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Buchberg J, de Stricker K, Pfeiffer P, Mortensen MB, Detlefsen S. Mutational profiling of 103 unresectable pancreatic ductal adenocarcinomas using EUS-guided fine-needle biopsy. Endosc Ultrasound 2024; 13:154-164. [PMID: 39318643 PMCID: PMC11419524 DOI: 10.1097/eus.0000000000000072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 05/27/2024] [Indexed: 09/26/2024] Open
Abstract
Background and Objective Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, with a 5-year survival rate of around 9%. Only 20% are candidates for surgery. Most unresectable patients undergo EUS-guided fine-needle biopsy (EUS-FNB) for diagnosis. Identification of targetable mutations using next-generation sequencing (NGS) is increasingly requested. Data on feasibility of EUS-FNB for NGS and knowledge regarding mutational profile of unresectable PDAC are scarce. We evaluated the "technical yield" of EUS-FNB for NGS in unresectable PDAC: relative fraction of diagnostic EUS-FNBs meeting technical criteria. We also investigated the "molecular yield": relative fraction of EUS-FNBs included in NGS containing sufficient DNA for detection of at least one mutation. Furthermore, we determined the relative frequency of cancer-associated mutations in unresectable PDAC. Patients and Methods Formalin-fixed and paraffin-embedded EUS-FNBs diagnostic of unresectable PDAC and fulfilling these criteria were included (n = 105): minimum 3-mm2 tissue, minimum of 2-mm2 tumor area, and minimum 20% relative tumor area. NGS was performed using Ion GeneStudio S5 Prime System and Oncomine™ Comprehensive Assay v.3 including 161 cancer-related genes. Results Technical yield was 48% (105/219) and molecular yield was 98% (103/105). Most frequently mutated genes were KRAS (89.3%) and TP53 (69.9%), followed by CDKN2A (24.3%), ARID1A (9.7%), SMAD4 (7.8%), TSC2 (7.8%), and CCND3 (6.8%). Conclusion EUS-FNB for NGS of unresectable PDAC is feasible. Our technical criteria for NGS, using leftovers in formalin-fixed and paraffin-embedded blocks after routine pathology diagnosis, were met by around half of EUS-FNBs. Almost all EUS-FNBs fulfilling the technical criteria yielded a successful NGS analysis.
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Affiliation(s)
- Julie Buchberg
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Karin de Stricker
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Per Pfeiffer
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Department of Oncology, Odense University Hospital, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | - Michael Bau Mortensen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Surgery, Upper GI and HPB Section, Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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Maillard M, Louveau B, Vilquin P, Goldwirt L, Thomas F, Mourah S. Pharmacogenomics in solid cancers and hematologic malignancies: Improving personalized drug prescription. Therapie 2021; 77:171-183. [PMID: 34922740 DOI: 10.1016/j.therap.2021.11.003] [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: 09/11/2021] [Accepted: 09/29/2021] [Indexed: 11/30/2022]
Abstract
The discovery of molecular alterations involved in oncogenesis is evolving rapidly and has led to the development of new innovative targeted therapies in oncology. High-throughput sequencing techniques help to identify genomic targets and to provide predictive molecular biomarkers of response to guide alternative therapeutic strategies. Besides the emergence of these theranostic markers for the new targeted treatments, pharmacogenetic markers (corresponding to genetic variants existing in the constitutional DNA, i.e., the host genome) can help to optimize the use of chemotherapy. In this review, we present the current clinical applications of constitutional PG and the recent concepts and advances in pharmacogenomics, a rapidly evolving field that focuses on various molecular alterations identified on constitutional or somatic (tumor) genome.
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Affiliation(s)
- Maud Maillard
- Institut Claudius-Regaud, Institut universitaire du cancer de Toulouse, IUCT-Oncopole, 31059 Toulouse, France; Centre de recherches en cancérologie de Toulouse CRCT, 31037 Toulouse, France; Université Paul-Sabatier Toulouse III, 31062 Toulouse, France
| | - Baptiste Louveau
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Paul Vilquin
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Lauriane Goldwirt
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Fabienne Thomas
- Institut Claudius-Regaud, Institut universitaire du cancer de Toulouse, IUCT-Oncopole, 31059 Toulouse, France; Centre de recherches en cancérologie de Toulouse CRCT, 31037 Toulouse, France; Université Paul-Sabatier Toulouse III, 31062 Toulouse, France
| | - Samia Mourah
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France.
