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Shaik R, Mounika V, Begum S, Rajkumar A, Mallikarjun B, Sri Harshini V, Kolure R, Sreevani B, Thakur S. Monoclonal Antibodies in Clinical Trials for Breast Cancer Treatment. Monoclon Antib Immunodiagn Immunother 2025; 44:17-39. [PMID: 40171653 DOI: 10.1089/mab.2024.0018] [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] [Indexed: 04/04/2025] Open
Abstract
One of the most potent therapeutic and diagnostic agents in contemporary medicine is the monoclonal antibody (mAb). mAbs can perform a variety of tasks in breast cancer (BC), including identifying and delivering therapeutic medications to targets, preventing cell development, and suppressing immune system inhibitors including directly attacking cancer cells. mAbs are one of the most effective therapeutic options, particularly for HER2, but they have not been well studied for their use in treating other forms of BC, particularly triple negative breast tumors. Bispecific and trispecific mAbs have created new opportunities for more targeted specific efficacy, which has a positive impact on the viability of antigen specificity. They are more versatile and effective than other forms of treatment, emerging as most popular option for treating BC. However, mAbs have a limit in treatment due to certain adverse effects, including fever, shaking, exhaustion, headache, nausea, and vomiting, as well as rashes, bleeding, and difficulty breathing. To examine the current and prospective future capacities of mAbs with regard to the detection and treatment of BC, the present review highlights advantages and disadvantages of mAb approach.
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Affiliation(s)
- Rahaman Shaik
- School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India
| | - Varikuppala Mounika
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Shireen Begum
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Agolapu Rajkumar
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Bathurasi Mallikarjun
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Vollala Sri Harshini
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | - Rajini Kolure
- Department of Pharmacology, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
| | | | - Sneha Thakur
- Department of Pharmacognosy, St. Pauls College of Pharmacy, Turkayamjal, Hyderabad-501510, India
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Uekusa S, Nakashin M, Hanai Y, Nemoto M, Yanagino S, Arita Y, Matsumoto T, Wakui N, Nagai H, Higai K, Matsuo K. Risk factors for lenvatinib-induced hypertension in patients with hepatocellular carcinoma: A retrospective study. Br J Clin Pharmacol 2025; 91:894-902. [PMID: 39568177 PMCID: PMC11862797 DOI: 10.1111/bcp.16337] [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: 03/31/2024] [Revised: 10/11/2024] [Accepted: 10/20/2024] [Indexed: 11/22/2024] Open
Abstract
AIMS Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used to treat various cancers, including hepatocellular carcinoma (HCC). LEN therapy for HCC is associated with a high incidence of adverse events, including hypertension (HTN). However, the risk factors associated with LEN therapy remain unclear. This study investigated the incidence of LEN-induced HTN (LENiHTN), and the relationship between HTN incidence and patient demographics in patients with HCC receiving LEN therapy. METHODS This was a single-centre, retrospective study of patients with HCC who received LEN therapy between 19 April 2018 and 30 September 2020. The observation period was from 1 week before the start to 1 month after the end of LEN administration. RESULTS Seventy-five patients with HCC were enrolled. Any grade LENiHTN was found in 74.7% of patients. Among patients with LENiHTN, the use of 2 or more antihypertensive agents before starting LEN was less common (P = .007); serum potassium (K) and albumin-bilirubin score (ALBI) were lower (P = .013 and 0.038, respectively); and albumin (Alb) was higher (P = .025). The cut-off values of K, Alb and ALBI for HTN were estimated at 4.1 mEq L-1, 3.1 g dL-1 and -1.736, respectively. In the multivariable analysis, low K (adjusted HR: 2.078) and low ALBI (adjusted HR: 2.845) were independent risk factors for LENiHTN. CONCLUSION Low K, high Alb and low ALBI were independent risk factors for LENiHTN. Systematic evaluation of HTN risk and early intervention for HTN prevention among high-risk patients can markedly enhance LEN therapy efficacy and use.
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Affiliation(s)
- Shusuke Uekusa
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Misaki Nakashin
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Yuki Hanai
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
| | - Maho Nemoto
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
- Toho University Ohashi Medical CenterTokyoJapan
| | | | | | | | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori)School of Medicine, Faculty of MedicineTokyoJapan
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori)School of Medicine, Faculty of MedicineTokyoJapan
| | - Koji Higai
- Laboratory of Medical BiochemistryFaculty of Pharmaceutical Sciences Toho UniversityChibaJapan
| | - Kazuhiro Matsuo
- Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesToho UniversityChibaJapan
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Wongkraisri C, Chusuwanrak K, Laocharoenkeat A, Chularojanamontri L, Nimmannit A, Ithimakin S. Randomized controlled trial on the efficacy of topical urea-based cream in preventing capecitabine-associated hand-foot syndrome. BMC Cancer 2025; 25:275. [PMID: 39962445 PMCID: PMC11831840 DOI: 10.1186/s12885-025-13684-1] [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: 08/09/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Hand-foot syndrome (HFS) is a common adverse event of capecitabine causing treatment modifications. Topical urea cream can reduce sorafenib-induced hand-foot skin reaction. However, its benefit in preventing capecitabine-associated HFS was not seen early in the course and had been unknown with long-term use. The aim of this study was to evaluate the efficacy of urea cream for HFS prophylaxis throughout capecitabine treatment. METHODS Patients with cancer who received capecitabine were randomized (1:1) to receive usual care alone or in combination with urea-based cream. The incidence and degree of HFS were assessed at each capecitabine cycle. The primary endpoint was the proportion of patients with any grade HFS. The secondary endpoints included the proportion of patients with severe (≥ grade 3) HFS, modifications in capecitabine because of HFS, and HFS onset. RESULTS After a median of six capecitabine cycles, any grade HFS was reported by 68 of 109 patients (62.4%) who received usual care and by 60 of 107 patients (56%) who used urea cream (p = 0.36). The patients who received usual care and urea cream had similar proportions of grade 3 HFS occurrence [52 (47.7%) vs. 44 (41.1%), respectively, p = 0.34] and needed capecitabine modification because of HFS [20 patients (18.3%) vs. 17 patients (15.9%), respectively, p = 0.89], as well as similar HFS onset. CONCLUSIONS Urea-based cream did not prevent capecitabine-associated HFS, reduce capecitabine modification, and delay HFS onset. However, it had a tendency to lessen HFS severity, especially in the later cycles of capecitabine. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT05348278, registered on April 21, 2022.
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Affiliation(s)
- Concord Wongkraisri
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kriengkrai Chusuwanrak
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Leena Chularojanamontri
- Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Akarin Nimmannit
- Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suthinee Ithimakin
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Yu Y, Li NJ, Wang J. Long-term survival with pemetrexed-based chemotherapy in a patient with metastatic lung adenocarcinoma of unclear primary origin harboring MTHFR C677T(T/T) mutation: a case report. Front Oncol 2025; 14:1435357. [PMID: 39906671 PMCID: PMC11790433 DOI: 10.3389/fonc.2024.1435357] [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: 05/20/2024] [Accepted: 12/16/2024] [Indexed: 02/06/2025] Open
Abstract
This case report presents a patient with metastatic adenocarcinoma of unclear primary focus at initial presentation and revealed lung adenocarcinoma in subsequent follow-up. The patient has been surviving for more than 10 years after pemetrexed-based treatment and local radiotherapy. Sequential gene tests showed kirsten rat sarcoma viral oncogene homolog (KRAS) G13D mutation and epidermal growth factor receptor (EGFR) 19ins. To further investigate the correlation between pemetrexed efficacy and genetic polymorphisms, genotyping tests on folate-metabolism-related genes [methylenetetrahydrofolate reductase (MTHFR) (C677T) and MTHFR (A1298C)] were performed, revealing that the patient exhibited the T/T genotype for MTHFR (C677T) and the A/A genotype for MTHFR (A1298C). The clinical data and gene analysis were discussed with literature review to explain the underlying explanation for the long survival.
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Affiliation(s)
- Yuan Yu
- Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- West China Medical School, Sichuan University, Chengdu, Sichuan, China
- West China Biomedical Big Data Center, Sichuan University, Chengdu, Sichuan, China
| | - Nan-Jing Li
- Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- West China Medical School, Sichuan University, Chengdu, Sichuan, China
- West China Biomedical Big Data Center, Sichuan University, Chengdu, Sichuan, China
- Division of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Wang
- Division of Thoracic Tumor Multimodality Treatment and Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- West China Medical School, Sichuan University, Chengdu, Sichuan, China
- West China Biomedical Big Data Center, Sichuan University, Chengdu, Sichuan, China
- Division of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Agrawal S, Lee C, Pierce WF, Everhart E, King-Ducre A, Royce M, Osgood CL, Amiri-Kordestani L, Chiu HJ, Ricks TK, Pan L, Fourie Zirkelbach J, Charlab R, Pacanowski M, Kim T, Pazdur R, Kluetz PG, Gao JJ. FDA Approval Summary: Capecitabine Labeling Update under Project Renewal. Clin Cancer Res 2024; 30:5508-5514. [PMID: 39377782 DOI: 10.1158/1078-0432.ccr-24-1708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/20/2024] [Accepted: 10/07/2024] [Indexed: 10/09/2024]
Abstract
On December 14, 2022, the FDA approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.
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Affiliation(s)
- Sundeep Agrawal
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Clara Lee
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - William F Pierce
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Elizabeth Everhart
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Adriene King-Ducre
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Melanie Royce
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Christy L Osgood
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Laleh Amiri-Kordestani
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Haw-Jyh Chiu
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Tiffany K Ricks
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Lili Pan
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Jeanne Fourie Zirkelbach
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Rosane Charlab
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Michael Pacanowski
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Tamy Kim
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Richard Pazdur
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Paul G Kluetz
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Jennifer J Gao
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, Maryland
- Oncology Center of Excellence (OCE), U.S. Food and Drug Administration, Silver Spring, Maryland
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Xiuli N, Hua C, Peng G, Hairong Y, Meili S, Peng Y. Feasibility of an artificial intelligence system for tumor response evaluation. BMC Med Imaging 2024; 24:280. [PMID: 39425045 PMCID: PMC11488245 DOI: 10.1186/s12880-024-01460-9] [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: 05/30/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024] Open
Abstract
PURPOSE The objective of this study was to evaluate the feasibility of using Artificial Intelligence (AI) to measure the long-diameter of tumors for evaluating treatment response. METHODS Our study included 48 patients with lung-specific target lesions and conducted 277 measurements. The radiologists recorded the long-diameter in axial imaging plane of the target lesions for each measurement. Meanwhile, AI software was utilized to measure the long-diameter in both the axial imaging plane and in three dimensions (3D). Statistical analyses including the Bland-Altman plot, Spearman correlation analysis, and paired t-test to ascertain the accuracy and reliability of our findings. RESULTS The Bland-Altman plot showed that the AI measurements had a bias of -0.28 mm and had limits of agreement ranging from - 13.78 to 13.22 mm (P = 0.497), indicating agreement with the manual measurements. However, there was no agreement between the 3D measurements and the manual measurements, with P < 0.001. The paired t-test revealed no statistically significant difference between the manual measurements and AI measurements (P = 0.497), whereas a statistically significant difference was observed between the manual measurements and 3D measurements (P < 0.001). CONCLUSIONS The application of AI in measuring the long-diameter of tumors had significantly improved efficiency and reduced the incidence of subjective measurement errors. This advancement facilitated more convenient and accurate tumor response evaluation.
