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Volders PJ, Aftimos P, Dedeurwaerdere F, Martens G, Canon JL, Beniuga G, Froyen G, Van Huysse J, De Pauw R, Prenen H, Lambin S, Decoster L, Vaeyens F, Rottey S, Van Dam PJ, Decoster L, Rutten A, Schreuer M, Loontiens S, Van der Meulen J, Mebis J, Cuppens K, Tejpar S, Vanden Bempt I, De Grève J, Schröder D, van Marcke C, Van Den Bulcke M, de Azambuja E, Punie K, Maes B. A nationwide comprehensive genomic profiling and molecular tumor board platform for patients with advanced cancer. NPJ Precis Oncol 2025; 9:66. [PMID: 40065106 PMCID: PMC11893761 DOI: 10.1038/s41698-025-00858-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) study assessed the feasibility of using comprehensive genomic profiling (CGP) in clinical decision-making for patients with advanced cancers. This multi-center study enrolled 872 patients from 12 Belgian hospitals. CGP was performed on tumor tissues using a standardized CGP panel (523 genes) across nine laboratories with success in 93% of patients and a median turnaround time of 29 days. Actionable genomic markers were identified in 81% of patients, substantially higher than the 21% using nationally reimbursed, small panels. A national molecular tumor board (nMTB) recommended treatments for 69% of patients, with 23% receiving matched therapies. Reasons for non-compliance were highly variable across clinical sites. Overall, BALLETT demonstrates the feasibility of implementing decentralized CGP and its potential to identify actionable targets in most patients with advanced cancers. BALLETT reinforces CGP's utility and emphasizes the importance of collaboration, standardization, and addressing implementation challenges.
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Affiliation(s)
- Pieter-Jan Volders
- Laboratory for Molecular Diagnostics, Jessa Hospital, Hasselt, Belgium
- Faculty of Medicine and Life Sciences, LCRC, University of Hasselt, Hasselt, Belgium
- Department of Biomolecular Medicine, Ghent University, Gent, Belgium
| | - Philippe Aftimos
- Clinical Trials Conduct Unit, Institut Jules Bordet-Université Libre de Bruxelles, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | | | - Geert Martens
- Department of Laboratory Medicine, AZ Delta Hospital, Roeselare, Belgium
| | - Jean-Luc Canon
- Department of Medical Oncology, Grand Hôpital de Charleroi, Charleroi, Belgium
| | | | - Guy Froyen
- Laboratory for Molecular Diagnostics, Jessa Hospital, Hasselt, Belgium
- Faculty of Medicine and Life Sciences, LCRC, University of Hasselt, Hasselt, Belgium
| | | | - Rebecca De Pauw
- Department of Pulmonology, AZ Sint-Jan Brugge, Bruges, Belgium
| | - Hans Prenen
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium
- Center for Oncological research, University of Antwerp, Wilrijk, Belgium
| | - Suzan Lambin
- Department of Pathology, University Hospital Antwerp, Edegem, Belgium
| | - Lore Decoster
- Department of Medical Oncology, University Hospital Brussels, Brussels, Belgium
- Laboratory for Medical and Molecular Oncology, Vrije Universiteit, Brussels, Belgium
| | - Freya Vaeyens
- Centre for Medical Genetics, University Hospital Brussels, Brussels, Belgium
| | - Sylvie Rottey
- Department of Medical Oncology, Ghent University, Ghent, Belgium
| | | | - Lynn Decoster
- Department of Pulmonology, AZ Turnhout, Turnhout, Belgium
| | - Annemie Rutten
- Department of Medical Oncology, ZAS hospitals, Antwerp, Belgium
| | - Max Schreuer
- Department of Medical Oncology, ASZ Aalst, Aalst, Belgium
| | - Siebe Loontiens
- Department of Biomolecular Medicine, Ghent University, Gent, Belgium
- Molecular Diagnostics, Ghent University Hospital, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Joni Van der Meulen
- Department of Biomolecular Medicine, Ghent University, Gent, Belgium
- Molecular Diagnostics, Ghent University Hospital, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Jeroen Mebis
- Faculty of Medicine and Life Sciences, LCRC, University of Hasselt, Hasselt, Belgium
- Department of Medical Oncology, Jessa Hospital, Hasselt, Belgium
| | - Kristof Cuppens
- Faculty of Medicine and Life Sciences, LCRC, University of Hasselt, Hasselt, Belgium
- Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium
| | - Sabine Tejpar
- Digestive Oncology, University Hospitals KU Leuven, Leuven, Belgium
| | | | - Jacques De Grève
- Laboratory for Medical and Molecular Oncology, Vrije Universiteit, Brussels, Belgium
- Centre for Medical Genetics, University Hospital Brussels, Brussels, Belgium
| | - David Schröder
- Department of Medical Oncology, Grand Hôpital de Charleroi, Charleroi, Belgium
| | - Cédric van Marcke
- Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium
- Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | | | - Evandro de Azambuja
- Institut Jules Bordet, Hôpital Universitaire de Bruxelles and l'Université Libre de Bruxelles, Brussels, Belgium
| | - Kevin Punie
- Department of Medical Oncology, ZAS hospitals, Antwerp, Belgium
| | - Brigitte Maes
- Laboratory for Molecular Diagnostics, Jessa Hospital, Hasselt, Belgium.
- Faculty of Medicine and Life Sciences, LCRC, University of Hasselt, Hasselt, Belgium.
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Nikanjam M, Kato S, Allen T, Sicklick JK, Kurzrock R. Novel clinical trial designs emerging from the molecular reclassification of cancer. CA Cancer J Clin 2025. [PMID: 39841128 DOI: 10.3322/caac.21880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 01/23/2025] Open
Abstract
Next-generation sequencing has revealed the disruptive reality that advanced/metastatic cancers have complex and individually distinct genomic landscapes, necessitating a rethinking of treatment strategies and clinical trial designs. Indeed, the molecular reclassification of cancer suggests that it is the molecular underpinnings of the disease, rather than the tissue of origin, that mostly drives outcomes. Consequently, oncology clinical trials have evolved from standard phase 1, 2, and 3 tissue-specific studies; to tissue-specific, biomarker-driven trials; to tissue-agnostic trials untethered from histology (all drug-centered designs); and, ultimately, to patient-centered, N-of-1 precision medicine studies in which each patient receives a personalized, biomarker-matched therapy/combination of drugs. Innovative technologies beyond genomics, including those that address transcriptomics, immunomics, proteomics, functional impact, epigenetic changes, and metabolomics, are enabling further refinement and customization of therapy. Decentralized studies have the potential to improve access to trials and precision medicine approaches for underserved minorities. Evaluation of real-world data, assessment of patient-reported outcomes, use of registry protocols, interrogation of exceptional responders, and exploitation of synthetic arms have all contributed to personalized therapeutic approaches. With greater than 1 × 1012 potential patterns of genomic alterations and greater than 4.5 million possible three-drug combinations, the deployment of artificial intelligence/machine learning may be necessary for the optimization of individual therapy and, in the near future, also may permit the discovery of new treatments in real time.
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Affiliation(s)
- Mina Nikanjam
- Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA
- Moores Cancer Center, University of California San Diego Health, La Jolla, California, USA
| | - Shumei Kato
- Division of Hematology-Oncology, University of California San Diego, La Jolla, California, USA
- Moores Cancer Center, University of California San Diego Health, La Jolla, California, USA
| | | | - Jason K Sicklick
- Moores Cancer Center, University of California San Diego Health, La Jolla, California, USA
- Division of Surgical Oncology, Department of Surgery, University of California San Diego, San Diego, California, USA
- Department of Pharmacology, University of California San Diego, San Diego, California, USA
| | - Razelle Kurzrock
- Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin, USA
- Worldwide Innovative Networking in Personalized Cancer Medicine Consortium, Paris, France
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3
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Navarro P, Beato C, Rodriguez-Moreno JF, Ruiz-Llorente S, Mielgo X, Pineda E, Navarro M, Bruixola G, Grazioso TP, Viudez A, Fuster J, Nogueron E, Mediano MD, Balaña C, Mendez C, Rodriguez RM, Del Barco Berron S, Gongora B, Carmona-Bayonas A, Garcia-Donas J. Prospective study of the real impact of fusion centered genomic assays in patient management in a national collaborative group: the GETHI-XX-16 study. Clin Transl Oncol 2024:10.1007/s12094-024-03745-5. [PMID: 39485597 DOI: 10.1007/s12094-024-03745-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/21/2024] [Indexed: 11/03/2024]
Abstract
PURPOSE Precision medicine represents a paradigm shift in oncology. Access to genetic testing and targeted therapies is frequently limited. Assays based on DNA sequencing can miss druggable alterations. We aimed to determine the impact of a free access program to RNA tests in patient management. METHODS We designed a multicenter prospective observational study within the Spanish National Group for Translational Oncology and Rare and Orphan Tumors (GETTHI). Eligible patients were adults with solid cancers that had progressed on standard therapies. Tumor samples were analyzed using two RNA sequencing assays (Trailblaze PharosTM and Archer FusionPlex Solid TumorTM). A central committee evaluated the actionability of genetic alterations and reported the findings to attending physicians, who made the final clinical management decisions. RESULTS Between November 2016 and April 2019, 395 patients with 41 different tumors across 30 hospitals were included. Molecular analysis revealed actionable genetic alterations in 57 individuals (14.4%). Targeted therapies were advised for 23 and seven received a matched targeted therapy: two lung cancers (EML4-ALK and CD74-ROS1 fusion), three glioblastomas (EGFR point mutations), one oligodendroglioma (FGFR3-TACC3 fusion) and a prostate cancer (SND1-BRAF fusion). The outcomes included two tumor responses, one disease stabilization, one early withdrawal due to toxicity, one progression, and one unknown. CONCLUSION Despite the growing knowledge of cancer biology and its translation to drug development, the overall impact of personalized treatments remains low. Access to comprehensive molecular tests covering properly all known actionable alterations and programs for a wide access to targeted therapies seem to be critical steps.
