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Falchetto L, Bender B, Erhard I, Zeiner KN, Stratmann JA, Koll FJ, Wagner S, Reiser M, Gasimli K, Stehle A, Voss M, Ballo O, Vehreschild JJ, Maier D. Concepts of lines of therapy in cancer treatment: findings from an expert interview-based study. BMC Res Notes 2024; 17:137. [PMID: 38750530 PMCID: PMC11094945 DOI: 10.1186/s13104-024-06789-6] [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: 07/28/2023] [Accepted: 04/25/2024] [Indexed: 05/19/2024] Open
Abstract
OBJECTIVE The concept of lines of therapy (LOT) in cancer treatment is often considered for decision making in tumor boards and clinical management, but lacks a common definition across medical specialties. The complexity and heterogeneity of malignancies and treatment modalities contribute to an inconsistent understanding of LOT among physicians. This study assesses the heterogeneity of understandings of the LOT concept, its major dimensions, and criteria from the perspective of physicians of different specialties with an oncological focus in Germany. Semi-structured expert interviews with nine physicians were conducted and evaluated using qualitative content analysis. RESULTS Most interviewees agreed that there is no single definition for LOT and found it difficult to explicate their understanding. A majority of experts stated that they had already encountered misunderstandings with colleagues regarding LOT and that they had problems with deciphering LOT from the medical records of their patients. Disagreement emerged about the roles of the following within the LOT concept: maintenance therapy, treatment intention, different therapy modalities, changing pharmaceutical agents, and therapy breaks. Respondents predominantly considered the same criteria as decisive for the definition of LOT as for a change in LOT (e.g., the occurrence of a progression event or tumor recurrence).
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Affiliation(s)
- Lisa Falchetto
- Institute for Digital Medicine and Clinical Data Science, Goethe University Frankfurt, Faculty of Medicine, Frankfurt, Germany
| | - Bernd Bender
- Institute for Digital Medicine and Clinical Data Science, Goethe University Frankfurt, Faculty of Medicine, Frankfurt, Germany.
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Ian Erhard
- Institute for Digital Medicine and Clinical Data Science, Goethe University Frankfurt, Faculty of Medicine, Frankfurt, Germany
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kim N Zeiner
- Department for Dermatology, Venerology and Allergology, University Hospital Frankfurt, Frankfurt, Germany
| | - Jan A Stratmann
- Medical Department 2 (Hematology/Oncology), Center for Internal Medicine, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
| | - Florestan J Koll
- Department of Urology, University Hospital Frankfurt, Frankfurt, Germany
| | - Sebastian Wagner
- Medical Department 2 (Hematology/Oncology), Center for Internal Medicine, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
| | - Marcel Reiser
- PIOH Praxis Internistischer Onkologie und Hämatologie, Cologne, Germany
| | - Khayal Gasimli
- Clinic for Gynecology and Obstetrics, University Hospital Frankfurt, Frankfurt, Germany
| | - Angelika Stehle
- Department for Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
| | - Martin Voss
- Department Neuro-Oncology, University Hospital Frankfurt, Frankfurt, Germany
| | - Olivier Ballo
- Medical Department 2 (Hematology/Oncology), Center for Internal Medicine, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
| | - Jörg Janne Vehreschild
- Institute for Digital Medicine and Clinical Data Science, Goethe University Frankfurt, Faculty of Medicine, Frankfurt, Germany
- Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
- German Center for Infection Research (DZIF) partner site Bonn Cologne, Cologne, Germany
| | - Daniel Maier
- Institute for Digital Medicine and Clinical Data Science, Goethe University Frankfurt, Faculty of Medicine, Frankfurt, Germany
- German Cancer Consortium (DKTK), partner site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Lorenzen S, Schwarz A, Pauligk C, Goekkurt E, Stocker G, Knorrenschild JR, Illerhaus G, Dechow T, Moehler M, Moulin JC, Pink D, Stahl M, Schaaf M, Goetze TO, Al-Batran SE. Ramucirumab plus irinotecan / leucovorin / 5-FU versus ramucirumab plus paclitaxel in patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, who failed one prior line of palliative chemotherapy: the phase II/III RAMIRIS study (AIO-STO-0415). BMC Cancer 2023; 23:561. [PMID: 37337155 PMCID: PMC10278289 DOI: 10.1186/s12885-023-11004-z] [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: 02/15/2022] [Accepted: 05/23/2023] [Indexed: 06/21/2023] Open
Abstract
BACKGROUND Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%-70%, making second-line taxane-containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. METHODS The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m2 over 46 h i.v., irinotecan 180 mg/m2 i.v.; 5-FU 400 mg/m2 bolus; leucovorin 400 mg/m2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire. DISCUSSION The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. TRIAL REGISTRATION NCT03081143 Date of registration: 13.11.2015.