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Affiliation(s)
- Nie Xiuli
- Department of Radiology, Jinan Central Hospital, Shandong First Medical University, Jinan, China
| | - Chen Hua
- Department of Oncology, Jinan Central Hospital, Shandong First Medical University, Jinan, China
| | - Gao Peng
- Department of Radiology, Jiaozhou Hospital of Tongji University Dongfang Hospital, Tongji University, Qingdao, China
| | - Yu Hairong
- Department of Radiology, Jinan Central Hospital, Shandong First Medical University, Jinan, China
| | - Sun Meili
- Department of Oncology, Jinan Central Hospital, Shandong First Medical University, Jinan, China
| | - Yan Peng
- Department of Oncology, Jinan Central Hospital, Shandong First Medical University, Jinan, China.
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Guelfi S, Hodivala-Dilke K, Bergers G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat Rev Cancer 2024; 24:655-675. [PMID: 39210063 DOI: 10.1038/s41568-024-00736-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
As angiogenesis was recognized as a core hallmark of cancer growth and survival, several strategies have been implemented to target the tumour vasculature. Yet to date, attempts have rarely been so diverse, ranging from vessel growth inhibition and destruction to vessel normalization, reprogramming and vessel growth promotion. Some of these strategies, combined with standard of care, have translated into improved cancer therapies, but their successes are constrained to certain cancer types. This Review provides an overview of these vascular targeting approaches and puts them into context based on our subsequent improved understanding of the tumour vasculature as an integral part of the tumour microenvironment with which it is functionally interlinked. This new knowledge has already led to dual targeting of the vascular and immune cell compartments and sets the scene for future investigations of possible alternative approaches that consider the vascular link with other tumour microenvironment components for improved cancer therapy.
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Affiliation(s)
- Sophie Guelfi
- Department of Oncology, VIB-KU Leuven Center for Cancer Biology and KU Leuven, Leuven, Belgium
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK.
| | - Gabriele Bergers
- Department of Oncology, VIB-KU Leuven Center for Cancer Biology and KU Leuven, Leuven, Belgium.
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Nihei S, Asaka J, Yaegashi M, Asahi K, Kudo K. Effect of blood pressure control on the risk of proteinuria during bevacizumab treatment in patients with colorectal cancer: a single-center retrospective cohort study. J Pharm Health Care Sci 2024; 10:51. [PMID: 39180119 PMCID: PMC11342735 DOI: 10.1186/s40780-024-00372-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
PURPOSE Pre-existing hypertension is reportedly a major risk factor for bevacizumab-induced proteinuria. However, few studies have focused on the effects of blood pressure (BP) control on proteinuria during bevacizumab treatment. We report a retrospective study of the association between poor BP control and the risk of developing proteinuria in patients with colorectal cancer (CRC). METHODS Data for CRC patients who received bevacizumab between April 2015 and March 2022 were retrospectively collected. Patients were categorized into two groups based on average systolic blood pressure (SBP) during treatment: normal SBP (< 140 mmHg) and high SBP (≥ 140 mmHg). To evaluate the association between average SBP and grade ≥ 2 proteinuria, we used a 3 month landmark analysis and a Cox regression model. RESULTS Of the 279 patients analyzed, 109 had high SBP and 170 had normal SBP. The cumulative incidence of grade ≥ 2 and severe proteinuria was significantly higher in the high compared to the normal SBP group (p < 0.001 and p = 0.028, respectively). Landmark analysis indicated significant differences in proteinuria between patients with and without high average SBP during the first 3 months of treatment (p = 0.002 and p = 0.015, respectively). Multivariate analysis showed that average SBP ≥ 140 mmHg was a significant independent risk factor for proteinuria (p = 0.008). CONCLUSION Landmark analysis showed that BP status during the first 3 months of bevacizumab treatment influences the risk of subsequent proteinuria. Therefore, timely diagnosis and stricter BP control are recommended for at least the first 3 months to avoid severe proteinuria.
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Affiliation(s)
- Satoru Nihei
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan.
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan.
| | - Junichi Asaka
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Mizunori Yaegashi
- Department of Surgery, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Koichi Asahi
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Kenzo Kudo
- Department of Pharmacy, Iwate Medical University Hospital, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3695, Japan
- Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical Pharmacy, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
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Lim AR, Kim B, Kim JH, Hyun MH, Park KH, Kim YH, Lee S. Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors. Front Oncol 2024; 14:1390452. [PMID: 39070139 PMCID: PMC11272611 DOI: 10.3389/fonc.2024.1390452] [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: 02/23/2024] [Accepted: 06/05/2024] [Indexed: 07/30/2024] Open
Abstract
Background This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Methods Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Results Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. Conclusions The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.
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Affiliation(s)
- Ah Reum Lim
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Boyeon Kim
- Korea University Cancer Research Institute, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jwa Hoon Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Myung Han Hyun
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyong Hwa Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yeul Hong Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soohyeon Lee
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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Hori A, Kennoki N, Hori S, Oka S, Nakamura T, Dejima I, Kumamoto A, Takao S, Sonomura T. Feasibility Study of Transarterial Chemotherapy Followed by Chemoembolization for Recurrent Breast Cancer. J Vasc Interv Radiol 2024; 35:516-522. [PMID: 38154745 DOI: 10.1016/j.jvir.2023.12.016] [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: 01/18/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 12/30/2023] Open
Abstract
PURPOSE To assess the treatment response to transarterial chemotherapy followed by chemoembolization for locally recurrent breast cancer. MATERIALS AND METHODS Thirty-nine women with locally recurrent breast cancer after standard therapy underwent selective intra-arterial chemotherapy followed by embolization using drug-eluting microspheres for locally recurrent tumors and axillary lymph node metastases. Tumor response and toxicity were assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and Common Terminology Criteria for Adverse Events (CTCAE), and survival was evaluated by the Kaplan‒Meier method. RESULTS The local responses of breast tumors at 3 and 6 months were as follows: complete response, 5.1% and 7.2%; partial response, 35.9% and 67.8%; stable disease, 59.0% and 21.4%; and progressive disease, 0.0% and 3.6%, respectively. All adverse events were mild and did not require treatment. The median overall survival (OS) was 46.5 months, and the OS rates for 1 and 2 years were 81.4% and 69.2%, respectively. The size of recurrent tumors and axillary lymph node metastases did not impact prognosis, but both liver and bone metastases adversely affected survival. CONCLUSION Transarterial chemotherapy followed by chemoembolization may provide a favorable tumor response in patients with locally recurrent breast cancer in whom conventional therapy has failed.
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Affiliation(s)
- Atsushi Hori
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Norifumi Kennoki
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Shinichi Hori
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan.
| | - Shuto Oka
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Tatsuya Nakamura
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Ikuo Dejima
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Akihiko Kumamoto
- Department of Interventional Radiology, Institute for Image Guided Therapy, Osaka, Japan
| | - Shintaro Takao
- Department of Breast Surgery, Konan Medical Center, Kobe, Japan
| | - Tetsuro Sonomura
- Department of Radiology, Wakayama Medical University, Wakayama, Japan
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11
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Ren X, Deng L, Dong X, Bai Y, Li G, Wang Y. Adverse reactions of immune checkpoint inhibitors combined with angiogenesis inhibitors: A pharmacovigilance analysis of drug-drug interactions. Int J Immunopathol Pharmacol 2024; 38:3946320241305390. [PMID: 39660594 PMCID: PMC11632882 DOI: 10.1177/03946320241305390] [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: 04/27/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024] Open
Abstract
The combination of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AGIs) is widely used in cancer treatment; however, drug-drug reactions (DDIs) remain unknown. We aimed to identify interaction signals for the concomitant use of ICIs and AGIs. Data were obtained from the US FDA Adverse Event Reporting System (FAERS) from January 1, 2015, to December 31, 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI). Adjusted RORs were analysed using logistic regression analysis, considering age, sex and reporting year. Further confirmation was assessed via additive and multiplicative models. We identified 75,936 reports on ICIs combined with AGIs. Significant interaction signals were observed for hepatobiliary disorders (RORcrude: 5.25, 95% CI: 5.07-5.44, RORadj: 5.01, 95% CI: 4.82-5.22, additive models: 0.2323), investigations (RORcrude: 1.66, 95% CI: 1.62-1.70, RORadj: 1.63, 95% CI: 1.58-1.67, additive models: 0.2187, multiplicative models: 1.1265), renal and urinary disorders (RORcrude: 1.87, 95% CI: 1.80-1.95, RORadj: 1.72, 95% CI: 1.64-1.79, additive models: 0.3239, multiplicative models: 1.1799) and vascular disorders (RORcrude: 1.94, 95% CI: 1.87-2.02, RORadj: 1.87, 95% CI: 1.80-1.95, additive models: 0.5823, multiplicative models: 1.5676). Subset data analysis showed positive interaction signals for PDL-1/CTLA-4 inhibitors + AGI in hepatobiliary disorders, PD-1 inhibitors + AGI in investigations, or PD-1/PDL-1 inhibitors + AGI in renal and urinary/ vascular disorders. Based on FAERS data, four systemic disorders were identified as having DDIs related to the combined use of ICIs and AGIs. Pre-clinical trials are required to explore the mechanisms underlying these interactions.
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Affiliation(s)
- Xiayang Ren
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Dong
- Department of Clinical Laboratory, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Bai
- Clinical Trials Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guohui Li
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Wang
- Department of Comprehensive Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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12
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Lim JSJ, Ow SGW, Wong ALA, Lee MXW, Chan GHJ, Low JL, Sundar R, Choo JRE, Chong WQ, Ang YLE, Tai BC, Lee SC. Phase II study of trifluridine/tipiracil in metastatic breast cancers with or without prior exposure to fluoropyrimidines. Eur J Cancer 2023; 193:113311. [PMID: 37717281 DOI: 10.1016/j.ejca.2023.113311] [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: 04/21/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.