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Affiliation(s)
- Paloma Navarro
- Laboratory of Innovation in Oncology; Gynecological, Genitourinary and Skin Tumor Unit, HM CIOCC (Clara Campal Comprehensive Cancer Centre), Sanchinarro HM Universitary Hospital, HM Hospitales, Madrid, Spain, Madrid, Spain
- HM Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain
- HM Hospitals Health Research Institute, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
| | - Carmen Beato
- Medical Oncology Department, Hospital Virgen de La Macarena, Seville, Spain
| | - Juan Francisco Rodriguez-Moreno
- Laboratory of Innovation in Oncology; Gynecological, Genitourinary and Skin Tumor Unit, HM CIOCC (Clara Campal Comprehensive Cancer Centre), Sanchinarro HM Universitary Hospital, HM Hospitales, Madrid, Spain, Madrid, Spain
- HM Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain
- HM Hospitals Health Research Institute, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
| | - Sergio Ruiz-Llorente
- Laboratory of Innovation in Oncology; Gynecological, Genitourinary and Skin Tumor Unit, HM CIOCC (Clara Campal Comprehensive Cancer Centre), Sanchinarro HM Universitary Hospital, HM Hospitales, Madrid, Spain, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
- Departamento de Biomedicina y Biotecnología, Área de Genética, Universidad de Alcalá, Madrid, Spain
| | - Xabier Mielgo
- Medical Oncology Department , Hospital Universitario Fundacion Alcorcon, Madrid, Spain
| | - Estela Pineda
- Medical Oncology Department, Hospital Clinic Barcelona, Barcelona, Spain
| | - Miguel Navarro
- Medical Oncology Department, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
| | - Gema Bruixola
- Medical Oncology Department, Hospital Clinico Universtario - INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Tatiana P Grazioso
- Laboratory of Innovation in Oncology; Gynecological, Genitourinary and Skin Tumor Unit, HM CIOCC (Clara Campal Comprehensive Cancer Centre), Sanchinarro HM Universitary Hospital, HM Hospitales, Madrid, Spain, Madrid, Spain
- HM Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain
- HM Hospitals Health Research Institute, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
| | - Antonio Viudez
- Medical Oncology Department, Hospital de Navarra, Pamplona, Spain
| | - Jose Fuster
- Medical Oncology Department, Hospital Universitario Son Espases, Palma, Spain
| | - Esther Nogueron
- Medical Oncology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
| | | | - Carmen Balaña
- Instituto Catalán de Oncología-Badalona, Barcelona, Spain
| | | | | | | | | | | | - Jesus Garcia-Donas
- Laboratory of Innovation in Oncology; Gynecological, Genitourinary and Skin Tumor Unit, HM CIOCC (Clara Campal Comprehensive Cancer Centre), Sanchinarro HM Universitary Hospital, HM Hospitales, Madrid, Spain, Madrid, Spain.
- HM Faculty of Health Sciences, Camilo José Cela University, Madrid, Spain.
- HM Hospitals Health Research Institute, Madrid, Spain.
- Institute of Applied Molecular Medicine (IMMA), School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain.
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Wegmann R, Bankel L, Festl Y, Lau K, Lee S, Arnold F, Cappelletti V, Fehr A, Picotti P, Dedes KJ, Franzen D, Lenggenhager D, Bode PK, Zoche M, Moch H, Britschgi C, Snijder B. Molecular and functional landscape of malignant serous effusions for precision oncology. Nat Commun 2024; 15:8544. [PMID: 39358333 PMCID: PMC11447229 DOI: 10.1038/s41467-024-52694-8] [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: 06/14/2024] [Accepted: 09/12/2024] [Indexed: 10/04/2024] Open
Abstract
Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.
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Affiliation(s)
- Rebekka Wegmann
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Lorenz Bankel
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland
| | - Yasmin Festl
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Kate Lau
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Sohyon Lee
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Fabian Arnold
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Valentina Cappelletti
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Aaron Fehr
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Paola Picotti
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Konstantin J Dedes
- Department of Gynecology, University Hospital Zurich, Zurich, Switzerland
| | - Daniel Franzen
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Peter K Bode
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Zoche
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Holger Moch
- Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
- University of Zurich, Zurich, Switzerland
| | - Christian Britschgi
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland
- Medical Oncology and Hematology, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - Berend Snijder
- Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland.
- Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland.
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
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5
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Kim TY, Kim SY, Kim JH, Jung HA, Choi YJ, Hwang IG, Cha Y, Lee GW, Lee YG, Kim TM, Lee SH, Lee S, Yun H, Choi YL, Yoon S, Han SW, Kim TY, Kim TW, Zang DY, Kang JH. Nationwide precision oncology pilot study: KOrean Precision Medicine Networking Group Study of MOlecular profiling-guided therapy based on genomic alterations in advanced solid tumors (KOSMOS) KCSG AL-20-05. ESMO Open 2024; 9:103709. [PMID: 39305545 PMCID: PMC11440300 DOI: 10.1016/j.esmoop.2024.103709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/14/2024] [Accepted: 08/16/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.
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Affiliation(s)
- T-Y Kim
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul
| | - S Y Kim
- Department of Oncology, University of Ulsan College of Medicine, Aan Medical Center, Seoul
| | - J H Kim
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam.
| | - H A Jung
- Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul
| | - Y J Choi
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul
| | - I G Hwang
- Department of Internal Medicine, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul
| | - Y Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang
| | - G-W Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, Jinju
| | - Y-G Lee
- Division of Hematology & Medical Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul
| | - T M Kim
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul
| | - S-H Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul
| | - S Lee
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul
| | - H Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul
| | - Y L Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - S Yoon
- Department of Oncology, University of Ulsan College of Medicine, Aan Medical Center, Seoul
| | - S W Han
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul
| | - T-Y Kim
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul
| | - T W Kim
- Department of Oncology, University of Ulsan College of Medicine, Aan Medical Center, Seoul
| | - D Y Zang
- Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical Center, Anyang
| | - J H Kang
- Department of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University College of Medicine, Seoul, Republic of Korea
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Boileve A, Smolenschi C, Lambert A, Boige V, Tarabay A, Valery M, Fuerea A, Pudlarz T, Conroy T, Hollebecque A, Ducreux M. Role of molecular biology in the management of pancreatic cancer. World J Gastrointest Oncol 2024; 16:2902-2914. [PMID: 39072173 PMCID: PMC11271790 DOI: 10.4251/wjgo.v16.i7.2902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/04/2024] [Accepted: 05/21/2024] [Indexed: 07/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in patient management due to a dismal prognosis, increasing incidence, and limited treatment options. In this regard, precision medicine, which personalizes treatments based on tumour molecular characteristics, has gained great interest. However, its widespread implementation is not fully endorsed in current recommendations. This review explores key molecular alterations in PDAC, while emphasizing differences between KRAS-mutated and KRAS-wild-type tumours. It assesses the practical application of precision medicine in clinical settings and outlines potential future directions with respect to PDAC. Actionable molecular targets are examined with the aim of enhancing our understanding of PDAC molecular biology. Insights from this analysis may contribute to a more refined and personalized approach to pancreatic cancer treatment, ultimately improving patient outcomes.
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Affiliation(s)
- Alice Boileve
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | | | - Aurélien Lambert
- Department of Medical Oncology, Institut de Cancérologie de Lorraine, Nancy 54519, France
| | - Valérie Boige
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | - Anthony Tarabay
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | - Marine Valery
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | - Alina Fuerea
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | - Thomas Pudlarz
- Department of Medical, Gustave Roussy, Villejuif 94800, France
| | - Thierry Conroy
- Department of Medical Oncology, Institut de Cancérologie de Lorraine, Nancy 54519, France
| | | | - Michel Ducreux
- Department of Medical, Gustave Roussy, Villejuif 94800, France
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7
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP. J Pathol Transl Med 2024; 58:147-164. [PMID: 39026440 PMCID: PMC11261170 DOI: 10.4132/jptm.2023.11.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 07/20/2024] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - 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
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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8
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP. Cancer Res Treat 2024; 56:721-742. [PMID: 38037319 PMCID: PMC11261187 DOI: 10.4143/crt.2023.1043] [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: 09/13/2023] [Accepted: 11/17/2023] [Indexed: 12/02/2023] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - 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
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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9
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El-Sayed MM, Bianco JR, Li Y, Fabian Z. Tumor-Agnostic Therapy-The Final Step Forward in the Cure for Human Neoplasms? Cells 2024; 13:1071. [PMID: 38920700 PMCID: PMC11201516 DOI: 10.3390/cells13121071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Cancer accounted for 10 million deaths in 2020, nearly one in every six deaths annually. Despite advancements, the contemporary clinical management of human neoplasms faces a number of challenges. Surgical removal of tumor tissues is often not possible technically, while radiation and chemotherapy pose the risk of damaging healthy cells, tissues, and organs, presenting complex clinical challenges. These require a paradigm shift in developing new therapeutic modalities moving towards a more personalized and targeted approach. The tumor-agnostic philosophy, one of these new modalities, focuses on characteristic molecular signatures of transformed cells independently of their traditional histopathological classification. These include commonly occurring DNA aberrations in cancer cells, shared metabolic features of their homeostasis or immune evasion measures of the tumor tissues. The first dedicated, FDA-approved tumor-agnostic agent's profound progression-free survival of 78% in mismatch repair-deficient colorectal cancer paved the way for the accelerated FDA approvals of novel tumor-agnostic therapeutic compounds. Here, we review the historical background, current status, and future perspectives of this new era of clinical oncology.
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Affiliation(s)
| | | | | | - Zsolt Fabian
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK; (M.M.E.-S.); (J.R.B.); (Y.L.)
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10
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Kim SY, Kim JH, Kim TY, Park SR, Yoon S, Lee S, Lee SH, Kim TM, Han SW, Kim HR, Yun H, Lee S, Kim J, Choi YL, Choi KS, Chae H, Ryu H, Lee GW, Zang DY, Ahn JB. Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09. BMC Cancer 2024; 24:574. [PMID: 38724991 PMCID: PMC11080169 DOI: 10.1186/s12885-024-12338-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 05/03/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION NCT05525858.
