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Valsecchi AA, Pisegna S, Antonuzzo A, Arpino G, Bianchini G, Biganzoli L, Colloca GF, Criscitiello C, Danesi R, Fabi A, Giusti R, Pau L, Di Maio M, Santini D. Delphi consensus on the management of adverse events in patients with metastatic triple-negative breast cancer treated with sacituzumab govitecan. Oncologist 2025; 30:oyaf088. [PMID: 40366333 PMCID: PMC12076644 DOI: 10.1093/oncolo/oyaf088] [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: 12/22/2024] [Accepted: 03/26/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Metastatic triple-negative breast cancer (BC; mTNBC) is one of the most aggressive cancers, difficult to treat due to the absence of hormone target receptors. Sacituzumab govitecan (SG) is a new therapeutic approach that exploits the combination of an antibody directed against the Trop-2 antigen expressed in solid epithelial tumors and the active metabolite SN-38, to precisely target cancer cells. The development of consensus recommendations requires synthesizing expert opinions, especially when direct evidence is limited. METHODS This study aimed to create a Delphi process to gather the perspectives of a panel of BC and supportive specialists on the use of SG in clinical practice. A scientific board discussed and defined a series of statements that were submitted to the panel through 2 rounds of voting. The process was designed to collect expert opinions to achieve consensus on key points regarding the safety, dosing regimens, and patient management for SG. Each round of the survey included targeted questions informed by current literature. Predefined criteria for consensus were set at ≥75% agreement. RESULTS In October 2024, 29 experts' opinions were collected by voting on 40 statements and reaching a 67% agreement. The reduction of the initial SG dose and the management of prophylaxis for patients with the UGT1A1 *28/*28 genotype were the most discussed topics. CONCLUSIONS The results provide a foundational framework for clinical decision-making, and highlight the importance of collaborative expert synthesis in forming practice guidelines. Future studies should focus on prospective SG trials to address the identified areas of uncertainty.
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Affiliation(s)
- Anna Amela Valsecchi
- Department of Oncology, University of Turin, A.O.U. Città della Salute e della Scienza di Torino, Ospedale Molinette, Turin, Italy
| | - Simona Pisegna
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Medical Oncology Unit, Sant’Andrea Hospital of Rome, Rome, Italy
| | - Andrea Antonuzzo
- Internistic and Geriatric Supportive Care, Fondazione IRCCS - National Cancer Institute, Milan, Italy
| | - Grazia Arpino
- Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giampaolo Bianchini
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milano, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milano, Italy
| | - Laura Biganzoli
- Department of Oncology, Hospital of Prato, Azienda USL Toscana Centro, Italy
| | - Giuseppe Ferdinando Colloca
- Department of Imaging Diagnostic, Oncologic Radiotherapy and Haematology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hematology-Oncology (DIPO), University of Milan, Milan, Italy
| | - Romano Danesi
- Department of Oncology and Hemato-Oncology, University of Milano “La Statale,”Milan, Italy
| | - Alessandra Fabi
- Precision Medicine Unit in Senology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | | | | | - Massimo Di Maio
- Department of Oncology, University of Turin, A.O.U. Città della Salute e della Scienza di Torino, Ospedale Molinette, Turin, Italy
| | - Daniele Santini
- Medical-Surgical Sciences and Biotechnology, La Sapienza University of Rome, Rome, Italy
- Medical Oncology A, Policlinico Umberto 1, Rome, Italy
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Li M, Zheng A, Song M, Jin F, Pang M, Zhang Y, Wu Y, Li X, Zhao M, Li Z. From text to insight: A natural language processing-based analysis of burst and research trends in HER2-low breast cancer patients. Ageing Res Rev 2025; 106:102692. [PMID: 39993452 DOI: 10.1016/j.arr.2025.102692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 01/01/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025]
Abstract
With the intensification of population aging, the proportion of elderly breast cancer patients is continuously increasing, among which those with low HER2 expression account for approximately 45 %-55 % of all cases within traditional HER2-negative breast cancer. Concurrently, the significant therapeutic effect of T-DXd on patients with HER2-low tumors has brought this group into the public spotlight. Since the clinical approval of T-DXd in 2019, there has been a significant vertical surge in the volume of publications within this domain. We analyzed 512 articles on HER2-low breast cancer from the Web of Science Core Collection using bibliometrics, topic modeling, and knowledge graph techniques to summarize the current state and trends of research in this domain. Research efforts are particularly concentrated in the United States and China. Our analysis revealed six main research directions: HER2 detection, omics and clinical biomarkers, basic and translational research, neoadjuvant therapy and prognosis, progress of ADC drugs and clinical trials. To enhance the therapeutic efficacy and safety of antibodydrug conjugates (ADCs), researchers are actively exploring potential drug candidates other than T-DXd, with numerous ADC drugs emerging in clinical practice and trials. By incorporating emerging treatment strategies such as immunotherapy and employing circulating tumor cell (CTC) detection techniques, progress has been made toward improving the prognosis of patients with low HER2 expression. We believe that these research efforts hold promise as compelling evidence that HER2-low breast cancer may constitute a distinct and independent subtype.
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Affiliation(s)
- Muyao Li
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Ang Zheng
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mingjie Song
- Department of General Medicine, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Feng Jin
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mengyang Pang
- Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Yuchong Zhang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Ying Wu
- Department of General Medicine, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Phase I Clinical Trails Center, The First Hospital of China Medical University, Shenyang, Liaoning 110101, China.
| | - Xin Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Mingfang Zhao
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Zhi Li
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China; National Clinical Research Center for Laboratory Medicine, Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China; Research Unit of Medical Laboratory, Chinese Academy of Medical Sciences, China.
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Arenos C, Lim S, Lominoque A, Reveldez I, Sison-Dimaano A, Pagandaman N, Tatoy V, Uy T, Juan MS. Survival analysis of HER2 receptor negative and HER2 receptor low breast cancer patients at a Philippine Tertiary Government Hospital. Ecancermedicalscience 2025; 19:1840. [PMID: 40248267 PMCID: PMC12003980 DOI: 10.3332/ecancer.2025.1840] [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: 06/12/2024] [Indexed: 04/19/2025] Open
Abstract
Background and objectives Human epidermal receptor 2 (HER2)-low breast cancer, characterised by specific immunohistochemistry (IHC) scores (+1 or +2) or negative fluorescence in-situ hybridiszation (FISH), has unique biological traits, therapeutic outcomes and prognosis. Recent studies highlight the effectiveness of Trastuzumab-Deruxtecan (T-Dxd) for HER2-low patients. This study seeks to deepen understanding of HER2 negative and low patients for tailored treatment by determining the 3-year disease-free survival (DFS) rates and prognostic variables of different subsets of HER2 negative (HER2 0) and HER2-low breast cancer patients (HER2 +1, HER2 +2 and HER2 FISH negative). Methodology We analysed the records of 138 patients with non-metastatic breast cancer, exhibiting HER2 IHC 0, +1 or +2/FISH negative. Data on 3-year DFS in months, age, stage (early stage versus locally advanced) and menopausal status were collected. Kaplan-Meier survival curves were used to plot 3-year DFS, while Cox Proportional Analysis assessed the prognostic significance of age and menopausal status in the HER2-low population. Results Three-year DFS for HER2 0 was 84.4%, HER2 +1 was 81.8% and HER2 +2/FISH negative was 52.9%, displaying statistically significant differences (p = 0.00012). Subgroup analyses revealed consistently worse DFS for HER2 +2/FISH negative patients in both early and advanced stages (p = 0.0042, 0.0057). Cox proportional analysis showed a recurrence hazard ratio of 4.0-4.5 for HER2 +2/FISH negative patients. Among prognostic factors, post-menopausal status correlated with a decreased risk of recurrence (HR 0.4387), signifying a 56.13% lower recurrence risk compared to pre-menopausal patients (p = 0.00723). On the other hand, patient age was not correlated with a reduced risk of recurrence (HR 0.97; p = 0.0544). Conclusion This study reveals a worse 3-year DFS in HER2 +2/FISH negative patients across both early and advanced disease stages. The findings highlight the prognostic importance of HER2-low status and may guide future therapeutic strategies, including the use of targeted therapies like T-Dxd in non-metastatic patients.