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Affiliation(s)
- Joline S J Lim
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore; Experimental Therapeutics Programme, Cancer Science Institute, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Samuel G W Ow
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Andrea L A Wong
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore; Experimental Therapeutics Programme, Cancer Science Institute, Singapore, Singapore
| | - Matilda X W Lee
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Gloria H J Chan
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Jia Li Low
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Raghav Sundar
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Joan R E Choo
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Wan Qin Chong
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Yvonne L E Ang
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Bee Choo Tai
- Saw Swee Hock School of Public Health, National University Singapore, Singapore
| | - Soo Chin Lee
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, Singapore; Experimental Therapeutics Programme, Cancer Science Institute, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore.
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13
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Ye F, Dewanjee S, Li Y, Jha NK, Chen ZS, Kumar A, Vishakha, Behl T, Jha SK, Tang H. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Mol Cancer 2023; 22:105. [PMID: 37415164 PMCID: PMC10324146 DOI: 10.1186/s12943-023-01805-y] [Citation(s) in RCA: 211] [Impact Index Per Article: 105.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/08/2023] [Indexed: 07/08/2023] Open
Abstract
Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
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Affiliation(s)
- Feng Ye
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India
| | - Yuehua Li
- Department of Medical Oncology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hengyang, China
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, 144411, India
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, 11439, USA
| | - Ankush Kumar
- Pharmaceutical and Health Sciences, Career Point University, Hamirpur, Himachal Pradesh, India
| | - Vishakha
- Pharmaceutical and Health Sciences, Career Point University, Hamirpur, Himachal Pradesh, India
| | - Tapan Behl
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun, Uttarakhand, India.
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India.
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India.
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India.
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Delgado-Bellido D, Oliver FJ, Vargas Padilla MV, Lobo-Selma L, Chacón-Barrado A, Díaz-Martin J, de Álava E. VE-Cadherin in Cancer-Associated Angiogenesis: A Deceptive Strategy of Blood Vessel Formation. Int J Mol Sci 2023; 24:ijms24119343. [PMID: 37298296 DOI: 10.3390/ijms24119343] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Tumor growth depends on the vascular system, either through the expansion of blood vessels or novel adaptation by tumor cells. One of these novel pathways is vasculogenic mimicry (VM), which is defined as a tumor-provided vascular system apart from endothelial cell-lined vessels, and its origin is partly unknown. It involves highly aggressive tumor cells expressing endothelial cell markers that line the tumor irrigation. VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients. In this review, we summarize the most relevant studies in the field of angiogenesis and cover the various aspects and functionality of aberrant angiogenesis by tumor cells. We also discuss the intracellular signaling mechanisms involved in the abnormal presence of VE-cadherin (CDH5) and its role in VM formation. Finally, we present the implications for the paradigm of tumor angiogenesis and how targeted therapy and individualized studies can be applied in scientific analysis and clinical settings.
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Affiliation(s)
- Daniel Delgado-Bellido
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, 18016 Granada, Spain
- Instituto de Salud Carlos III, CIBERONC, 28220 Madrid, Spain
- Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocío, 41013 Seville, Spain
| | - F J Oliver
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, 18016 Granada, Spain
| | | | - Laura Lobo-Selma
- Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocío, 41013 Seville, Spain
| | | | - Juan Díaz-Martin
- Instituto de Salud Carlos III, CIBERONC, 28220 Madrid, Spain
- Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocío, 41013 Seville, Spain
| | - Enrique de Álava
- Instituto de Salud Carlos III, CIBERONC, 28220 Madrid, Spain
- Instituto de Biomedicina de Sevilla, Hospital Virgen del Rocío, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
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15
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Borlongan MC, Wang H. Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics. Front Cell Dev Biol 2023; 11:1125174. [PMID: 37305676 PMCID: PMC10247984 DOI: 10.3389/fcell.2023.1125174] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/15/2023] [Indexed: 06/13/2023] Open
Abstract
Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs' unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs' unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways' ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFβ (transforming growth factor-β)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.
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Affiliation(s)
- Mia C. Borlongan
- Master Program of Pharmaceutical Science College of Graduate Studies, Elk Grove, CA, United States
| | - Hongbin Wang
- Master Program of Pharmaceutical Science College of Graduate Studies, Elk Grove, CA, United States
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, Elk Grove, CA, United States
- Department of Basic Science College of Medicine, California Northstate University, Elk Grove, CA, United States
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16
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Zhang Y, Popel AS, Bazzazi H. Combining Multikinase Tyrosine Kinase Inhibitors Targeting the Vascular Endothelial Growth Factor and Cluster of Differentiation 47 Signaling Pathways Is Predicted to Increase the Efficacy of Antiangiogenic Combination Therapies. ACS Pharmacol Transl Sci 2023; 6:710-726. [PMID: 37200806 PMCID: PMC10186363 DOI: 10.1021/acsptsci.3c00008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Indexed: 05/20/2023]
Abstract
Angiogenesis is a critical step in tumor growth, development, and invasion. Nascent tumor cells secrete vascular endothelial growth factor (VEGF) that significantly remodels the tumor microenvironment through interaction with multiple receptors on vascular endothelial cells, including type 2 VEGF receptor (VEGFR2). The complex pathways initiated by VEGF binding to VEGFR2 lead to enhanced proliferation, survival, and motility of vascular endothelial cells and formation of a new vascular network, enabling tumor growth. Antiangiogenic therapies that inhibit VEGF signaling pathways were among the first drugs that targeted stroma rather than tumor cells. Despite improvements in progression-free survival and higher response rates relative to chemotherapy in some types of solid tumors, the impact on overall survival (OS) has been limited, with the majority of tumors eventually relapsing due to resistance or activation of alternate angiogenic pathways. Here, we developed a molecularly detailed computational model of endothelial cell signaling and angiogenesis-driven tumor growth to investigate combination therapies targeting different nodes of the endothelial VEGF/VEGFR2 signaling pathway. Simulations predicted a strong threshold-like behavior in extracellular signal-regulated kinases 1/2 (ERK1/2) activation relative to phosphorylated VEGFR2 levels, as continuous inhibition of at least 95% of receptors was necessary to abrogate phosphorylated ERK1/2 (pERK1/2). Combinations with mitogen-activated protein kinase/ERK kinase (MEK) and spingosine-1-phosphate inhibitors were found to be effective in overcoming the ERK1/2 activation threshold and abolishing activation of the pathway. Modeling results also identified a mechanism of resistance whereby tumor cells could reduce pERK1/2 sensitivity to inhibitors of VEGFR2 by upregulation of Raf, MEK, and sphingosine kinase 1 (SphK1), thus highlighting the need for deeper investigation of the dynamics of the crosstalk between VEGFR2 and SphK1 pathways. Inhibition of VEGFR2 phosphorylation was found to be more effective at blocking protein kinase B, also known as AKT, activation; however, to effectively abolish AKT activation, simulations identified Axl autophosphorylation or the Src kinase domain as potent targets. Simulations also supported activating cluster of differentiation 47 (CD47) on endothelial cells as an effective combination partner with tyrosine kinase inhibitors to inhibit angiogenesis signaling and tumor growth. Virtual patient simulations supported the effectiveness of CD47 agonism in combination with inhibitors of VEGFR2 and SphK1 pathways. Overall, the rule-based system model developed here provides new insights, generates novel hypothesis, and makes predictions regarding combinations that may enhance the OS with currently approved antiangiogenic therapies.
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Affiliation(s)
- Yu Zhang
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Aleksander S. Popel
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Hojjat Bazzazi
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
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Demirkiran A, Eryilmaz MK, Karaagac M, Araz M, Korkmaz M, Koçak MZ, Artac M. Low-dose (7.5 mg/kg) bevacizumab may be a viable option in recurrent ovarian cancer: A retrospective study. J Cancer Res Ther 2023; 19:595-600. [PMID: 37470581 DOI: 10.4103/jcrt.jcrt_1879_20] [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] [Indexed: 12/24/2022]
Abstract
Objective Bevacizumab (BEV) is a humanized monoclonal antibody of vascular endothelial growth factor receptors and, as a result of clinical trials, was approved for the treatment of recurrent ovarian cancer (ROC). The aim of this study was to assess the clinical utility of BEV in patients with ROC in real-world practice beyond clinical trials. Materials and Methods In this single-center retrospective cohort study, we evaluated the medical data of all patients with ROC who were treated with BEV between October 2013 and March 2020. Results A total of 76 females were evaluated. Forty-nine (64.5%) patients were platinum sensitive and 27 (35.5%) patients were platinum resistant. BEV was used in combination with chemotherapy agents in all patients, and the most preferred combinations were gemcitabine/carboplatin (GC) (78.9%) and carboplatin/paclitaxel (14.5%). In all patients, the BEV dose was 7.5 mg/kg every 3 weeks. The median progression-free survival (PFS) was 11.1 months (95% confidence interval [CI]: 9.6-12.6), and the median overall survival (OS) was 22.3 months (95% CI: 17.5-27.2). In multivariate analysis, serous histological type (P = 0.01), maintenance BEV administration (P = 0.001), and combination of GC-BEV (P < 0.001) were associated with better PFS, while serous histological type (P = 0.016) and good performance status (P = 0.006) were associated with prolonged OS. Conclusions Low-dose (7.5 mg/kg) BEV was found to be effective in the second-line treatment of patients with ROC in our real-life study. In addition, the combination of BEV with GC was shown to be a viable option, especially in the treatment selection of platinum-resistant patients.
