drug for patients with heavily pre-treated OC as demonstrated in several distinctive settings. However, it has never been evaluated prospectively in a maintenance setting for ovarian cancer after standard of care. The here proposed trial aims to define a population of EOC patients, who would benefit from the effectiveness of the generic agent letrozole, with little expected toxicity and thus beneficial impact on overall quality of life (QoL). Methods In this international multicenter randomized, placebo-controlled phase III trial at clinical centers in Switzerland, Germany and Austria, we plan to include 540 patients with primary, newly diagnosed FIGO Stage II to IV and histologically confirmed low- or high-grade serous or endometrioid epithelial ovarian/fallopian tube/peritoneal cancer. Patients are randomized in a 1:1 ratio into two groups: receiving blinded study treatment (letrozole or placebo tablets). When assuming a HR of 0.7, a median PFS of 18 months in the control arm and a median PFS of 25.7 months in the treatment arm, a two-sided alpha level of 5%, 3.5 years recruitment and 1.5 years observation time, we expect 330 events to have occurred within these 5 years in the total cohort yielding a power of 90%. Follow-up data for the whole cohort will be collected for up to 10 years and for the low-grade cancer for up to 12 years. Discussion The here proposed randomized phase III trial aims to identify patients with EOC in the maintenance setting, who benefit from the effectiveness of the letrozole, by proving its efficacy whilst maintaining a high standard of QoL due to the limited toxicity expected in comparison to the current alternative drugs on the market for this treatment phase. Trial registration This trial is registered at clinicaltrials.gov under the identifier NCT04111978. Registered 02 October 2019. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09555-8.
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Bacry MC, Philippe AC, Riethmuller D, Faucheron JL, Pomel C. INTERVAL DEBULKING SURGERY AFTER NEOADJUVANT CHEMOTHERAPY IN ADVANCED OVARIAN CANCER - RETROSPECTIVE STUDY COMPARING SURGERY AFTER 3 CYCLES OR MORE OF CHEMOTHERAPY. J Gynecol Obstet Hum Reprod 2022; 51:102409. [DOI: 10.1016/j.jogoh.2022.102409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/22/2022] [Accepted: 05/12/2022] [Indexed: 10/18/2022]
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Grafodatskaya D, O'Rielly DD, Bedard K, Butcher DT, Howlett CJ, Lytwyn A, McCready E, Parboosingh J, Spriggs EL, Vaags AK, Stockley TL. Practice guidelines for BRCA1/2 tumour testing in ovarian cancer. J Med Genet 2022; 59:727-736. [PMID: 35393334 PMCID: PMC9340048 DOI: 10.1136/jmedgenet-2021-108238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 02/24/2022] [Indexed: 12/26/2022]
Abstract
The purpose of this document is to provide pre-analytical, analytical and post-analytical considerations and recommendations to Canadian clinical laboratories developing, validating and offering next-generation sequencing (NGS)-based BRCA1 and BRCA2 (BRCA1/2) tumour testing in ovarian cancers. This document was drafted by the members of the Canadian College of Medical Geneticists (CCMG) somatic BRCA Ad Hoc Working Group, and representatives from the Canadian Association of Pathologists. The document was circulated to the CCMG members for comment. Following incorporation of feedback, this document has been approved by the CCMG board of directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada; however, they are not inclusive of all information laboratories should consider in the validation and use of NGS for BRCA1/2 tumour testing in ovarian cancers.