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Affiliation(s)
| | - Steven Lim
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Andreu Lominoque
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Isabela Reveldez
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Angeli Sison-Dimaano
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Nehar Pagandaman
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Vincent Tatoy
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Timothy Uy
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
| | - Michael San Juan
- Division of Medical Oncology, Department of Medicine, University of the Philippines-Philippine General Hospital (UP-PGH), Manila 1008, Philippines
- https://orcid.org/0009-0001-6070-6924
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Matsubara J, Li YF, Koul S, Mukohyama J, Salazar LEV, Isobe T, Qian D, Clarke MF, Sahoo D, Altman RB, Dalerba P. The E2F4 transcriptional repressor is a key mechanistic regulator of colon cancer resistance to irinotecan (CPT-11). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.633435. [PMID: 39896677 PMCID: PMC11785039 DOI: 10.1101/2025.01.22.633435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Background Colorectal carcinomas (CRCs) are seldom eradicated by cytotoxic chemotherapy. Cancer cells with stem-like functional properties, often referred to as "cancer stem cells" (CSCs), display preferential resistance to several anti-tumor agents used in cancer chemotherapy, but the molecular mechanisms underpinning their selective survival remain only partially understood. Methods In this study, we used Transcription Factor Target Genes (TFTG) enrichment analysis to identify transcriptional regulators (activators or repressors) that undergo preferential activation by chemotherapy in CRC cells with a "bottom-of-the-crypt" phenotype (EPCAM+/CD44+/CD166+; CSC-enriched) as compared to CRC cells with a "top-of-the-crypt" phenotype (EPCAM+/CD44neg/CD166neg; CSC-depleted). The two cell populations were purified in parallel by fluorescence-activated cell sorting (FACS) from a patient-derived xenograft (PDX) line representative of a moderately differentiated human CRC, following in vivo chemotherapy with irinotecan (CPT-11). The transcriptional regulators identified as differentially activated were tested for differential expression in normal vs. cancer tissues, and in cell populations enriched in stem/progenitor cell-types as compared to differentiated lineages (goblet cells, enterocytes) in the mouse colon epithelium. Finally, the top candidate was tested for mechanistic contribution to drug-resistance by selective down-regulation using short-hairpin RNAs (shRNAs). Results Our analysis identified E2F4 and TFDP1, two core components of the DREAM transcriptional repression complex, as transcriptional modulators preferentially activated by irinotecan in EPCAM+/CD44+/CD166+ as compared to EPCAM+/CD44neg/CD166neg cancer cells. The expression levels of both genes (E2F4, TFDP1) were found up-regulated in CRCs as compared to human normal colon tissues, and in a sub-population of mouse colon epithelial cells enriched in stem/progenitor elements (Epcam+/Cd44+/Cd66alow/Kitneg) as compared to other sub-populations enriched in either goblet cells (Epcam+/Cd44+/Cd66alow/Kit+) or enterocytes (Epcam+/Cd44neg/Cd66ahigh). Most importantly, E2F4 down-regulation using shRNAs dramatically enhanced the sensitivity of human CRCs to in vivo treatment with irinotecan, across three independent PDX models. Conclusions Our data identified E2F4 and the DREAM repressor complex as critical regulators of human CRC resistance to irinotecan, and as candidate targets for the development of chemo-sensitizing agents.
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Affiliation(s)
- Junichi Matsubara
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA (USA)
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto (Japan)
| | - Yong Fuga Li
- Department of Genetics, Stanford University, Stanford, CA (USA)
- Department of Bioengineering, Stanford University, Stanford, CA (USA)
- Illumina Inc., San Diego, CA (USA)
| | - Sanjay Koul
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health (HMH), Nutley, NJ (USA)
- Department of Biological Sciences and Geology, Queensborough Community College (QCC), The City University of New York (CUNY), Bayside, NY (USA)
- Department of Pathology and Cell Biology, Columbia University, New York, NY (USA)
- Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY (USA)
- Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY (USA)
| | - Junko Mukohyama
- Department of Pathology and Cell Biology, Columbia University, New York, NY (USA)
- Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY (USA)
- Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY (USA)
- Department of Surgery, Institute of Medical Science, University of Tokyo, Tokyo (Japan)
| | - Luis E. Valencia Salazar
- Department of Pathology and Cell Biology, Columbia University, New York, NY (USA)
- Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY (USA)
- Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY (USA)
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY (USA)
| | - Taichi Isobe
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA (USA)
- Department of Comprehensive Oncology, Graduate School of Medicine, Kyushu University, Fukuoka (Japan)
| | - Dalong Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA (USA)
| | - Michael F. Clarke
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA (USA)
| | - Debashis Sahoo
- Department of Computer Science and Engineering, University of California San Diego (UCSD), San Diego, CA (USA)
- Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA (USA); Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY (USA)
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, CA (USA)
- Department of Bioengineering, Stanford University, Stanford, CA (USA)
| | - Piero Dalerba
- Center for Discovery and Innovation (CDI), Hackensack Meridian Health (HMH), Nutley, NJ (USA)
- Department of Pathology and Cell Biology, Columbia University, New York, NY (USA)
- Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY (USA)
- Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY (USA)
- Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY (USA)
- Department of Medical Sciences, Hackensack Meridian School of Medicine (HMSOM), Nutley, NJ (USA)
- Lombardi Comprehensive Cancer Center (LCCC), Georgetown University, Washington, DC (USA)
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Gupta G, Hussain MS, Pant K, Ali H, Thapa R, Bhat AA. Antibody-Drug Conjugates (ADCs): A Novel Therapy for Triple-Negative Breast Cancer (TNBC). Curr Cancer Drug Targets 2025; 25:108-112. [PMID: 39248064 DOI: 10.2174/0115680096343056240828190900] [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: 07/30/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/10/2024]
Affiliation(s)
- Gaurav Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Chandigarh, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Md Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India
| | - Kumud Pant
- Graphic Era (Deemed to be University) Clement Town Dehradun- 248002, India
- Graphic Era Hill University, School of Pharmaceutical Sciences, Clement Town Dehradun- 248002, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Riya Thapa
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India
| | - Asif Ahmad Bhat
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India
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Chen G, Cai XH, Tang J, Chomicki G, Renner SS. Anticancer drugs imperil Asian tree species. Science 2024; 385:1173. [PMID: 39265026 DOI: 10.1126/science.adr0965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2024]
Affiliation(s)
- Gao Chen
- Key Laboratory of Phytochemistry and Natural Medicines, Chinese Academy of Sciences, Kunming, China
- Yunnan Key Laboratory for Integrative Conservation of Plants Species with Extremely Small Populations, Kunming, China
| | - Xiang-Hai Cai
- Key Laboratory of Phytochemistry and Natural Medicines, Chinese Academy of Sciences, Kunming, China
| | - Jia Tang
- Key Laboratory of Phytochemistry and Natural Medicines, Chinese Academy of Sciences, Kunming, China
| | | | - Susanne S Renner
- Department of Biology, Washington University, St. Louis, St. Louis, MO, USA
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Schäffler H, Jakob D, Huesmann S, Pfister K, Veselinovic K, Schochter F, Leinert E, Fink V, Rack B, Englisch A, Volmer LL, Engler T, Frevert ML, Juhasz-Böss I, Brucker S, Heublein S, Janni W, Taran FA, Hartkopf A, Dannehl D. Novel Antibody-Drug-Conjugates in Routine Clinical Practice for the Treatment of Metastatic Breast Cancer: Adherence, Efficacy and Tolerability - Real-World Data from German Breast Centers. Geburtshilfe Frauenheilkd 2024; 84:855-865. [PMID: 39229630 PMCID: PMC11368468 DOI: 10.1055/a-2375-5194] [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: 05/11/2024] [Accepted: 07/28/2024] [Indexed: 09/05/2024] Open
Abstract
Introduction The third-generation antibody-drug conjugates (ADC), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), recently obtained approval for metastatic breast cancer treatment across various subtypes and therapeutic contexts. Materials and Methods This retrospective, multicentric study evaluated real-world tolerability, feasibility and efficacy in a pre-treated, real-world cohort at three major German breast cancer centers. Results 125 patients treated with T-DXd or SG from November 2020 to June 2023 were included (T-DXd: 77 patients; SG: 48 patients). The median treatment duration was 6.0 months for T-DXd and 3.5 months for SG therapy, with a median follow-up duration of 10.4 months for T-DXd (95% CI: 8.4-11.6) and 11.8 months for SG (95% CI: 8.0-14.4). Severe neutropenia (CTC ≥ III°) occurred in 33.3% during SG therapy, with a numerical reduction observed following primary, prophylactic use of G-CSF. T-DXd-associated pneumonitis occurred in 8 out of 77 patients (10.4 %). Median progression-free survival (mPFS) was 8.6 months (95% CI: 5.8-12.4) with T-DXd (HER2+: 10.8; HER2-low: 4.7) and 4.9 months (95% CI: 2.8-6.3) with SG (TNBC 4.9; HR+/HER2-: not reached). Median overall survival (OS) was 23.8 months (95% CI: 16.1-not estimable) with T-DXd (HER2+: 27.1; HER2-low: not reached), and 12.4 months (95% CI: 8.7-not estimable) with SG therapy (TNBC: 12.4, HR+/HER2-: not reached). 95.7% of the protocol-specified, therapeutic dose was administered for T-DXd and 89.6% for SG. Conclusion Overall, this indicates good feasibility, tolerability, and effectiveness of ADC therapies in the real-world setting.