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Affiliation(s)
- Aykut Demirkiran
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Melek Karakurt Eryilmaz
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Mustafa Karaagac
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Murat Araz
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Mustafa Korkmaz
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Mehmet Zahid Koçak
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
| | - Mehmet Artac
- Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Akyokuş, Konya, Turkey
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Efficacy Evaluation of Bevacizumab Combined with Capecitabine in the Treatment of HER2-Negative Metastatic Breast Cancer: A Meta-Analysis. JOURNAL OF ONCOLOGY 2023; 2023:8740221. [PMID: 36816360 PMCID: PMC9931458 DOI: 10.1155/2023/8740221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/23/2022] [Accepted: 11/25/2022] [Indexed: 02/11/2023]
Abstract
Objective This study aims to evaluate the efficacy of bevacizumab combined with capecitabine in treating HER2-negative metastatic breast cancer through meta-analysis. Methods We searched literature from databases, including PubMed, Web of Science, Wiley Online Library, Ovid, CNKI, and Wanfang databases, for randomized controlled trials (RCTs) of bevacizumab combined with capecitabine (experimental group) and other treatments (control group) for HER2-negative metastatic breast cancer. Retrieved articles were published from the establishment of the database to August 9, 2022. The main outcome indicators were disease progression rate (RDP), disease progression-free survival (PFS), 1-year survival rate (OSR), the occurrence of serious adverse events (SAEs), and objective remission rate (ORR). The risk of bias was assessed according to the Cochrane systematic evaluation tool. Then, the meta-analysis was carried out using Stata16.0 software, and subgroup analysis was carried out based on various intervention methods in the control group. Results 8 RCTs were finally included in this study, including 2470 patients with HER2-negative metastatic breast cancer. The results of meta-analysis showed that bevacizumab combined with capecitabine had no significant advantage over the control group in terms of RDP, but the results of subgroup analysis were consistent and significant (subgroup 1 (bevacizumab or chemotherapy): DR = -0.03, 95% CI (-0.14, 0.09), P = 0.01; subgroup 2 (bevacizumab plus paclitaxel therapy): DR = -0.03, 95% CI (-0.14, 0.09), P = 0.03). Furthermore, there was no statistical difference in terms of PFS of the experimental group (MD = 9.24, 95% CI (7.88, 32.67), P = 0.05). However, the subgroup analysis showed that the combination of bevacizumab and capecitabine demonstrated a more significant significance than bevacizumab or chemotherapy alone (subgroup 1: MD = 10.11, 95% CI (7.88, 12.34), P = 0.00). Compared with the control group, the experimental group had significant differences in OSR (DR = 0.07, 95% CI (-0.01, 0.15), P = 0.00) and ORR (DR = 0.07, 95% CI (-0.01, 0.15), P = 0.00). In terms of safety, the incidence of serious adverse events in the experimental group did not show a statistically significant difference (MD = 0.01, 95% CI (-0.21, 0.19), P = 0.82). When subgroup analyses were performed, the bevacizumab plus capecitabine regimen was associated with an increased incidence of serious adverse events compared with the drug alone (subgroup 1: MD = 0.02, 95% CI (-0.16, 0.20), P = 0.00) but a reduction in serious adverse events compared with the bevacizumab plus paclitaxel regimen (subgroup 2: DR = -0.01, 95% CI (-0.21, 0.19), P = 0.00). Conclusion The combination therapy of bevacizumab and capecitabine can significantly improve the RDP and OSR of patients compared with the control group. The PFS and ORR of the experimental group are significantly higher than those of bevacizumab or chemotherapy alone. Still, no statistical difference was observed for these outcome indicators between two combined treatments of bevacizumab with capecitabine or paclitaxel. Although this combined treatment scheme may increase the incidence of serious adverse events compared with that of bevacizumab or chemotherapy alone, the incidence of adverse events was decreased compared with bevacizumab combined with paclitaxel. Therefore, the chemotherapy regimen for HER2-negative metastatic breast cancer in clinical practice can be selected according to the actual situation of the patients.
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Xun X, Ai J, Feng F, Hong P, Rai S, Liu R, Zhang B, Zhou Y, Hu H. Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis. Front Pharmacol 2023; 14:1108772. [PMID: 36794276 PMCID: PMC9922898 DOI: 10.3389/fphar.2023.1108772] [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: 11/26/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC. Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab. Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30-1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04-1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41-1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07-1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73-3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49-18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46-26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47-19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59-30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84-6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios. Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].
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Affiliation(s)
- Xueqiong Xun
- Department of thyroid and breast Surgery, First People’s Hospital of Qujing, Qujing, China
| | - Jun Ai
- Department of thyroid and breast Surgery, First People’s Hospital of Qujing, Qujing, China
| | - Fuhui Feng
- Department of thyroid and breast Surgery, First People’s Hospital of Qujing, Qujing, China
| | - Pan Hong
- Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Saroj Rai
- Department of Orthopedics, Al Ahalia Hospital, Abu Dhabi, United Arab Emirates
| | - Ruikang Liu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baowen Zhang
- Basic medical school, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yeming Zhou
- Basic medical school, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Yeming Zhou, ; Huiyong Hu,
| | - Huiyong Hu
- Department of thyroid and breast Surgery, First People’s Hospital of Qujing, Qujing, China,*Correspondence: Yeming Zhou, ; Huiyong Hu,
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Kanbayashi Y, Uchida M, Kashiwagi M, Akiba H, Shimizu T. Evaluation of lung toxicity with bevacizumab using the spontaneous reporting database. Sci Rep 2022; 12:15619. [PMID: 36114412 PMCID: PMC9481601 DOI: 10.1038/s41598-022-19887-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 09/06/2022] [Indexed: 12/02/2022] Open
Abstract
This study was undertaken to determine the risk of bevacizumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analysed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analysed 5,273,115 reports and identified 20,399 reports of AEs caused by bevacizumab. Of these, 1679 lung toxicities were reportedly associated with bevacizumab. Signals were detected for nine lung toxicities. A histogram of times to onset showed occurrence from 35 to 238 days, but some cases occurred even more than one year after the start of administration. Approximately 20% of AEs were thromboembolic events. Among these, pulmonary embolism was the most frequently reported and fatal cases were also reported. The AEs showing the highest fatality rates were pulmonary haemorrhage, pulmonary infarction, and pulmonary thrombosis. In conclusion, we focused on lung toxicities caused by bevacizumab as post-marketing AEs. Some cases could potentially result in serious outcomes, patients should be monitored for signs of onset of AEs not only at the start of administration, but also over a longer period of time.
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21
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Shao Y, Luo Z, Yu Y, He Y, Liu C, Chen Q, Zhu F, Nie B, Liu H. A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer. Front Oncol 2022; 12:939343. [PMID: 35965587 PMCID: PMC9366600 DOI: 10.3389/fonc.2022.939343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/05/2022] [Indexed: 11/26/2022] Open
Abstract
Background Antiangiogenic agents provides an optional treatment strategy for patients with metastatic breast cancer. The present study was conducted to evaluate the efficacy and safety of anlotinib as third-line or above therapy for patients with HER-2 negative metastatic breast cancer. Methods Patients with HER-2 negative metastatic breast cancer who have failed from prior therapy and treated with anlotinib monotherapy or combined with chemotherapy or immunotherapy from June 2018 to December 2020 were retrospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results 47 patients with HER-2 negative metastatic breast cancer received anlotinib monotherapy or combination therapy as third-line or above therapy. In the general population, 10 patients achieved PR, 25 patients had SD and 12 patients had PD. The overall ORR and DCR were 21.3% and 74.5%, respectively. Subgroup analysis suggested that there were no statistically significant differences in ORR and DCR with respect to HR status (positive vs. negative), treatment programs (monotherapy vs. combination) and treatment type in combination group (chemotherapy vs. immunotherapy). The patients who did not received previously anti-angiogenesis therapy had superior DCR (84.8% vs. 50.0%, P=0.012). Median PFS and OS were 5.0 months (95% CI=4.3-5.7) and 21.0 (95% CI=14.9-27.1) months, respectively. The PFS (6.5m vs. 3.5m, P=0.042)and OS (28.2m vs. 12.6m, P=0.040) were better in HR positive patients than HR negative patients. And simultaneously, patients who received anlotinib combination therapy obtained better PFS (5.5m vs. 3.0m, P=0.045). The incidence of Grade 3-4 adverse events(AEs) was 31.9%. Conclusions Anlotinib monotherapy or combination therapy provide a viable third-line or above therapeutic strategy in patients with HER-2 negative metastatic breast cancer, a median PFS of 5.0 months was obtained with well tolerated toxicity.
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Affiliation(s)
- Yingbo Shao
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Zhifen Luo
- Department of Medical Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Medical Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Yang Yu
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Yaning He
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Chaojun Liu
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Qi Chen
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Fangyuan Zhu
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Bing Nie
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
| | - Hui Liu
- Department of Breast Oncology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, China
- Department of Breast Oncology, Henan Provincial People’s Hospital; Henan University People’s Hospital, Zhengzhou, China
- *Correspondence: Hui Liu,
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Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, Chupradit S, AL-Ghamdi HS, Shomali N, Zamani A, Mohammadi A, Dadashpour M. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal 2022; 20:49. [PMID: 35392964 PMCID: PMC8991477 DOI: 10.1186/s12964-022-00838-y] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 02/06/2023] Open
Abstract
Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
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Affiliation(s)
- Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991 Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow, 109240 Russian Federation
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation
- Industrial University, Tyumen, Russian Federation
| | - Abduladheem Turki Jalil
- Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, 230023 Grodno, Belarus
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- Department of Dentistry, Kut University College, Kut, Wasit 52001 Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
| | - Hasan S. AL-Ghamdi
- Internal Medicine Department, Division of Dermatology, Albaha University, Al Bahah, Kingdom of Saudi Arabia
| | - Navid Shomali
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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23
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Ayoub NM, Jaradat SK, Al-Shami KM, Alkhalifa AE. Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches. Front Pharmacol 2022; 13:838133. [PMID: 35281942 PMCID: PMC8913593 DOI: 10.3389/fphar.2022.838133] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.
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Affiliation(s)
- Nehad M. Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
- *Correspondence: Nehad M. Ayoub,
| | - Sara K. Jaradat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
| | - Kamal M. Al-Shami
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Amer E. Alkhalifa
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology (JUST), Irbid, Jordan
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24
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Symonds LK, Jenkins I, Linden HM, Kurland B, Gralow JR, Gadi VK, Ellis GK, Wu Q, Rodler E, Chalasani P, Chai X, Riedel J, Stopeck A, Brown-Glaberman U, Specht JM. A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer. Clin Breast Cancer 2022; 22:32-42. [PMID: 34158245 PMCID: PMC8611115 DOI: 10.1016/j.clbc.2021.05.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/01/2021] [Accepted: 05/17/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). RESULTS Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.
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Affiliation(s)
- LK Symonds
- Medical Oncology, University of Washington, Seattle, WA
| | - I Jenkins
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - HM Linden
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - B Kurland
- eResearch Technologies, Inc. (ERT), Pittsburgh, PA
| | - JR Gralow
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - VK Gadi
- Medical Oncology, University of Illinois Cancer Center, Chicago, IL
| | - GK Ellis
- Medical Oncology, University of Washington, Seattle, WA
| | - Q Wu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - E Rodler
- Hematology and Oncology, UC Davis, Sacramento, CA
| | - P Chalasani
- Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ
| | | | - J Riedel
- Clinical Cancer Genetics, Duke Cancer Institute, Durham, NC
| | | | - A Stopeck
- Hematology and Oncology, Stony Brook University, Stonybrook, NY
| | | | - JM Specht
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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Afrin H, Salazar CJ, Kazi M, Ahamad SR, Alharbi M, Nurunnabi M. Methods of screening, monitoring and management of cardiac toxicity induced by chemotherapeutics. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Veliparib monotherapy following carboplatin/paclitaxel plus veliparib combination therapy in patients with germline BRCA-associated advanced breast cancer: results of exploratory analyses from the phase III BROCADE3 trial. Ann Oncol 2021; 33:299-309. [PMID: 34861374 DOI: 10.1016/j.annonc.2021.11.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 10/13/2021] [Accepted: 11/23/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND In the BROCADE3 trial (NCT02163694), addition of the poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio [HR] 0.71, 95% confidence interval 0.57-0.88; P=0.002) in patients with advanced HER2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel prior to progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS Patients were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily [BID]) or placebo was given on days -2 to 5, carboplatin (AUC 6 mg/mL) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel prior to progression received blinded study drug monotherapy at an increased dose of 300-400 mg BID continuously. PFS was the primary endpoint. Exploratory analyses were performed in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel prior to progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. HRs from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events (AEs) occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 AEs were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy.
