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1
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Liu D, Jee J, Drilon A, Heilmann AM, Allen JM, Schrock AB, Keller-Evans RB, Li BT. Diverse ERBB2/ERBB3 Activating Alterations and Coalterations Have Implications for HER2/3-Targeted Therapies across Solid Tumors. CANCER RESEARCH COMMUNICATIONS 2025; 5:680-693. [PMID: 40178042 PMCID: PMC12022956 DOI: 10.1158/2767-9764.crc-24-0620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 03/06/2025] [Accepted: 04/01/2025] [Indexed: 04/05/2025]
Abstract
SIGNIFICANCE CGP provides genomic context for HER2 status beyond the information provided by IHC and FISH, including detection of ERBB2 mutations and co-alterations that may suggest sensitivity/resistance to HER2-directed therapies, and is therefore crucial for guiding treatment choice and understanding individual patient response.
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Affiliation(s)
- Dazhi Liu
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Justin Jee
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alexander Drilon
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | | | | | | | | | - Bob T. Li
- Memorial Sloan Kettering Cancer Center, New York, New York
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2
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Cai J, Wang W, Cong D, Bai Y, Zhang W. Development of treatment strategies for advanced HER2-positive gastric cancer: Insights from clinical trials. Crit Rev Oncol Hematol 2025; 207:104617. [PMID: 39805409 DOI: 10.1016/j.critrevonc.2025.104617] [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: 04/05/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.
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Affiliation(s)
- Jing Cai
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wanning Wang
- Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China
| | - Dan Cong
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yuansong Bai
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wenlong Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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3
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Mo C, Sterpi M, Jeon H, Bteich F. Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies. Cancers (Basel) 2024; 16:2854. [PMID: 39199625 PMCID: PMC11352490 DOI: 10.3390/cancers16162854] [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: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.
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Affiliation(s)
- Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
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4
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Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Sakamoto Y, Nishina T, Inaki K, Kuwahara Y, Wada N, Suto F, Arita T, Sugihara M, Tsuchihashi Z, Saito K, Kojima A, Yamaguchi K. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nat Med 2024; 30:1933-1942. [PMID: 38745009 PMCID: PMC11271396 DOI: 10.1038/s41591-024-02992-x] [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: 11/09/2023] [Accepted: 04/11/2024] [Indexed: 05/16/2024]
Abstract
Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.
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Affiliation(s)
- Kohei Shitara
- National Cancer Center Hospital East, Kashiwa, Japan.
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Yung-Jue Bang
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | | | - Min-Hee Ryu
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | - Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | | | - Tomohiro Nishina
- National Hospital Organization Shikoku Cancer Center, Ehime, Japan
| | | | | | - Naoya Wada
- Daiichi Sankyo RD Novare Co. Ltd, Tokyo, Japan
| | | | | | | | | | - Kaku Saito
- Daiichi Sankyo Inc., Basking Ridge, NJ, USA
| | | | - Kensei Yamaguchi
- Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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5
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Rustgi N, Wu S, Samec T, Walker P, Xiu J, Lou E, Goel S, Saeed A, Moy RH. Molecular Landscape and Clinical Implication of CCNE1-amplified Esophagogastric Cancer. CANCER RESEARCH COMMUNICATIONS 2024; 4:1399-1409. [PMID: 38717153 PMCID: PMC11146286 DOI: 10.1158/2767-9764.crc-23-0496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/26/2024] [Accepted: 05/03/2024] [Indexed: 06/05/2024]
Abstract
Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted. SIGNIFICANCE Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.
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Affiliation(s)
- Naryan Rustgi
- Department of Surgery, Division of Surgical Sciences, Columbia University Irving Medical Center, New York, New York
| | - Sharon Wu
- Caris Life Sciences, Phoenix, Arizona
| | | | | | | | - Emil Lou
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Sanjay Goel
- Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Ryan H. Moy
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, New York
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6
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Yamaguchi K, Ito M, Isobe T, Koreishi S, Taguchi R, Uehara K, Ueno S, Imajima T, Kitazono T, Tsuchihashi K, Ohmura H, Yoshihiro T, Tanoue K, Nishiyori S, Iwama E, Maeda T, Akashi K, Baba E. Impact of Genomic Alterations on Efficacy of Trastuzumab Deruxtecan Against Human Epidermal Growth Factor Receptor-2-Positive Advanced Gastric Cancer. JCO Precis Oncol 2024; 8:e2300681. [PMID: 38748981 DOI: 10.1200/po.23.00681] [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: 12/08/2023] [Revised: 02/09/2024] [Accepted: 03/15/2024] [Indexed: 08/07/2024] Open
Abstract
PURPOSE The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. METHODS We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. RESULTS In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046). CONCLUSION CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.
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Affiliation(s)
- Kyoko Yamaguchi
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
- Department of Clinical Education Center, Kyushu University Hospital, Fukuoka, Japan
| | - Mamoru Ito
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Taichi Isobe
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sakuya Koreishi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryosuke Taguchi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koki Uehara
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Ueno
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Imajima
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takafumi Kitazono
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenji Tsuchihashi
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hirofumi Ohmura
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoyasu Yoshihiro
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kenro Tanoue
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Satoshi Nishiyori
- Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Iwama
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Maeda
- Division of Precision Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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7
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Kim IH. Emerging Targets for Systemic Treatment of Gastric Cancer: HER2 and Beyond. J Gastric Cancer 2024; 24:29-56. [PMID: 38225765 PMCID: PMC10774754 DOI: 10.5230/jgc.2024.24.e6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/17/2024] Open
Abstract
In recent years, remarkable progress has been made in the molecular profiling of gastric cancer. This progress has led to the development of various molecular classifications to uncover subtype-specific dependencies that can be targeted for therapeutic interventions. Human epidermal growth factor receptor 2 (HER2) is a crucial biomarker for advanced gastric cancer. The recent promising results of novel approaches, including combination therapies or newer potent agents such as antibody-drug conjugates, have once again brought attention to anti-HER2 targeted treatments. In HER2-negative diseases, the combination of cytotoxic chemotherapy and programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors has become the established standard of care in first-line settings. In the context of gastric cancer, potential biomarkers such as PD-L1 expression, Epstein-Barr virus, microsatellite instability, and tumor mutational burden are being considered for immunotherapy. Recently, promising results have been reported in studies on anti-Claudin18.2 and fibroblast growth factor receptor 2 treatments. Currently, many ongoing trials are aimed at identifying potential targets using novel approaches. Further investigations will be conducted to enhance the progress of these therapies, addressing challenges such as primary and acquired resistance, tumor heterogeneity, and clonal evolution. We believe that these efforts will improve patient prognoses. Herein, we discuss the current evidence of potential targets for systemic treatment, clinical considerations, and future perspectives.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastric Cancer Centre, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea,.