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Affiliation(s)
- Henning Schäffler
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Dorothee Jakob
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Sophia Huesmann
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Kerstin Pfister
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | | | - Fabienne Schochter
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Elena Leinert
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Visnja Fink
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Brigitte Rack
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | | | - Lea-Louise Volmer
- Department of Women's Health, Tübingen University, Tübingen, Germany
| | - Tobias Engler
- Department of Women's Health, Tübingen University, Tübingen, Germany
| | - Marie Louise Frevert
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Sara Brucker
- Department of Women's Health, Tübingen University, Tübingen, Germany
| | - Sabine Heublein
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Florin-Andrei Taran
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Andreas Hartkopf
- Department of Women's Health, Tübingen University, Tübingen, Germany
| | - Dominik Dannehl
- Department of Women's Health, Tübingen University, Tübingen, Germany
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8
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Wong MH, Jones VC, Yu W, Bosserman LD, Lavasani SM, Patel N, Sedrak MS, Stewart DB, Waisman JR, Yuan Y, Mortimer JE. UGT1A1*28 polymorphism and the risk of toxicity and disease progression in patients with breast cancer receiving sacituzumab govitecan. Cancer Med 2024; 13:e70096. [PMID: 39157928 PMCID: PMC11331244 DOI: 10.1002/cam4.70096] [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: 12/13/2023] [Revised: 05/31/2024] [Accepted: 08/01/2024] [Indexed: 08/20/2024] Open
Abstract
BACKGROUND Sacituzumab govitecan (sacituzumab) emerged as an important agent in metastatic and locally recurrent HER2-negative breast cancer treatment. UGT1A1 polymorphisms have also been shown to predict sacituzumab toxicity. METHODS In this retrospective study, we sought to evaluate the associations between UGT1A1 status, toxicity, and therapeutic outcomes in sacituzumab recipients with advanced breast cancer who underwent genotype testing for UGT1A1 alleles (N = 68). RESULTS We found 17 (25%) of our patients to be homozygous for UGT1A1*28 and 24 (35.3%) were heterozygous. Of seven African American patients with triple-negative breast cancer, five were homozygous for UGT1A1*28 and two were heterozygous. Patients with a homozygous UGT1A1*28 genotype were significantly more likely to have treatment terminated because of adverse effects. However, the polymorphism was not associated with treatment discontinuation because of disease progression. CONCLUSION This retrospective, real-world analysis suggests potential clinical utility in UGT1A1 testing for patients receiving sacituzumab, but future trials are needed to confirm the association between genotypes and treatment outcomes.
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Affiliation(s)
- Megan H. Wong
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Veronica C. Jones
- Department of Breast SurgeryCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Wai Yu
- Department of Ambulatory PharmacyCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Linda D. Bosserman
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Sayeh M. Lavasani
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Niki Patel
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Mina S. Sedrak
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Daphne B. Stewart
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - James R. Waisman
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Yuan Yuan
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Joanne E. Mortimer
- Department of Medical Oncology & Therapeutics ResearchCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
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Zhang Y, Yun X, Ouyang L, Zhang X, Gong L, Qin Q. Development of an ELISA with acidification treatment for an antibody conjugate incorporating Exatecans. Anal Biochem 2024; 690:115530. [PMID: 38570023 DOI: 10.1016/j.ab.2024.115530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/17/2024] [Accepted: 03/31/2024] [Indexed: 04/05/2024]
Abstract
The successful development of Sacituzumab Govitecan and Trastuzumab Deruxtecan has made camptothecin derivatives one of the most popular payloads for antibody-drug conjugates (ADCs). Camptothecin and its derivatives all exist in a pH-dependent equilibrium between the carboxylate and lactone forms. Such transformation may lead to differences in the ratio of the two molecular forms in calibration standards and biological matrix (bio-matrix) samples, thereby leading to inaccurate conjugated antibody results. In this study, we reported an enzyme-linked immunosorbent assay (ELISA) free of the aforementioned influence for the detection of the Exatecans-conjugated antibody (conjugated SM001) in cynomolgus monkey serum. The assay was developed by first acidifying all samples with glacial acetic acid (HAc), then performing neutralization and thereafter capturing conjugated SM001 with anti-Exatecan monoclonal antibody (mAb) and detecting it with biotinylated Nectin4 (hNectin4-Bio) and horseradish peroxidase-labeled streptavidin (SA-HRP). Results showed that all tested performance parameters met the acceptance criteria. The conjugated SM001 concentrations obtained were in parallel to but slightly lower than total antibody (TAb) throughout the pharmacokinetic (PK) study, revealing that the assay strategy implemented for conjugated SM001 measurement worked well for the elimination of interference triggered by the heterogeneous existence of the lactone and carboxylate forms of Exatecan (lactone-Exatecan and carboxylate-Exatecan).
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Affiliation(s)
- Yingying Zhang
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China; Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, China
| | - Xi Yun
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China
| | - Lu Ouyang
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China
| | - Xianjing Zhang
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China
| | - Likun Gong
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China; Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 101408, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
| | - Qiuping Qin
- Department of Immunoassay and Immunochemistry, Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai, 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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10
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Parit S, Manchare A, Gholap AD, Mundhe P, Hatvate N, Rojekar S, Patravale V. Antibody-Drug Conjugates: A promising breakthrough in cancer therapy. Int J Pharm 2024; 659:124211. [PMID: 38750981 DOI: 10.1016/j.ijpharm.2024.124211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 06/03/2024]
Abstract
Antibody-drug conjugates (ADCs) provide effective cancer treatment through the selective delivery of cytotoxic payloads to the cancer cells. They offer unparalleled precision and specificity in directing drugs to cancer cells while minimizing off-target effects. Despite several advantages, there is a requirement for innovations in the molecular design of ADC owing to drug resistance, cancer heterogeneity along the adverse effects of treatment. The review critically analyses ADC function mechanisms, unraveling the intricate interplay between antibodies, linkers, and payloads in facilitating targeted drug delivery to cancer cells. The article also highlights notable advancements in antibody engineering, which aid in creating highly selective and potent ADCs. Additionally, the review details significant progress in clinical ADC development with an in-depth examination of pivotal trials and approved formulations. Antibody Drug Conjugates (ADCs) are a ground-breaking approach to targeted drug delivery, especially in cancer treatment. They offer unparalleled precision and specificity in directing drugs to cancer cells while minimizing off-target effects. This review provides a comprehensive examination of the current state of ADC development, covering their design, mechanisms of action, and clinical applications. The article emphasizes the need for greater precision in drug delivery and explains why ADCs are necessary.
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Affiliation(s)
- Swapnali Parit
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, Maharashtra, India
| | - Ajit Manchare
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, Maharashtra, India
| | - Amol D Gholap
- Department of Pharmaceutics, St. John Institute of Pharmacy and Research, Palghar 401404, Maharashtra, India
| | - Prashant Mundhe
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, Maharashtra, India
| | - Navnath Hatvate
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, Maharashtra, India
| | - Satish Rojekar
- Institute of Chemical Technology, Marathwada Campus, Jalna 431203, Maharashtra, India; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Vandana Patravale
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, India.
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11
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Oey O, Wijaya W, Redfern A. Eribulin in breast cancer: Current insights and therapeutic perspectives. World J Exp Med 2024; 14:92558. [PMID: 38948420 PMCID: PMC11212747 DOI: 10.5493/wjem.v14.i2.92558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/21/2024] [Accepted: 03/20/2024] [Indexed: 06/19/2024] Open
Abstract
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Nedlands 6009, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands 6009, WA, Australia
| | - Wynne Wijaya
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
- Department of Internal Medicine, Universitas Gadjah Mada, Sleman 55281, Indonesia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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12
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Zhang H, Shen G, Yang P, Li J, Li Z, Liu Z, Wang M, Zhao F, Ren D, Liu Z, Zhao J, Zhao Y. Incidence of antibody-drug conjugate-related fatigue in patients with breast cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2024; 196:104292. [PMID: 38403093 DOI: 10.1016/j.critrevonc.2024.104292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/27/2024] [Accepted: 02/07/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Numerous studies have reported the efficacy of antibody-drug conjugates (ADCs) for treating breast cancer. However, during cytotoxic drug treatment, long-term disabling fatigue is common. Moreover, studies in the relevant literature have indicated that fatigue can significantly increase the incidence of depression and sleep disorders. Therefore, this meta-analysis aims to evaluate the incidence of fatigue in breast cancer survivors treated with ADCs. METHODS PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for articles and conference abstracts published before March 16, 2023. Further, two authors independently extracted data from the included studies. The primary outcome of this study was the incidence of all-grade fatigue caused by the use of ADCs in patients with breast cancer. Finally, a random-effects model was used to calculate the incidence and 95% confidence intervals (CIs) of the outcome. RESULTS Overall, 7963 patients from 31 studies were included in this meta-analysis to assess the incidence of fatigue caused by the use of approved and marketed ADCs in patients with breast cancer. Notably, the incidence of all-grade fatigue during ADC monotherapy was 39.84% (95% CI, 35.09%-44.69%). In subgroup analyses, among ADCs, the incidence of trastuzumab deruxtecan-induced fatigue was the highest, with an all-grade fatigue incidence of 47.05% (95% CI, 42.38%-51.75%). Meanwhile, the incidence of trastuzumab emtansine (T-DM1)-induced all-grade fatigue was 35.17% (95% CI, 28.87%-41.74%), which was the lowest among ADCs. Further, the incidence of all-grade fatigue due to sacituzumab govitecan was 42.82% (95% CI, 34.54%-51.32%), which was higher than that due to T-DM1. Moreover, the incidence of fatigue was higher with T-DM1 combination therapy than with monotherapy. CONCLUSIONS Clinicians have highlighted the high incidence of ADC-related fatigue and its negative impact on patients' physical and mental health, making fatigue an important research variable. The results of this study will further contribute to a comprehensive understanding of ADCs, which have some clinical importance and are of great benefit to patients with breast cancer.