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Nervo A, Retta F, Ragni A, Piovesan A, Mella A, Biancone L, Manganaro M, Gallo M, Arvat E. Nephrotoxicity in advanced thyroid cancer treated with tyrosine kinase inhibitors: An update. Crit Rev Oncol Hematol 2021; 168:103533. [PMID: 34801702 DOI: 10.1016/j.critrevonc.2021.103533] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 11/05/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Over the past decade, the prognosis of advanced thyroid cancer (TC) patients has dramatically improved thanks to the introduction of tyrosine kinase inhibitors (TKIs). Despite their effectiveness, these drugs are burdened with several side effects that can negatively affect quality of life and compromise therapy continuation. Among renal adverse events (RAEs), proteinuria is the most frequently reported in clinical trials and real-life experiences, especially during treatment with lenvatinib or cabozantinib. This peculiar toxicity is commonly associated with targeted therapies with anti-angiogenic activity, even if the mechanisms underlying its onset and progression are not entirely clear. RAEs should be early recognized and properly managed to avoid renal function worsening and life-threatening consequences. Aiming at providing a comprehensive summary that can help clinicians to identify and manage TKIs-related RAEs in TC patients, we reviewed the current evidence about this topic, from pathogenesis and potential risk factors to diagnosis and treatment.
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Affiliation(s)
- Alice Nervo
- Oncological Endocrinology Unit, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
| | - Francesca Retta
- Oncological Endocrinology Unit, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
| | - Alberto Ragni
- Oncological Endocrinology Unit, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy; Endocrinology and Metabolic Diseases Unit, AO SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
| | - Alessandro Piovesan
- Oncological Endocrinology Unit, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
| | - Alberto Mella
- Division of Nephrology Dialysis and Transplantation, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
| | - Luigi Biancone
- Division of Nephrology Dialysis and Transplantation, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
| | - Marco Manganaro
- Nephrology and Dialysis Unit, AO SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
| | - Marco Gallo
- Endocrinology and Metabolic Diseases Unit, AO SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
| | - Emanuela Arvat
- Oncological Endocrinology Unit, Department of Medical Sciences, Città Della Salute e Della Scienza Hospital, University of Turin, Turin, Italy.
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Rinnerthaler G, Gampenrieder SP, Petzer A, Hubalek M, Petru E, Sandholzer M, Andel J, Balic M, Melchardt T, Hauser-Kronberger C, Schmitt CA, Ulmer H, Greil R. Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6). Ther Adv Med Oncol 2021; 13:17588359211042301. [PMID: 34691243 PMCID: PMC8529308 DOI: 10.1177/17588359211042301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/09/2021] [Indexed: 11/15/2022] Open
Abstract
Background: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin
lymphoma, has already shown anticancer activity in metastatic breast cancer
(MBC). Here, we present the results of a phase II trial of bendamustine in
combination with capecitabine in pre-treated patients with MBC. Patients and methods: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in
HER2-negative MBC. All patients were pre-treated with anthracyclines and/or
taxans and had measurable disease. Patients received per os
1000 mg/m2 capecitabine twice daily on days 1 to 14 in
combination with 80 mg/m2 bendamustine intravenously on days 1
and 8 of a 3-week cycle for a maximum of eight cycles, followed by a
capecitabine maintenance therapy. The primary endpoint was overall response
rate (ORR). Results: From September 2013 to May 2015, 40 patients were recruited in eight Austrian
centres. The median age was 60 years (range 29–77). Twenty-five per cent of
patients had triple-negative breast cancer (TNBC) and 93% showed visceral
involvement. With 17 partial and one complete remission, ORR was 46%. Median
progression-free survival (PFS) was 7.5 months [95% confidence interval (CI)
6.1–10.7]. The most common non-haematological adverse events (AEs) of grade
3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea
(8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4
haematological AEs (neutropenia) were observed. One patient died of
restrictive cardiomyopathy, in which a relationship to capecitabine cannot
be excluded, but seems unlikely. Conclusion: The combination of capecitabine and bendamustine shows promising efficacy and
moderate toxicity. Further evaluation of this drug combination is
warranted. The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov,
(https://clinicaltrials.gov/; identifier: NCT01891227).
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Affiliation(s)
- Gabriel Rinnerthaler
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Simon Peter Gampenrieder
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Andreas Petzer
- Internal Department I for Medical Oncology and Hematology, Barmherzige Schwestern Hospital/Linz, Linz, Austria
| | - Michael Hubalek
- Department of Obstetrics and Gynaecology, Innsbruck Medical University, Innsbruck, Austria
| | - Edgar Petru
- Department of Obstetrics and Gynaecology, Medical University Graz, Graz, Austria
| | - Margit Sandholzer
- Department of Oncology, Hematology and Gastroenterology, Infectiology, Academic Teaching Hospital Feldkirch, Austria
| | - Johannes Andel
- Department of Internal Medicine II, Pyhrn-Eisenwurzen Klinikum Steyr, Steyr, Austria
| | - Marija Balic
- Division of Oncology, Department of Internal Medicine, Medical University Graz, Graz, Austria
| | - Thomas Melchardt
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, AustriaSalzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, Salzburg, Austria
| | | | - Clemens A Schmitt
- Department of Internal Medicine 3 - Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria
| | - Hanno Ulmer
- Department of Medical Statistics and Informatics, Medical University Innsbruck, Innsbruck, Austria
| | - Richard Greil
- IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria
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Twelves C, Bartsch R, Ben-Baruch NE, Borstnar S, Dirix L, Tesarova P, Timcheva C, Zhukova L, Pivot X. The Place of Chemotherapy in The Evolving Treatment Landscape for Patients With HR-positive/HER2-negative MBC. Clin Breast Cancer 2021; 22:223-234. [PMID: 34844889 DOI: 10.1016/j.clbc.2021.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/23/2021] [Accepted: 10/19/2021] [Indexed: 11/19/2022]
Abstract
Endocrine therapy (ET) for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (MBC) has changed markedly over recent years with the emergence of new ETs and the use of molecularly targeted agents. Cytotoxic chemotherapy continues, however, to have an important role in these patients and it is important to maximize its efficacy while minimizing toxicity to optimize outcomes. This review examines current HR-positive/HER2-negative MBC clinical guidelines and addresses key questions around the use of chemotherapy in the face of emerging therapeutic options. Specifically, the indications for chemotherapy in patients with HR-positive/HER2-negative MBC and the choice of optimal chemotherapy are discussed.
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Affiliation(s)
- Chris Twelves
- Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, University of Leeds and Leeds Teaching Hospitals Trust Leeds.
| | - Rupert Bartsch
- Department of Medicine 1, Division of Oncology, Medical University of Vienna, Austria
| | | | - Simona Borstnar
- Division of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia
| | - Luc Dirix
- Medical Oncology, Sint-Augustinus Hospital, Antwerp, Belgium
| | - Petra Tesarova
- First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic
| | | | | | - Xavier Pivot
- ICANS - Strasbourg Europe Cancerology Institute, Strasbourg, France
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30
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Chen S, Ren Y, Dai H, Li Y, Lan B, Ma F. Drug-induced pulmonary toxicity in breast cancer patients treated with systemic therapy: a systematic literature review. Expert Rev Anticancer Ther 2021; 21:1399-1410. [PMID: 34672214 DOI: 10.1080/14737140.2021.1996229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Drug-induced pulmonary toxicity (DIPT) associated with breast cancer (BC) therapy has been a major concern in recent times. DIPT may not be attributed to a single type of therapy because of the concomitant use of other anticancer drugs or along with radiotherapy, which is an independent risk factor for pulmonary toxicity. AREAS COVERED In this systematic literature review, we evaluated the probable cause and prevalence of DIPT in various systemic therapies used in BC treatment. A literature search was conducted in PubMed, Embase and Cochrane database, up to October 2020. Clinical studies reporting DIPT and related clinical manifestations due to systemic therapy in BC treatment were included. A total of 1749 articles were retrieved, and 193 articles were included. EXPERT OPINION : The leading cause of DIPT among patients with BC was targeted therapy followed by chemotherapy containing regimens. A total of 17 studies reported 35 deaths (15 deaths in chemotherapy) due to DIPT. Physicians must take extra precaution while prescribing systemic therapy known to be associated with DIPT and need to be familiar with early diagnosis of DIPT in order to avoid respiratory-related complications during treatment in BC patients.
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Affiliation(s)
- Shanshan Chen
- Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China
| | - Yanhong Ren
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Disease, Beijing, China
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Disease, Beijing, China
| | - Yiqun Li
- Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China
| | - Bo Lan
- Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Ma
- Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China
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31
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Guo X, Qian X, Jin Y, Kong X, Qi Z, Cai T, Zhang L, Wu C, Li W. Hypertension Induced by Combination Therapy of Cancer: A Systematic Review and Meta-Analysis of Global Clinical Trials. Front Pharmacol 2021; 12:712995. [PMID: 34552487 PMCID: PMC8451955 DOI: 10.3389/fphar.2021.712995] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/20/2021] [Indexed: 12/26/2022] Open
Abstract
Background: Nowadays, due to the limitation of single therapy, combination therapy for cancer treatments has become important strategy. With the advancement of research on cardiotoxicities induced by anti-cancer treatment, among which cancer treatment-induced hypertension is the most frequent case. However, due to the small sample size and the absence of comparison (single-arm study alone), these studies have limitations to produce a feasible conclusion. Therefore, it is necessary to carry out a meta-analysis focusing on hypertension caused by cancer combination therapy. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and CNKI, from database inception to November 31, 2020, with randomized controlled trials (RCTs) associated with hypertension induced by cancer combination drugs. The main endpoint of which was to assess the difference in the incidence of hypertension in cancer patients with monotherapy or combination therapy. We calculated the corresponding 95% confidence interval (95% CIs) according to the random effect model and evaluated the heterogeneity between different groups. Results: According to the preset specific inclusion and exclusion criteria, a total of 23 eligible RCTs have been included in the present meta-analysis, including 6,241 patients (Among them, 2872 patients were the control group and 3369 patients were the experimental group). The results showed that cancer patients with combination therapy led to a higher risk of hypertension (All-grade: RR 2.85, 95% CI 2.52∼3.22; 1∼2 grade: RR 2.43, 95% CI 2.10∼2.81; 3∼4 grade: RR 4.37, 95% CI 3.33∼5.72). Furthermore, compared with the control group who received or did not receive a placebo, there was a higher risk of grade 3-4 hypertension caused by cancer combination treatment. Conclusion: The present meta-analysis carries out a comprehensive analysis on the risk of patients suffering from hypertension in the process of multiple cancer combination therapies. Findings in our study support that the risk of hypertension may increase significantly in cancer patients with multiple cancer combination therapies. The outcomes of this meta-analysis may provide a reference value for clinical practice and may supply insights in reducing the incidence of hypertension caused by cancer combined treatment.