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8
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Byeon S, Jung J, Kim ST, Kim KM, Lee J. Clinical Implication of Concurrent Amplification of MET and FGFR2 in Metastatic Gastric Cancer. Biomedicines 2023; 11:3172. [PMID: 38137393 PMCID: PMC10740780 DOI: 10.3390/biomedicines11123172] [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: 10/13/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND c-mesenchymal epithelial transition factor receptor (c-MET) and fibroblast growth factor receptor 2 (FGFR2) amplification have been identified as factors associated with advanced stage and poor prognosis in gastric cancer (GC). While they are typically considered mutually exclusive, concurrent amplifications have been reported in a small subset of GC patients. METHODS in this retrospective study, we analyzed the clinical outcomes of GC patients with MET and FGFR2 amplification using the next-generation sequencing (NGS) database cohort at Samsung Medical Center, which included a total of 2119 patients between October 2019 and April 2021. RESULTS Of 2119 cancer patients surveyed, the number of GC patients was 614 (29.0%). Out of 614 GC patients, 39 (6.4%) had FGFR2 amplification alone, 22 (3.6%) had MET amplification, and 2 GC patients (0.3%) had concurrent FGFR2 and MET amplification. Two patients with concurrent FGFR2 and MET amplification did not respond to first-line chemotherapy. These two patients had significantly shorter overall survival (3.6 months) compared to patients with FGFR2 or MET amplification alone (13.6 months and 8.4 months, respectively) (p = 0.004). Lastly, we tested the existence of FGFR2 and MET in tumor specimens from different organ sites. Initially, the NGS was tested in a primary tumor specimen from stomach cancer, where the MET copy number was 14.1 and the FGFR2 copy number was 5.3. We confirmed that both MET and FGFR2 were highly amplified in the primary tumor using FISH (MET-CEP7 ratio = 5 and FGFR2-CEP7 ratio = 3). However, although the MET copy number was normal in peritoneal seeding using FISH, FGFR2 remained amplified using FISH (FGFR2-CEP7 ratio = 7) with high FGFR2 protein overexpression. Hence, there was intra-patient molecular heterogeneity. CONCLUSIONS our findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.
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Affiliation(s)
- Seonggyu Byeon
- Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University Seoul Hospital, Seoul 07804, Republic of Korea;
| | - Jaeyun Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
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9
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DiPeri TP, Evans KW, Raso MG, Zhao M, Rizvi YQ, Zheng X, Wang B, Kirby BP, Kong K, Kahle M, Yap TA, Dumbrava EE, Ajani JA, Fu S, Keyomarsi K, Meric-Bernstam F. Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers. Clin Cancer Res 2023; 29:4385-4398. [PMID: 37279095 PMCID: PMC10618648 DOI: 10.1158/1078-0432.ccr-23-0103] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/22/2023] [Accepted: 06/02/2023] [Indexed: 06/08/2023]
Abstract
PURPOSE Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. EXPERIMENTAL DESIGN Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array. RESULTS Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model. CONCLUSIONS We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317.
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Affiliation(s)
- Timothy P. DiPeri
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kurt W. Evans
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria Gabriela Raso
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ming Zhao
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yasmeen Q. Rizvi
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaofeng Zheng
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bailiang Wang
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bryce P. Kirby
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kathleen Kong
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael Kahle
- Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Timothy A. Yap
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ecaterina E. Dumbrava
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Funda Meric-Bernstam
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas
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10
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Rolfo C, Del Re M, Russo A. Empower the Potential of Trastuzumab Deruxtecan with Novel Combinations. Clin Cancer Res 2023; 29:4317-4319. [PMID: 37656059 DOI: 10.1158/1078-0432.ccr-23-1700] [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: 07/06/2023] [Revised: 08/15/2023] [Accepted: 08/24/2023] [Indexed: 09/02/2023]
Abstract
Trastuzumab deruxtecan (T-DXd) is reshaping the therapeutic landscape of HER2-positive tumors. A recent article reports on the preclinical activity of the combination of T-DXd plus adavosertib, WEE1 kinase inhibitor, which promises to expand the use of this antibody-drug conjugate in HER2-positive tumors with CCNE1 coamplification. See related article by DiPeri et al., p. 4385.
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Affiliation(s)
- Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marzia Del Re
- Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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11
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Guan WL, He Y, Xu RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol 2023; 16:57. [PMID: 37245017 DOI: 10.1186/s13045-023-01451-3] [Citation(s) in RCA: 349] [Impact Index Per Article: 174.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/10/2023] [Indexed: 05/29/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.
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Affiliation(s)
- Wen-Long Guan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China
| | - Ye He
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China
| | - Rui-Hua Xu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China.
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12
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Kwon HJ, Park Y, Nam SK, Kang E, Kim KK, Jeong I, Kwak Y, Yoon J, Kim TY, Lee KW, Oh DY, Im SA, Kong SH, Park DJ, Lee HJ, Kim HH, Yang HK, Lee HS. Genetic and immune microenvironment characterization of HER2-positive gastric cancer: Their association with response to trastuzumab-based treatment. Cancer Med 2023; 12:10371-10384. [PMID: 36916290 DOI: 10.1002/cam4.5769] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/07/2023] [Accepted: 02/22/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. METHODS Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. RESULTS Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3- CD57+ NK cells and PD-L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). CONCLUSION HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3- CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.