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Grants
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- HA22C0052 Ministry of Health and Welfare, Republic of Korea
- Roche, Basel, Switzerland
- Lunit, Seoul, Republic of Korea
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Affiliation(s)
- Sun Young Kim
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Sook Ryun Park
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Shinkyo Yoon
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Soohyeon Lee
- Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - Se-Hoon Lee
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Tae Min Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Cancer Center, Seoul, South Korea
| | - Hongseok Yun
- Center for Genomic Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Sejoon Lee
- Center for Precision Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jihun Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Yoon-La Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kui Son Choi
- Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea
| | - Heejung Chae
- Department of Internal Medicine, National Cancer Center, Goyang, South Korea
| | - Hyewon Ryu
- Division of Hematology and Oncology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Gyeong-Won Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Institute of Health Science, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, South Korea
| | - Dae Young Zang
- Department of Internal Medicine, Hallym University College of Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea
| | - Joong Bae Ahn
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei Cancer Center, Seoul, South Korea
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11
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Banerjee S. Cost-Effectiveness and the Economics of Genomic Testing and Molecularly Matched Therapies. Surg Oncol Clin N Am 2024; 33:231-242. [PMID: 38401907 DOI: 10.1016/j.soc.2023.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Abstract
Cost-effectiveness analysis of precision oncology can help guide value-driven care. Next-generation sequencing is increasingly cost-efficient over single gene testing because diagnostic algorithms require multiple individual gene tests to determine biomarker status. Matched targeted therapy is often not cost-effective due to the high cost associated with drug treatment. However, genomic profiling can promote cost-effective care by identifying patients who are unlikely to benefit from therapy. Additional applications of genomic profiling such as universal testing for hereditary cancer syndromes and germline testing in patients with cancer may represent cost-effective approaches compared with traditional history-based diagnostic methods.
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Affiliation(s)
- Sudeep Banerjee
- Division of Colorectal Surgery, Department of General Surgery, Kaiser Permanente San Jose Medical Center, Kaiser Permanente Northern California, 280 Hospital Parkway, Building B, San Jose, CA 95119, USA.
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12
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Anderson EC, DiPalazzo J, Lucas FL, Hall MJ, Antov A, Helbig P, Bourne J, Graham L, Gaitor L, Lu-Emerson C, Bradford LS, Inhorn R, Sinclair SJ, Brooks PL, Thomas CA, Rasmussen K, Han PKJ, Liu ET, Rueter J. Genome-matched treatments and patient outcomes in the Maine Cancer Genomics Initiative (MCGI). NPJ Precis Oncol 2024; 8:67. [PMID: 38461318 PMCID: PMC10924947 DOI: 10.1038/s41698-024-00547-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 02/16/2024] [Indexed: 03/11/2024] Open
Abstract
Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.
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Affiliation(s)
- Eric C Anderson
- Center for Interdisciplinary Population and Health Research, MaineHealth Institute for Research, Portland, ME, USA
- Tufts University School of Medicine, Boston, MA, USA
| | - John DiPalazzo
- Center for Interdisciplinary Population and Health Research, MaineHealth Institute for Research, Portland, ME, USA
| | - F Lee Lucas
- Center for Interdisciplinary Population and Health Research, MaineHealth Institute for Research, Portland, ME, USA
| | | | | | | | | | | | | | | | - Leslie S Bradford
- Maine Medical Partners Women's Health, Gynecologic Oncology, Scarborough, ME, USA
| | - Roger Inhorn
- PenBay Medical Center Oncology, Rockport, ME, USA
| | | | | | | | | | - Paul K J Han
- Center for Interdisciplinary Population and Health Research, MaineHealth Institute for Research, Portland, ME, USA
- National Cancer Institute, Bethesda, MD, USA
| | - Edison T Liu
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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13
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Tsimberidou AM, Kahle M, Vo HH, Baysal MA, Johnson A, Meric-Bernstam F. Molecular tumour boards - current and future considerations for precision oncology. Nat Rev Clin Oncol 2023; 20:843-863. [PMID: 37845306 DOI: 10.1038/s41571-023-00824-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/18/2023]
Abstract
Over the past 15 years, rapid progress has been made in developmental therapeutics, especially regarding the use of matched targeted therapies against specific oncogenic molecular alterations across cancer types. Molecular tumour boards (MTBs) are panels of expert physicians, scientists, health-care providers and patient advocates who review and interpret molecular-profiling results for individual patients with cancer and match each patient to available therapies, which can include investigational drugs. Interpretation of the molecular alterations found in each patient is a complicated task that requires an understanding of their contextual functional effects and their correlations with sensitivity or resistance to specific treatments. The criteria for determining the actionability of molecular alterations and selecting matched treatments are constantly evolving. Therefore, MTBs have an increasingly necessary role in optimizing the allocation of biomarker-directed therapies and the implementation of precision oncology. Ultimately, increased MTB availability, accessibility and performance are likely to improve patient care. The challenges faced by MTBs are increasing, owing to the plethora of identifiable molecular alterations and immune markers in tumours of individual patients and their evolving clinical significance as more and more data on patient outcomes and results from clinical trials become available. Beyond next-generation sequencing, broader biomarker analyses can provide useful information. However, greater funding, resources and expertise are needed to ensure the sustainability of MTBs and expand their outreach to underserved populations. Harmonization between practice and policy will be required to optimally implement precision oncology. Herein, we discuss the evolving role of MTBs and current and future considerations for their use in precision oncology.
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Affiliation(s)
- Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Michael Kahle
- Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Henry Hiep Vo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mehmet A Baysal
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amber Johnson
- Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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14
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Martens UM, Schröder J, Bengsch F, Sellmann L, Busies S, Frank-Gleich S, Zaiss M, Decker T, Schneeweiss A, Schuler M, Grebhardt S, Zacharias S, Marschner N, Kasenda B, Potthoff K, Vannier C. The INFINITY study protocol: a retrospective cohort study on decision making and clinical impact of biomarker-driven precision oncology in routine clinical practice. BMC Cancer 2023; 23:543. [PMID: 37312086 DOI: 10.1186/s12885-023-11046-3] [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: 05/05/2022] [Accepted: 06/04/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap. METHODS INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome. DISCUSSION INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications. TRIAL REGISTRATION The study is registered at ClinicalTrials.gov, NCT04389541.
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Affiliation(s)
- Uwe M Martens
- Clinic for Hematology, Oncology and Palliative Care, SLK Kliniken Heilbronn, Heilbronn, Germany
- MOLIT Institute for Personalized Medicine, Heilbronn, Germany
| | - Jan Schröder
- Practice for Hematology and Internal Oncology, Mülheim a.d.R, Germany
| | - Fee Bengsch
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
| | | | - Sabine Busies
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
| | - Stefanie Frank-Gleich
- Joint Practice for Internal Medicine, Hematology, Oncology, Gastroenterology, Halle (Saale), Germany
| | - Matthias Zaiss
- Center for Interdisciplinary Oncology & Hematology, Freiburg, Germany
| | - Thomas Decker
- Study Center for Oncology Ravensburg, Ravensburg, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Research Center, Heidelberg, Germany
| | - Martin Schuler
- West German Cancer Center, Department of Medical Oncology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sina Grebhardt
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
| | - Stefan Zacharias
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
| | - Norbert Marschner
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
| | - Benjamin Kasenda
- Medical Oncology, University Hospital and University of Basel, Basel, Switzerland
| | - Karin Potthoff
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany.
| | - Corinne Vannier
- iOMEDICO, Ellen-Gottlieb-Straße 19, 79106, Freiburg im Breisgau, Germany
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15
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Carmagnani Pestana R, Moyers JT, Roszik J, Sen S, Hong DS, Naing A, Herzog CE, Fu S, Piha-Paul SA, Rodon J, Yap TA, Karp DD, Tsimberidou AM, Pant S, Zarzour MA, Ratan R, Ravi V, Benjamin RS, Lazar AJ, Wang WL, Daw N, Gill JB, Harrison DJ, Lewis VO, Roland CL, Patel SR, Livingston JA, Somaiah N, Ludwig JA, Conley AP, Hamerschlak N, Gorlick R, Meric-Bernstam F, Subbiah V. Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101). Clin Cancer Res 2023; 29:1708-1718. [PMID: 37058010 PMCID: PMC10150251 DOI: 10.1158/1078-0432.ccr-22-3629] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/30/2022] [Accepted: 02/24/2023] [Indexed: 04/15/2023]
Abstract
PURPOSE Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma. EXPERIMENTAL DESIGN In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021. RESULTS Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P < 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P < 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P < 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P < 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis. CONCLUSIONS Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.
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Affiliation(s)
- Roberto Carmagnani Pestana
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Justin T. Moyers
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Medicine, Division of Hematology and Oncology, The University of California, Irvine, Orange, California
| | - Jason Roszik
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shiraj Sen
- Sarah Cannon Research Institute, Nashville, Tennessee
| | - David S. Hong
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aung Naing
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cynthia E. Herzog
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina A. Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Timothy A. Yap
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel D. Karp
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shubham Pant
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Maria A. Zarzour
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ravin Ratan
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert S. Benjamin
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexander J. Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei-Lien Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Najat Daw
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jonathan B. Gill
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Douglas J. Harrison
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Valerae O. Lewis
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christina L. Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shreyaskumar R. Patel
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - J. Andrew Livingston
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joseph A. Ludwig
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anthony P. Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Richard Gorlick
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
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16
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Shaya J, Kato S, Adashek JJ, Patel H, Fanta PT, Botta GP, Sicklick JK, Kurzrock R. Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis. NPJ Genom Med 2023; 8:1. [PMID: 36670111 PMCID: PMC9860045 DOI: 10.1038/s41525-022-00346-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/07/2022] [Indexed: 01/21/2023] Open
Abstract
Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3-4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.