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Affiliation(s)
- Hengheng Zhang
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - GuoShuang Shen
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Ping Yang
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Jinming Li
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Zitao Li
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Zhen Liu
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Miaozhou Wang
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Fuxing Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Dengfeng Ren
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Zhilin Liu
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Jiuda Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China
| | - Yi Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China.
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13
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Sarfraz Z, Sarfraz A, Mehak O, Akhund R, Bano S, Aftab H. Racial and socioeconomic disparities in triple-negative breast cancer treatment. Expert Rev Anticancer Ther 2024; 24:107-116. [PMID: 38436305 DOI: 10.1080/14737140.2024.2326575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 02/29/2024] [Indexed: 03/05/2024]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) continues to be a significant concern, especially among minority populations, where treatment disparities are notably pronounced. Addressing these disparities, especially among African American women and other minorities, is crucial for ensuring equitable healthcare. AREAS COVERED This review delves into the continuum of TNBC treatment, noting that the standard of care, previously restricted to chemotherapy, has now expanded due to emerging clinical trial results. With advances like PARP inhibitors, immunotherapy, and antibody-drug conjugates, a more personalized treatment approach is on the horizon. The review highlights innovative interventions tailored for minorities, such as utilizing technology like text messaging, smartphone apps, and targeted radio programming, coupled with church-based behavioral interventions. EXPERT OPINION Addressing TNBC treatment disparities demands a multifaceted approach, blending advanced medical treatments with culturally sensitive community outreach. The potential of technology, especially in the realm of promoting health awareness, is yet to be fully harnessed. As the field progresses, understanding and integrating the socio-economic, biological, and access-related challenges faced by minorities will be pivotal for achieving health equity in TNBC care.
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Affiliation(s)
- Zouina Sarfraz
- Department of Medicine, Fatima Jinnah Medical University, Lahore, Pakistan
| | - Azza Sarfraz
- Department of Pediatrics, Aga Khan University, Karachi, Pakistan
| | - Onaiza Mehak
- Department of Medicine, Aziz Fatimah Medical and Dental College, Faisalabad, Pakistan
| | - Ramsha Akhund
- Department of Surgery, University of Alabama at Birmingham, Tuscaloosa, AL, USA
| | - Shehar Bano
- Department of Medicine, Fatima Jinnah Medical University, Lahore, Pakistan
| | - Hinna Aftab
- Department of Medicine, CMH Lahore Medical College, Lahore, Pakistan
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14
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Zhou L, Lu Y, Liu W, Wang S, Wang L, Zheng P, Zi G, Liu H, Liu W, Wei S. Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice. Exp Hematol Oncol 2024; 13:26. [PMID: 38429828 PMCID: PMC10908151 DOI: 10.1186/s40164-024-00493-8] [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: 01/06/2024] [Accepted: 02/21/2024] [Indexed: 03/03/2024] Open
Abstract
A drug conjugate consists of a cytotoxic drug bound via a linker to a targeted ligand, allowing the targeted delivery of the drug to one or more tumor sites. This approach simultaneously reduces drug toxicity and increases efficacy, with a powerful combination of efficient killing and precise targeting. Antibody‒drug conjugates (ADCs) are the best-known type of drug conjugate, combining the specificity of antibodies with the cytotoxicity of chemotherapeutic drugs to reduce adverse reactions by preferentially targeting the payload to the tumor. The structure of ADCs has also provided inspiration for the development of additional drug conjugates. In recent years, drug conjugates such as ADCs, peptide‒drug conjugates (PDCs) and radionuclide drug conjugates (RDCs) have been approved by the Food and Drug Administration (FDA). The scope and application of drug conjugates have been expanding, including combination therapy and precise drug delivery, and a variety of new conjugation technology concepts have emerged. Additionally, new conjugation technology-based drugs have been developed in industry. In addition to chemotherapy, targeted therapy and immunotherapy, drug conjugate therapy has undergone continuous development and made significant progress in treating lung cancer in recent years, offering a promising strategy for the treatment of this disease. In this review, we discuss recent advances in the use of drug conjugates for lung cancer treatment, including structure-based drug design, mechanisms of action, clinical trials, and side effects. Furthermore, challenges, potential approaches and future prospects are presented.
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Affiliation(s)
- Ling Zhou
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunlong Lu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wei Liu
- Department of Geriatrics, Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shanglong Wang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Lingling Wang
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pengdou Zheng
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guisha Zi
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiguo Liu
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wukun Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030000, China.
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030000, China.
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15
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Shi M, Li Z, Wang T, Wang M, Liu Z, Zhao F, Ren D, Zhao J. Third-line Treatment for Metastatic Triple-negative Breast Cancer: A Systematic Review and Network Meta-analysis. Am J Clin Oncol 2024; 47:91-98. [PMID: 38108387 DOI: 10.1097/coc.0000000000001073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
OBJECTIVE Metastatic triple-negative breast cancer (mTNBC) is an invasive histologic subtype with a poor prognosis and rapid progression. Currently, there is no standard therapy for the third-line treatment of mTNBC. In this study, we conducted a network meta-analysis to compare regimens and determine treatment outcomes. METHODS We performed a systematic search of PubMed, EMBASE, the Cochrane Central Register of Controlled Bases, and the minutes of major conferences. Progression-free survival, overall survival, and objective response rate were analyzed through network meta-analysis using the R software (R Core Team). The efficacy of the treatment regimens was compared using hazard ratios, odds ratios, and 95% CIs. RESULTS We evaluated 15 randomized controlled trials involving 6,010 patients. Compared with the physician's choice treatment, sacituzumab govitecan showed significant advantages in progression-free survival and overall survival, with hazard ratio values of 0.41 (95% CI: 0.32-0.52) and 0.48 (95% CI, 0.39-0.60). In terms of objective response rate, sacituzumab govitecan is the best-performing therapy (odds ratio: 10.82; 95% CI: 5.58-20.97). Adverse events among grades 3 to 5 adverse reactions, the incidence of neutropenia and leukopenia in each regimen was higher, whereas the incidence of fever, headache, hypertension, and rash was lower. CONCLUSION Compared with the treatment of the physician's choice, sacituzumab govitecan appears more efficacious and is the preferred third-line treatment for mTNBC.
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Affiliation(s)
- Mingqiang Shi
- Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, Qinghai, China
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Kathpalia M, Sharma A, Kaur N. Sacituzumab Govitecan as a Second-Line Treatment in Relapsed/Refractory Metastatic Triple-Negative Breast Cancer Patients: A Systematic Review and Meta-analysis. Ann Pharmacother 2024; 58:44-53. [PMID: 37026168 DOI: 10.1177/10600280231164110] [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: 04/08/2023] Open
Abstract
BACKGROUND Chemotherapy, the only treatment option for metastatic triple-negative breast cancer (mTNBC), showed decreased survival rates. Trophoblast cell surface antigen-2 (Trop-2) could be a possible target for antibody-drug conjugates (ADCs). OBJECTIVE Sacituzumab govitecan (SG), an anti-Trop-2 ADC for pretreating relapsed/refractory mTNBC patients, was studied to know the efficacy and safety profile of the drug in mTNBC. METHODS The present review searched MEDLINE (via PubMed), WHO Clinical Trial Registry, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials until December 25, 2022. The studies searched comprised randomized trials and observational studies (retrospective [case-control, cross-sectional] and prospective [cohort designs]). Efficacy assessment was performed in terms of complete response (CR), partial response (PR), objective response rate (ORR), stable disease (SD), progressive disease (PD), and clinical benefit rate (CBR), and safety in terms of adverse events. RESULTS The overall random-effects pooled prevalence of CR was 4.9 (95% CI: 3.2-7.1), PR was 35.6 (95% CI: 31.5-39.9), ORR was 6.8 (95% CI: 5.9-7.8), SD was 8.0 (95% CI: 6.7-9.4), PD was 5.1 (95% CI: 4.1-6.3), and CBR was 13.4 (95% CI: 11.8-15.1). Adverse events associated with the drug were neutropenia, fatigue, anemia, nausea, and others. CONCLUSION AND RELEVANCE This is the first meta-analysis conducted in relapsed/refractory mTNBC patients and found that SG is efficacious but associated with some adverse effects that are related to exposure to the drug. The application of these results will allow clinicians to use SG in the management of patients with mTNBC.