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Affiliation(s)
- Hyun Jung Kwon
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yujun Park
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Enoch Kang
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | | | - Yoonjin Kwak
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeesun Yoon
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do-Youn Oh
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seock-Ah Im
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Do Joong Park
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyuk-Joon Lee
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Han-Kwang Yang
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.,Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
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13
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Coutzac C, Funk-Debleds P, Cattey-Javouhey A, Desseigne F, Guibert P, Marolleau P, Rochefort P, de la Fouchardière C. Targeting HER2 in metastatic gastroesophageal adenocarcinomas: What is new? Bull Cancer 2022; 110:552-559. [PMID: 36229267 DOI: 10.1016/j.bulcan.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/19/2022] [Accepted: 08/27/2022] [Indexed: 11/07/2022]
Abstract
Gastric and esophageal adenocarcinomas represent a biologically heterogeneous disease. The identification, in early eighties, of human epidermal growth factor receptor 2 (HER2) overexpression, being present in 12 to 20% of the cases, marked a major milestone in the efforts of unraveling the molecular complexity of this disease. This led to the development of anti-HER2-therapies, trastuzumab being the first to demonstrate, in combination with cisplatin and 5FU/capecitabine chemotherapy, an improvement in response rate and survival in the first-line setting of patients with metastatic, HER2-positive gastroesophageal adenocarcinomas. Afterwards, during a decade, several studies have tried new strategies either to block HER2 pathway differently or to combine different anti-HER2, without efficacy. Everything changed with studies demonstrating additive effect between anti-HER2 and immune checkpoint inhibitors and leading to phase III clinical trials combining anti-HER2 and anti-PD-L1/PD1 therapies. Pembrolizumab, a PD-1 inhibitor, was recently granted by FDA an accelerated approval, in patients with HER2-positive gastro-oesophageal adenocarcinomas, in combination with trastuzumab and platinum-based chemotherapy following meaningful improvement in overall response rate over standard treatment. Progression-free and overall-survival results are still awaited to change our first-line standard treatment. Furthermore, new HER2 inhibitors have been developed, blocking HER2-mediated pathway signaling via different mechanisms from pan-HER inhibition to anti-HER2 antibody drug conjugates with promising results in pretreated patients. Trastuzumab-deruxtecan has in particular showed interesting results in pretreated patients. We present here a review of the recent data and perspectives in HER2-positive metastatic gastroesophageal adenocarcinomas.
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14
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Hino K, Nishina T, Kajiwara T, Bando H, Nakamura M, Kadowaki S, Minashi K, Yuki S, Ohta T, Hara H, Mizukami T, Moriwaki T, Ohtsubo K, Komoda M, Mitani S, Nagashima F, Kato K, Yamada T, Hasegawa H, Yamazaki K, Yoshino T, Hyodo I. Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2-Positive Esophagogastric and Gastric Cancer. JCO Precis Oncol 2022; 6:e2200135. [PMID: 35952320 PMCID: PMC9384954 DOI: 10.1200/po.22.00135] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)–positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy.
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Affiliation(s)
- Kaori Hino
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Takeshi Kajiwara
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Maho Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Keiko Minashi
- Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Takuro Mizukami
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Masato Komoda
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Seiichiro Mitani
- Department of Medical Oncology, Kindai University Hospital, Osaka-sayama, Japan
| | - Fumio Nagashima
- Department of Medical Oncology, Kyorin University Hospital, Mitaka, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Japan
| | - Takanobu Yamada
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroko Hasegawa
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Kentaro Yamazaki
- Clinical Trial Coordination Unit and Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
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15
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Choi S, Park S, Kim H, Kang SY, Ahn S, Kim KM. Gastric Cancer: Mechanisms, Biomarkers, and Therapeutic Approaches. Biomedicines 2022; 10:543. [PMID: 35327345 PMCID: PMC8945014 DOI: 10.3390/biomedicines10030543] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) remains one of the most common deadly malignancies worldwide. Recently, several targeted therapeutics for treating unresectable or metastatic GC have been developed. Comprehensive characterization of the molecular profile and of the tumor immune microenvironment of GC has allowed researchers to explore promising biomarkers for GC treatment and has enabled a new paradigm in precision-targeted immunotherapy. In this article, we review established and promising new biomarkers relevant in GC, with a focus on their clinical implications, diagnostic methods, and the efficacy of targeted agents.
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Affiliation(s)
- Sangjoon Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Sujin Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Hyunjin Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
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16
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Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel) 2021; 13:cancers13205216. [PMID: 34680363 PMCID: PMC8533881 DOI: 10.3390/cancers13205216] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.
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17
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Liao H, Tian T, Sheng Y, Peng Z, Li Z, Wang J, Li Y, Zhang C, Gao J. The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer. Front Oncol 2021; 11:719217. [PMID: 34557411 PMCID: PMC8453156 DOI: 10.3389/fonc.2021.719217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 11/18/2022] Open
Abstract
Background Accurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC). Methods MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot. Results MET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity. Conclusions MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.
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Affiliation(s)
- Haiyan Liao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Tiantian Tian
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.,Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yuling Sheng
- School of Medicine, The Southern University of Science and Technology, Shenzhen, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jingyuan Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Cheng Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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18
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Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021; 18:473-487. [PMID: 33790428 DOI: 10.1038/s41571-021-00492-2] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.
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19
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Lu J, Ding Y, Chen Y, Jiang J, Chen Y, Huang Y, Wu M, Li C, Kong M, Zhao W, Wang H, Zhang J, Li Z, Lu Y, Yu X, Jin K, Zhou D, Zhou T, Teng F, Zhang H, Zhou Z, Wang H, Teng L. Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets. Nat Commun 2021; 12:3946. [PMID: 34168152 PMCID: PMC8225795 DOI: 10.1038/s41467-021-24170-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease.
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Affiliation(s)
- Jun Lu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanyan Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junjie Jiang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yiran Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yingying Huang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mengjie Wu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chengzhi Li
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mei Kong
- Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenyi Zhao
- Innovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences and Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, Hangzhou, China
| | - Haohao Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Zhang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongqi Li
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yimin Lu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiongfei Yu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ketao Jin
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Donghui Zhou
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tianhua Zhou
- Institute of Gastroenterology, Cancer center, Zhejiang University, Hangzhou, China
| | - Fei Teng
- Hangzhou Oncocare Co. Ltd, Hangzhou, China
| | - Haibin Zhang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhan Zhou
- Innovation Institute for Artificial Intelligence in Medicine and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences and Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, Hangzhou, China.
| | - Haiyong Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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20
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Mezynski MJ, Farrelly AM, Cremona M, Carr A, Morgan C, Workman J, Armstrong P, McAuley J, Madden S, Fay J, Sheehan KM, Kay EW, Holohan C, Elamin Y, Rafee S, Morris PG, Breathnach O, Grogan L, Hennessy BT, Toomey S. Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer. J Transl Med 2021; 19:184. [PMID: 33933113 PMCID: PMC8088633 DOI: 10.1186/s12967-021-02842-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/18/2021] [Indexed: 12/24/2022] Open
Abstract
Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02842-1.