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Affiliation(s)
- Justin Shaya
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Shumei Kato
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
| | - Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Hitendra Patel
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Paul T Fanta
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Gregory P Botta
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Jason K Sicklick
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD, USA
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
- Department of Pharmacology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
| | - Razelle Kurzrock
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA
- WIN Consortium, Paris, France
- University of Nebraska, Lincoln, NE, USA
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17
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Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology. NPJ Precis Oncol 2022; 6:78. [PMID: 36302890 PMCID: PMC9612600 DOI: 10.1038/s41698-022-00317-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 10/04/2022] [Indexed: 11/08/2022] Open
Abstract
We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient’s/physician’s choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.
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18
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Fountzilas E, Tsimberidou AM, Vo HH, Kurzrock R. Clinical trial design in the era of precision medicine. Genome Med 2022; 14:101. [PMID: 36045401 PMCID: PMC9428375 DOI: 10.1186/s13073-022-01102-1] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/09/2022] [Indexed: 12/24/2022] Open
Abstract
Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
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Affiliation(s)
- Elena Fountzilas
- Department of Medical Oncology, St. Lukes's Hospital, Thessaloniki, Greece
- European University Cyprus, Limassol, Cyprus
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Henry Hiep Vo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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19
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Precision neuro-oncology: a pilot analysis of personalized treatment in recurrent glioma. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04050-w. [PMID: 35953681 DOI: 10.1007/s00432-022-04050-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/29/2022] [Indexed: 10/15/2022]
Abstract
PURPOSE When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSION These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.
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20
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Schaffrin-Nabe D, Schuster S, Tannapfel A, Voigtmann R. Case Report: Extensive Tumor Profiling in Primary Neuroendocrine Breast Cancer Cases as a Role Model for Personalized Treatment in Rare and Aggressive Cancer Types. Front Med (Lausanne) 2022; 9:841441. [PMID: 35721079 PMCID: PMC9203716 DOI: 10.3389/fmed.2022.841441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/25/2022] [Indexed: 12/17/2022] Open
Abstract
Neuroendocrine breast cancer (NEBC) is a rare entity accounting for <0.1% of all breast carcinomas and <0.1% of all neuroendocrine carcinomas. In most cases treatment strategies in NEBC are empirical in absence of prospective trial data on NEBC cohorts. Herein, we present two case reports diagnosed with anaplastic and small cell NEBC. After initial therapies failed, comprehensive tumor profiling was applied, leading to individualized treatment options for both patients. In both patients, targetable alterations of the PI3K/AKT/mTOR pathway were found, including a PIK3CA mutation itself and an STK11 mutation that negatively regulates the mTOR complex. The epicrisis of the two patients exemplifies how to manage rare and difficult to treat cancers and how new diagnostic tools contribute to medical management.
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Affiliation(s)
- Dörthe Schaffrin-Nabe
- Praxis für Hämatologie und Onkologie, Bochum, Germany
- *Correspondence: Dörthe Schaffrin-Nabe
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21
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Helland Å, Russnes HG, Fagereng GL, Al-Shibli K, Andersson Y, Berg T, Bjørge L, Blix E, Bjerkehagen B, Brabrand S, Cameron MG, Dalhaug A, Dietzel D, Dønnem T, Enerly E, Flobak Å, Fluge S, Gilje B, Gjertsen BT, Grønberg BH, Grønås K, Guren T, Hamre H, Haug Å, Heinrich D, Hjortland GO, Hovig E, Hovland R, Iversen AC, Janssen E, Kyte JA, von der Lippe Gythfeldt H, Lothe R, Lund JÅ, Meza-Zepeda L, Munthe-Kaas MC, Nguyen OTD, Niehusmann P, NilsenPuco HK, Ree AH, Riste TB, Semb K, Steinskog ESS, Stensvold A, Suhrke P, Tennøe Ø, Tjønnfjord GE, Vassbotn LJ, Aas E, Aasebø K, Tasken K, Smeland S. Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. J Transl Med 2022; 20:225. [PMID: 35568909 PMCID: PMC9107632 DOI: 10.1186/s12967-022-03432-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/04/2022] [Indexed: 11/28/2022] Open
Abstract
Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. Discussion Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public–private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.
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Affiliation(s)
- Åslaug Helland
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Hege G Russnes
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Gro Live Fagereng
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | | | | | - Thomas Berg
- Department of Pathology, University Hospital in North of Norway, Tromsø, Norway.,Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
| | - Line Bjørge
- Haukeland University Hospital, Bergen, Norway.,Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Egil Blix
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Oncology, University Hospital in North of Norway, Tromsø, Norway
| | - Bodil Bjerkehagen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Sigmund Brabrand
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Astrid Dalhaug
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Oncology and Palliative Medicine, Nordland Hospital Trust, Bodø, Norway
| | | | - Tom Dønnem
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.,Department of Oncology, University Hospital in North of Norway, Tromsø, Norway
| | - Espen Enerly
- Department of Research, The Cancer Registry of Norway, Oslo, Norway
| | - Åsmund Flobak
- Department of Oncology, The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, The Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | | | | | - Bjørn Tore Gjertsen
- Haukeland University Hospital, Bergen, Norway.,Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Bjørn Henning Grønberg
- Department of Oncology, The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, The Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Kari Grønås
- Patient Representative, Oslo University Hospital, Oslo, Norway
| | - Tormod Guren
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Hanne Hamre
- Akershus University Hospital, Lørenskog, Norway
| | - Åse Haug
- Haukeland University Hospital, Bergen, Norway
| | | | - Geir Olav Hjortland
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Eivind Hovig
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Centre of Bioinformatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Randi Hovland
- Head of Section for Cancergenomics Section for Cancer Genomics, Haukeland University Hospital, Bergen, Norway
| | | | - Emiel Janssen
- Section for Cancergenomics, Department of Pathology, Stavanger University Hospital, Stavanger, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
| | - Jon Amund Kyte
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Ragnhild Lothe
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jo-Åsmund Lund
- Dept of Oncology, Helse Møre and Romsdal Health Trust, Ålesund, Norway.,Dept of Health Sciences, NTNU, Ålesund, Norway
| | - Leonardo Meza-Zepeda
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | | | | | - Pitt Niehusmann
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Hilde Katarina NilsenPuco
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Haematology and Palliative Care, Lovisenberg Diaconal Hospital, Oslo, Norway
| | - Anne Hansen Ree
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Akershus University Hospital, Lørenskog, Norway
| | | | - Karin Semb
- Department of Oncology, Vestfold Hospital Trust, Tønsberg, Norway
| | | | | | - Pål Suhrke
- Department of Pathology, Vestfold Hospital Trust, Tønsberg, Norway
| | - Øyvind Tennøe
- Department of Oncology, Kalnes Hospital, Grålum, Norway
| | - Geir E Tjønnfjord
- Department of Haematology, Oslo University Hospital, Tønsberg, Norway
| | | | - Eline Aas
- Institute of Health and Society, Department of Health Management and Health Economics, University of Oslo, Oslo, Norway.,Division for Health Services, Norwegian Institute of Public Health, Oslo, Norway
| | | | - Kjetil Tasken
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Sigbjørn Smeland
- Institute for Cancer Research/Department of Oncology /Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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22
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Molecular Profiles of Advanced Urological Cancers in the PERMED-01 Precision Medicine Clinical Trial. Cancers (Basel) 2022; 14:cancers14092275. [PMID: 35565404 PMCID: PMC9100924 DOI: 10.3390/cancers14092275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/02/2022] Open
Abstract
Simple Summary The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the “matched therapy group” than in the “non-matched therapy group”. Abstract Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the “non-matched therapy group” (n = 25). The objective response and disease control rates were higher in the “matched therapy group” (33% and 58%, respectively) than in the “non-matched therapy group” (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to “matched therapy” in 19%, and provided clinical benefit in 8%.
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Ipilimumab, Pembrolizumab, or Nivolumab in Combination with BBI608 in Patients with Advanced Cancers Treated at MD Anderson Cancer Center. Cancers (Basel) 2022; 14:cancers14051330. [PMID: 35267638 PMCID: PMC8909492 DOI: 10.3390/cancers14051330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/26/2022] [Accepted: 03/01/2022] [Indexed: 12/10/2022] Open
Abstract
Background: BBI608 is an investigational reactive oxygen species generator that affects several molecular pathways. We investigated BBI608 combined with immune checkpoint inhibitors in patients with advanced cancers. Methods: BBI608 (orally twice daily) was combined with ipilimumab (3 mg/kg IV every 3 weeks); pembrolizumab (2 mg/kg IV every 3 weeks); or nivolumab (3 mg/kg IV every 4 weeks). We assessed the safety, antitumor activity and the pharmacokinetic profile of BBI combined with immunotherapy. Results: From 1/2017 to 3/2017, 12 patients were treated (median age, 54 years; range, 31–78; 6 men). Treatment was overall well tolerated. No dose-limiting toxicity was observed. The most common adverse events were diarrhea (5 patients: grade (G)1–2, n = 3; G3, n = 2) and nausea (4 patients, all G1). Prolonged disease stabilization was noted in five patients treated with BBI608/nivolumab lasting for 12.1, 10.1, 8.0, 7.7 and 7.4 months. The median progression-free survival was 2.73 months. The median overall survival was 7.56 months. Four patients had prolonged overall survival (53.0, 48.7, 51.9 and 48.2 months). Conclusions: Checkpoint inhibitors combined with BBI608 were well tolerated. Several patients had prolonged disease stabilization and overall survival. Prospective studies to elucidate the mechanisms of response and resistance to BBI608 are warranted.