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Hammel P, Vitellius C, Boisteau É, Wisniewski M, Colle E, Hilmi M, Dengremont C, Granier S, Turpin A, de Mestier L, Neuzillet C. Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors. Ther Adv Med Oncol 2020; 12:1758835920937949. [PMID: 32695234 PMCID: PMC7350045 DOI: 10.1177/1758835920937949] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/05/2020] [Indexed: 12/17/2022] Open
Abstract
Metastatic pancreatic ductal adenocarcinomas (PDACs) are now more effectively controlled using chemotherapy combinations such as FOLFIRINOX and gemcitabine plus nab-paclitaxel (NabP) regimens with a subset of patients who achieve a sustained tumor stabilization or response. The next challenge is to design maintenance therapies that result in continued tumor control with minimal toxicity. Quality of life should always be a priority in these patients with prolonged survival. Gradually tapering off the intensity of chemotherapy by suppressing drug(s) in the combination is one option. Thus, maintenance with 5-fluorouracil or gemcitabine as single agents after FOLFIRINOX or gemcitabine-NabP induction, respectively, seems to be a promising approach to minimize neurotoxicity while maintaining efficacy. Another option is to introduce maintenance drug(s) with different anti-tumoral actions. The recent example of olaparib in patients with BRCA mutated PDAC provides a promising proof-of-concept of a switch maintenance strategy in this setting.
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Affiliation(s)
- Pascal Hammel
- Digestive Oncology, hôpital Beaujon (APHP), University of Paris, 100 boulevard Leclerc, Clichy, 92110, France
| | - Carole Vitellius
- Gastroenterology and Digestive Oncology, and laboratoire HIFIH UPRES EA 3859, SFR 4208, CHU and University of Angers, Angers, France
| | - Émeric Boisteau
- Gastroenterology and Hepatology CHU Pontchaillou and University of Rennes, Rennes, France
| | - Mathilde Wisniewski
- Digestive Oncology, hôpital Beaujon (APHP), Clichy, and University of Paris, Clichy, France
| | - Elise Colle
- Digestive Oncology, hôpital Beaujon (APHP), Clichy, and University of Paris, Clichy, France
| | - Marc Hilmi
- Gastrointestinal Oncology Unit, Gustave Roussy Cancer Campus Grand Paris, University Paris-Saclay, Villejuif, France
| | | | - Sandra Granier
- Medical Oncology, Groupe hospitalier Saint-Joseph, Paris, France
| | - Anthony Turpin
- Medical Oncology, Lille University Hospital, Lille, France
| | - Louis de Mestier
- Gastroenterology and Pancreatology, hôpital Beaujon (APHP), Clichy, and University of Paris, France
| | - Cindy Neuzillet
- GI Oncology, Medical Oncology Department, Institut Curie Saint-Cloud, Versailles Saint-Quentin University, Saint-Cloud, France
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5
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Golan T, Kindler HL, Park JO, Reni M, Macarulla T, Hammel P, Van Cutsem E, Arnold D, Hochhauser D, McGuinness D, Locker GY, Goranova T, Schatz P, Liu YZ, Hall MJ. Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial. J Clin Oncol 2020; 38:1442-1454. [PMID: 32073954 DOI: 10.1200/jco.19.01890] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Germline BRCA1 and/or BRCA2 mutations (gBRCAms) are risk factors for pancreatic cancer. The extent to which demographic and geographic factors affect the uptake of gBRCAm testing in pancreatic cancer (PC) is unknown. METHODS We conducted a retrospective, descriptive analysis of demographic/geographic data from the first 2,206 patients with metastatic PC (mPC) screened for eligibility to enter the phase III POLO trial of maintenance olaparib. No formal statistical tests were performed. RESULTS Of 2,167 patients with previously unknown gBRCAm status, 128 (5.9%) had a newly identified gBRCAm; rates were highest in the United States, France, and Israel (9.5%, 7.6%, and 7.4%, respectively). When including patients with a previously known gBRCAm, prevalence rose to 7.2% (or 5.8% after excluding populations enriched in Ashkenazi Jews, who are known to have a high rate of BRCA1 and BRCA2 founder mutations). Patients with a gBRCAm were slightly younger (57.9 v 61.1 years) and more likely to have early-onset mPC than those without. Higher newly identified gBRCAm prevalence was observed among African American (n = 28) versus white (n = 1,808), Asian (n = 218), and other (n = 61) patients (10.7% v 6.1%, 5.0%, and 1.6%, respectively). Of 139 white patients with a gBRCAm, 110 were newly identified during screening; the majority of gBRCAms in African American, Asian, and Hispanic patients (n = 3, n = 11, and n = 5, respectively) were newly identified. CONCLUSION We identified substantial geographic and some racial variability in gBRCAm prevalence among patients with mPC, an important consideration given the increased use of familial screening and possible future use of targeted therapies in this setting. Although our study included small numbers of nonwhite patients, prior knowledge of their gBRCAm status was limited compared with their white counterparts, which suggests disparities in genetic testing uptake.