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Affiliation(s)
- M Janusz Mezynski
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Angela M Farrelly
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Mattia Cremona
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Aoife Carr
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Clare Morgan
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Julie Workman
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Paul Armstrong
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Jennifer McAuley
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Stephen Madden
- Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Joanna Fay
- Department of Histopathology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Katherine M Sheehan
- Department of Histopathology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Elaine W Kay
- Department of Histopathology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ciara Holohan
- Department of Medical Oncology, St. James's Hospital, Dublin, Ireland
| | - Yasir Elamin
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland
| | - Shereen Rafee
- Department of Medical Oncology, St. James's Hospital, Dublin, Ireland
| | - Patrick G Morris
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | - Oscar Breathnach
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | - Liam Grogan
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | - Bryan T Hennessy
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.,Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland
| | - Sinead Toomey
- Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
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21
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Zhu Y, Zhu X, Wei X, Tang C, Zhang W. HER2-targeted therapies in gastric cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188549. [PMID: 33894300 DOI: 10.1016/j.bbcan.2021.188549] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/27/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023]
Abstract
Molecular targeted therapy of cancer has always been the focus of clinicians. Among those therapeutic targets, the human epidermal growth factor receptor-2 (HER-2) signaling pathway is one of the most popular targets for translational research in cancer. However, unlike prospect in breast cancer, HER-2 inhibitor trastuzumab is the only molecular targeted drug approved by US Food and Drug Administration (FDA) for the first-line treatment of HER-2 positive advanced gastric cancer. On this basis, a variety of novel HER2- targeted drugs for gastric cancer are under development, and related clinical researches are in full swing, including small molecular kinase inhibitors (e.g., afatinib, neratinib, pyrotinib), antibody-drug conjugates (e.g., DS-8201a, RC48-ADC) and other novel therapies (e.g., ZW25, CAR-T, BVAC-B). In this study, we will summarize the recent advances in anti-HER-2 agents, potential mechanisms of resistance to HER2-targeted therapy in HER2-positive gastric cancer. We will also discuss the future prospects of potential strategies to overcome anti-HER-2 resistance and development of novel anti-HER-2 approaches for the treatment of HER2-positive gastric cancer patients.
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Affiliation(s)
- Yinxing Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xuedan Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
| | - Wenwen Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
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22
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Liu Z, Shi M, Li X, Song S, Liu N, Du H, Ye J, Li H, Zhang Z, Zhang L. HER2 copy number as predictor of disease-free survival in HER2-positive resectable gastric adenocarcinoma. J Cancer Res Clin Oncol 2021; 147:1315-1324. [PMID: 33543328 PMCID: PMC8021510 DOI: 10.1007/s00432-021-03522-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 01/10/2021] [Indexed: 01/28/2023]
Abstract
Purpose The identification of HER2 overexpression in a subset of gastric adenocarcinoma (GA) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GA patients has been investigated. However, its predictive value in resectable patients remains elusive. Methods We enrolled 98 treatment-naïve resectable Chinese GA patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer-related genes was performed on tumor tissues. Furthermore, we also investigated the correlation between HER2 copy number (CN) and survival outcomes. Results Of the 98 HER2-overexpressed patients, 90 had HER2 CN amplification assessed using next-generation sequencing, achieving 92% concordance. The most commonly seen concurrent mutations were occurring in TP53, EGFR and PIK3CA. We found HER2 CN as a continuous variable was an independent predictor associated with DFS (p = 0.029). Our study revealed HER2 CN-high patients showed a trend of intestinal-type GA predominant (p = 0.075) and older age (p = 0.07). The median HER2 CN was 15.34, which was used to divide the cohort into CN-high and CN-low groups. Patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002). Furthermore, HER2 CN as a categorical variable was also an independent predictor associated with DFS in patients. Conclusion We elucidated the mutation spectrum of HER2-positive resectable Chinese GA patients and the association between HER2 CN and DFS. Our work revealed HER2 CN as an independent risk factor predicted unfavorable prognosis in HER2-positive GA patients and allowed us to further stratify HER2-positive resectable GA patients for disease management.
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Affiliation(s)
- Zimin Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
| | - Mingpeng Shi
- Operating Room of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Xiaoxiao Li
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Shanai Song
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Ning Liu
- Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Haiwei Du
- Burning Rock Biotech, Guangzhou, China
| | - Junyi Ye
- Burning Rock Biotech, Guangzhou, China
| | - Haiyan Li
- Burning Rock Biotech, Guangzhou, China
| | | | - Lu Zhang
- Burning Rock Biotech, Guangzhou, China
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23
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Chen C, Di Bartolomeo M, Corallo S, Strickler JH, Goyal L. Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come. Am Soc Clin Oncol Educ Book 2021; 40:161-173. [PMID: 32421451 DOI: 10.1200/edbk_280871] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in RAS wild-type colorectal cancer, anti-HER2 therapy in HER2- amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in FGFR2 fusion-positive and IDH1-mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.
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Affiliation(s)
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Lipika Goyal
- Massachusetts General Hospital Cancer Center, Boston, MA
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24
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Kim B, Kang SY, Kim D, Heo YJ, Kim KM. PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression. Cancers (Basel) 2020; 12:cancers12071724. [PMID: 32610572 PMCID: PMC7407887 DOI: 10.3390/cancers12071724] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 12/21/2022] Open
Abstract
Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein–Barr virus (EBV), HER2 overexpression, and PD-L1 expression on PTEN mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic PTEN mutations, of which 19 (55.9%) showed PTEN protein loss. The most common PTEN variants associated with protein loss were p.R130 (n = 4) followed by p.R335, p.L265fs, and deletions (n = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type PTEN, protein loss was found in 35 cases (12.2%). Thus, PTEN mutations were significantly associated with PTEN protein loss (p = 5.232 × 10−10), high MSI (p = 3.936 × 10−8), and EBV-positivity (p = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in PTEN are a frequent genetic mechanism of PTEN inactivation in GC.