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Marret G, Bièche I, Dupain C, Borcoman E, du Rusquec P, Ricci F, Hescot S, Sablin MP, Tresca P, Bello D, Dubot C, Loirat D, Frelaut M, Lecerf C, Le Tourneau C, Kamal M. Genomic Alterations in Head and Neck Squamous Cell Carcinoma: Level of Evidence According to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). JCO Precis Oncol 2022; 5:215-226. [PMID: 34994597 DOI: 10.1200/po.20.00280] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Development of high-throughput technologies helped to decipher tumor genomic landscapes revealing actionable molecular alterations. We aimed to rank the level of evidence of recurrent actionable molecular alterations in head and neck squamous cell carcinoma (HNSCC) on the basis of the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) to help the clinicians prioritize treatment. We identified actionable alterations in 33 genes. HRAS-activating mutations were ranked in tier IB because of the efficacy of tipifarnib (farnesyltransferase inhibitor) in HRAS-mutated patients with HNSCC (nonrandomized clinical trial). Microsatellite instability (MSI), high tumor mutational burden (TMB), and NTRK fusions were ranked in tier IC because of PD-1 and TRK tyrosine kinase inhibitors tissue-agnostic approvals. CDKN2A-inactivating alterations and EGFR amplification were ranked in tier IIA because of the efficacy of palbociclib (CDK4/6 inhibitor) and afatinib (tyrosine kinase inhibitor) in these respective molecular subgroups in retrospective analyses of clinical trials. Molecular alterations in several genes, including PIK3CA gene, were ranked in tier IIIA because of clinical benefit in other tumor types, whereas molecular alterations in IGF1R and TP53 genes were ranked in tier IVA and tier V, respectively. The most compelling actionable molecular alterations in HNSCC according to ESCAT include HRAS-activating mutations, MSI, high TMB, NTRK fusions, CDKN2A-inactivating alterations, and EGFR amplification.
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Affiliation(s)
| | - Ivan Bièche
- Department of Genetics, Institut Curie, Paris Descartes University, Paris, France.,INSERM U1016 Research Unit, Cochin Institute, Paris, France
| | - Célia Dupain
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Edith Borcoman
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Pauline du Rusquec
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Francesco Ricci
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Ségolène Hescot
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Marie-Paule Sablin
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Patricia Tresca
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Diana Bello
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Coraline Dubot
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Delphine Loirat
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Maxime Frelaut
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Charlotte Lecerf
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
| | - Christophe Le Tourneau
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.,INSERM U900, Institut Curie, Mines Paris Tech, Saint-Cloud, France.,Paris-Saclay University, Paris, France
| | - Maud Kamal
- Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France
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Frank MS, Bodtger U, Gehl J, Ahlborn LB. Actionable Molecular Alterations Are Revealed in Majority of Advanced Non-Small Cell Lung Cancer Patients by Genomic Tumor Profiling at Progression after First Line Treatment. Cancers (Basel) 2021; 14:cancers14010132. [PMID: 35008297 PMCID: PMC8749927 DOI: 10.3390/cancers14010132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Genomic profiling in advanced Non-Small Cell Lung cancer (NSCLC) can reveal Actionable Molecular Alterations (AMAs). Our study aims to investigate clinical relevance of re-biopsy after first line treatment, by reporting on acquired and persistent AMAs and potential targeted treatments in a real-time cohort of NSCLC patients. Methods: Patients with advanced NSCLC receiving first-line treatment were prospectively included in an observational study (NCT03512847). Genomic profiling was performed by TruSight Oncology 500 HT gene panel on tumor tissue collected at diagnosis and at time of progression. Results: The 92 patients re-biopsied at progression had received immunotherapy (n = 44), chemotherapy (n = 44), or combination treatment (n = 4). In 87 of these patients (95%), successful genomic profiling was performed at both the diagnostic biopsy and the re-biopsy. In 74 patients (85%), ≥1 AMA were found. The AMAs were acquired in 28%. The most frequent AMAs were observed in TP53 (45%), KRAS (24%), PIK3CA (6%), and FGFR1 (6%). Only five patients (5%) received targeted treatment mainly due to deterioration in performance status. Conclusions: Re-biopsy at progression revealed acquired AMAs in approximately one third of patients, and 85% had at least one AMA with the potential of receiving targeted treatment, thus strengthening the clinical relevance of re-biopsy.
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Affiliation(s)
- Malene Støchkel Frank
- Department of Clinical Oncology and Palliative Care, Zealand University Hospital, 4000 Roskilde, Denmark;
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Correspondence: ; Tel.: +45-28-574-392
| | - Uffe Bodtger
- Department of Respiratory Medicine, Zealand University Hospital, 4700 Naestved, Denmark;
- Institute for Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Julie Gehl
- Department of Clinical Oncology and Palliative Care, Zealand University Hospital, 4000 Roskilde, Denmark;
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lise Barlebo Ahlborn
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark;
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Pose Lapausa P, Soria Comes T, Calabria I, Maestu Maiques I. Molecular Characterization, Via Next-Generation Sequencing, of Refractory or Resistant Invasive Breast Carcinoma. Cureus 2021; 13:e19528. [PMID: 34934548 PMCID: PMC8668050 DOI: 10.7759/cureus.19528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2021] [Indexed: 11/05/2022] Open
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Wagner AH, Babb L, Alterovitz G, Baudis M, Brush M, Cameron DL, Cline M, Griffith M, Griffith OL, Hunt SE, Kreda D, Lee JM, Li S, Lopez J, Moyer E, Nelson T, Patel RY, Riehle K, Robinson PN, Rynearson S, Schuilenburg H, Tsukanov K, Walsh B, Konopko M, Rehm HL, Yates AD, Freimuth RR, Hart RK. The GA4GH Variation Representation Specification: A computational framework for variation representation and federated identification. CELL GENOMICS 2021; 1:100027. [PMID: 35311178 PMCID: PMC8929418 DOI: 10.1016/j.xgen.2021.100027] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 07/12/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022]
Abstract
Maximizing the personal, public, research, and clinical value of genomic information will require the reliable exchange of genetic variation data. We report here the Variation Representation Specification (VRS, pronounced "verse"), an extensible framework for the computable representation of variation that complements contemporary human-readable and flat file standards for genomic variation representation. VRS provides semantically precise representations of variation and leverages this design to enable federated identification of biomolecular variation with globally consistent and unique computed identifiers. The VRS framework includes a terminology and information model, machine-readable schema, data sharing conventions, and a reference implementation, each of which is intended to be broadly useful and freely available for community use. VRS was developed by a partnership among national information resource providers, public initiatives, and diagnostic testing laboratories under the auspices of the Global Alliance for Genomics and Health (GA4GH).
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Affiliation(s)
- Alex H. Wagner
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43215, USA
| | - Lawrence Babb
- Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Gil Alterovitz
- Harvard Medical School, Boston, MA 02115, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Michael Baudis
- University of Zurich and Swiss Institute of Bioinformatics, Zurich, Switzerland
| | - Matthew Brush
- Oregon Health & Science University, Portland, OR 97239, USA
| | - Daniel L. Cameron
- Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Melissa Cline
- UC Santa Cruz Genomics Institute, Santa Cruz, CA 95060, USA
| | - Malachi Griffith
- Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Obi L. Griffith
- Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Sarah E. Hunt
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - David Kreda
- Department of Biomedical Informatics, Harvard Medical School, Boston MA 02115, USA
| | - Jennifer M. Lee
- Essex Management LLC and National Cancer Institute, Rockville, MD 20850, USA
| | - Stephanie Li
- The Global Alliance for Genomics and Health, Toronto, ON, Canada
| | | | - Eric Moyer
- National Center for Biotechnology Information, National Library of Medicine National Institutes of Health, Bethesda, MD 20894, USA
| | | | | | - Kevin Riehle
- Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Shawn Rynearson
- Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT 84112, USA
| | - Helen Schuilenburg
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - Kirill Tsukanov
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - Brian Walsh
- Oregon Health & Science University, Portland, OR 97239, USA
| | - Melissa Konopko
- The Global Alliance for Genomics and Health, Toronto, ON, Canada
| | - Heidi L. Rehm
- Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Cambridge, MA 02142, USA
| | - Andrew D. Yates
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - Robert R. Freimuth
- Center for Individualized Medicine, Department of Artificial Intelligence and Informatics, Mayo Clinic, Rochester, MN 55905, USA
| | - Reece K. Hart
- Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- MyOme, Inc., Menlo Park, CA 94070, USA
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Langenberg KPS, Looze EJ, Molenaar JJ. The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development. Cancers (Basel) 2021; 13:4324. [PMID: 34503139 PMCID: PMC8431194 DOI: 10.3390/cancers13174324] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 12/20/2022] Open
Abstract
Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies.
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Affiliation(s)
- Karin P. S. Langenberg
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (E.J.L.); (J.J.M.)
| | - Eleonora J. Looze
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (E.J.L.); (J.J.M.)
| | - Jan J. Molenaar
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (E.J.L.); (J.J.M.)
- Department of Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands
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Tsimberidou AM, Shaw JV, Juric D, Verschraegen C, Weise AM, Sarantopoulos J, Lopes G, Nemunaitis J, Mita M, Park H, Ellers-Lenz B, Tian H, Xiong W, Kaleta R, Kurzrock R. Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer. J Hematol Oncol 2021; 14:127. [PMID: 34407844 PMCID: PMC8371902 DOI: 10.1186/s13045-021-01132-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. METHODS M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen. RESULTS Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. CONCLUSIONS M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.