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Affiliation(s)
- Daria Grafodatskaya
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Darren D O'Rielly
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.,Centre for Translational Genomes & Division of Genetics, Eastern Regional Health Authority, St. John's, Newfoundland, Canada
| | - Karine Bedard
- Département de Pathologie et Biologie cellulaire, Université de Montréal, Montreal, Québec, Canada.,Laboratoire de Diagnostic Moléculaire, Centre hospitalier de l'Université de Montréal, Montreal, Québec, Canada
| | - Darci T Butcher
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Christopher J Howlett
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Wester University, London, Ontario, Canada
| | - Alice Lytwyn
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Elizabeth McCready
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Jillian Parboosingh
- Department of Medical Genetics, Alberta Children's Hospital Research Institute for Child and Maternal Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Genetics and Genomics, Alberta Precision Laboratories, Calgary, Alberta, Canada
| | - Elizabeth L Spriggs
- Genomics, Diagnostic Services, Shared Health Manitoba, Winnipeg, Manitoba, Canada.,Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Andrea K Vaags
- Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Tracy L Stockley
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Department of Clinical Laboratory Genetics, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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Goenka L, Dubashi B, Selvarajan S, Ganesan P. Use of "Repurposed" Drugs in the Treatment of Epithelial Ovarian Cancer: A Systematic Review. Am J Clin Oncol 2022; 45:168-174. [PMID: 35320817 DOI: 10.1097/coc.0000000000000900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Epithelial ovarian cancer has poor outcomes with standard therapy and limited options for treatment of recurrent disease. This systematic review summarizes the data on the clinical use of repurposed drugs. We searched for clinical studies using "repurposed" agents for the treatment of ovarian cancer in the following databases: PubMed, clinicaltrials.gov, Clinical Trial Registry of India, European Clinical Trials Registry, and Chinese Clinical Trial Registry. We excluded reviews, preclinical studies, and non-English language studies. We assessed the quality of included studies. The following agents/class of agents were included: statins, hydroxychloroquine, metformin, itraconazole, nonsteroidal anti-inflammatory drugs, vitamin D, proton pump inhibitors, beta-blockers, and sodium valproate. Only one randomized controlled trial investigated metformin, which found no benefit of metformin. However, this had a high risk of bias (no details of randomization). Among the observational studies, 70% were of high quality (Newcastle-Ottawa scale ≥7). Clinical benefit was seen for itraconazole, beta-blockers, metformin, statins, and proton pump inhibitors. Though multiple studies aim to repurpose agents in epithelial ovarian cancer, the most published literature is observational, and none are practice-changing. Given the solid preclinical data regarding the anticancer efficacy of these agents, well-designed clinical trials are urgently required.
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Li Y, Zhang Y, Yang Q, Zhou X, Guo Y, Ding F, Liu Z, Luo A. Silencing of FANCI Promotes DNA Damage and Sensitizes Ovarian Cancer Cells to Carboplatin. Curr Cancer Drug Targets 2022; 22:591-602. [PMID: 35362384 DOI: 10.2174/1568009622666220331091709] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/31/2022] [Accepted: 02/25/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Ovarian cancer (OVCA) has unique epigenetic alterations and defects in homologous recombination (HR). Despite initial sensitivity to platinum-based chemotherapy, HR dysfunctional tumors eventually acquire drug resistance. Fanconi anemia (FA) is characterized by bone marrow failure (BMF) and a reduced ability to eradicate DNA interstrand cross-links (ICL). However, the mechanism of chemoresistance mediated by FANCI was unclear in OVCA. OBJECTIVE We explore to identify whether FANCI was involved in chemoresistance in OVCA. METHODS FANCI expression and epigenetic alterations were analyzed, respectively, using TIMER and cBioPortal. The correlation between FANCI expression and the survival of OVCA patients was analyzed using Kaplan-Meier Plotter, GSE63885 and TCGA-OVCA database. FANCI expression in OVCA was detected by immunohistochemistry. Cell proliferation, migration, and invasion in FANCI inhibiting cells were assessed by CCK8 and Transwell. Apoptosis and DNA damage were examined by flow cytometry and immunofluorescence. Meanwhile, the activity of caspase 3/7 was detected by Caspase-Glo® 3/7 kit. In addition, the expression of FANCI, γH2AX, and apoptosis effectors was examined by western blot. RESULTS FANCI has copy number variations (CNVs) in OVCA. The high expression of FANCI in OVCA patients was associated with poor survival. Moreover, FANCI expression was correlated with the response to chemotherapy in OVCA. FANCI expression in OVCA cells was induced by carboplatin in a time-dependent manner. Silencing of FANCI had no effect on cell proliferation, but it hindered OVCA cell migration and invasion. Mechanically, knockdown of FANCI enhanced DNA damage induced apoptosis through CHK1/2-P53-P21 pathway. CONCLUSION FANCI may be a potential therapeutic target for OVCA patients.
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Affiliation(s)
- Yuqing Li
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Yanan Zhang
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Qi Yang
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Xuantong Zhou
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Yuanyuan Guo
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Fang Ding
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Zhihua Liu
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
| | - Aiping Luo
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China
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