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Affiliation(s)
- Binnari Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
| | - Deokgeun Kim
- Department of Clinical Genomics, Samsung Medical Center, Seoul 06351, Korea;
| | - You Jeong Heo
- The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (B.K.); (S.Y.K.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
- Correspondence: ; Tel.: +82-2-3410-2807; Fax: +82-2-3410-6396
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25
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Mitani S, Kawakami H. Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance. Cancers (Basel) 2020; 12:E400. [PMID: 32050652 PMCID: PMC7072407 DOI: 10.3390/cancers12020400] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/25/2020] [Accepted: 02/06/2020] [Indexed: 12/15/2022] Open
Abstract
Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies.
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Affiliation(s)
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan;
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Nagaraja AK, Kikuchi O, Bass AJ. Genomics and Targeted Therapies in Gastroesophageal Adenocarcinoma. Cancer Discov 2019; 9:1656-1672. [PMID: 31727671 PMCID: PMC7232941 DOI: 10.1158/2159-8290.cd-19-0487] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 08/09/2019] [Accepted: 09/06/2019] [Indexed: 12/23/2022]
Abstract
Gastroesophageal adenocarcinomas (GEA) are devastating diseases with stark global presence. Over the past 10 years, there have been minimal improvements in treatment approach despite numerous clinical trials. Here, we review recent progress toward understanding the molecular features of these cancers and the diagnostic and therapeutic challenges posed by their intrinsic genomic instability and heterogeneity. We highlight the potential of genomic heterogeneity to influence clinical trial outcomes for targeted therapies and emphasize the need for comprehensive molecular profiling to guide treatment selection and adapt treatment to resistance and genomic evolution. Revising our clinical approach to GEA by leveraging genomic advances will be integral to the success of current and future treatments, especially as novel targets become therapeutically tractable. SIGNIFICANCE: GEAs are deadly cancers with few treatment options. Characterization of the genomic landscape of these cancers has revealed considerable genetic diversity and spatial heterogeneity. Understanding these fundamental properties of GEA will be critical for overcoming barriers to the development of novel, more effective therapeutic strategies.
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Affiliation(s)
- Ankur K Nagaraja
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Osamu Kikuchi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Adam J Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
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27
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Kim ST, Banks KC, Pectasides E, Kim SY, Kim K, Lanman RB, Talasaz A, An J, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Park SH, Park JO, Park YS, Lim HY, Kim NKD, Park W, Lee H, Bass AJ, Kim K, Kang WK, Lee J. Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients. Ann Oncol 2019; 29:1037-1048. [PMID: 29409051 PMCID: PMC5913644 DOI: 10.1093/annonc/mdy034] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
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Affiliation(s)
- S T Kim
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - K C Banks
- Department of Medical Affair, Guardant Health, Dana-Farber Cancer Institute, Boston, USA
| | - E Pectasides
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, USA
| | - S Y Kim
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - K Kim
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - R B Lanman
- Department of Medical Affair, Guardant Health, Dana-Farber Cancer Institute, Boston, USA
| | - A Talasaz
- Department of Medical Affair, Guardant Health, Dana-Farber Cancer Institute, Boston, USA
| | - J An
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - M G Choi
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - J H Lee
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - T S Sohn
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - J M Bae
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - S Kim
- Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - S H Park
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - J O Park
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Y S Park
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - H Y Lim
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - N K D Kim
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - W Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - H Lee
- Sungkyunkwan University School of Medicine, Seoul, Korea; Division of Gastroenterolog, Department of Medicine, Samsung Medical Center, Seoul, Korea
| | - A J Bass
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, USA
| | - K Kim
- Pathology and Translational Genomics, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - W K Kang
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea
| | - J Lee
- Division of Hematology-Oncolog, Department of Medicine, Samsung Medical Center, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea.
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Biane C, Delaplace F. Causal Reasoning on Boolean Control Networks Based on Abduction: Theory and Application to Cancer Drug Discovery. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2019; 16:1574-1585. [PMID: 30582550 DOI: 10.1109/tcbb.2018.2889102] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Complex diseases such as Cancer or Alzheimer's are caused by multiple molecular perturbations leading to pathological cellular behavior. However, the identification of disease-induced molecular perturbations and subsequent development of efficient therapies are challenged by the complexity of the genotype-phenotype relationship. Accordingly, a key issue is to develop frameworks relating molecular perturbations and drug effects to their consequences on cellular phenotypes. Such framework would aim at identifying the sets of causal molecular factors leading to phenotypic reprogramming. In this article, we propose a theoretical framework, called Boolean Control Networks, where disease-induced molecular perturbations and drug actions are seen as topological perturbations/actions on molecular networks leading to cell phenotype reprogramming. We present a new method using abductive reasoning principles inferring the minimal causal topological actions leading to an expected behavior at stable state. Then, we compare different implementations of the algorithm and finally, show a proof-of-concept of the approach on a model of network regulating the proliferation/apoptosis switch in breast cancer by automatically discovering driver genes and their synthetic lethal drug target partner.
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Klempner SJ, Chao J. Toward optimizing outcomes in Her2-positive gastric cancer: timing and genomic context matter. Ann Oncol 2019; 29:801-802. [PMID: 29462252 DOI: 10.1093/annonc/mdy066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- S J Klempner
- The Angeles Clinic and Research Institute, Los Angeles, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
| | - J Chao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, USA
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30
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Choi S, Chu J, Kim B, Ha SY, Kim ST, Lee J, Kang WK, Han H, Sohn I, Kim KM. Tumor Heterogeneity Index to Detect Human Epidermal Growth Factor Receptor 2 Amplification by Next-Generation Sequencing. J Mol Diagn 2019; 21:612-622. [DOI: 10.1016/j.jmoldx.2019.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/08/2019] [Accepted: 02/19/2019] [Indexed: 12/12/2022] Open
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Kawazoe A, Shitara K. Next-generation sequencing and biomarkers for gastric cancer: what is the future? Ther Adv Med Oncol 2019; 11:1758835919848189. [PMID: 31258627 PMCID: PMC6589985 DOI: 10.1177/1758835919848189] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/12/2019] [Indexed: 12/18/2022] Open
Abstract
Recent years have witnessed an improved understanding of tumour biology and the molecular features of gastric cancer. Remarkable advances in next-generation sequencing technologies have defined the genomic landscape of gastric cancer. In fact, several molecular classifications have been proposed, and distinct molecular subtypes have been identified, which could serve as a roadmap for patient stratification and trials of targeted therapies. At present, clinical trials of new agents, such as receptor tyrosine kinases inhibitors, antibody-drug conjugates and IMAB362 (anti-Claudin 18.2), are ongoing. Furthermore, biomarkers of immune checkpoint inhibitors or combination therapy have been ardently investigated. These developments could facilitate precision medicine for gastric cancer in the near future.