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Affiliation(s)
- Apostolia-Maria Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
| | - Jamie V Shaw
- EMD Serono Research and Development Institute, Inc., Billerica, MA, USA
| | - Dejan Juric
- Massachusetts General Hospital, Boston, MA, USA
| | | | | | - John Sarantopoulos
- Institute for Drug Development, Mays Cancer Center at University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, TX, USA
| | | | | | - Monica Mita
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | | | - Hui Tian
- EMD Serono Research and Development Institute, Inc., Billerica, MA, USA
| | - Wenyuan Xiong
- Merck Institute of Pharmacometrics, Merck Serono SA, Lausanne, Switzerland
| | - Remigiusz Kaleta
- EMD Serono Research and Development Institute, Inc., Billerica, MA, USA
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Morgan G. New Tool Allows for Tracking Changes in the Tumor Microenvironment That Could Possibly Guide Next-Line Cancer Therapies. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2021; 4:170. [PMID: 35663106 PMCID: PMC9138442 DOI: 10.36401/jipo-21-x4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 06/15/2023]
Affiliation(s)
- Gilberto Morgan
- Department of Clinical Oncology, Skane University Hospital, Lund, Sweden
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Affolter A, Lammert A, Kern J, Scherl C, Rotter N. Precision Medicine Gains Momentum: Novel 3D Models and Stem Cell-Based Approaches in Head and Neck Cancer. Front Cell Dev Biol 2021; 9:666515. [PMID: 34307351 PMCID: PMC8296983 DOI: 10.3389/fcell.2021.666515] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/30/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the current progress in the development of new concepts of precision medicine for head and neck squamous cell carcinoma (HNSCC), in particular targeted therapies and immune checkpoint inhibition (CPI), overall survival rates have not improved during the last decades. This is, on the one hand, caused by the fact that a significant number of patients presents with late stage disease at the time of diagnosis, on the other hand HNSCC frequently develop therapeutic resistance. Distinct intratumoral and intertumoral heterogeneity is one of the strongest features in HNSCC and has hindered both the identification of specific biomarkers and the establishment of targeted therapies for this disease so far. To date, there is a paucity of reliable preclinical models, particularly those that can predict responses to immune CPI, as these models require an intact tumor microenvironment (TME). The "ideal" preclinical cancer model is supposed to take both the TME as well as tumor heterogeneity into account. Although HNSCC patients are frequently studied in clinical trials, there is a lack of reliable prognostic biomarkers allowing a better stratification of individuals who might benefit from new concepts of targeted or immunotherapeutic strategies. Emerging evidence indicates that cancer stem cells (CSCs) are highly tumorigenic. Through the process of stemness, epithelial cells acquire an invasive phenotype contributing to metastasis and recurrence. Specific markers for CSC such as CD133 and CD44 expression and ALDH activity help to identify CSC in HNSCC. For the majority of patients, allocation of treatment regimens is simply based on histological diagnosis and on tumor location and disease staging (clinical risk assessments) rather than on specific or individual tumor biology. Hence there is an urgent need for tools to stratify HNSCC patients and pave the way for personalized therapeutic options. This work reviews the current literature on novel approaches in implementing three-dimensional (3D) HNSCC in vitro and in vivo tumor models in the clinical daily routine. Stem-cell based assays will be particularly discussed. Those models are highly anticipated to serve as a preclinical prediction platform for the evaluation of stable biomarkers and for therapeutic efficacy testing.
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Affiliation(s)
- Annette Affolter
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Criteria-based curation of a therapy-focused compendium to support treatment recommendations in precision oncology. NPJ Precis Oncol 2021; 5:58. [PMID: 34162978 PMCID: PMC8222322 DOI: 10.1038/s41698-021-00194-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 05/26/2021] [Indexed: 11/09/2022] Open
Abstract
While several resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. To this end, we have structured a compendium of approved and experimental therapies with associated biomarkers following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was categorised using a tiering system reflective of key therapeutic considerations: approved and reimbursed therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1) or antitumor activity (Tier R2). Based on this framework, we curated a digital resource focused on drugs relevant in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 biomarkers, and 106 cancer types. In the 345 therapies catalogued, 84 (24%) and 65 (19%) were designated Tiers 1 and 2, respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A companion algorithm was also developed to support rational, context-appropriate treatment selection informed by molecular biomarkers. This framework can be readily adapted to build similar resources in other jurisdictions to support therapeutic decision-making.
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Roosan MR, Mambetsariev I, Pharaon R, Fricke J, Baroz AR, Chao J, Chen C, Nasser MW, Chirravuri-Venkata R, Jain M, Smith L, Yost SE, Reckamp KL, Pillai R, Arvanitis L, Afkhami M, Wang EW, Chung V, Cristea M, Fakih M, Koczywas M, Massarelli E, Mortimer J, Yuan Y, Batra SK, Pal S, Salgia R. Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients. Cancers (Basel) 2021; 13:2776. [PMID: 34204917 PMCID: PMC8199748 DOI: 10.3390/cancers13112776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34-2.21, p < 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7-11.9 months) compared to 9.1 months (CI: 8.1-10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers.
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Affiliation(s)
- Moom R. Roosan
- School of Pharmacy, Chapman University, Irvine, CA 92618, USA;
| | - Isa Mambetsariev
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Rebecca Pharaon
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Jeremy Fricke
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Angel R. Baroz
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Joseph Chao
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Chen Chen
- Applied AI and Data Science, City of Hope, Duarte, CA 91010, USA;
| | - Mohd W. Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Ramakanth Chirravuri-Venkata
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Susan E. Yost
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Karen L. Reckamp
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
- Cedars-Sinai Medical Center, Department of Medicine, Division of Medical Oncology, Los Angeles, CA 90048, USA
| | - Raju Pillai
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Leonidas Arvanitis
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Michelle Afkhami
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Edward W. Wang
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Vincent Chung
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Mihaela Cristea
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Marwan Fakih
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Marianna Koczywas
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Erminia Massarelli
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Joanne Mortimer
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Yuan Yuan
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Sumanta Pal
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
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Bertucci F, Gonçalves A, Guille A, Adelaïde J, Garnier S, Carbuccia N, Billon E, Finetti P, Sfumato P, Monneur A, Pécheux C, Khran M, Brunelle S, Mescam L, Thomassin-Piana J, Poizat F, Charafe-Jauffret E, Turrini O, Lambaudie E, Provansal M, Extra JM, Madroszyk A, Gilabert M, Sabatier R, Vicier C, Mamessier E, Chabannon C, Pakradouni J, Viens P, André F, Gravis G, Popovici C, Birnbaum D, Chaffanet M. Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial. Genome Med 2021; 13:87. [PMID: 34006291 PMCID: PMC8132379 DOI: 10.1186/s13073-021-00897-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 04/27/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. METHODS Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). RESULTS Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. CONCLUSIONS Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. TRIAL REGISTRATION ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .
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Affiliation(s)
- François Bertucci
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France.
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
| | - Anthony Gonçalves
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Arnaud Guille
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - José Adelaïde
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Séverine Garnier
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Nadine Carbuccia
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Emilien Billon
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Pascal Finetti
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Patrick Sfumato
- Biostatistics Unit, Institut Paoli-Calmettes, Marseille, France
| | - Audrey Monneur
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Christophe Pécheux
- Department of Medical genetics, Hôpital Timone Enfants, AP-HM, Marseille, France
| | - Martin Khran
- Department of Medical genetics, Hôpital Timone Enfants, AP-HM, Marseille, France
- Aix-Marseille University, Inserm, U1251-MMG, Marseille Medical Genetics, Marseille, France
| | - Serge Brunelle
- Department of Imaging, Institut Paoli-Calmettes, Marseille, France
| | - Lenaïg Mescam
- Department of Biopathology, Institut Paoli-Calmettes, Marseille, France
| | | | - Flora Poizat
- Department of Biopathology, Institut Paoli-Calmettes, Marseille, France
| | | | - Olivier Turrini
- Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Eric Lambaudie
- Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Magali Provansal
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Jean-Marc Extra
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Anne Madroszyk
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Marine Gilabert
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Renaud Sabatier
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Cécile Vicier
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Emilie Mamessier
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Christian Chabannon
- Biobank, Department of Hematology, Institut Paoli-Calmettes, Marseille, France
| | - Jihane Pakradouni
- Department of Clinical Research and Innovation, Institut Paoli-Calmettes, Marseille, France
| | - Patrice Viens
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Fabrice André
- Department of Medical Oncology, Gustave Roussy Cancer Campus, UMR981 Inserm, Villejuif, France
- Paris Sud University, Orsay, France
| | - Gwenaelle Gravis
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Cornel Popovici
- Department of Oncogenetics, Institut Paoli-Calmettes, Marseille, France
| | - Daniel Birnbaum
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
| | - Max Chaffanet
- Laboratory of Predictive Oncology, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille University, 232 Boulevard Sainte-Marguerite, 13009, Marseille, France
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Xu M, Tapia C, Hajjar J, Sabir S, Colen R, Nagarajan P, Aung PP, Gong J, Rodon J, Fu S, Stephen B, Roy-Chowdhuri S, Le H, Yang V, Zarifa A, Abdelsalam ME, Jhingran A, Javle M, Pant S, Carter B, Milton DR, Sun R, Karp DD, Koay EJ, Yang Y, Wistuba II, Hwu P, Meric-Bernstam F, Naing A. Implementation of a Novel Web-Based Lesion Selection Tool to Improve Acquisition of Tumor Biopsy Specimens. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2021; 4:45-52. [PMID: 35663531 DOI: 10.36401/jipo-21-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 12/17/2022]
Abstract
Introduction For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections. Methods Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups. Results The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy. Conclusions The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted.
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Affiliation(s)
- Mingxuan Xu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Coya Tapia
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joud Hajjar
- Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
| | - Sharjeel Sabir
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rivka Colen
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Phyu P Aung
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Gong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bettzy Stephen
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sinchita Roy-Chowdhuri
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hung Le
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vincent Yang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abdulrazzak Zarifa
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mohamed Elsayed Abdelsalam
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anuja Jhingran
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shubham Pant
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brett Carter
- Section of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Denai R Milton
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel D Karp
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eugene Jon Koay
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yali Yang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick Hwu
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Flaherty KT, Gray R, Chen A, Li S, Patton D, Hamilton SR, Williams PM, Mitchell EP, Iafrate AJ, Sklar J, Harris LN, McShane LM, Rubinstein LV, Sims DJ, Routbort M, Coffey B, Fu T, Zwiebel JA, Little RF, Marinucci D, Catalano R, Magnan R, Kibbe W, Weil C, Tricoli JV, Alexander B, Kumar S, Schwartz GK, Meric-Bernstam F, Lih CJ, McCaskill-Stevens W, Caimi P, Takebe N, Datta V, Arteaga CL, Abrams JS, Comis R, O'Dwyer PJ, Conley BA. The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design. J Natl Cancer Inst 2021; 112:1021-1029. [PMID: 31922567 PMCID: PMC7566320 DOI: 10.1093/jnci/djz245] [Citation(s) in RCA: 151] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 12/02/2019] [Accepted: 12/26/2019] [Indexed: 12/22/2022] Open
Abstract
Background The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology. Methods Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial. Results At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround). Conclusions The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.