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Affiliation(s)
- Sylvie Lorenzen
- Klinikum rechts der Isar, Technische Universität München, III. Medizinische Klinik und Poliklinik, München, Germany.
| | - Alix Schwarz
- Klinikum rechts der Isar, Technische Universität München, III. Medizinische Klinik und Poliklinik, München, Germany
| | - Claudia Pauligk
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt/Main, Germany
| | - Eray Goekkurt
- Hämatologisch-Onkologische Praxis Eppendorf (HOPE), und Universitäres Cancer Center Hamburg (UCCH), Hamburg, Germany
| | - Gertraud Stocker
- Universitäres Krebszentrum Leipzig (UCCL), Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie - Bereich Onkologie Leipzig, Leipzig, Germany
| | - Jorge Riera Knorrenschild
- Universitätsklinikum Marburg, Klinik für Innere Medizin, Hämatologie, Onkologie und Immunologie, Marburg, Germany
| | - Gerald Illerhaus
- Klinikum Stuttgart, Klinik für Hämatologie, Onkologie und Palliativmedizin, Stuttgart, Germany
| | - Tobias Dechow
- Studienzentrum Onkologie Ravensburg, Ravensburg, Germany
| | - Markus Moehler
- I. Department of Internal Medicine, University Cancer Center Mainz, Mainz, Germany
| | - Jean-Charles Moulin
- Ortenau Klinikum Lahr, Medizinische Klinik, Sektion Hämatologie/Onkologie, Lahr, Germany
| | - Daniel Pink
- Klinik und Poliklinik für Innere Medizin C, Hämatologie und Onkologie, Transplantationszentrum, Palliativmedizin, Universität Greifswald, Greifswald, and Klinik für Hämatologie, Onkologie und Palliativmedizin, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Bad-Saarow, Bad Saarow, Germany
| | - Michael Stahl
- Evang. Kliniken Essen-Mitte, Klinik für Internistische Onkologie und Hämatologie, Essen, Germany
| | - Marina Schaaf
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt/Main, Germany
| | - Thorsten Oliver Goetze
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt/Main, Germany
- University Cancer Center Frankfurt, Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung, Frankfurt/Main, Germany
| | - Salah-Eddin Al-Batran
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt/Main, Germany
- University Cancer Center Frankfurt, Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung, Frankfurt/Main, Germany
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Davis JA, Cui ZL, Ghias M, Li X, Goodloe R, Wang C, Liepa AM, Hess LM. Treatment heterogeneity and overall survival in patients with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma in the United States. J Gastrointest Oncol 2022; 13:949-957. [PMID: 35837150 PMCID: PMC9274038 DOI: 10.21037/jgo-21-890] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/20/2022] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Gastric or gastroesophageal junction (GEJ) adenocarcinoma is the most common form of gastric cancer diagnosed in the United States (US) each year. Diagnosis typically is in later stages of disease when it has advanced. Patients have been treated with a variety of regimens. METHODS The goal of this retrospective study was to understand if treatment patterns were becoming more homogeneous or remaining heterogeneous using the Herfindahl-Hirschman index (HHI) and if treatments were becoming more concordant to treatment guidelines published by the National Comprehensive Cancer Network (NCCN). HHI scores were calculated for each site by 2-year increments. Trend analyses were conducted for HHI scores over time using a linear regression model. Concordance to Category 1 and any category NCCN guidelines was determined based on the date treatment was initiated with the version of the NCCN guidelines at that time. Time trend analyses were conducted using linear regression models. This study utilized data from the Flatiron Advanced Gastric/Esophageal cohort. This study also examined overall survival (OS) rates estimated by the Kaplan-Meier method by line of therapy. RESULTS There were no statistically significant differences in HHI scores in the first-line setting over time, suggesting heterogeneity has not improved. Concordance to NCCN treatment guidelines for any category significantly increased over time, however Category 1 regimen concordance remained low in the first-line setting. Concordance over time improved in second-line treatment. Median OS from the start of first-line therapy was 13.57 months. There was no relationship between OS time from initiation of first-line therapy and HHI score, concordance with NCCN guidelines, or concordance with NCCN Category 1 guidelines in the first-line setting. CONCLUSIONS Treatment heterogeneity persists in gastric cancer care, though there is a significant association between heterogeneity and concordance with both Category 1 and any category in the NCCN treatment guidelines, and that concordance has increased over time.