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Affiliation(s)
- Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
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Shitara K, Iwata H, Takahashi S, Tamura K, Park H, Modi S, Tsurutani J, Kadowaki S, Yamaguchi K, Iwasa S, Saito K, Fujisaki Y, Sugihara M, Shahidi J, Doi T. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol 2019; 20:827-836. [PMID: 31047804 DOI: 10.1016/s1470-2045(19)30088-9] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 01/17/2019] [Accepted: 01/23/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion. METHODS This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. FINDINGS Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3-59·0) of 44 patients had a confirmed objective response. INTERPRETATION Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. FUNDING Daiichi Sankyo Co, Ltd.
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Affiliation(s)
- Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Shunji Takahashi
- Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kenji Tamura
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Haeseong Park
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Shanu Modi
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Junji Tsurutani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan; Department of Medical Oncology, Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
| | - Shigenori Kadowaki
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Kensei Yamaguchi
- Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoru Iwasa
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kaku Saito
- Research and Development, Daiichi Sankyo Co, Ltd, Tokyo, Japan
| | | | - Masahiro Sugihara
- Biostatistics and Data Management, Daiichi Sankyo Co, Ltd, Tokyo, Japan
| | - Javad Shahidi
- Research and Development, Daiichi Sankyo, Inc, Basking Ridge, NJ, USA
| | - Toshihiko Doi
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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Ishii T, Kawazoe A, Shitara K. Dawn of precision medicine on gastric cancer. Int J Clin Oncol 2019; 24:779-788. [PMID: 30976939 DOI: 10.1007/s10147-019-01441-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/02/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND In recent years, a better understanding of tumor biology and molecular features of gastric cancer has been reached. It may serve as a roadmap for patient stratification and trials of targeted therapies. The apparent efficacy of PD-1 blockade might be limited to a relatively small subset of advanced gastric cancer patients. MATERIALS AND METHODS In this study, preclinical and clinical studies, which investigated molecular features, promising treatment targets, and immune checkpoint inhibitor in gastric cancer, were reviewed via PubMed and the congress webpages of the American Society of Clinical Oncology and European Society of Medical Oncology. RESULTS Next-generation sequencing technologies have defined the genomic landscape of gastric cancer. Indeed, several molecular classifications have been proposed, and distinct molecular subtypes have been identified. Based on these molecular profiles, clinical trials of new agents such as receptor tyrosine kinases inhibitors, antibody-drug conjugates, and IMAB362 (anti-Claudin 18.2) are ongoing. In addition, biomarkers to predict response during immune checkpoint inhibitors and combination therapy have been enthusiastically investigated. CONCLUSION Remarkable advances in an understanding of molecular profiles of gastric cancer enable the development of novel agents. The better treatment selection of immune checkpoint inhibitors or combination therapy should be established. These developments could facilitate precision medicine on gastric cancer in the near future.
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Affiliation(s)
- Takahiro Ishii
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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Nagahashi M, Shimada Y, Ichikawa H, Kameyama H, Takabe K, Okuda S, Wakai T. Next generation sequencing-based gene panel tests for the management of solid tumors. Cancer Sci 2019; 110:6-15. [PMID: 30338623 PMCID: PMC6317963 DOI: 10.1111/cas.13837] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 10/13/2018] [Accepted: 10/16/2018] [Indexed: 12/16/2022] Open
Abstract
Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS-based gene panel tests has generated practical diagnostic tools that enable individualized cancer-patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double-strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS-based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.
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Affiliation(s)
- Masayuki Nagahashi
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Yoshifumi Shimada
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Hiroshi Ichikawa
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Hitoshi Kameyama
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Kazuaki Takabe
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
- Breast SurgeryRoswell Park Cancer InstituteBuffaloNew York
- Department of SurgeryThe State University of New York Jacobs School of Medicine and Biomedical SciencesUniversity at BuffaloBuffaloNew York
| | - Shujiro Okuda
- Division of BioinformaticsGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
| | - Toshifumi Wakai
- Division of Digestive and General SurgeryGraduate School of Medical and Dental SciencesNiigata UniversityNiigataJapan
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Raimondi A, Nichetti F, Peverelli G, Di Bartolomeo M, De Braud F, Pietrantonio F. Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies. Pharmacogenomics 2018; 19:1047-1068. [PMID: 30041572 DOI: 10.2217/pgs-2018-0077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is a highly heterogeneous disease, displaying a complex genomic landscape and an unfavorable outcome with standard therapies. Based on distinctive genomic alterations, novel targeted agents have been developed with the aim of personalizing treatments and improving patient outcome. However, a subgroup of patients is primarily treatment-resistant, and even in the initially sensitive population, secondary resistance emerges, thus limiting therapeutic benefit. In this review, we summarize the clinical data about standard targeted agents in gastric cancer, specifically anti-HER2 treatments and antivascular therapies. We also illustrate the available evidence regarding molecular mechanisms of resistance to these agents and we discuss potential strategies for new targeted treatments that could overcome such resistance.