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Affiliation(s)
- Xiaodan Guo
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Xiaoyu Qian
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Ying Jin
- Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhihong Qi
- Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Tie Cai
- State Key Laboratory of Coal Resources and Safe Mining, School of Chemical and Environmental Engineering, China University of Mining and Technology, Beijing, China
| | - Lin Zhang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
| | - Caisheng Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Weihua Li
- Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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Abstract
Recent decades have demonstrated significant strides in cancer screening, diagnostics and therapeutics. As such there have been dramatic changes in survival following a diagnosis of cancer.
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Affiliation(s)
- Matthew R D Brown
- The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
| | | | - David J Magee
- The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK.
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López-Vega JM, Álvarez I, Antón A, Illarramendi JJ, Llombart A, Boni V, García-Velloso MJ, Martí-Climent JM, Pina L, García-Foncillas J. Early Imaging and Molecular Changes with Neoadjuvant Bevacizumab in Stage II/III Breast Cancer. Cancers (Basel) 2021; 13:3511. [PMID: 34298725 PMCID: PMC8307791 DOI: 10.3390/cancers13143511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/28/2021] [Accepted: 07/05/2021] [Indexed: 11/24/2022] Open
Abstract
This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2-C5). Tumour proliferation and hypoxic status were evaluated using 18F-fluoro-3'-deoxy-3'-L-fluorothymidine (FLT)- and 18F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p ≤ 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.
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Affiliation(s)
- José Manuel López-Vega
- Department of Medical Oncology, Marqués de Valdecilla University Hospital, 39008 Santander, Spain;
| | - Isabel Álvarez
- Department of Medical Oncology, University Hospital Donostia, 20080 Donostia-San Sebastián, Spain;
| | - Antonio Antón
- Department of Medical Oncology, University Hospital Miguel Servet, 50009 Zaragoza, Spain;
| | | | - Antonio Llombart
- Department of Medical Oncology, Hospital Arnau de Vilanova, 46015 Lleida, Spain;
| | - Valentina Boni
- START Madrid CIOCC, Hospital Universitario HM Sanchinarro, 28050 Madrid, Spain;
| | | | - Josep María Martí-Climent
- Department of Medical Physics and Radiation Safety, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
| | - Luis Pina
- Department of Radiology, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
| | - Jesús García-Foncillas
- Translational Oncology Division, OncoHealth Institute, University Hospital “Fundación Jiménez Díaz”, Autonomous University of Madrid, 28040 Madrid, Spain
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Yin G, Zhao L. Risk of hypertension with anti-VEGF monoclonal antibodies in cancer patients: a systematic review and meta-analysis of 105 phase II/III randomized controlled trials. J Chemother 2021; 34:221-234. [PMID: 34229563 DOI: 10.1080/1120009x.2021.1947022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
We performed a meta-analysis to fully investigate the hypertension of anti-VEGF mAbs in cancer patients. Databases were searched for randomized controlled trials (RCTs) treated with anti-VEGF mAbs till January 2021. The relevant RCTs in cancer patients treated with anti-VEGF mAbs were retrieved and the systematic evaluation was conducted. One hundred and five RCTs and 65358 patients were included. Our study suggests that anti-VEGF mAbs significantly increased the risks of all-grade (RR, 3.22; 95%CI, 2.83-3.65; p < 0.00001; I2=71%) and high-grade (RR, 6.15; 95%CI, 5.58-6.78; p < 0.00001; I2=48%) hypertension in cancer patients. Those risks may be dependent on drug type. Icrucumab did not association with an increased risk of hypertension. The RR of hypertension did not vary significantly according to the type of cancer, line of therapy, and treatment duration. The available data suggested that the use of anti-VEGF mAbs were associated with a significantly increased risk of hypertension.
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Affiliation(s)
- Gang Yin
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China.,Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of pharmacy, Chengdu University, Chengdu, Sichuan, P.R. China
| | - Ling Zhao
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China
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35
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Chung WP, Yang CT, Chen HY, Su CY, Su HW, Ou HT. Treatment-associated survival outcomes in real-world patients with de novo metastatic triple-negative breast cancer: Age as a significant treatment effect-modifier. J Formos Med Assoc 2021; 121:319-328. [PMID: 34006465 DOI: 10.1016/j.jfma.2021.04.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/18/2021] [Accepted: 04/27/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Evidence for optimizing the first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC) is lacking. This study assessed the utilization patterns of chemotherapy and associated survival outcomes in de novo mTNBC patients. METHODS Taiwan's cancer registry was utilized to extract study patients with newly-diagnosed breast cancer during 2011-2015 and confirmed metastatic triple-negative status. The patients' medical records (e.g., diseases, treatments) and death status were obtained from the National Health Insurance Research Database. Utilization of first-line chemotherapy regimens was analyzed and associated survival outcomes were assessed using Cox models. RESULTS 93.60% of the mTNBC patients (n = 297) received chemotherapy, where combination regimens (75.54%) were more common than single-agent regimens (24.46%) in the first-line setting. A non-statistically lower all-cause death associated with combination versus single-agent chemotherapy (hazard ratio: 0.830 [0.589, 1.168]) was observed. Age was identified as a significant effect-modifier in treatment-associated survival outcomes (p = 0.008); younger patients (aged < 40 and 40-59 years) versus older patients (aged ≥ 60 years) had a lower all-cause mortality when receiving combination versus single-agent chemotherapy. A lower all-cause mortality associated with taxane- versus non-taxane-based therapy was revealed among those on single-agent chemotherapy (hazard ratio: 0.557 [0.311, 0.999]). CONCLUSION Generally, single-agent and combination chemotherapies yielded comparable survival outcomes as the first-line treatment for de novo mTNBC. Younger patients may benefit more from combination regimens, in terms of better survival outcomes. Single-agent chemotherapy may be preferable as the first-line choice for elderly patients who are vulnerable to the toxicity of multiple chemotherapy agents.
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Affiliation(s)
- Wei-Pang Chung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Ting Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsuan-Ying Chen
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Yen Su
- Medical Division, Roche Products Ltd, Taipei, Taiwan
| | - Hsin-Wei Su
- Medical Division, Roche Products Ltd, Taipei, Taiwan
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan.
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36
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Sadiq MT, Servante J, Madhusudan S. Precision medicine for the treatment of triple negative breast cancer: opportunities and challenges. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1920834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Maaz Tahir Sadiq
- Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | | | - Srinivasan Madhusudan
- Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
- Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
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37
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Hamid MA, Moustafa MT, Nashine S, Costa RD, Schneider K, Atilano SR, Kuppermann BD, Kenney MC. Anti-VEGF Drugs Influence Epigenetic Regulation and AMD-Specific Molecular Markers in ARPE-19 Cells. Cells 2021; 10:cells10040878. [PMID: 33921543 PMCID: PMC8069662 DOI: 10.3390/cells10040878] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/03/2021] [Accepted: 04/06/2021] [Indexed: 12/16/2022] Open
Abstract
Our study assesses the effects of anti-VEGF (Vascular Endothelial Growth Factor) drugs and Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC) activity, on cultured ARPE-19 (Adult Retinal Pigment Epithelial-19) cells that are immortalized human retinal pigment epithelial cells. ARPE-19 cells were treated with the following anti-VEGF drugs: aflibercept, ranibizumab, or bevacizumab at 1× and 2× concentrations of the clinical intravitreal dose (12.5 μL/mL and 25 μL/mL, respectively) and analyzed for transcription profiles of genes associated with the pathogenesis age-related macular degeneration (AMD). HDAC activity was measured using the Fluorometric Histone Deacetylase assay. TSA downregulated HIF-1α and IL-1β genes, and upregulated BCL2L13, CASPASE-9, and IL-18 genes. TSA alone or bevacizumab plus TSA showed a significant reduction of HDAC activity compared to untreated ARPE-19 cells. Bevacizumab alone did not significantly alter HDAC activity, but increased gene expression of SOD2, BCL2L13, CASPASE-3, and IL-18 and caused downregulation of HIF-1α and IL-18. Combination of bevacizumab plus TSA increased gene expression of SOD2, HIF-1α, GPX3A, BCL2L13, and CASPASE-3, and reduced CASPASE-9 and IL-β. In conclusion, we demonstrated that anti-VEGF drugs can: (1) alter expression of genes involved in oxidative stress (GPX3A and SOD2), inflammation (IL-18 and IL-1β) and apoptosis (BCL2L13, CASPASE-3, and CASPASE-9), and (2) TSA-induced deacetylation altered transcription for angiogenesis (HIF-1α), apoptosis, and inflammation genes.
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Affiliation(s)
- Mohamed A. Hamid
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
- Ophthalmology Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
| | - M. Tarek Moustafa
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
- Ophthalmology Department, Faculty of Medicine, Minia University, Minia 61111, Egypt
| | - Sonali Nashine
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
| | - Rodrigo Donato Costa
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
- Instituto Donato Oftalmologia, Poςos de Caldas, MG 37701-528, Brazil
| | - Kevin Schneider
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
| | - Shari R. Atilano
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
| | - Baruch D. Kuppermann
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA
| | - M. Cristina Kenney
- Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA; (M.A.H.); (M.T.M.); (S.N.); (R.D.C.); (K.S.); (S.R.A.); (B.D.K.)
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697, USA
- Correspondence: ; Tel.: +1-949-824-7603
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Sukumar J, Gast K, Quiroga D, Lustberg M, Williams N. Triple-negative breast cancer: promising prognostic biomarkers currently in development. Expert Rev Anticancer Ther 2021; 21:135-148. [PMID: 33198517 PMCID: PMC8174647 DOI: 10.1080/14737140.2021.1840984] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. Validated prognostic and predictive biomarkers are needed to guide treatment decisions and prognostication.Areas covered: In this review, we discuss established and developing prognostic and predictive biomarkers in TNBC and associated emerging and approved therapies. Biomarkers reviewed include epidermal growth factor receptor (EGFR), vascular endothelial growth factors (VEGF), fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), androgen receptor, NOTCH signaling, oxidative stress/redox signaling, microRNAs, TP53 mutation, breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutation/homologous recombination deficiency (HRD), NTRK gene fusion, PI3K/AKT/mTOR, immune biomarkers (programmed death-ligand 1 (PDL1), tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), neoantigens, defects in DNA mismatch repair proteins (dMMR)/microsatellite instability-high (MSI-H)), circulating tumor cells/cell-free DNA, novel targets of antibody-drug conjugates, and residual disease.Expert opinion: Biomarker-driven care in the management of TNBC is increasing and has helped expand options for patients diagnosed with this subtype of breast cancer. Research efforts are ongoing to identify additional biomarkers and targeted treatment options with the ultimate goal of improving clinical outcomes and survivorship.