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Affiliation(s)
| | | | | | - Xiaohong Li
- Eli Lilly and Company, Indianapolis, IN, USA
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The tRNA-Derived Fragment tRF-24-V29K9UV3IU Functions as a miRNA-like RNA to Prevent Gastric Cancer Progression by Inhibiting GPR78 Expression. JOURNAL OF ONCOLOGY 2022; 2022:8777697. [PMID: 35535309 PMCID: PMC9077451 DOI: 10.1155/2022/8777697] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/10/2022] [Indexed: 02/05/2023]
Abstract
Emerging studies have proved that tRNA-derived fragments (tRFs) play vital roles in tumor metastasis; however, the function of tRFs in gastric cancer (GC) remains largely unclear. We investigated the role of tRF-24-V29K9UV3IU in growth and metastasis of GC using a xenograft mouse model. Differential gene expression downstream of tRF-24-V29K9UV3IU was identified by transcriptome sequencing, and interaction was then verified by a dual luciferase reporter and RNA immunoprecipitation. MKN-45 cells were also used to explore the biological functions of tRF-24-V29K9UV3IU in vitro. Here, knockdown of tRF-24-V29K9UV3IU promoted tumor growth and metastasis of GC in vivo. The expression of tRF-24-V29K9UV3IU and E-cadherin (epithelial cell marker) was down-regulated in tumors of mice following tRF-24-V29K9UV3IU knockdown, whereas the mesenchymal cell markers N-cadherin and vimentin displayed an opposite trend. Transcriptome sequencing identified 87 differentially expressed genes (DEGs) down-regulated in the tRF-24-V29K9UV3IU-overexpressed groups compared with the control group. Among them, G-protein–coupled receptor 78 (GPR78), the most significantly down-regulated DEG, was also predicted to be a target of tRF-24-V29K9UV3IU. Moreover, tRF-24-V29K9UV3IU could function as a miRNA-like fragment and bind to AGO2 and directly silence GPR78 expression by complementing with the 3′-untranslated region of the GPR78 mRNA. Functionally, overexpression of tRF-24-V29K9UV3IU significantly suppressed proliferation, migration, and invasion and promoted apoptosis of MKN-45 cells, whereas GPR78 attenuated these effects. Therefore, our data suggest that tRF-24-V29K9UV3IU functions as a miRNA-like fragment to suppress GPR78 expression and thus inhibit GC progression. These observations suggest that the tRF-24-V29K9UV3IU/GPR78 axis serves as a potential therapeutic target in GC.
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Zhuang SH, Meng CC, Fu JJ, Huang J. Long non-coding RNA ELFN1-AS1-mediated ZBTB16 inhibition augments the progression of gastric cancer by activating the PI3K/AKT axis. Kaohsiung J Med Sci 2022; 38:621-632. [PMID: 35451560 DOI: 10.1002/kjm2.12548] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 02/07/2022] [Accepted: 03/07/2022] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNA ELFN1 antisense RNA 1 (ELFN1-AS1) has been reported as a cancer driver in many human malignancies. This study was conducted to investigate the function of ELFN1-AS1 in gastric cancer (GC) and its mechanism of action. Bioinformatics analysis revealed increased expression of ELFN1-AS1 in GC, and abundant expression of ELFN1-AS1 was observed in the acquired GC cell lines. Knockdown of ELFN1-AS1 in GC cells weakened cell proliferation, invasion, migration, and resistance to apoptosis. ELFN1-AS1 was mainly localized in the nuclei of GC cells. ELFN1-AS1 recruited DNA methyltransferases to the promoter region of ZBTB16 and induced transcriptional repression of ZBTB16 through methylation modification. Furthermore, downregulation of ZBTB16 activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and restored the proliferation and invasiveness of GC cells. In vivo, downregulation of ELFN1-AS1 reduced the growth rate of xenograft tumors in mice. In summary, this study demonstrates that ELFN1-AS1 recruits DNA methyltransferases to the promoter region of ZBTB16 to induce its transcriptional repression, which further augments the development of GC by activating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Shao-Hua Zhuang
- Department of Gastroenterology, Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Chu-Chen Meng
- Department of Endocrinology, Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jin-Jin Fu
- Department of Gastroenterology, Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
| | - Jian Huang
- Department of Gastroenterology, Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, China
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Catenacci DV, Chao J, Muro K, Al‐Batran SE, Klempner SJ, Wainberg ZA, Shah MA, Rha SY, Ohtsu A, Liepa AM, Knoderer H, Chatterjee A, Van Cutsem E. Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma. Oncologist 2021; 26:e1704-e1729. [PMID: 34288262 PMCID: PMC8488781 DOI: 10.1002/onco.13907] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/02/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. MATERIALS AND METHODS We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. RESULTS In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. CONCLUSION For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. IMPLICATIONS FOR PRACTICE The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.