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Affiliation(s)
- Talia Golan
- The Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel
| | | | - Joon Oh Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Michele Reni
- IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy
| | - Teresa Macarulla
- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Pascal Hammel
- Hôpital Beaujon (AP-HP), Clichy, and University Paris VII, Paris, France
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven, and KU Leuven, Leuven, Belgium
| | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg AK Altona, Hamburg, Germany
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Obazee O, Archibugi L, Andriulli A, Soucek P, Małecka-Panas E, Ivanauskas A, Johnson T, Gazouli M, Pausch T, Lawlor RT, Cavestro GM, Milanetto AC, Di Leo M, Pasquali C, Hegyi P, Szentesi A, Radu CE, Gheorghe C, Theodoropoulos GE, Bergmann F, Brenner H, Vodickova L, Katzke V, Campa D, Strobel O, Kaiser J, Pezzilli R, Federici F, Mohelnikova-Duchonova B, Boggi U, Lemstrova R, Johansen JS, Bojesen SE, Chen I, Jensen BV, Capurso G, Pazienza V, Dervenis C, Sperti C, Mambrini A, Hackert T, Kaaks R, Basso D, Talar-Wojnarowska R, Maiello E, Izbicki JR, Cuk K, Saum KU, Cantore M, Kupcinskas J, Palmieri O, Delle Fave G, Landi S, Salvia R, Fogar P, Vashist YK, Scarpa A, Vodicka P, Tjaden C, Iskierka-Jazdzewska E, Canzian F. Germline BRCA2
K3326X and CHEK2
I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma. Int J Cancer 2019; 145:686-693. [PMID: 30672594 DOI: 10.1002/ijc.32127] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/23/2018] [Accepted: 12/05/2018] [Indexed: 02/05/2023]
Affiliation(s)
- O. Obazee
- Genomic Epidemiology Group; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - L. Archibugi
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic; S. Andrea Hospital, University of Sapienza; Rome Italy
- Pancreatico/Biliary Endoscopy and Endosonography Division; Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute; Milan Italy
| | - A. Andriulli
- Division of Gastroenterology and Research Laboratory, Department of Oncology; IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”; San Giovanni Rotondo Italy
| | - P. Soucek
- Laboratory of Pharmacogenomics, Biomedical Centre, Faculty of Medicine in Plzen; Charles University in Prague; Plzen Czech Republic
| | - E. Małecka-Panas
- Department of Digestive Tract Diseases; Medical University of Lodz; Lodz Poland
| | - A. Ivanauskas
- Department of Gastroenterology; Lithuanian University of Health Sciences; Kaunas Lithuania
| | - T. Johnson
- Division of Cancer Epidemiology; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - M. Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology; Medical School National and Kapodistrian University of Athens; Athens Greece
| | - T. Pausch
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie; Heidelberg Germany
| | - R. T. Lawlor
- ARC-Net, Applied Research on Cancer Centre; University of Verona; Verona Italy
| | - G. M. Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit; Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute; Milan Italy
| | - A. C. Milanetto
- Department of Surgery, Oncology and Gastroenterology -DiSCOG; University of Padova; Padova Italy
| | - M. Di Leo
- Gastroenterology and Gastrointestinal Endoscopy Unit; Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute; Milan Italy
| | - C. Pasquali
- Department of Surgery, Oncology and Gastroenterology -DiSCOG; University of Padova; Padova Italy
| | - P. Hegyi
- Institute for Translational Medicine and 1st Department of Medicine; University of Pécs; Pécs Hungary
| | - A. Szentesi
- Institute for Translational Medicine and 1st Department of Medicine; University of Pécs; Pécs Hungary
| | - C. E. Radu
- Fundeni Clinical Institute; Bucharest Romania
| | - C. Gheorghe
- Fundeni Clinical Institute; Bucharest Romania
| | - G. E. Theodoropoulos
- First Propaedeutic Surgical Department, "Hippocratio" General Hospital Athens Medical School; National and Kapodistrian University of Athens; Athens Greece
| | - F. Bergmann
- Pathologisches Institut der Universität Heidelberg; Heidelberg Germany
| | - H. Brenner
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