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Affiliation(s)
- Jasmine Sukumar
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Kelly Gast
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Dionisia Quiroga
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Maryam Lustberg
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
| | - Nicole Williams
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute, Columbus, OH, USA
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Abstract
ABSTRACT Triple-negative breast cancer is increasingly recognized as a heterogeneous entity that can be categorized according to histologic, molecular, and clinical subtypes. While chemotherapy remains the backbone of treatment for this disease, there are now several available targeted agents including immunotherapy, poly(adenosine diphosphate-ribose) polymerase inhibitors, and most recently a Food and Drug Administration-approved antibody-drug conjugate sacituzumab govitecan-hziy as a third-line treatment of metastatic triple-negative breast cancer. We review several actionable targets for triple-negative breast cancer and describe promising nonimmunotherapeutic agents including cyclin-dependent kinase inhibitors, androgen receptor inhibitors, mitogen-activated protein kinase inhibitors, phosphoinositide 3-kinase inhibitors, AKT (also known as protein kinase B) inhibitors, and antibody-drug conjugates.
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Celik E, Samanci NS, Karadag M, Demirci NS, Demirelli FH, Ozguroglu M. The relationship between eGFR and capecitabine efficacy/toxicity in metastatic breast cancer. Med Oncol 2021; 38:11. [PMID: 33452614 DOI: 10.1007/s12032-021-01457-2] [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: 11/02/2020] [Accepted: 01/01/2021] [Indexed: 11/27/2022]
Abstract
The objective of this study was to evaluate the efficacy and toxicity of capecitabine in metastatic breast cancer (mBC) according to the estimated glomerular filtration rate (eGFR). A total of 135 patients included in the final analysis were stratified into 3 categories according to baseline eGFR, i.e., eGFR <60 mL/min/1.73 m2 (Group 1), eGFR 60-90 mL/min/1.73 m2 (Group 2) and eGFR >90 mL/min/1.73 m2 (Group 3). If a patient developed a level of toxicity that would lead to capecitabine dose reduction, this was recognized as dose-limiting toxicity (DLT). The dose was reduced due to toxicity in 95 cycles. A total of 95 DLTs were seen in 76 (56.2%) of the 135 patients. When 76 patients with DLT were evaluated according to eGFR, DLT was observed in 93.3% of those in Group 1, 72.5% of those in Group 2 and 41.3% of those in Group 3 (p < 0.001). The median time to progression (TTP) of all patients was 7.4 months. No significant difference in TTP was observed in patients stratified into 3 groups according to eGFR. When the patients were divided into two groups as DLT and without DLT, the median TTP was 8.68 months (95% CI, 7.53-9.81 months) in those with toxicity and 6.23 months (95% CI, 4.04-8.43 months) in those without toxicity (log-rank p = 0.004). We found a significant relationship between low eGFR and increased risk of DLT. Having a DLT was associated with a longer TTP. It indicates the need for more data/larger study investigating these discrepancies.
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Affiliation(s)
- Emir Celik
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey.
| | - Nilay Sengul Samanci
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Mehmet Karadag
- Faculty of Medicine, Department of Biostatistics, Hatay Mustafa Kemal University, Antakya, Turkey
| | - Nebi Serkan Demirci
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Fuat Hulusi Demirelli
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
| | - Mustafa Ozguroglu
- Cerrahpaşa Faculty of Medicine, Department of Medical Oncology, Istanbul University-Cerrahpaşa, Kocamustafapasa Cd. No:53 Cerrahpasa, 34098, Fatih/Istanbul, Turkey
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Han L, Korangath P, Nguyen NK, Diehl A, Cho S, Teo WW, Cope L, Gessler M, Romer L, Sukumar S. HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium. Front Oncol 2021; 10:581459. [PMID: 33520697 PMCID: PMC7845423 DOI: 10.3389/fonc.2020.581459] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/30/2020] [Indexed: 12/20/2022] Open
Abstract
Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL's angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.
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Affiliation(s)
- Liangfeng Han
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Preethi Korangath
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Nguyen K Nguyen
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Adam Diehl
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Soonweng Cho
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Wei Wen Teo
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Leslie Cope
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Manfred Gessler
- Developmental Biochemistry, Comprehensive Cancer Center Mainfraken and Theodor-Boveri-Institute/Biocenter, University of Wurzburg, Wurzburg, Germany
| | - Lewis Romer
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,The Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Dobbin SJ, Petrie MC, Myles RC, Touyz RM, Lang NN. Cardiotoxic effects of angiogenesis inhibitors. Clin Sci (Lond) 2021; 135:71-100. [PMID: 33404052 PMCID: PMC7812690 DOI: 10.1042/cs20200305] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
The development of new therapies for cancer has led to dramatic improvements in survivorship. Angiogenesis inhibitors represent one such advancement, revolutionising treatment for a wide range of malignancies. However, these drugs are associated with cardiovascular toxicities which can impact optimal cancer treatment in the short-term and may lead to increased morbidity and mortality in the longer term. Vascular endothelial growth factor inhibitors (VEGFIs) are associated with hypertension, left ventricular systolic dysfunction (LVSD) and heart failure as well as arterial and venous thromboembolism, QTc interval prolongation and arrhythmia. The mechanisms behind the development of VEGFI-associated LVSD and heart failure likely involve the combination of a number of myocardial insults. These include direct myocardial effects, as well as secondary toxicity via coronary or peripheral vascular damage. Cardiac toxicity may result from the 'on-target' effects of VEGF inhibition or 'off-target' effects resulting from inhibition of other tyrosine kinases. Similar mechanisms may be involved in the development of VEGFI-associated right ventricular (RV) dysfunction. Some VEGFIs can be associated with QTc interval prolongation and an increased risk of ventricular and atrial arrhythmia. Further pre-clinical and clinical studies and trials are needed to better understand the impact of VEGFI on the cardiovascular system. Once mechanisms are elucidated, therapies can be investigated in clinical trials and surveillance strategies for identifying VEGFI-associated cardiovascular complications can be developed.
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Affiliation(s)
- Stephen J.H. Dobbin
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, United Kingdom, G12 8TA
| | - Mark C. Petrie
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, United Kingdom, G12 8TA
| | - Rachel C. Myles
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, United Kingdom, G12 8TA
| | - Rhian M. Touyz
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, United Kingdom, G12 8TA
| | - Ninian N. Lang
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, United Kingdom, G12 8TA
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Li H, Geng C, Zhao H, Jiang H, Song G, Zhang J, Liu Y, Gui X, Wang J, Li K, Tong Z, Zhao F, Yang J, Chen G, Liu Q, Liang X. Multicenter phase II study of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis. Chin J Cancer Res 2021; 33:243-255. [PMID: 34158743 PMCID: PMC8181870 DOI: 10.21147/j.issn.1000-9604.2021.02.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective Breast cancer (BC) with chest wall metastasis (CWM) usually shows rich neovascularization. This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2 (HER2)-negative advanced BC involving CWM. Methods This trial involved four centers in China and was conducted from September 2016 to March 2020. Patients received apatinib 500 mg/d [either alone or with endocrine therapy if hormone receptor-positive (HR+)] until disease progression or unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint. Results We evaluated 26 patients for efficacy. The median PFS (mPFS) and median overall survival (mOS) were 4.9 [range: 2.0−28.5; 95% confidence interval (95% CI): 2.1−8.3] months and 18 (range: 3−55; 95% CI: 12.9−23.1) months, respectively. The objective response rate (ORR) was 42.3% (11/26), and the disease-control rate was 76.9% (20/26). In the subgroup analysis, HR+ patients compared with HR-negative patients had significantly improved mPFS of 7.0 (95% CI: 2.2−11.8) monthsvs. 2.3 (95% CI: 1.2−3.4) months, respectively (P=0.001); and mPFS in patients without or with chest wall radiotherapy was 6.4 (95% CI: 1.6−19.5) monthsvs. 3.0 (95% CI: 1.3−4.6) months, respectively (P=0.041). In the multivariate analysis, HR+ status was the only independent predictive factor for favorable PFS (P=0.014).
Conclusions Apatinib was highly effective for BC patients with CWM, especially when combined with endocrine therapy. PFS improved significantly in patients with HR+ status who did not receive chest wall radiotherapy. However, adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.
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Affiliation(s)
- Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Cuizhi Geng
- Breast Disease Diagnostic and Therapeutic Center, the Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050019, China
| | - Hongmei Zhao
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Hanfang Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Guohong Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jiayang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yaxin Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xinyu Gui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jing Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Kun Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhongsheng Tong
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 30060, China
| | - Fangyuan Zhao
- Department of the Public Health Sciences, University of Chicago, Chicago 60637, USA
| | - Junlan Yang
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Guoliang Chen
- Jiangsu Hengrui Medicine Co. Ltd., Shanghai 200120, China
| | - Qianyu Liu
- Jiangsu Hengrui Medicine Co. Ltd., Shanghai 200120, China
| | - Xu Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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44
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Chen Y, Guan Y, Wang J, Ma F, Luo Y, Chen S, Zhang P, Li Q, Cai R, Li Q, Mo H, Fan Y, Zhao W, Xu B. Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:109. [PMID: 33569411 PMCID: PMC7867954 DOI: 10.21037/atm-20-4590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis. Methods TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups. Results A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity. Conclusions For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
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Affiliation(s)
- Yimeng Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yin Guan
- Department of Medical Oncology, Beijing Chao-Yang Hospital, Beijing, China
| | - Jiayu Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanshan Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pin Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qing Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruigang Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Medical Oncology, Beijing Sanhuan Cancer Hospital, Beijing, China
| | - Qiao Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongnan Mo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Fan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weihong Zhao
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ren T, Wang S, Shen Z, Xu C, Zhang Y, Hui F, Qi X, Zhao Q. Efficacy and Safety of Bevacizumab Plus Oxaliplatin- or Irinotecan-Based Doublet Backbone Chemotherapy as the First-Line Treatment of Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis. Drug Saf 2021; 44:29-40. [PMID: 33180265 DOI: 10.1007/s40264-020-00997-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVE Guidelines recommend combined doublet backbone chemotherapy based on 5-fluorouracil and oxaliplatin (OX) or irinotecan (IR) as the first-line treatment options for metastatic colorectal cancer. However, it is still unknown which is better when combined with bevacizumab (BEV). This systematic review and meta-analysis were performed to compare BEV-IR with BEV-OX regimens in terms of efficacy and safety. METHODS We searched studies from databases including MEDLINE, EMBASE, CENTRAL, and conference papers. The outcomes were overall response rate, overall survival, progression-free survival, and the incidence of the most common adverse events. The dichotomous data were reported as the risk ratio (RR) and the survival outcomes were extracted as the hazard ratio with 95% confidence interval (CI). RESULTS Eleven studies including 5632 patients were identified. No difference was found in overall survival or overall response rate between BEV-IR and BEV-OX regimens. The pooled progression-free survival was significantly longer in the BEV-IR group than the BEV-OX group (hazard ratio = 0.92, 95% CI 0.87-0.98, p = 0.08). Compared with the BEV-OX group, the BEV-IR group was related to a higher risk of bleeding events (RR = 0.80, 95% CI 0.64-0.98, p = 0.03), venous thromboembolism (RR = 0.60, 95% CI 0.46-0.79, p = 0.0002), and diarrhea (RR = 0.71, 95% CI 0.62-0.80, p < 0.00001). Conversely, the BEV-OX group was related to a higher risk of thrombocytopenia (RR 2.39, 95% CI 1.67-3.42, p < 0.00001) and neuropathy (RR 3.80, 95% CI 1.90-7.64, p = 0.0002). CONCLUSIONS The BEV-IR regimen was superior in improving progression-free survival as the first-line treatment for metastatic colorectal cancer. The two different doublet regimens combined with BEV had their specific features of adverse events.