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Affiliation(s)
- Meghavi Kathpalia
- Amity Institute of Biotechnology, Amity University Uttar Pradesh (AUUP), Noida, India
| | - Anurag Sharma
- Department of Statistics, Ram Lal Anand College, University of Delhi, New Delhi, India
| | - Navkiran Kaur
- Amity Institute of Biotechnology, Amity University Uttar Pradesh (AUUP), Noida, India
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Gadaleta-Caldarola G, Lanotte L, Infusino S, Gadaleta-Caldarola A, Schipilliti FM, Citrigno C, Petrarota C, Cusmai A, Rizzo A. Safety evaluation of Datopotamab deruxtecan for triple-negative breast cancer: a meta-analysis. Cancer Treat Res Commun 2023; 37:100775. [PMID: 37956525 DOI: 10.1016/j.ctarc.2023.100775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/21/2023] [Accepted: 11/05/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND TROP-2 is emerging as a valid and fruitful strategy in triple-negative breast cancer (TNBC) patients, and several agents are currently under evaluation, including Datopotamab deruxtecan (Dato-DXd). RESEARCH DESIGN AND METHODS Herein, we performed a meta-analysis aimed to evaluate any grade adverse events, grade 3-4 adverse events, dose reduction, and serious adverse events in TNBC patients treated with Dato-DXd in clinical trials. RESULTS The pooled results suggests that Dato-DXd is associated with a favorable safety profile: while any grade treatment-related toxicities were common, grade 3-4 events were not particularly frequent and mainly represented by stomatitis (13.88%; 95% CI, 10.68 - 17.09). CONCLUSIONS These findings may help to comprehensively define the safety profile of Dato-DXd and to assist in the design of future clinical trials in this setting.
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Affiliation(s)
- Gennaro Gadaleta-Caldarola
- Unità Operativa Complessa di Oncologia Medica, Ospedale "Mons. A.R. Dimiccoli" Asl BT, Viale Ippocrate, 15, 70051 Barletta (BT), Italy
| | - Laura Lanotte
- Unità Operativa Complessa di Oncologia Medica, Ospedale "Mons. A.R. Dimiccoli" Asl BT, Viale Ippocrate, 15, 70051 Barletta (BT), Italy
| | - Stefania Infusino
- Unità Operativa Complessa di Oncologia Medica, Ospedale "SS. Annunziata", 87100 Cosenza, Italy
| | | | | | - Claudia Citrigno
- Facoltà di Medicina e Chirurgia, Università degli Studi Magna Graecia di Catanzaro, 88100 Catanzaro, Italy
| | - Cataldo Petrarota
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello", I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Antonio Cusmai
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello", I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello", I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy..
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Heater NK, Franco S, Shah A. Treatment of endocrine resistant metastatic breast cancer in the era of antibody drug conjugates. ANNALS OF TRANSLATIONAL MEDICINE 2023; 11:399. [PMID: 37970594 PMCID: PMC10632570 DOI: 10.21037/atm-23-314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/24/2023] [Indexed: 11/17/2023]
Affiliation(s)
- Natalie K. Heater
- Department of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Stephanie Franco
- Department of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ami Shah
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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Fayad E, Altalhi SA, Abualnaja MM, Alrohaimi AH, Elsaid FG, Abu Almaaty AH, Saleem RM, Bazuhair MA, Ahmed Maghrabi AH, Beshay BY, Zaki I. Novel Acrylate-Based Derivatives: Design, Synthesis, Antiproliferative Screening, and Docking Study as Potential Combretastatin Analogues. ACS OMEGA 2023; 8:38394-38405. [PMID: 37867686 PMCID: PMC10586439 DOI: 10.1021/acsomega.3c05051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/22/2023] [Indexed: 10/24/2023]
Abstract
A variety of 3-(4-chlorophenyl) acrylic acids 4a,b and 3-(4-chlorophenyl)acrylate esters 5a-i were synthesized and structurally proven by spectroscopic studies such as IR, 1H NMR, and 13C NMR as well as mass spectrometry. All substances were investigated for their antiproliferative efficacy against the MDA-MB-231 cell line. Among these, acrylic acid compound 4b demonstrated the most potent cytotoxic effect with an IC50 value of 3.24 ± 0.13 μM, as compared to CA-4 (IC50 = 1.27 ± 09 μM). Additionally, acrylic acid molecule 4b displayed an inhibitory effect against β-tubulin polymerization with a percentage inhibition of 80.07%. Furthermore, compound 4b was found to produce considerable cell cycle arrest at the G2/M stage and cellular death, as demonstrated by FACS analysis. In addition, the in vivo antitumor screening of the sodium salt of acrylic acid 4b was carried out, and the results have shown that the tested molecule showed a significant decrease in viable EAC count and EAC volume, accompanied by a considerable increase in the life span prolongation, if compared to the positive control group. Furthermore, molecular modeling studies were performed to understand how the highly efficient chemicals 4b and 5e interact with the colchicine-binding region on tubulin. This work aims to shed light on the reasons behind their exceptional cytotoxicity and their better capacity to inhibit tubulin in comparison to CA-4.
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Affiliation(s)
- Eman Fayad
- Department
of Biotechnology, College of Sciences, Taif
University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Sarah Awwadh Altalhi
- Department
of Biotechnology, College of Sciences, Taif
University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Matokah M. Abualnaja
- Department
of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah
Al Mukarrama 24230, Saudi Arabia
| | - Abdulmohsen H. Alrohaimi
- Department
of Pharmacy Practice, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
| | - Fahmy G. Elsaid
- Biology
Department, College of Science, King Khalid
University, P.O.Box 960, Asir, Abha 61421, Saudi Arabia
| | - Ali H. Abu Almaaty
- Zoology
Department, Faculty of Science Port Said
University, Port Said 42526, Egypt
| | - Rasha Mohammed Saleem
- Department
of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65431, Saudi Arabia
| | - Mohammed A. Bazuhair
- Department
of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ali Hassan Ahmed Maghrabi
- Department
of Biology, Faculty of Applied Science, Umm Al-Qura University, Makkah 24381, Saudi Arabia
| | - Botros Y. Beshay
- Pharmaceutical
Sciences (Pharmaceutical Chemistry) Department, College of Pharmacy, Arab Academy for Science, Technology and Maritime
Transport, Alexandria 21913, Egypt
| | - Islam Zaki
- Pharmaceutical
Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt
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Zhu S, Wu Y, Song B, Yi M, Yan Y, Mei Q, Wu K. Recent advances in targeted strategies for triple-negative breast cancer. J Hematol Oncol 2023; 16:100. [PMID: 37641116 PMCID: PMC10464091 DOI: 10.1186/s13045-023-01497-3] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023] Open
Abstract
Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, negatively expresses estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is the main form of treatment for patients with TNBC, the effectiveness of chemotherapy for TNBC is still limited. The search for more effective therapies is urgent. Multiple targeted therapeutic strategies have emerged according to the specific molecules and signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, epidermal growth factor receptor inhibitors, Notch inhibitors, poly ADP-ribose polymerase inhibitors, and antibody-drug conjugates. Moreover, immune checkpoint inhibitors, for example, pembrolizumab, atezolizumab, and durvalumab, are widely explored in the clinic. We summarize recent advances in targeted therapy and immunotherapy in TNBC, with the aim of serving as a reference for the development of individualized treatment of patients with TNBC in the future.
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Affiliation(s)
- Shuangli Zhu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bin Song
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, China
| | - Yuheng Yan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
- Cancer Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Shi D, Liang X, Li Y, Chen L. Cost-effectiveness of trastuzumab deruxtecan for previously treated HER2-low advanced breast cancer. PLoS One 2023; 18:e0290507. [PMID: 37616309 PMCID: PMC10449172 DOI: 10.1371/journal.pone.0290507] [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: 02/16/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
OBJECTIVE The clinical efficacy and safety profile of trastuzumab deruxtecan (T-DXd) have been demonstrated in previously treated patients with human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer (BC). It is, however, necessary to evaluate the value of T-DXd considering both its clinical efficacy and its cost, given that it is high. This study aimed to evaluate the cost-effectiveness of T-DXd versus chemotherapy in patients with previously treated HER2-low advanced BC. METHODS We used a partitioned survival model that included three mutually exclusive health states. The patients in the model were identified based on their clinical characteristics and outcomes from the DESTINY-Breast04. Probabilistic and one-way sensitivity analyses were performed to evaluate the model's robustness. Subgroup analyses were also conducted. The measures included costs, life years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs). RESULTS The ICERs of T-DXd vs. chemotherapy were $83,892/QALY, $82,808/QALY, and $93,358/QALY in all HER2-low advanced BC patients, HER2-positive (HER2+) advanced BC patients and HER2-negative (HER2-) advanced BC patients, respectively. In one-way sensitivity analysis, the cost of T-DXd and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were also identified as key drivers. If the price of T-DXd decreased to $17.00/mg, $17.13/mg, and $14.07/mg, it would be cost-effective at a willingness to pay (WTP) threshold of $50,000/QALY in all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. At a WTP threshold of $100,000/QALY, the probability of T-DXd being cost-effective was 81.10%, 82.27%, and 73.78% compared to chemotherapy for all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. Most subgroups of patients with HER2+ disease had a cost-effectiveness probability of > 50%. CONCLUSION From a third-party payer's perspective in the United States, the findings of the cost-effectiveness analysis revealed that, at the current price, T-DXd is a cost-effective alternative to chemotherapy for patients with prior HER2-low advanced BC, at WTP threshold of $100,000/QALY.