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Affiliation(s)
- Daniel V. Catenacci
- University of Chicago Medical Center & Biological SciencesChicagoIllinoisUSA
| | - Joseph Chao
- City of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Kei Muro
- Aichi Cancer Center HospitalNagoyaJapan
| | | | | | | | | | - Sun Young Rha
- Yonsei Cancer Center, Yonsei University College of MedicineSeoulKorea
| | | | | | | | | | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU LeuvenLeuvenBelgium
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Gu J, Chu K. Increased Mars2 expression upon microRNA-4661-5p-mediated KDM5D downregulation is correlated with malignant degree of gastric cancer cells. Cell Biol Int 2021; 45:2118-2128. [PMID: 34273914 DOI: 10.1002/cbin.11661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/28/2021] [Accepted: 07/05/2021] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related mortality worldwide. Methionyl-tRNA synthetase 2 (Mars2) has been suggested as a biomarker indicating poor prognosis of cancers. This study focuses on the function of Mars2 in GC and the responsible molecules. Mars2 was highly expressed in GC patients according to a transcriptome analysis and the data from the public database, and its high expression was confirmed in the acquired GC cell lines. Downregulation of Mars2 significantly weakened the proliferation, resistance to death, migration and invasion of GC cells. The H3K4me3 modification level was increased in the promoter region of Mars2, which was attributed to reduced abundance of lysine demethylase 5D (KDM5D) in the Mars2 promoter. MicroRNA (miR)-4661-5p was identified as an upstream regulator of KDM5D. Downregulation of miR-4661-5p led to an increase in the expression of KDM5D while a decline in the expression of Mars2, which reduced the malignant behaviors of GC cells; however, the malignant behaviors of GC cells was restored after further inhibition of KDM5D. To conclude, this study suggested that increased Mars2 expression upon miR-4661-5p-mediated KDM5D downregulation is correlated with malignant degree of GC cells.
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Affiliation(s)
- Jie Gu
- Department of Gastroenterology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, China
| | - Kaifeng Chu
- Department of Hepatology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, China
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Hess LM, Li X, Wu Y, Goodloe RJ, Cui ZL. Defining treatment regimens and lines of therapy using real-world data in oncology. Future Oncol 2021; 17:1865-1877. [DOI: 10.2217/fon-2020-1041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Retrospective observational research relies on databases that do not routinely record lines of therapy or reasons for treatment change. Standardized approaches to estimate lines of therapy were developed and evaluated in this study. A number of rules were developed, assumptions varied and macros developed to apply to large datasets. Results were investigated in an iterative process to refine line of therapy algorithms in three different cancers (lung, colorectal and gastric). Three primary factors were evaluated and included in the estimation of lines of therapy in oncology: defining a treatment regimen, addition/removal of drugs and gap periods. Algorithms and associated Statistical Analysis Software (SAS®) macros for line of therapy identification are provided to facilitate and standardize the use of real-world databases for oncology research.
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Affiliation(s)
- Lisa M Hess
- Eli Lilly & Company, Indianapolis, IN 46285, USA
| | - Xiaohong Li
- Eli Lilly & Company, Indianapolis, IN 46285, USA
| | - Yixun Wu
- Eli Lilly & Company, Indianapolis, IN 46285, USA
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Fornaro L, Spallanzani A, de Vita F, D’Ugo D, Falcone A, Lorenzon L, Tirino G, Cascinu S. Beyond the Guidelines: The Grey Zones of the Management of Gastric Cancer. Consensus Statements from the Gastric Cancer Italian Network (GAIN). Cancers (Basel) 2021; 13:1304. [PMID: 33804024 PMCID: PMC8001719 DOI: 10.3390/cancers13061304] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 03/11/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Management of gastric and gastroesophageal junction (GEJ) adenocarcinoma remains challenging, because of the heterogeneity in tumor biology within the upper gastrointestinal tract. Daily clinical practice is full of grey areas regarding the complexity of diagnostic, staging, and therapeutic procedures. The aim of this paper is to provide a guide for clinicians facing challenging situations in routine practice, taking a multidisciplinary consensus approach based on available literature. METHODS The GAIN (GAstric cancer Italian Network) group was established with the aims of reviewing literature evidence, discussing key issues in prevention, diagnosis, and management of gastric and GEJ adenocarcinoma, and offering a summary of statements. A Delphi consensus method was used to obtain opinions from the expert panel of specialists. RESULTS Forty-nine clinical questions were identified in six areas of interest: role of multidisciplinary team; risk factors; diagnosis; management of early gastric cancer and multimodal approach to localized gastric cancer; treatment of elderly patients with locally advanced resectable disease; and treatment of locally advanced and metastatic cancer. CONCLUSIONS The statements presented may guide clinicians in practical management of this disease.