- Division of Preventive Oncology; German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT); Heidelberg Germany
- German Cancer Consortium (DKTK); German Cancer Research Center (DKFZ); Heidelberg Germany
| | - L. Vodickova
- Institute of Biology and Medical Genetics; 1st Medical Faculty, Charles University, Prague and Biomedical Center, Faculty of Medicine in Pilsen, Charles University; Prague Czech Republic
| | - V. Katzke
- Division of Cancer Epidemiology; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - D. Campa
- Dipartimento di Biologia; Università di Pisa; Pisa Italy
| | - O. Strobel
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie; Heidelberg Germany
| | - J. Kaiser
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie; Heidelberg Germany
| | - R. Pezzilli
- Pancreas Unit, Department of Digestive System; Sant'Orsola-Malpighi Hospital; Bologna Italy
| | - F. Federici
- Department of Massa Carrara Oncological; Azienda USL Toscana Nord Ovest; Carrara Italy
| | - B. Mohelnikova-Duchonova
- Department of Oncology, Faculty of Medicine and Dentistry; Palacky University Olomouc and University Hospital Olomouc; Olomouc Czech Republic
| | - U. Boggi
- Division of General and Transplant Surgery; Pisa University Hospital; Pisa Italy
| | - R. Lemstrova
- Department of Oncology, Faculty of Medicine and Dentistry; Palacky University Olomouc and University Hospital Olomouc; Olomouc Czech Republic
| | - J. S. Johansen
- Department of Oncology; Herlev and Gentofte Hospital, Copenhagen University Hospital; Copenhagen Denmark
| | - S. E. Bojesen
- Department of Clinical Biochemistry; Herlev and Gentofte Hospital, Copenhagen University Hospital; Copenhagen Denmark
| | - I. Chen
- Department of Oncology; Herlev and Gentofte Hospital, Copenhagen University Hospital; Copenhagen Denmark
| | - B. V. Jensen
- Department of Oncology; Herlev and Gentofte Hospital, Copenhagen University Hospital; Copenhagen Denmark
| | - G. Capurso
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic; S. Andrea Hospital, University of Sapienza; Rome Italy
- Pancreatico/Biliary Endoscopy and Endosonography Division; Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute; Milan Italy
| | - V. Pazienza
- Division of Gastroenterology and Research Laboratory, Department of Oncology; IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”; San Giovanni Rotondo Italy
| | - C. Dervenis
- Department of Surgery; Konstantopouleion General Hospital of Athens; Athens Greece
| | - C. Sperti
- Department of Surgery, Oncology and Gastroenterology -DiSCOG; University of Padova; Padova Italy
| | - A. Mambrini
- Department of Massa Carrara Oncological; Azienda USL Toscana Nord Ovest; Carrara Italy
| | - T. Hackert
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie; Heidelberg Germany
| | - R. Kaaks
- Division of Cancer Epidemiology; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - D. Basso
- Department of Laboratory Medicine; University-Hospital of Padova; Padova Italy
| | | | - E. Maiello
- Division of Gastroenterology and Research Laboratory, Department of Oncology; IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”; San Giovanni Rotondo Italy
| | - J. R. Izbicki
- Department of General; Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf; Hamburg Germany
| | - K. Cuk
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - K. U. Saum
- Division of Clinical Epidemiology and Aging Research; German Cancer Research Center (DKFZ); Heidelberg Germany
| | - M. Cantore
- Department of Massa Carrara Oncological; Azienda USL Toscana Nord Ovest; Carrara Italy
| | - J. Kupcinskas
- Department of Gastroenterology; Lithuanian University of Health Sciences; Kaunas Lithuania
| | - O. Palmieri
- Division of Gastroenterology and Research Laboratory, Department of Oncology; IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”; San Giovanni Rotondo Italy
| | - G. Delle Fave
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic; S. Andrea Hospital, University of Sapienza; Rome Italy
| | - S. Landi
- Dipartimento di Biologia; Università di Pisa; Pisa Italy
| | - R. Salvia
- Department of Surgery; Pancreas Institute, University and Hospital Trust of Verona; Verona Italy
| | - P. Fogar