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Affiliation(s)
| | - Robert Gray
- Dana Farber Cancer Institute ECOG-ACRIN Biostatistics Center, Boston, MA, USA
| | - Alice Chen
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Shuli Li
- Dana Farber Cancer Institute ECOG-ACRIN Biostatistics Center, Boston, MA, USA
| | - David Patton
- Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Bethesda, MD, USA
| | | | - Paul M Williams
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | | | - A John Iafrate
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | | | - Lyndsay N Harris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Lisa M McShane
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Larry V Rubinstein
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - David J Sims
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Mark Routbort
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brent Coffey
- Center for Biomedical Informatics and Information Technology, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Tony Fu
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - James A Zwiebel
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Richard F Little
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | | | | | - Rick Magnan
- ECOG-ACRIN Cancer Research Group, Boston, MA, USA
| | - Warren Kibbe
- Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Carol Weil
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - James V Tricoli
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Brian Alexander
- Radiation Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | | | - Gary K Schwartz
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | | | - Chih-Jian Lih
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | | | - Paolo Caimi
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Vivekananda Datta
- Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Carlos L Arteaga
- University of Texas Southwestern Simmons Cancer Center, Dallas, TX, USA
| | - Jeffrey S Abrams
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Robert Comis
- ECOG-ACRIN Cancer Research Group, Philadelphia, PA, USA
| | | | - Barbara A Conley
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
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Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study. NPJ Precis Oncol 2021; 5:21. [PMID: 33742104 PMCID: PMC7979841 DOI: 10.1038/s41698-021-00159-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.
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Huang CC, Tsai YF, Liu CY, Chao TC, Lien PJ, Lin YS, Feng CJ, Chiu JH, Hsu CY, Tseng LM. Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses. BMC Cancer 2021; 21:199. [PMID: 33632156 PMCID: PMC7908797 DOI: 10.1186/s12885-021-07931-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 02/18/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. METHODS The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher™ Oncomine™ Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). RESULTS A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). CONCLUSION Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.
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Affiliation(s)
- Chi-Cheng Huang
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yi-Fang Tsai
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, College of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Yu Liu
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, College of Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ta-Chung Chao
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Faculty of Medicine, College of Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Chemotherapy, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Pei-Ju Lien
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yen-Shu Lin
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chin-Jung Feng
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Jen-Hwey Chiu
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chih-Yi Hsu
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ling-Ming Tseng
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan.
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
- Faculty of Medicine, College of Medicine, National Yang-Ming University, Taipei, Taiwan.
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Hasan ME, Matin M, Haque ME, Aziz MA, Millat MS, Uddin MS, Moghal MMR, Islam MS. Polymorphic variants INSIG2 rs6726538, HLA-DRB1 rs9272143, and GCNT1P5 rs7780883 contribute to the susceptibility of cervical cancer in the Bangladeshi women. Cancer Med 2021; 10:1829-1838. [PMID: 33586351 PMCID: PMC7940232 DOI: 10.1002/cam4.3782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 01/16/2021] [Accepted: 01/27/2021] [Indexed: 01/13/2023] Open
Abstract
Objective Cervical cancer is a gynecological health problem, affecting nearly 500,000 women each year worldwide. Genome‐wide association studies have revealed multiple susceptible genes and their polymorphisms for cervical carcinoma risk. We have carried out this case‐control study to investigate the association of INSIG2 rs6726538 (A; T), HLA‐DRB1 rs9272143 (T; C), and GCNT1P5 rs7780883 (G; A) with cervical cancer. Methods The present study recruited 234 cervical cancer patients as cases and 212 healthy females as controls. We have applied the tetra‐primer amplification refractory mutation system polymerase chain reaction (T‐ARMS‐PCR) method for genotyping. Results The SNP rs6726538 was significantly associated with increased risk of cervical cancer in all genetic models (AT vs. AA: OR = 3.30, 95% CI = 2.19–4.97, p < 0.0001; TT vs. AA: OR = 8.72, 95% CI = 3.87–19.7, p < 0.0001; AT+TT vs. AA: OR = 3.87, 95% CI = 2.61–5.73, p < 0.0001; T vs. A: OR = 2.97, 95% CI = 2.20–4.01, p < 0.0001) except the recessive model which showed a significantly reduced risk (TT vs. AA+AT: OR = 0.20, 95% CI = 0.09–0.44, p = 0.0001). rs9272143 showed significantly reduced risk for the additive model 1, dominant model, and allelic model (TC vs. TT: OR = 0.46, 95% CI = 0.31–0.70, p = 0.0004; TC+CC vs. TT: OR = 0.47 95% CI = 0.32–0.70, p = 0.0002; C vs. T: OR = 0.56, 95% CI = 0.40–0.78, p = 0.0006, respectively). The third variant, rs7780883, was significantly associated with increased risk in additive model 2, dominant, and allelic models (AA vs. GG: OR = 5.08, 95% CI = 2.45–10.5, p < 0.0001; GA+AA vs. GG: OR = 1.54, 95% CI = 1.06–2.24, p = 0.0237; A vs. G: OR = 1.88, 95% CI = 1.34–2.52, p < 0.0001, consecutively), whereas recessive model reduced the risk of cervical cancer (AA vs. GG+GA: OR = 0.20, 95% CI = 0.09–0.41, p < 0.0001). Other models of these SNPs were not associated with cervical cancer. All significant associations for three SNPs withstand after Bonferroni correction except the additive model 2 of rs7780883. Conclusion Our study concludes that INSIG2 rs6726538, HLA‐DRB1 rs9272143, and GCNT1P5 rs7780883 polymorphisms may contribute to the development of cervical cancer in the Bangladeshi population.
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Affiliation(s)
- Md Emtiaz Hasan
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Maliha Matin
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md Enamul Haque
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md Abdul Aziz
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md Shalahuddin Millat
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Mohammad Sarowar Uddin
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | | | - Mohammad Safiqul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
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Fumagalli C, Guerini-Rocco E, Barberis M. Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC). Cancers (Basel) 2021; 13:609. [PMID: 33557047 PMCID: PMC7913872 DOI: 10.3390/cancers13040609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 12/26/2022] Open
Abstract
Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...].
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Affiliation(s)
- Caterina Fumagalli
- Division of Pathology, IEO, European Institute of Oncology, IRCCS, 20141 Milano, Italy; (E.G.-R.); (M.B.)
| | - Elena Guerini-Rocco
- Division of Pathology, IEO, European Institute of Oncology, IRCCS, 20141 Milano, Italy; (E.G.-R.); (M.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Massimo Barberis
- Division of Pathology, IEO, European Institute of Oncology, IRCCS, 20141 Milano, Italy; (E.G.-R.); (M.B.)
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Okamura R, Kurzrock R, Mallory RJ, Fanta PT, Burgoyne AM, Clary BM, Kato S, Sicklick JK. Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers. Int J Cancer 2021; 148:702-712. [PMID: 32700810 PMCID: PMC7739197 DOI: 10.1002/ijc.33230] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/21/2020] [Accepted: 06/23/2020] [Indexed: 12/14/2022]
Abstract
Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.
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Affiliation(s)
- Ryosuke Okamura
- Center for Personalized Cancer TherapyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
- Division of Hematology‐OncologyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Razelle Kurzrock
- Center for Personalized Cancer TherapyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
- Division of Hematology‐OncologyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Robert J. Mallory
- Division of Surgical Oncology, Department of SurgeryUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Paul T. Fanta
- Division of Hematology‐OncologyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Adam M. Burgoyne
- Division of Hematology‐OncologyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Bryan M. Clary
- Division of Surgical Oncology, Department of SurgeryUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Shumei Kato
- Center for Personalized Cancer TherapyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
- Division of Hematology‐OncologyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
| | - Jason K. Sicklick
- Center for Personalized Cancer TherapyUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
- Division of Surgical Oncology, Department of SurgeryUC San Diego Moores Cancer CenterLa JollaCaliforniaUSA
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Laprovitera N, Riefolo M, Ambrosini E, Klec C, Pichler M, Ferracin M. Cancer of Unknown Primary: Challenges and Progress in Clinical Management. Cancers (Basel) 2021; 13:451. [PMID: 33504059 PMCID: PMC7866161 DOI: 10.3390/cancers13030451] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3-5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.
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Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Elisa Ambrosini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Christiane Klec
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Martin Pichler
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
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Results and Clinical Utilization of Foundation Medicine Molecular Tumor Profiling in Uterine and Ovarian Cancers. Target Oncol 2021; 16:109-118. [PMID: 33400095 DOI: 10.1007/s11523-020-00785-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling. OBJECTIVE We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers. PATIENTS AND METHODS We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data. RESULTS Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results. CONCLUSIONS The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.
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Lai TS, Manrriquez E, Neal A, Memarzadeh S. Matched sequential tumor molecular profiling in solid malignancies may impact clinical practice. Cancer Genet 2020; 252-253:73-79. [PMID: 33434795 DOI: 10.1016/j.cancergen.2020.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/15/2020] [Accepted: 12/28/2020] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To determine if performing repeat tumor molecular profiling in solid malignancies over time can identify new findings that impact clinical care. METHODS All patients with a solid malignancy and more than 1 tumor molecular analysis were identified at a single institution. Each test report was examined to identify the genomic alterations. Chart review was performed to determine subsequent therapies following each test result and the impact of tumor profiling on clinical practice. RESULTS At a single institution, 110 patients were identified with having more than 1 tumor molecular analysis, with 98 subjects having test results available for review. Eighty-seven patients had differences in reported results at the time of subsequent analysis. These differences may reflect changes in tumor biology, be attributed to intra-patient or intra-tumor heterogeneity or be due to technical updates of the next generation sequencing platforms. Among the 98 subjects with solid tumors, the median time between tests was 10 months (range 0.5-66 months), with the majority of tests performed at the time of disease progression or recurrence. In this population, a total of 30 patients received targeted therapies that were associated with actionable findings on any tumor molecular analysis. Of these, 6 patients had new genomic findings identified on sequential testing that affected treatment. CONCLUSIONS The future of cancer care must include precision medicine approaches. Evolution of next generation sequencing has contributed to this effort. Results of this single institution study summarize the reported findings on tumor molecular testing and suggest that subsequent testing may impact clinical care in a subset of patients. While only 6% of patients in this study saw a change in treatment based on new findings on sequential testing reports, this approach may be more clinically relevant in the future with the development of novel targeted therapies. This may be especially significant in a patient population that has progressed on standard therapies and where treatment options are limited.