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Affiliation(s)
- Lorenzo Fornaro
- Department of Translational Medicine, Division of Medical Oncology, AOU Pisana, 56126 Pisa, Italy;
| | - Andrea Spallanzani
- Department of Oncology and Hematology, University Hospital of Modena, 41125 Modena, Italy;
| | - Ferdinando de Vita
- Department of Precision Medicine, Division of Medical Oncology, School of Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Caserta, Italy; (F.d.V.); (G.T.)
| | - Domenico D’Ugo
- General Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, 00168 Rome, Italy; (D.D.); (L.L.)
| | - Alfredo Falcone
- Department of Translational Medicine, Division of Medical Oncology, University of Pisa, 56126 Pisa, Italy;
| | - Laura Lorenzon
- General Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, 00168 Rome, Italy; (D.D.); (L.L.)
| | - Giuseppe Tirino
- Department of Precision Medicine, Division of Medical Oncology, School of Medicine, University of Campania ‘Luigi Vanvitelli’, 81100 Caserta, Italy; (F.d.V.); (G.T.)
| | - Stefano Cascinu
- Medical Oncology, Università Vita-Salute San Raffaele, 20132 Milan, Italy
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10
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Hess LM, Zhu YE, Fang Y, Liepa AM. Health care resource utilization and treatment variability in the care of patients with advanced or metastatic colorectal or gastric cancer. J Med Econ 2021; 24:930-938. [PMID: 34289799 DOI: 10.1080/13696998.2021.1958607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
AIMS This study was designed to describe health care resource utilization (HCRU) of patients with metastatic colorectal cancer (CRC) or gastric cancer to test the hypothesis that greater treatment variability would be associated with increased HCRU. METHODS A retrospective observational study using Marketscan claims data was conducted. Eligible patients had a first diagnosis of metastatic CRC or gastric cancer between 2004 and 2015 and must have received systemic anti-cancer therapy after diagnosis. Treatment variability was measured using the Herfindahl-Hirschman Index (HHI). HHI scores were stratified by quartile. HCRU variables were evaluated throughout the follow-up period and described by 6-month periods. Chi-square test was used for categorical variables and ANOVA for continuous variables. RESULTS A total of 55,403 CRC and 9,073 gastric cancer patients were eligible. First-line HHI scores ranged from 0.1304-0.2778 for CRC and 0.0383-0.1778 for gastric cancer by state of residence. Statistically significant differences by HHI quartiles for HCRU in CRC included hospitalizations (p = 0.0003), ER visits (p < 0.0001), ER visits leading to hospitalization (p < 0.0001), and supportive care (all agents studied, p < 0.01). For gastric cancer, significant differences by HHI quartile were observed for ER visits (p = 0.002) and selected supportive care (G-CSF, erythropoiesis-stimulating agents, bisphosphonates, nutritional support, and antiemetics, each p < 0.05). No consistent increasing or decreasing trends were observed across the quartiles for either cohort. LIMITATIONS Large sample sizes could lead to statistical significance without being clinically meaningful. High treatment heterogeneity in the gastric cancer cohort and lack of a homogeneous quartile for comparisons limited the ability to evaluate HCRU by different levels of treatment variability. CONCLUSIONS Statistically significant relationships were observed between treatment variability as measured by HHI and increased HCRU, but no consistent directional trends in HCRU variables were observed. Therefore, this study failed to reject the null hypothesis of equivalent HCRU by level of treatment variability.
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Affiliation(s)
- Lisa M Hess
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Yun Fang
- Syneos Health, Inc, Indianapolis, IN, USA
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Huang X, Liu F, Jiang Z, Guan H, Jia Q. CREB1 Suppresses Transcription of microRNA-186 to Promote Growth, Invasion and Epithelial-Mesenchymal Transition of Gastric Cancer Cells Through the KRT8/HIF-1α Axis. Cancer Manag Res 2020; 12:9097-9111. [PMID: 33061604 PMCID: PMC7526476 DOI: 10.2147/cmar.s265187] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
Background The cAMP response element-binding protein 1 (CREB1) was initiated as a potential target for cancer treatment. This research was conducted to probe the effect of CREB1 in the progression of gastric cancer (GC) and the molecules involved. Materials and Methods CREB1 expression in GC tissues and cell lines (AGS and MKN-45) as well as that in normal tissues and in gastric mucosa cell line (GES-1) was detected. The correlation between CREB1 expression and prognosis of GC patients was determined. Artificial silencing of CREB1 was introduced to evaluate its effect on biological behaviors of GC cells. The target microRNA (miRNA) of CREB1 and the target mRNA of miR-186 were predicted and validated. Altered expression of miR-186, KRT8 and HIF-1α was introduced to confirm their functions in GC progression. Results CREB1 was abundantly expressed in GC tissues and cells and linked to dismal prognosis in patients. Silencing of CREB1 or upregulation of miR-186 suppressed the malignant behaviors such as growth, epithelial-mesenchymal transition (EMT) and invasion of GC cells, while artificial overexpression of KRT8 led to reversed trends. KRT8 was a target mRNA of miR-186, and CREB1 transcriptionally suppressed miR-186 expression to further up-regulate KRT8. KRT8 was also found to increase HIF-1α expression. Upregulation of HIF-1α was found to block the suppressing role of CREB1 silencing in GC cell malignancy. Conclusion This study evidenced that silencing of CREB1 inhibits growth, invasion, EMT and resistance to apoptosis of GC cells involving the upregulation of miR-186 and the following downregulation of KRT8 and HIF-1α.