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Affiliation(s)
- Demin Shi
- Department of Reproductive Medicine, The People’s Hospital of Hechi, Hechi, Guangxi, People’s Republic of China
| | - Xueyan Liang
- Department of Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China
| | - Yan Li
- Department of Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China
| | - Lingyuan Chen
- Department of Pharmacy, The People’s Hospital of Hechi, Hechi, Guangxi, People’s Republic of China
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Yang T, Li W, Huang T, Zhou J. Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions. Int J Mol Sci 2023; 24:11903. [PMID: 37569276 PMCID: PMC10418918 DOI: 10.3390/ijms241511903] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/21/2023] [Accepted: 07/23/2023] [Indexed: 08/13/2023] Open
Abstract
To achieve the scheme of "magic bullets" in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific antigens, chemical linkers, and cytotoxic payloads that powerfully kill cancer cells. With the approval of ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), the therapeutic potentials of ADCs in breast cancer have come into the spotlight. Nearly 30 ADCs for breast cancer are under exploration to move targeted therapy forward. In this review, we summarize the presenting and emerging agents and targets of ADCs. The ADC structure and development history are also concluded. Moreover, the challenges faced and prospected future directions in this field are reviewed, which give insights into novel treatments with ADCs for breast cancer.
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Affiliation(s)
| | | | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jun Zhou
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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23
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Fontaine SD, Carreras CW, Reid RR, Ashley GW, Santi DV. A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors. CANCER RESEARCH COMMUNICATIONS 2023; 3:908-916. [PMID: 37377899 PMCID: PMC10208276 DOI: 10.1158/2767-9764.crc-22-0517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/03/2023] [Accepted: 04/18/2023] [Indexed: 06/29/2023]
Abstract
Exatecan (Exa) is a very potent inhibitor of topoisomerase I and anticancer agent. It has been intensively studied as a single agent, a large macromolecular conjugate and as the payload component of antigen-dependent antibody-drug conjugates. The current work describes an antigen-independent conjugate of Exa with polyethylene glycol (PEG) that slowly releases free Exa. Exa was conjugated to a 4-arm 40 kDa PEG through a β-eliminative cleavable linker. Pharmacokinetic studies in mice showed that the conjugate has an apparent circulating half-life of 12 hours, which reflects a composite of both the rate of renal elimination (half-life ∼18 hours) and release of Exa (half-life ∼40 hours). Remarkably, a single low dose of 10 μmol/kg PEG-Exa-only approximately 0.2 μmol/mouse-caused complete suppression of tumor growth of BRCA1-deficient MX-1 xenografts lasting over 40 days. A single low dose of 2.5 μmol/kg PEG-Exa administered with low but efficacious doses of the PARP inhibitor talazoparib showed strong synergy and caused significant tumor regression. Furthermore, the same low, single dose of PEG-Exa administered with the ATR inhibitor VX970 at doses of the DNA damage response inhibitor that do not affect tumor growth show high tumor regression, strong synergy, and synthetic lethality. Significance A circulating conjugate that slowly releases Exa is described. It is efficacious after a single dose and synergistic with ATR and PARP inhibitors.
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Li Y, Si R, Wang J, Hai P, Zheng Y, Zhang Q, Pan X, Zhang J. Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects. Bioorg Chem 2023; 137:106575. [PMID: 37148706 DOI: 10.1016/j.bioorg.2023.106575] [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: 12/18/2022] [Revised: 04/12/2023] [Accepted: 04/24/2023] [Indexed: 05/08/2023]
Abstract
Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a "biological missile" to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.
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Affiliation(s)
- Yanchen Li
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ru Si
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jin Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ping Hai
- NMPA Key Laboratory for Quality Control of Traditional Chinese and Tibetan Medicine, Qinghai Provincial Drug Inspection and Testing Institute, Xining 810016, China
| | - Yongbiao Zheng
- NMPA Key Laboratory for Quality Control of Traditional Chinese and Tibetan Medicine, Qinghai Provincial Drug Inspection and Testing Institute, Xining 810016, China
| | - Qingqing Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiaoyan Pan
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jie Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
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Tada H, Gonda K, Kitamura N, Ishida T. Clinical Significance of ABCG2/BCRP Quantified by Fluorescent Nanoparticles in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy. Cancers (Basel) 2023; 15:cancers15082365. [PMID: 37190293 DOI: 10.3390/cancers15082365] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Breast cancer resistance protein (BCRP), also known as ATP-binding cassette transporter G2 (ABCG2), is associated with chemotherapy resistance. BCRP is also implicated in breast cancer stem cells, and is reported as a poor prognostic factor. However, the relationship of BCRP levels in breast cancer tissues with chemotherapy resistance and prognosis has not been clarified. We aimed to evaluate the correlation between BCRP expression and prognosis in breast cancer using immunohistochemistry with fluorescent phosphor-integrated dots (IHC-PIDs). A total of 37 breast cancer patients with residual cancer in the primary tumor and axillary lymph nodes were evaluated. BCRP levels in breast cancer tissue and metastatic lymph nodes were quantitatively detected after neoadjuvant chemotherapy (NAC). Among these 37 patients, 24 had corresponding core needle biopsies obtained before NAC. Biomarker assay with IHC-PIDs showed high accuracy for the quantitative assessment of BCRP with low expression. High BCRP expression in the primary tumor and metastatic lymph nodes after preoperative chemotherapy was associated with worse overall survival. In conclusion, high BCRP levels may be associated with poor prognosis in patients with breast cancer, having residual tumors within the primary tumor and lymph nodes after preoperative chemotherapy. These findings provide a basis for further appropriate adjuvant therapy in these patients.
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Affiliation(s)
- Hiroshi Tada
- Division of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Kohsuke Gonda
- Department of Medical Physics, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Narufumi Kitamura
- Department of Medical Physics, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Takanori Ishida
- Division of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
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Wu H, Feng J, Zhong W, Zouxu X, Xiong Z, Huang W, Zhang C, Wang X, Yi J. Model for predicting immunotherapy based on M2 macrophage infiltration in TNBC. Front Immunol 2023; 14:1151800. [PMID: 36999020 PMCID: PMC10043239 DOI: 10.3389/fimmu.2023.1151800] [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: 01/26/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
IntroductionCompared to other types of breast cancer, triple-negative breast cancer (TNBC) does not effectively respond to hormone therapy and HER2 targeted therapy, showing a poor prognosis. There are currently a limited number of immunotherapeutic drugs available for TNBC, a field that requires additional development.MethodsCo-expressing genes with M2 macrophages were analyzed based on the infiltration of M2 macrophages in TNBC and the sequencing data in The Cancer Genome Atlas (TCGA) database. Consequently, the influence of these genes on the prognoses of TNBC patients was analyzed. GO analysis and KEGG analysis were performed for exploring potential signal pathways. Lasso regression analysis was conducted for model construction. The TNBC patients were scored by the model, and patients were divided into high- and low-risk groups. Subsequently, the accuracy of model was further verified using GEO database and patients information from the Cancer Center of Sun Yat-sen University. On this basis, we analyzed the accuracy of prognosis prediction, correlation with immune checkpoint, and immunotherapy drug sensitivity in different groups.ResultsOur findings revealed that OLFML2B, MS4A7, SPARC, POSTN, THY1, and CD300C genes significantly influenced the prognosis of TNBC. Moreover, MS4A7, SPARC, and CD300C were finally determined for model construction, and the model showed good accuracy in prognosis prediction. And 50 immunotherapy drugs with therapeutic significance in different groups were screened, which were assessed possible immunotherapeutics that have potential application and demonstrated the high precision of our prognostic model for predictive analysis.ConclusionMS4A7, SPARC, and CD300C, the three main genes used in our prognostic model, offer good precision and clinical application potential. Fifty immune medications were assessed for their ability to predict immunotherapy drugs, providing a novel approach to immunotherapy for TNBC patients and a more reliable foundation for applying drugs in subsequent treatments.