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Affiliation(s)
- Tiffany S Lai
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
| | - Erica Manrriquez
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Adam Neal
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Sanaz Memarzadeh
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA; UCLA Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA; UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA; The VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA
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Clifton K, Luo J, Tao Y, Saam J, Rich T, Roshal A, Frith A, Rigden C, Ademuyiwa F, Weilbaecher K, Hernandez-Aya L, Peterson LL, Bagegni N, Suresh R, Bose R, Opyrchal M, Wildes TM, Ma C. Mutation profile differences in younger and older patients with advanced breast cancer using circulating tumor DNA (ctDNA). Breast Cancer Res Treat 2020; 185:639-646. [PMID: 33219484 DOI: 10.1007/s10549-020-06019-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/13/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Little is known regarding the mutation profiles of ctDNA in the older adult breast cancer population. The objective of this study is to assess differences in mutation profiles in the older adult breast cancer population using a ctDNA assay as well as assess utilization of testing results. METHODS Patients with advanced breast cancer underwent molecular profiling using a plasma-based ctDNA NGS assay (Guardant360) between 5/2015 and 10/2019 at Siteman Cancer Center. The profiling results of a multi-institutional database of patients with advanced breast cancer who had undergone molecular profiling were obtained. Associations between mutations and age group (≥ 65 vs. < 65) were examined using a Fisher's exact test. RESULTS In the single-institutional cohort, 148 patients (69.2%) were < 65 years old and 66 patients (30.8%) ≥ 65 years old. ATM, BRAF, and PIK3CA mutations were found more frequently in older patients with ER + HER2- breast cancers (p < 0.01). In the multi-institutional cohort, 5367 (61.1%) were < 65 years old and 3417 (38.9%) ≥ 65 years old. ATM, PIK3CA, and TP53 mutations were more common in the older cohort (p < 0.0001) and MYC and GATA3 mutations were less common in the older cohort (p < 0.0001). CtDNA testing influenced next-line treatment management in 40 (19.8%) patients in the single-institutional cohort. CONCLUSION When controlling for subtype, results from a single institution were similar to the multi-institutional cohort showing that ATM and PIK3CA were more common in older adults. These data suggest there may be additional molecular differences in older adults with advanced breast cancers.
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Affiliation(s)
- Katherine Clifton
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA.
| | - Jingqin Luo
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Yu Tao
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | | | | | - Anna Roshal
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Ashley Frith
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Caron Rigden
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Foluso Ademuyiwa
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Katherine Weilbaecher
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Leonel Hernandez-Aya
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Lindsay L Peterson
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Nusayba Bagegni
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Rama Suresh
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Ron Bose
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Mateusz Opyrchal
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Tanya M Wildes
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
| | - Cynthia Ma
- Washington University, 660 South Euclid Avenue, Campus Box 8056, Saint Louis, MO, 63110, USA
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47
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Zhang Q, Fu Q, Bai X, Liang T. Molecular Profiling-Based Precision Medicine in Cancer: A Review of Current Evidence and Challenges. Front Oncol 2020; 10:532403. [PMID: 33194591 PMCID: PMC7652987 DOI: 10.3389/fonc.2020.532403] [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: 02/04/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022] Open
Abstract
Matched therapy based on next-generation sequencing is now a part of routine care to guide the treatment of patients with advanced solid tumors. However, whether and to what extent patients can benefit from this strategy on a large scale remains uncertain. In the past decade, several clinical studies were performed in this field, among which only one was a randomized trial. We reviewed the literature on this topic and summarize the existing data about the efficacy of this treatment strategy. Currently, the evidence is promising but not solid. Multiple ongoing trials are also summarized. We also discuss the limitations of this treatment strategy and certain unsolved important problems, including how to select the sample and target level, how to interpret the results, and the problem of drug accessibility. All these issues should receive more attention in future clinical trial design and the application of target therapy in cancer treatment.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Qihan Fu
- The Key Laboratory of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
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48
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Flaherty KT, Gray RJ, Chen AP, Li S, McShane LM, Patton D, Hamilton SR, Williams PM, Iafrate AJ, Sklar J, Mitchell EP, Harris LN, Takebe N, Sims DJ, Coffey B, Fu T, Routbort M, Zwiebel JA, Rubinstein LV, Little RF, Arteaga CL, Comis R, Abrams JS, O'Dwyer PJ, Conley BA. Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). J Clin Oncol 2020; 38:3883-3894. [PMID: 33048619 PMCID: PMC7676882 DOI: 10.1200/jco.19.03010] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.
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Affiliation(s)
| | - Robert J Gray
- ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA
| | - Alice P Chen
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Shuli Li
- ECOG-ACRIN Cancer Research Group Biostatistics Center, Dana Farber Cancer Institute Boston, MA
| | - Lisa M McShane
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - David Patton
- Center for Biomedical Informatics and Information Technology, NCI, NIH, Bethesda, MD
| | | | | | - A John Iafrate
- Massachusetts General Hospital, Boston, MA.,Harvard University, Boston, MA
| | | | | | - Lyndsay N Harris
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - David J Sims
- Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Brent Coffey
- Center for Biomedical Informatics and Information Technology, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Tony Fu
- Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Mark Routbort
- University of Texas MD Anderson Cancer Center, Houston, TX
| | - James A Zwiebel
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Larry V Rubinstein
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Richard F Little
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Carlos L Arteaga
- University of Texas Southwestern Simmons Cancer Center, Dallas, TX
| | - Robert Comis
- ECOG-ACRIN Cancer Research Group, Philadelphia, PA.,Deceased
| | - Jeffrey S Abrams
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Peter J O'Dwyer
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
| | - Barbara A Conley
- Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD
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Iacobas DA. Powerful quantifiers for cancer transcriptomics. World J Clin Oncol 2020; 11:679-704. [PMID: 33033692 PMCID: PMC7522543 DOI: 10.5306/wjco.v11.i9.679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 06/06/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023] Open
Abstract
Every day, investigators find a new link between a form of cancer and a particular alteration in the sequence or/and expression level of a key gene, awarding this gene the title of “biomarker”. The clinician may choose from numerous available panels to assess the type of cancer based on the mutation or expression regulation (“transcriptomic signature”) of “driver” genes. However, cancer is not a “one-gene show” and, together with the alleged biomarker, hundreds other genes are found as mutated or/and regulated in cancer samples. Regardless of the platform, a well-designed transcriptomic study produces three independent features for each gene: Average expression level, expression variability and coordination with expression of each other gene. While the average expression level is used in all studies to identify what genes were up-/down-regulated or turn on/off, the other two features are unfairly ignored. We use all three features to quantify the transcriptomic change during the progression of the disease and recovery in response to a treatment. Data from our published microarray experiments on cancer nodules and surrounding normal tissue from surgically removed tumors prove that the transcriptomic topologies are not only different in histopathologically distinct regions of a tumor but also dynamic and unique for each human being. We show also that the most influential genes in cancer nodules [the Gene Master Regulators (GMRs)] are significantly less influential in the normal tissue. As such, “smart” manipulation of the cancer GMRs expression may selectively kill cancer cells with little consequences on the normal ones. Therefore, we strongly recommend a really personalized approach of cancer medicine and present the experimental procedure and the mathematical algorithm to identify the most legitimate targets (GMRs) for gene therapy.
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Affiliation(s)
- Dumitru Andrei Iacobas
- Personalized Genomics Laboratory, CRI Center for Computational Systems Biology, Roy G Perry College of Engineering, Prairie View A&M University, Prairie View, TX 77446, United States
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50
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Bohan SS, Sicklick JK, Kato S, Okamura R, Miller VA, Leyland-Jones B, Lippman SM, Kurzrock R. Attrition of Patients on a Precision Oncology Trial: Analysis of the I-PREDICT Experience. Oncologist 2020; 25:e1803-e1806. [PMID: 32949172 PMCID: PMC7648352 DOI: 10.1002/onco.13532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 07/10/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Precision oncology uses molecular profiling of tumors to identify biomarker-tailored therapies for patients in the hope of improving outcomes. Typically, only a minority of patients receives evaluable matched treatment. This study explored the reasons for attrition on a precision medicine trial. MATERIALS AND METHODS Study participants were 190 adult patients who consented to the I-PREDICT (Investigation of molecular Profile-Related Evidence Determining Individualized Cancer Therapy) trial. Patients had metastatic and/or unresectable incurable malignancies. Patients who were not evaluable were analyzed. RESULTS Of consented patients, 44% were not evaluable. Men were twice as likely to be not evaluable as women. Prominently, 45% of patients who were not evaluable dropped off because of death, hospice referral, or decline in organ function. CONCLUSION Health deterioration of consented patients is a significant barrier to being evaluable on the I-PREDICT trial. These data suggest that patients are enrolled on precision oncology trials too late in their disease course or with excessive disease burden.
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Affiliation(s)
- Sandy S Bohan
- San Diego State University/University of California, San Diego, San Diego, California, USA
| | - Jason K Sicklick
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego, La Jolla, California, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.,Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, California, USA
| | - Shumei Kato
- Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.,Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, California, USA
| | - Ryosuke Okamura
- Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.,Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, California, USA
| | | | | | - Scott M Lippman
- Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.,Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, California, USA
| | - Razelle Kurzrock
- Moores Cancer Center, University of California, San Diego, La Jolla, California, USA.,Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla, California, USA
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