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Affiliation(s)
- Xue Huang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, People's Republic of China
| | - Fujian Liu
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, People's Republic of China
| | - Zhiyong Jiang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, People's Republic of China
| | - Hang Guan
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, People's Republic of China
| | - Qiuhong Jia
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, People's Republic of China
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12
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Kim S, DiPeri TP, Guan M, Placencio-Hickok VR, Kim H, Liu JY, Hendifar A, Klempner SJ, Nipp R, Gangi A, Burch M, Waters K, Cho M, Chao J, Atkins K, Kamrava M, Tuli R, Gong J. Impact of palliative therapies in metastatic esophageal cancer patients not receiving chemotherapy. World J Gastrointest Surg 2020; 12:377-389. [PMID: 33024512 PMCID: PMC7520571 DOI: 10.4240/wjgs.v12.i9.377] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/02/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Palliative therapy has been associated with improved overall survival (OS) in several tumor types. Not all patients with metastatic esophageal cancer receive palliative chemotherapy, and the roles of other palliative therapies in these patients are limited.
AIM To investigate the impact of other palliative therapies in patients with metastatic esophageal cancer not receiving chemotherapy.
METHODS The National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined chemotherapy and had known palliative therapy status [palliative therapies were defined as surgery, radiotherapy (RT), pain management, or any combination thereof] were included. Cases with unknown chemotherapy, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Cox proportional hazards regression models were employed to examine factors influencing survival.
RESULTS Among 140234 esophageal cancer cases, we identified 1493 patients who did not receive chemotherapy and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. The majority (72.7%) did not receive other palliative therapies. On both univariate and multivariable analyses, there was no difference in OS between those receiving other palliative therapy (median 2.83 mo, 95%CI: 2.53-3.12) vs no palliative therapy (2.37 no, 95%CI: 2.2-2.56; multivariable P = 0.290). On univariate, but not multivariable analysis, treatment at an academic center was predictive of improved OS [Hazard ratio (HR) 0.90, 95%CI: 0.80-1.00; P = 0.047]. On multivariable analysis, female sex (HR 0.81, 95%CI: 0.71-0.92) and non-black, other race compared to white race (HR 0.72, 95%CI: 0.56-0.93) were associated with reduced mortality, while South geographic region relative to West region (HR 1.23, 95%CI: 1.04-1.46) and CCI of 1 relative to CCI of 0 (HR 1.17, 95%CI: 1.03-1.32) were associated with increased mortality. Higher histologic grade and T-stage were also associated with worse OS (P < 0.05).
CONCLUSION Palliative therapies other than chemotherapy conferred a numerically higher, but not statistically significant difference in OS among patients with metastatic esophageal cancer not receiving chemotherapy. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative therapies other than chemotherapy in metastatic esophageal cancer and future studies are warranted.
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Affiliation(s)
- Sungjin Kim
- Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Timothy P DiPeri
- Division of Surgical Oncology, Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Michelle Guan
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Veronica R Placencio-Hickok
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Haesoo Kim
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Jar-Yee Liu
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Andrew Hendifar
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Samuel J Klempner
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, United States
| | - Ryan Nipp
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, United States
| | - Alexandra Gangi
- Division of Surgical Oncology, Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Miguel Burch
- Division of Surgical Oncology, Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Kevin Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - May Cho
- Division of Hematology and Oncology, Department of Medicine, University of California, Davis, Sacramento, CA 95817, United States
| | - Joseph Chao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States
| | - Katelyn Atkins
- Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Mitchell Kamrava
- Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Richard Tuli
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| | - Jun Gong
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
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13
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Chaudhary SP, Kwak EL, Hwang KL, Lennerz JK, Corcoran RB, Heist RS, Russo AL, Parikh A, Borger DR, Blaszkowsky LS, Faris JE, Murphy JE, Azzoli CG, Roeland EJ, Goyal L, Allen J, Mullen JT, Ryan DP, Iafrate AJ, Klempner SJ, Clark JW, Hong TS. Revisiting MET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic, MET-Amplified Esophagogastric Cancers. Oncologist 2020; 25:e1691-e1700. [PMID: 32820577 DOI: 10.1634/theoncologist.2020-0274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/16/2020] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.