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Affiliation(s)
- Haoming Wu
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
- The Breast Center, Cancer Hospital of Shantou University Medical College, Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou, Guangdong, China
| | - Jikun Feng
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Wenjing Zhong
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xiazi Zouxu
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Zhengchong Xiong
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Weiling Huang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Chao Zhang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Xi Wang
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
- *Correspondence: Xi Wang, ; Jiarong Yi,
| | - Jiarong Yi
- Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
- *Correspondence: Xi Wang, ; Jiarong Yi,
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Sánchez-León ML, Jiménez-Cortegana C, Silva Romeiro S, Garnacho C, de la Cruz-Merino L, García-Domínguez DJ, Hontecillas-Prieto L, Sánchez-Margalet V. Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells. Int J Mol Sci 2023; 24:5208. [PMID: 36982282 PMCID: PMC10048951 DOI: 10.3390/ijms24065208] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/24/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.
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Affiliation(s)
- María Luisa Sánchez-León
- Laboratory Service, Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Carlos Jiménez-Cortegana
- Laboratory Service, Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Silvia Silva Romeiro
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Carmen Garnacho
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Luis de la Cruz-Merino
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Daniel J. García-Domínguez
- Laboratory Service, Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Lourdes Hontecillas-Prieto
- Laboratory Service, Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Virgen Macarena University Hospital, Department of Medicine, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Víctor Sánchez-Margalet
- Laboratory Service, Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
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Hegedüs L, Okumus Ö, Mairinger F, Ploenes T, Reuter S, Schuler M, Welt A, Vega-Rubin-de-Celis S, Theegarten D, Bankfalvi A, Aigner C, Hegedüs B. TROP2 expression and SN38 antitumor activity in malignant pleural mesothelioma cells provide a rationale for antibody-drug conjugate therapy. Lung Cancer 2023; 178:237-246. [PMID: 36907051 DOI: 10.1016/j.lungcan.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023]
Abstract
OBJECTIVES Malignant pleural mesothelioma (MPM) is an aggressive cancer which at large is not amenable to curative surgery. Despite the recent approval of immune checkpoint inhibitor therapy, the response rates and survival following systemic therapy is still limited. Sacituzumab govitecan is an antibody-drug conjugate targeting the topoisomerase I inhibitor SN38 to trophoblast cell-surface antigen 2 (TROP-2)-positive cells. Here we have explored the therapeutic potential of sacituzumab govitecan in MPM models. MATERIALS AND METHODS TROP2 expression was analyzed in a panel of two well established and 15 pleural effusion derived novel lines by RT-QPCR and immunoblotting, TROP2 membrane-localization was studied by flow cytometry and immunohistochemistry. Cultured mesothelial cells and pneumothorax pleura served as controls. The sensitivity of MPM cell lines to irinotecan and SN38 was studied using cell viability, cell cycle, apoptosis and DNA damage assays. Drug sensitivity of cell lines was correlated with RNA expression of DNA repair genes. Drug sensitivity was defined as an IC50 below 5 nM in the cell viability assay. RESULTS TROP2 expression was detected at RNA and protein level in 6 of the 17 MPM cell lines, but not in in cultured mesothelial control cells or in the mesothelial layer of the pleura. TROP2 was detectable on the cell membrane in 5 MPM lines and was present in the nucleus in 6 cell models. Ten of 17 MPM cell lines showed sensitivity to SN38 treatment, among those 4 expressed TROP2. High AURKA RNA expression and high proliferation rate correlated with sensitivity to SN38-induced cell death, DNA damage response, cell cycle arrest and cell death. Sacituzumab govitecan treatment effectively induced cell cycle arrest and cell death in TROP2-positive MPM cells. CONCLUSION TROP2 expression and sensitivity to SN38 in MPM cell lines support biomarker-selected clinical exploration of sacituzumab govitecan in patients with MPM.
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Affiliation(s)
- Luca Hegedüs
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany
| | - Özlem Okumus
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany
| | - Fabian Mairinger
- Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Till Ploenes
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany
| | - Sebastian Reuter
- Department of Pulmonology, University Medicine Essen - Ruhrlandklinik, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Anja Welt
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Silvia Vega-Rubin-de-Celis
- Institute of Cell Biology (Cancer Research), University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Dirk Theegarten
- Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Agnes Bankfalvi
- Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany
| | - Clemens Aigner
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany
| | - Balazs Hegedüs
- Department of Thoracic Surgery, University Medicine Essen - Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany.
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Small-molecule inhibitor of Fam20C in combination with paclitaxel suppresses tumor growth by LIF-JAK2/STAT3-modulated apoptosis in triple-negative breast cancer. J Taiwan Inst Chem Eng 2023. [DOI: 10.1016/j.jtice.2023.104673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Zhang H, Peng Y. Current Biological, Pathological and Clinical Landscape of HER2-Low Breast Cancer. Cancers (Basel) 2022; 15:126. [PMID: 36612123 PMCID: PMC9817919 DOI: 10.3390/cancers15010126] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/21/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC that has HER2 immunohistochemical (IHC) score of 1+ or score of 2+/in situ hybridization (ISH) negative phenotype. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating this group of tumors. Trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC was recently approved by the U.S. Food and Drug Administration as the first targeted therapy to treat HER2-low BC. However, HER2-low BC is still not well characterized clinically and pathologically. This review aims to update the current biological, pathological and clinical landscape of HER2-low BC based on the English literature published in the past two years and to propose the future directions on clinical management, pathology practice, and translational research in this subset of BC. We hope it would help better understand the tumor biology of HER2-low BC and the current efforts for identifying and treating this newly recognized targetable group of BC.
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Affiliation(s)
- Huina Zhang
- Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Yan Peng
- Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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31
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Apatinib plus vinorelbine versus vinorelbine for metastatic triple-negative breast cancer who failed first/second-line treatment: the NAN trial. NPJ Breast Cancer 2022; 8:110. [PMID: 36127351 PMCID: PMC9489776 DOI: 10.1038/s41523-022-00462-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 07/05/2022] [Indexed: 11/20/2022] Open
Abstract
While therapies such as chemotherapy combined with immunotherapy, sacituzumab govitecan, and PARP inhibitors are available for metastatic TNBC, on disease progression after these therapies, the mainstay of therapy is chemotherapy. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with advanced TNBC with failed first/second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine or vinorelbine with apatinib in 28-day cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.9 months vs. 2.0 months; hazard ratio, 1.82; 95% confidence interval [CI], 1.06 to 3.11; P = 0.026). Median OS was 11.5 months with apatinib plus vinorelbine and 9.9 months with vinorelbine (HR,1.01; 95% CI, 0.51 to 1.97; P = 0.985). The ORR was 9.1% in the apatinib plus vinorelbine group and 6.3% in the vinorelbine group (P = 0.667). The most common treatment-related hematologic grade 3–4 adverse events in apatinib plus vinorelbine group, were leukopenia, granulocytopenia, anemia, and thrombocytopenia. no treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Collectively, adding apatinib to vinorelbine shows a promising benefit in PFS compared to vinorelbine monotherapy, with an excellent toxicity profile, warranting further exploration.
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Morphometrical, Morphological, and Immunocytochemical Characterization of a Tool for Cytotoxicity Research: 3D Cultures of Breast Cell Lines Grown in Ultra-Low Attachment Plates. TOXICS 2022; 10:toxics10080415. [PMID: 35893848 PMCID: PMC9394479 DOI: 10.3390/toxics10080415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/15/2022] [Accepted: 07/20/2022] [Indexed: 02/06/2023]
Abstract
Three-dimensional cell cultures may better mimic avascular tumors. Yet, they still lack characterization and standardization. Therefore, this study aimed to (a) generate multicellular aggregates (MCAs) of four breast cell lines: MCF7, MDA-MB-231, and SKBR3 (tumoral) and MCF12A (non-tumoral) using ultra-low attachment (ULA) plates, (b) detail the methodology used for their formation and analysis, providing technical tips, and (c) characterize the MCAs using morphometry, qualitative cytology (at light and electron microscopy), and quantitative immunocytochemistry (ICC) analysis. Each cell line generated uniform MCAs with structural differences among cell lines: MCF7 and MDA-MB-231 MCAs showed an ellipsoid/discoid shape and compact structure, while MCF12A and SKBR3 MCAs were loose, more flattened, and presented bigger areas. MCF7 MCAs revealed glandular breast differentiation features. ICC showed a random distribution of the proliferating and apoptotic cells throughout the MCAs, not fitting in the traditional spheroid model. ICC for cytokeratin, vimentin, and E-cadherin showed different results according to the cell lines. Estrogen (ER) and progesterone (PR) receptors were positive only in MCF7 and human epidermal growth factor receptor 2 (HER-2) in SKBR3. The presented characterization of the MCAs in non-exposed conditions provided a good baseline to evaluate the cytotoxic effects of potential anticancer compounds.