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Affiliation(s)
- Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federico Nichetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giorgia Peverelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo De Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology & Hemato-oncology, University of Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology & Hemato-oncology, University of Milan, Italy
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Feng W, Zhu X. Efficacy prediction of targeted therapy for gastric cancer: The current status (Review). Mol Med Rep 2018; 18:1238-1246. [PMID: 29901092 DOI: 10.3892/mmr.2018.9145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 05/03/2018] [Indexed: 11/05/2022] Open
Abstract
Despite significant progress in the treatment of gastric cancer (GC), the prognosis remains poor and the mortality is high. Targeted drugs have been incorporated into routine treatment to improve treatment efficacy. However, the therapy response is still below 50%. Therefore, there is a need to identify predictive factors for patient response to a specific drug in order to improve the efficacy of drug therapy. The present article reviewed the predictive factors for target therapy in GC, including epidermal growth factor receptor, human epidermal receptor 2, vascular endothelial growth factor family, molecules in the mesenchymal‑epithelial transition pathway and the mammalian target of rapamycin. Additionally, the present review described the interactions between these molecules and signaling pathways.
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Affiliation(s)
- Wanjing Feng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Xiaodong Zhu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
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Alessandrini L, Manchi M, De Re V, Dolcetti R, Canzonieri V. Proposed Molecular and miRNA Classification of Gastric Cancer. Int J Mol Sci 2018; 19:E1683. [PMID: 29882766 PMCID: PMC6032377 DOI: 10.3390/ijms19061683] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC.
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Affiliation(s)
- Lara Alessandrini
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Melissa Manchi
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Riccardo Dolcetti
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
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Díaz-Serrano A, Angulo B, Dominguez C, Pazo-Cid R, Salud A, Jiménez-Fonseca P, Leon A, Galan MC, Alsina M, Rivera F, Plaza JC, Paz-Ares L, Lopez-Rios F, Gómez-Martín C. Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab. Oncologist 2018; 23:1092-1102. [PMID: 29700210 DOI: 10.1634/theoncologist.2017-0379] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 02/22/2018] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.
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Affiliation(s)
| | - Barbara Angulo
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carolina Dominguez
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Roberto Pazo-Cid
- Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Antonieta Salud
- Medical Oncology Unit, Hospital Universitario Arnau de Vilanova, Lérida, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana Leon
- Medical Oncology Unit, Fundación Jimenez Diaz, Madrid, Spain
| | - Maria Carmen Galan
- Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Alsina
- Medical Oncology Department, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
| | - Fernando Rivera
- Medical Oncology Deparment, Hospital Universitario Marques de Valdecilla, Santander, Spain
| | - J Carlos Plaza
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Luis Paz-Ares
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Fernando Lopez-Rios
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carlos Gómez-Martín
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
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Janjigian YY, Sanchez-Vega F, Jonsson P, Chatila WK, Hechtman JF, Ku GY, Riches JC, Tuvy Y, Kundra R, Bouvier N, Vakiani E, Gao J, Heins ZJ, Gross BE, Kelsen DP, Zhang L, Strong VE, Schattner M, Gerdes H, Coit DG, Bains M, Stadler ZK, Rusch VW, Jones DR, Molena D, Shia J, Robson ME, Capanu M, Middha S, Zehir A, Hyman DM, Scaltriti M, Ladanyi M, Rosen N, Ilson DH, Berger MF, Tang L, Taylor BS, Solit DB, Schultz N. Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer. Cancer Discov 2018; 8:49-58. [PMID: 29122777 PMCID: PMC5813492 DOI: 10.1158/2159-8290.cd-17-0787] [Citation(s) in RCA: 297] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/20/2017] [Accepted: 11/06/2017] [Indexed: 12/14/2022]
Abstract
The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Pectasides et al., p. 37This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Yelena Y Janjigian
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
| | - Francisco Sanchez-Vega
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip Jonsson
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Walid K Chatila
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jaclyn F Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Geoffrey Y Ku
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Jamie C Riches
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Yaelle Tuvy
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Ritika Kundra
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy Bouvier
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Efsevia Vakiani
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jianjiong Gao
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zachary J Heins
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin E Gross
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David P Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Liying Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vivian E Strong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mark Schattner
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Hans Gerdes
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Daniel G Coit
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Manjit Bains
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Valerie W Rusch
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David R Jones
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Daniela Molena
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mark E Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Marinela Capanu
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sumit Middha
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David M Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Maurizio Scaltriti
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marc Ladanyi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Neal Rosen
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - David H Ilson
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - Michael F Berger
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Barry S Taylor
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David B Solit
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nikolaus Schultz
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
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Pietrantonio F, Fucà G, Morano F, Gloghini A, Corso S, Aprile G, Perrone F, De Vita F, Tamborini E, Tomasello G, Gualeni AV, Ongaro E, Busico A, Giommoni E, Volpi CC, Laterza MM, Corallo S, Prisciandaro M, Antista M, Pellegrinelli A, Castagnoli L, Pupa SM, Pruneri G, de Braud F, Giordano S, Cremolini C, Di Bartolomeo M. Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study. Clin Cancer Res 2017; 24:1082-1089. [PMID: 29208673 DOI: 10.1158/1078-0432.ccr-17-2781] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 10/27/2017] [Accepted: 11/30/2017] [Indexed: 01/12/2023]
Abstract
Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways.Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed.Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients (P < 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07-0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09-0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%.Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082-9. ©2017 AACR.
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Affiliation(s)
- Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Giovanni Fucà
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Annunziata Gloghini
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Simona Corso
- University of Torino, Department of Oncology and Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Giuseppe Aprile
- Department of Oncology, ULSS8 Berica, San Bortolo General Hospital, Vicenza, Italy
| | - Federica Perrone
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Clinical and Experimental Medicine and Surgery, University of Campania 'Luigi Vanvitelli', School of Medicine, Naples, Italy
| | - Elena Tamborini
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Ambra Vittoria Gualeni
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elena Ongaro
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Adele Busico
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elisa Giommoni
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Chiara Costanza Volpi
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Maddalena Laterza
- Division of Medical Oncology, Department of Clinical and Experimental Medicine and Surgery, University of Campania 'Luigi Vanvitelli', School of Medicine, Naples, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Antista
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Pellegrinelli
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lorenzo Castagnoli
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Serenella M Pupa
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giancarlo Pruneri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Oncology and Haemato-Oncology Department, University of Milan, Università degli Studi di Milano, Milan, Italy
| | - Silvia Giordano
- University of Torino, Department of Oncology and Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Chiara Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Ichikawa H, Nagahashi M, Shimada Y, Hanyu T, Ishikawa T, Kameyama H, Kobayashi T, Sakata J, Yabusaki H, Nakagawa S, Sato N, Hirata Y, Kitagawa Y, Tanahashi T, Yoshida K, Nakanishi R, Oki E, Vuzman D, Lyle S, Takabe K, Ling Y, Okuda S, Akazawa K, Wakai T. Actionable gene-based classification toward precision medicine in gastric cancer. Genome Med 2017; 9:93. [PMID: 29089060 PMCID: PMC5664811 DOI: 10.1186/s13073-017-0484-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 10/17/2017] [Indexed: 12/27/2022] Open
Abstract
Background Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. Methods A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status. Results Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster. Conclusions This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0484-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Yoshifumi Shimada
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takaaki Hanyu
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takashi Ishikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Hitoshi Kameyama
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takashi Kobayashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Hiroshi Yabusaki
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata City, Niigata, 951-8566, Japan
| | - Satoru Nakagawa
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata City, Niigata, 951-8566, Japan
| | - Nobuaki Sato
- Department of Breast Oncology, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, Chuo-ku, Niigata City, Niigata, 951-8566, Japan
| | - Yuki Hirata
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjyuku-ku, Tokyo, 160-8582, Japan
| | - Toshiyuki Tanahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Dana Vuzman
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA.,Broad Institute of Harvard and MIT, Cambridge, Massachusetts, 02142, USA
| | - Stephen Lyle
- Molecular, Cell & Cancer Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts, 01655, USA.