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Affiliation(s)
- Surendra Pal Chaudhary
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Eunice L Kwak
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Katie L Hwang
- Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jochen K Lennerz
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Ryan B Corcoran
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Rebecca S Heist
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Andrea L Russo
- Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Aparna Parikh
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Darrell R Borger
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Lawrence S Blaszkowsky
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jason E Faris
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
- Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
| | - Janet E Murphy
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher G Azzoli
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Eric J Roeland
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Lipika Goyal
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jill Allen
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - John T Mullen
- Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - David P Ryan
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - A John Iafrate
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Samuel J Klempner
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey W Clark
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
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14
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Wall JA, Klempner SJ, Arend RC. The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer. Expert Opin Investig Drugs 2020; 29:639-644. [PMID: 32408777 DOI: 10.1080/13543784.2020.1769065] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The Wnt/beta-catenin pathway is a complex signaling pathway known to be dysregulated in several cancers; Dickkopf-1 (Dkk1) is an inhibitor of canonical Wnt signaling via negative feedback. Elevated Dkk1 is associated with a poor prognosis in several cancers, including gynecologic and gastroesophageal malignancies. This review focuses on the potential therapeutic benefit of targeting Dkk1 with the IgG4 monoclonal antibody, DKN-01. AREAS COVERED We highlight current treatment approaches for advanced gynecologic and esophageal malignancies highlighting the need for more effective therapies, specifically improved immune-modulating agents and combinations. Our discussion of DKN-01 addresses the rationale for targeting Dkk1, available safety, pharmacokinetic and efficacy data. EXPERT OPINION DKN-01 presents an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies. It has been especially promising in patients with high-Dkk1-expressing tumors or known Wnt mutations. We postulate that the complementary mechanisms, limited adverse effects and emerging biomarker data position DKN-01 as a promising agent for combination therapy in patients with advanced malignancies. Specifically, we believe this occurs through an immuno-modulatory effect, primarily acting through the innate arm of the immune system. This highlights the possibility for addressing innate immune resistance and expanding the portion of patients who may benefit, possibly in a biomarker-selected manner.
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Affiliation(s)
- Jaclyn A Wall
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama , Birmingham, AL, USA
| | - Samuel J Klempner
- Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center , Boston, MA, USA.,Department of Internal Medicine, Division of Hematology-Oncology, Harvard Medical School , Boston, MA, USA
| | - Rebecca C Arend
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama , Birmingham, AL, USA
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15
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VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma. Sci Rep 2020; 10:1355. [PMID: 31992826 PMCID: PMC6987121 DOI: 10.1038/s41598-020-58493-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 01/15/2020] [Indexed: 12/19/2022] Open
Abstract
Due to its poor clinical outcome, there is an urgent need to identify novel prognostic markers for stomach adenocarcinoma (STAD). Here, we aimed to explore the relationship between VGLL3 expression and clinico-pathological features, dendritic cells, macrophages, and prognosis of STAD. VGLL3 expression levels were significantly associated with histological grade, T stage, and TNM stage. VGLL3 levels and patient’s age were also independent prognostic factors of the clinical outcome of STAD. In addition, VGLL3 was associated with the abundance of macrophages and dendritic cells in tumor infiltrates, of which only VGLL3 and macrophage counts were the independent prognostic factors of immune cell infiltration in the TIMER Database. Extracellular matrix receptor interaction, focal adhesion, pathways in cancer, MAPK, JAK STAT, and WNT signaling pathways were enriched in VGLL3 high-expressing datasets as determined by Gene Set Enrichment Analysis (GSEA), while DNA replication, glyoxylate, and dicarboxylate metabolism, glutathione metabolism, homologous recombination, and glycosylphosphatidylinositol gpi banchor biosynthesis were enriched in VGLL3 low-expressing datasets. Thus, VGLL3 is a novel prognostic biomarker of both the clinical outcome and immune infiltration in STAD, and may therefore be a promising therapeutic target.
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16
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Barzi A, Hess LM, Zhu YE, Liepa AM, Sugihara T, Beyrer J, Chao J. Real-World Outcomes and Factors Associated With the Second-Line Treatment of Patients With Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma. Cancer Control 2019; 26:1073274819847642. [PMID: 31056940 PMCID: PMC6503607 DOI: 10.1177/1073274819847642] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This retrospective observational study was designed to evaluate overall survival
in a real-world patient population and to identify predictive factors associated
with receipt of second-line therapy. A retrospective analysis of electronic
medical records (Flatiron Health, New York) was conducted among patients
initiating first-line therapy from January 1, 2013, through April 30, 2018.
Eligible patients were diagnosed with advanced gastric, gastroesophageal
junction, or esophageal adenocarcinoma and ≥18 years of age at the time of
treatment initiation. Patients alive 45 days after discontinuation of first-line
therapy were considered potentially eligible for continued therapy and were
categorized into those who received and those who did not receive second-line
therapy. Survival analyses were conducted using Kaplan-Meier method and log-rank
test without adjusting for any baseline covariates. Factors associated with
further treatment were evaluated using logistic regression. A total of 3850
patients met eligibility criteria. Among the 2516 patients available to receive
second-line therapy, 1515 (60.2%) received second-line therapy and 1001 (39.8%)
did not receive further therapy. Among those potentially eligible to receive
second-line therapy, median survival was 15.4 months (95% confidence interval
[CI]: 14.6-16.0) from initiation of first-line therapy for those who received
second-line therapy and 10.0 months (95% CI: 9.3-10.7) for those who did not.