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Bai CC, Chen MY, Zhou TC, Jiang RL, Dong LY, Wei HW, Kong XJ, Wang XH. Hydrophilic rhodamine B-loaded / boronic acid-modified graphene oxide nanocomposite as a substitute of enzyme-labeled second antibody for ultrasensitive detection of antibodies. J Pharm Biomed Anal 2022; 216:114804. [DOI: 10.1016/j.jpba.2022.114804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/13/2022] [Accepted: 04/23/2022] [Indexed: 11/16/2022]
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Rizzo A, Massafra R, Fanizzi A, Rinaldi L, Cusmai A, Latorre A, Zaccaria GM, Ronchi M, Telegrafo M, Gadaleta-Caldarola G, Giotta F, Lorusso V, Palmiotti G. Adenosine pathway inhibitors: novel investigational agents for the treatment of metastatic breast cancer. Expert Opin Investig Drugs 2022; 31:707-713. [DOI: 10.1080/13543784.2022.2078191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Raffaella Massafra
- Struttura Semplice Dipartimentale di Fisica Sanitaria, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Annarita Fanizzi
- Struttura Semplice Dipartimentale di Fisica Sanitaria, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Lucia Rinaldi
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Antonio Cusmai
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Agnese Latorre
- Unità Operativa Complessa di Oncologia Medica, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Gian Maria Zaccaria
- Unit of Hematology and Cell Therapy, IRCCS-Istituto Tumori ‘Giovanni Paolo II’, 70124 Bari, Italy
| | - Maria Ronchi
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Michele Telegrafo
- DETO, Department of Emergency and Organ Transplantations, Breast Care Unit, Aldo Moro University of Bari Medical School, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gennaro Gadaleta-Caldarola
- Medical Oncology Unit, ‘Mons. R. Dimiccoli’ Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Francesco Giotta
- Unità Operativa Complessa di Oncologia Medica, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Vito Lorusso
- Unità Operativa Complessa di Oncologia Medica, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Gennaro Palmiotti
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
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35
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Hildebrandt MG, Naghavi-Behzad M, Vogsen M. A role of FDG-PET/CT for response evaluation in metastatic breast cancer? Semin Nucl Med 2022; 52:520-530. [PMID: 35525631 DOI: 10.1053/j.semnuclmed.2022.03.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/27/2022] [Indexed: 01/19/2023]
Abstract
Breast cancer prognosis is steadily improving due to early detection of primary cancer in screening programs and revolutionizing treatment development. In the metastatic setting, therapy improvements render breast cancer a chronic disease. Although FDG-PET/CT has emerged as a highly accurate method for staging metastatic breast cancer, there has been no change in response evaluation methods for decades. FDG-PET/CT has proven high prognostic values in patients with metastatic breast cancer when using quantitative PET methods. It has also shown a higher predictive value than conventional CT when applying the respective response evaluation criteria, RECIST and PERCIST. Response categorization using FDG-PET/CT is more sensitive in detecting progressive and regressive disease, while conventional imaging such as CT and bone scintigraphy deem stable disease more often. These findings reflect the higher accuracy of FDG-PET/CT for response evaluation in this patient group. But does the higher accuracy of FDG-PET/CT translate into a patient benefit when implementing it for monitoring response to palliative treatment? We have evidence of survival benefit from a retrospective study indicating the superiority of using FDG-PET/CT compared with conventional imaging for response evaluation in metastatic breast cancer patients. The survival benefit seems to result from earlier detection of progression with FDG-PET/CT than conventional imaging, leading to an earlier change in treatment with potentially better efficacy of the subsequent treatment line. FDG-PET/CT can be used semiquantitatively as suggested in PERCIST. However, we still need to improve clinically applicable methods based on neural network modeling to better integrate the quantitative information in a smart and standardized way, enabling relevant comparability between scans, patients, and institutions. Such innovation is warranted to support imaging specialists in diagnostic response assessment. Prospective multicenter studies analyzing patients' survival, quality of life, societal and patient costs of replacing conventional imaging with FDG-PET/CT are needed before firm conclusions can be drawn on which type of scan to recommend in future clinical guidelines.
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Affiliation(s)
- Malene Grubbe Hildebrandt
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Center for Personalized Response Monitoring in Oncology, PREMIO, Odense University Hospital, Odense, Denmark; Center for Innovative Medical Technology, CIMT, Odense University Hospital, Odense, Denmark.
| | - Mohammad Naghavi-Behzad
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Center for Personalized Response Monitoring in Oncology, PREMIO, Odense University Hospital, Odense, Denmark
| | - Marianne Vogsen
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Center for Personalized Response Monitoring in Oncology, PREMIO, Odense University Hospital, Odense, Denmark; Department of Oncology, Odense University Hospital, Odense, Denmark
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Tan AC, Boggs DH, Lee EQ, Kim MM, Mehta MP, Khasraw M. Clinical Trial Eligibility Criteria and Recently Approved Cancer Therapies for Patients With Brain Metastases. Front Oncol 2022; 11:780379. [PMID: 35047397 PMCID: PMC8761732 DOI: 10.3389/fonc.2021.780379] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/09/2021] [Indexed: 12/24/2022] Open
Abstract
Brain metastases cause significant morbidity and mortality in patients with advanced cancer. In the era of precision oncology and immunotherapy, there are rapidly evolving systemic treatment options. These novel therapies may have variable intracranial efficacy, and patients with brain metastases remain a population of special interest. Typically, only patients with stable, asymptomatic and/or treated brain metastases are enrolled in clinical trials, or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis. Consequently, this leads to significant concerns on the external validity of clinical trial evidence to real-world clinical practice. Here we describe the current trends in cancer clinical trial eligibility for patients with brain metastases in both early and late phase trials, with a focus on targeted and immunotherapies. We evaluate recent newly FDA approved therapies and the clinical trial evidence base leading to approval. This includes analysis of inclusion and exclusion criteria, requirements for baseline screening for brain metastases, surveillance cerebral imaging and incorporation of trial endpoints for patients with brain metastases. Finally, the use of alternative sources of data such as real-world evidence with registries and collaborative studies will be discussed.
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Affiliation(s)
- Aaron C Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Drexell H Boggs
- Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United States
| | - Eudocia Q Lee
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Michelle M Kim
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Minesh P Mehta
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States
| | - Mustafa Khasraw
- Duke Cancer Institute, Duke University, Durham, NC, United States
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Fabian KP, Hodge JW. The emerging role of off-the-shelf engineered natural killer cells in targeted cancer immunotherapy. MOLECULAR THERAPY-ONCOLYTICS 2021; 23:266-276. [PMID: 34761106 PMCID: PMC8560822 DOI: 10.1016/j.omto.2021.10.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Natural killer (NK) cells are innate lymphocytes that recognize and clear infected and transformed cells. The importance of NK cells in tumor surveillance underlies the development of NK cell therapy as cancer treatment. The NK-92 cell line has been successfully modified to express high-affinity CD16 receptor for antibody-dependent cellular cytotoxicity and/or chimeric antigen receptors (CARs) that can recognize antigens expressed on tumor cells and mediate NK cell activation. Since there is no need for human leukocyte antigen matching or prior exposure to the tumor antigens, NK-92 provides an opportunity for the development of next-generation off-the-shelf cell therapy platforms. CAR-engineered NK-92 cells have demonstrated robust antitumor activity in in vitro and in vivo preclinical studies, propelling the clinical development of CAR NK-92 cells. Preliminary phase 1 data indicate that CAR NK-92 can be safely administered in the clinic. In this review, we provide an overview of recent advances in the research and clinical application of this novel cell immunotherapy.
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Affiliation(s)
- Kellsye P Fabian
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
| | - James W Hodge
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA
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38
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Rizzo A, Ricci AD, Lanotte L, Lombardi L, Di Federico A, Brandi G, Gadaleta-Caldarola G. Immune-based combinations for metastatic triple negative breast cancer in clinical trials: current knowledge and therapeutic prospects. Expert Opin Investig Drugs 2021; 31:557-565. [PMID: 34802383 DOI: 10.1080/13543784.2022.2009456] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitor (ICI) monotherapy appears to be effective in a small cohort of patients with metastatic triple negative breast cancer (mTNBC). This supports the exploration of strategies for increasing the efficacy of immunotherapy. To enhance overall response and clinical outcomes, several immune-based combinations are being investigated. AREAS COVERED The authors present a synopsis of current, state-of-art immune-based combinations in this setting and reflect on future possibilities. They shed light on recently presented and published clinical trials and ongoing studies. A literature search was conducted in October 2021; in addition, abstracts of international cancer meetings were reviewed. EXPERT OPINION Clinical trials suggest that ICI monotherapy could be beneficial in a minority of mTNBC patients; conversely, several immune-based combinations have reported notable results in recently presented or published studies. Some of these combination strategies have been approved for mTNBC - as in the case of chemoimmunotherapy in PD-L1 positive patients. Numerous trials are investigating novel ICI-based combinations and their results are eagerly awaited.
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Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia.,Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia.,Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Laura Lanotte
- Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | - Lucia Lombardi
- Medical Oncology Unit, "Mons. R. Dimiccoli" Hospital, Barletta (BT), ASL BT, Barletta, Italy
| | | | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia
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