| | - Kazuaki Takabe
- Breast Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York, 14263, USA.,Department of Surgery, University at Buffalo the State University of New York, 100 High Street, Buffalo, New York, 14203, USA
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Kohei Akazawa
- Department of Medical Informatics, Niigata University Medical and Dental Hospital, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
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Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, Negri FV, Berenato R, Ermacora P, Cardellino GG, Giovannoni M, Pella N, Scartozzi M, Antonuzzo L, Silvestris N, Fasola G, Aprile G. Molecular classifications of gastric cancers: Novel insights and possible future applications. World J Gastrointest Oncol 2017; 9:194-208. [PMID: 28567184 PMCID: PMC5434387 DOI: 10.4251/wjgo.v9.i5.194] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/04/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.
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Bai L, Guo CH, Zhao Y, Gao JG, Li M, Shen C, Guo YM, Duan XY. SUVmax of 18F-FDG PET/CT correlates to expression of major chemotherapy-related tumor markers and serum tumor markers in gastric adenocarcinoma patients. Oncol Rep 2017; 37:3433-3440. [DOI: 10.3892/or.2017.5631] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 04/24/2017] [Indexed: 11/05/2022] Open
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Ooi A, Oyama T, Nakamura R, Tajiri R, Ikeda H, Fushida S, Dobashi Y. Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Hum Pathol 2016; 61:58-67. [PMID: 27864121 DOI: 10.1016/j.humpath.2016.10.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/19/2016] [Accepted: 10/28/2016] [Indexed: 12/18/2022]
Abstract
New and effective treatments for advanced gastric cancer are urgently needed. Cyclins E and D1 form a complex with cyclin-dependent kinase 2, 4, or 6 to regulate G1-S transition. The G1-S regulatory genes encoding cyclin E (CCNE1), cyclin D1 (CCND1), and CDK6 (CDK6) are frequently amplified in gastric cancer and may therefore influence molecularly targeted therapies against ERBB2 or EGFR when coamplified. A total of 179 formalin-fixed and paraffin-embedded gastric cancer specimens were examined for these gene amplifications by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Amplification of at least 1 G1-S regulatory gene was found in 35 tumors (CCNE1 amplification, 15% of samples; CCND1, 6%; CDK6, 1%). In 13 of the 35 tumors, dual-color fluorescence in situ hybridization identified coamplification of the G1-S regulatory genes with ERBB2, EGFR, and/or KRAS in single cancer nuclei. The observation that cells with G1-S regulatory gene amplification contained clonal subpopulations with coamplification of ERBB2, EGFR, or KRAS in 5 early and 3 advanced cancers suggests that amplification of the G1-S regulatory genes represents an early event, which precedes ERBB2, EGFR, or KRAS amplification. Amplified CCNE1, CCND1, and CDK6 in advanced gastric cancer may be potentially useful as direct targets for molecular therapy or for combination therapy with ERBB2 or EGFR inhibitors. Multiplex ligation-dependent probe amplification could be a useful tool for identification of patients who would benefit from such therapies.
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Affiliation(s)
- Akishi Ooi
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan; Pathology Section, University Hospital, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Takeru Oyama
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Ritsuko Nakamura
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Ryousuke Tajiri
- Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Hiroko Ikeda
- Pathology Section, University Hospital, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Ishikawa 920-8641, Japan.
| | - Yoh Dobashi
- Department of Pathology, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.
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Adem BF, Bastos NRA, Dias F, Teixeira AL, Medeiros R. miRNAs: mediators of ErbB family targeted therapy resistance. Pharmacogenomics 2016; 17:1175-1187. [PMID: 27359187 DOI: 10.2217/pgs-2016-0038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The ErbB/HER tyrosine kinase receptors family plays a key regulatory role in different cellular processes by activating several signaling pathways. In different tumor types, mutations or overexpression of the ErbB family members are a common feature, which led to the development of targeted therapies against this receptors. Although with this kind of treatment we are heading to a more personalized medicine, the development of acquired resistance is still an issue, therefore, several studies focused on discovering the mechanisms behind it. More recently, miRNAs have been described as important mediators of acquired resistance, specifically, acquired resistance to ErbB family targeted therapies. Ultimately, miRNA-based therapeutics using exosomes as a drug delivery model can revolutionize today's approach of cancer treatment.
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Affiliation(s)
- Bárbara Filipa Adem
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,FMUP, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Nuno Ricardo Alves Bastos
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,FMUP, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Francisca Dias
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal.,ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.,LPCC, Research Department Portuguese League Against Cancer (NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal.,CEBIMED, Health Sciences of Fernando Pessoa University, Rua Carlos da Maia 296, 4200-150 Porto, Portugal
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Yoo C, Park YS. Companion diagnostics for the targeted therapy of gastric cancer. World J Gastroenterol 2015; 21:10948-55. [PMID: 26494953 PMCID: PMC4607896 DOI: 10.3748/wjg.v21.i39.10948] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 07/09/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fourth most common type of cancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer.
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