Longer duration of first-line therapy (≥169 vs ≤84 days), HER2-positive tumors,
initially diagnosed with stage IV disease, less weight loss during first-line
therapy, and younger age were associated with receipt of second-line therapy
(all P < .001). Longer survival was associated with multiple
lines of therapy; however, these results should be interpreted with caution, and
no causal relationship can be inferred.
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Affiliation(s)
- Afsaneh Barzi
- 1 Norris Comprehensive Cancer Center, University of Southern California, Los Angles, CA, USA
| | - Lisa M Hess
- 2 Global Patient Outcomes and Real-World Evidence, Eli Lilly and Company, Indianapolis, IN, USA
| | - Yajun E Zhu
- 2 Global Patient Outcomes and Real-World Evidence, Eli Lilly and Company, Indianapolis, IN, USA
| | - Astra M Liepa
- 2 Global Patient Outcomes and Real-World Evidence, Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Julie Beyrer
- 2 Global Patient Outcomes and Real-World Evidence, Eli Lilly and Company, Indianapolis, IN, USA
| | - Joseph Chao
- 4 City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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17
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Klempner SJ, Maron SB, Chase L, Lomnicki S, Wainberg ZA, Catenacci DVT. Initial Report of Second-Line FOLFIRI in Combination with Ramucirumab in Advanced Gastroesophageal Adenocarcinomas: A Multi-Institutional Retrospective Analysis. Oncologist 2019; 24:475-482. [PMID: 30470690 PMCID: PMC6459251 DOI: 10.1634/theoncologist.2018-0602] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 10/16/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The randomized phase III RAINBOW trial established paclitaxel (pac) plus ramucirumab (ram) as a global standard for second-line (2L) therapy in advanced gastric and gastroesophageal junction adenocarcinoma, together gastroesophageal adenocarcinoma (GEA). Patients (pts) receiving first-line (1L) FOLFOX often develop neuropathy that renders continued neurotoxic agents in the 2L setting unappealing and other regimens more desirable. As such, FOLFIRI-ram has become an option for patients with 2L GEA. FOLFIRI-ramucirumab (ram) has demonstrated safety and activity in 2L colorectal cancer, but efficacy/safety data in GEA are lacking. SUBJECTS, MATERIALS, AND METHODS Patients with GEA treated with 2L FOLFIRI-ram between August 2014 and April 2018 were identified. Clinicopathologic data including oxaliplatin neurotoxicity rates/grades (G), 2L treatment response, progression-free survival (PFS), overall survival (OS), safety, and molecular features were abstracted from three U.S. academic institutions. Kaplan-Meier survival analysis was used to generate PFS/OS; the likelihood ratio test was used to determine statistical significance. RESULTS We identified 29 pts who received 2L FOLFIRI-ram. All pts received 1L platinum + fluoropyrimidine, and 23 of 29 (79%) had post-1L neuropathy; 12 (41%) had G1, and 11 (38%) had G2. Patients were evenly split between esophagus/gastroesophageal junction (12; 41%) and gastric cancer (17; 59%). Among evaluable pts (26/29), the overall response rate was 23% (all partial response) with a disease control rate of 79%. Median PFS was 6.0 months and median OS was 13.4 months among all evaluable pts. Six- and 12-month OS were 90% (n = 18/20) and 41% (n = 7/17). There were no new safety signals. CONCLUSION We provide the first data suggesting FOLFIRI-ram is a safe, non-neurotoxic regimen comparing favorably with the combination of pac + ram used in the seminal RAINBOW trial. IMPLICATIONS FOR PRACTICE Results of this study provide initial support for the safety and efficacy of second-line (2L) FOLFIRI-ramucirumab (ram) after progression on first-line platinum/fluoropyrimidine in patients with gastroesophageal adenocarcinoma (GEA). The overall response, progression-free survival, overall survival, and toxicity profile compare favorably with paclitaxel (pac) + ram and highlight the importance of the ongoing phase II RAMIRIS trial examining FOLFIRI-ram versus pac + ram in 2L GEA (NCT03081143). FOLFIRI-ram may warrant consideration for inclusion as an alternate regimen in consensus guidelines for GEA.
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Affiliation(s)
- Samuel J Klempner
- The Angeles Clinic and Research Institute, Los Angeles, California, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Steven B Maron
- Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois, USA
| | - Leah Chase
- Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois, USA
| | - Samantha Lomnicki
- Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois, USA
| | - Zev A Wainberg
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Daniel V T Catenacci
- Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois, USA
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