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Affiliation(s)
- Tianshu Ren
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Shu Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Zexu Shen
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Chang Xu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Yingshi Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Fuhai Hui
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Qingchun Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China.
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Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Turner N, Ciruelos EM, Muñoz M, Bermejo B, Margeli M, Anton A, Kahan Z, Csöszi T, Casas MI, Murillo L, Morales S, Alba E, Gal-Yam E, Guerrero-Zotano A, Calvo L, de la Haba-Rodriguez J, Ramos M, Alvarez I, Garcia-Palomo A, Huang Bartlett C, Koehler M, Caballero R, Corsaro M, Huang X, Garcia-Sáenz JA, Chacón JI, Swift C, Thallinger C, Gil-Gil M. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol 2020; 32:488-499. [PMID: 33385521 DOI: 10.1016/j.annonc.2020.12.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.
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Affiliation(s)
- M Martin
- Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Medicine Department, Universidad Complutense, Madrid, Spain; Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; GEICAM Spanish Breast Cancer Group, Madrid, Spain.
| | - C Zielinski
- Medical Oncology, Central European Cancer Center, Wiener Privatklinik Hospital, Vienna, Austria; CECOG Central European Cooperative Oncology Group, Vienna, Austria
| | - M Ruiz-Borrego
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain
| | - E Carrasco
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
| | - N Turner
- Institute of Cancer Research and Royal Marsden, London, UK
| | - E M Ciruelos
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain; Medical Oncology, HM Hospitales Madrid, Madrid, Spain; SOLTI Group on Breast Cancer Research, Barcelona, Spain
| | - M Muñoz
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors (IDIBAPS), Barcelona, Spain
| | - B Bermejo
- Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia, Spain; Biomedical Research Institute INCLIVA, Valencia, Spain
| | - M Margeli
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; B-ARGO Group, Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - A Anton
- Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Z Kahan
- Department of Oncotherapy, University of Szeged, Szeged, Hungary
| | - T Csöszi
- Department of Oncology, Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelőintezet, Szolnok, Hungary
| | - M I Casas
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
| | - L Murillo
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Clínico de Zaragoza Lozano Blesa, Zaragoza, Spain
| | - S Morales
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | - E Alba
- Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; GEICAM Spanish Breast Cancer Group, Madrid, Spain; UGCI Medical Oncology, Hospitales Regional y Virgen de la Victoria, IBIMA, Málaga, Spain
| | - E Gal-Yam
- Department of Oncology, Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Israel
| | - A Guerrero-Zotano
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain
| | - L Calvo
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Complejo Hospitalario A Coruña, Coruña, Spain
| | - J de la Haba-Rodriguez
- Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario Reina Sofia, Córdoba; Instituto Maimonides de Investigación Biomédica (IMIBIC); Universidad de Córdoba, Córdoba, Spain
| | - M Ramos
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Centro Oncológico de Galicia, A Coruña, Coruña, Spain
| | - I Alvarez
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Universitario Donostia-Biodonostia, San Sebastián, Spain
| | - A Garcia-Palomo
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital de León, León, Spain
| | | | - M Koehler
- Pfizer, USA; Repare Therapeutics, Cambridge, USA
| | - R Caballero
- GEICAM Spanish Breast Cancer Group, Madrid, Spain
| | | | | | - J A Garcia-Sáenz
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Clínico Universitario San Carlos, Madrid, Spain
| | - J I Chacón
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Medical Oncology, Hospital Virgen de la Salud, Toledo, Spain
| | - C Swift
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden, London, UK
| | - C Thallinger
- CECOG Central European Cooperative Oncology Group, Vienna, Austria; Department of Oncology, Medical University of Vienna, Department of Oncology, Vienna, Austria
| | - M Gil-Gil
- GEICAM Spanish Breast Cancer Group, Madrid, Spain; Institut Català d'Oncologia (ICO) & IDIBELL, L'Hospitalet, Barcelona, Spain
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Boyle ST, Johan MZ, Samuel MS. Tumour-directed microenvironment remodelling at a glance. J Cell Sci 2020; 133:133/24/jcs247783. [PMID: 33443095 DOI: 10.1242/jcs.247783] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The tissue microenvironment supports normal tissue function and regulates the behaviour of parenchymal cells. Tumour cell behaviour, on the other hand, diverges significantly from that of their normal counterparts, rendering the microenvironment hostile to tumour cells. To overcome this problem, tumours can co-opt and remodel the microenvironment to facilitate their growth and spread. This involves modifying both the biochemistry and the biophysics of the normal microenvironment to produce a tumour microenvironment. In this Cell Science at a Glance article and accompanying poster, we outline the key processes by which epithelial tumours influence the establishment of the tumour microenvironment. As the microenvironment is populated by genetically normal cells, we discuss how controlling the microenvironment is both a significant challenge and a key vulnerability for tumours. Finally, we review how new insights into tumour-microenvironment interactions has led to the current consensus on how these processes may be targeted as novel anti-cancer therapies.
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Affiliation(s)
- Sarah T Boyle
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - M Zahied Johan
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - Michael S Samuel
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia .,Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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Chemotherapy Options beyond the First Line in HER-Negative Metastatic Breast Cancer. JOURNAL OF ONCOLOGY 2020; 2020:9645294. [PMID: 33312203 PMCID: PMC7719522 DOI: 10.1155/2020/9645294] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/05/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022]
Abstract
Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease. Different agents are available as mono-chemotherapy options in patients with locally advanced or metastatic BC (MBC) who progress after a first- and second-line treatment with anthracyclines and taxanes. However, no clear indication exists on what the best option is in some populations, such as heavily pretreated, elderly patients, triple-negative BC (TNBC), and those who do not respond to the first-line therapy. In this article, we summarize available literature evidence on different chemotherapy agents used beyond the first-line, in locally advanced or MBC patients, including rechallenge with anthracyclines and taxanes, antimetabolite and antimicrotubule agents, such as vinorelbine, capecitabine, eribulin, ixabepilone, and the newest developed agents, such as vinflunine, irinotecan, and etirinotecan.
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Schneeweiss A, Bauerfeind I, Fehm T, Janni W, Thomssen C, Witzel I, Wöckel A, Müller V. Therapy Algorithms for the Diagnosis and Treatment of Patients with Early and Advanced Breast Cancer. Breast Care (Basel) 2020; 15:608-618. [PMID: 33447235 DOI: 10.1159/000511925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
Background In order to offer optimal treatment approaches based on available evidence, the Commission Breast of the Working Group Gynecologic Oncology (AGO) of the German Cancer Society developed therapy algorithms for eight complex treatment situations in primary and advanced breast cancer. Summary Therapy algorithms for the following complex treatment situations are outlined in this paper: (neo)adjuvant therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer; axillary surgery and neoadjuvant chemotherapy; adjuvant endocrine therapy in premenopausal patients; adjuvant endocrine therapy in postmenopausal patients; hormone receptor (HR)-positive/HER2-negative metastatic breast cancer: strategies; HR-positive/HER2-negative metastatic breast cancer: endocrine-based first-line treatment; HER2-positive metastatic breast cancer: first to third-line; metastatic triple-negative breast cancer. Key Messages The therapy options shown in these algorithms are based on the current AGO recommendations updated in January 2020 but cannot represent all evidence-based treatment options. Prior therapies, performance status, comorbidities, patient preference, etc. must be taken into account for the actual treatment choice. Therefore, in individual cases, other evidence-based treatment options not listed here may also be appropriate and justified.
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Affiliation(s)
- Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | | | - Tanja Fehm
- Department of Gynecology and Obstetrics, University Hospital, Düsseldorf, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital, Ulm, Germany
| | - Christoph Thomssen
- Department of Gynecology and Obstetrics, University Hospital, Halle, Germany
| | - Isabell Witzel
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital, Würzburg, Germany
| | - Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Tkaczuk A, Trivedi S, Mody MD, Steuer CE, Shin DM, Klein AM, Saba NF. Parenteral Bevacizumab for the Treatment of Severe Respiratory Papillomatosis in an Adult Population. Laryngoscope 2020; 131:E921-E928. [PMID: 33107615 DOI: 10.1002/lary.29133] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/14/2020] [Accepted: 08/30/2020] [Indexed: 11/07/2022]
Abstract
OBJECTIVES/HYPOTHESIS Recurrent respiratory papillomatosis (RRP) is a rare, potentially life-threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults. STUDY DESIGN This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3-week intervals. Bevacizumab dosing and frequency was then individually titrated down. RESULTS Fourteen adults received a median of 8.5 (range 2-17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2-11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1-2), elevated creatinine (grades 1-2), and epistaxis (grade 3). CONCLUSIONS Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted. LEVEL OF EVIDENCE 4. Laryngoscope, 131:E921-E928, 2021.
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Affiliation(s)
- Andrew Tkaczuk
- Division of Laryngology, Department of Otolaryngology-Head and Neck Surgery, Emory University, Atlanta, Georgia, U.S.A
| | - Sumita Trivedi
- Department of Hematology and Medical Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A
| | - Mayur D Mody
- Division of Medical Oncology, Department of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Conor E Steuer
- Division of Medical Oncology, Department of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Dong M Shin
- Division of Medical Oncology, Department of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Adam M Klein
- Division of Laryngology, Department of Otolaryngology-Head and Neck Surgery, Emory University, Atlanta, Georgia, U.S.A
| | - Nabil F Saba
- Division of Medical Oncology, Department of Medicine, Emory University, Atlanta, Georgia, U.S.A
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