- Department of Laboratory Medicine; University-Hospital of Padova; Padova Italy
| | - Y. K. Vashist
- Department of General; Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf; Hamburg Germany
- Section for Visceral Surgery; Department of Surgery, Kantonsspital Aarau AG; Aarau Switzerland
| | - A. Scarpa
- ARC-Net, Applied Research on Cancer Centre; University of Verona; Verona Italy
| | - P. Vodicka
- Institute of Experimental Medicine, Czech Academy of Science, Prague and Institute of Biology and Medical Genetics, 1 Medical Faculty, Charles University; Prague Czech Republic
| | - C. Tjaden
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie; Heidelberg Germany
| | | | - F. Canzian
- Genomic Epidemiology Group; German Cancer Research Center (DKFZ); Heidelberg Germany
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de Mestier L, Muller M, Cros J, Vullierme MP, Vernerey D, Maire F, Dokmak S, Rebours V, Sauvanet A, Lévy P, Hammel P. Appropriateness of pancreatic resection in high-risk individuals for familial pancreatic ductal adenocarcinoma: a patient-level meta-analysis and proposition of the Beaujon score. United European Gastroenterol J 2019; 7:358-368. [PMID: 31019704 DOI: 10.1177/2050640618824910] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023] Open
Abstract
Background About 5% of pancreatic ductal adenocarcinomas are inherited due to a deleterious germline mutation detected in 20% or fewer families. Pancreatic screening in high-risk individuals is proposed to allow early surgical treatment of (pre)malignant lesions. The outcomes of pancreatic surgery in high-risk individuals have never been correctly explored. Objectives To evaluate surgical appropriateness and search for associated factors in high-risk individuals. Methods A patient-level meta-analysis was performed including studies published since 1999. Individual classification distinguished the highest risk imaging abnormality into low-risk or high-risk abnormality, and the highest pathological degree of malignancy of lesions into no/low malignant potential or potentially/frankly malignant. Surgical appropriateness was considered when potentially/frankly malignant lesions were resected. Results Thirteen out of 24 studies were selected, which reported 90 high-risk individuals operated on. Low-risk/high-risk abnormalities were preoperatively detected in 46.7%/53.3% of operated high-risk individuals, respectively. Surgical appropriateness was consistent in 38 (42.2%) high-risk individuals, including 20 pancreatic ductal adenocarcinomas (22.2%). Identification of high-risk abnormalities was strongly associated with surgical appropriateness at multivariate analysis (P = 0.001). We proposed a score and nomogram predictive of surgical appropriateness, including high-risk abnormalities, age and existence of deleterious germline mutation. Conclusion Overall, 42.2% of high-risk individuals underwent appropriate surgery. The proposed score might help selecting the best candidates among high-risk individuals for pancreatic resection.
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Affiliation(s)
- Louis de Mestier
- Department of Gastroenterology and Pancreatology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Marie Muller
- Department of Digestive Oncology and Genetic Counselling, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Jérôme Cros
- Department of Pathology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Marie-Pierre Vullierme
- Department of Radiology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Dewi Vernerey
- Department of Methodology and Quality of Life in Oncology Unit, EA 3181, Minjoz University Hospital, Besançon, France
| | - Frédérique Maire
- Department of Gastroenterology and Pancreatology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Safi Dokmak
- Department of Hepatobiliary and Pancreatic Surgery, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Vinciane Rebours
- Department of Gastroenterology and Pancreatology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Alain Sauvanet
- Department of Hepatobiliary and Pancreatic Surgery, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Philippe Lévy
- Department of Gastroenterology and Pancreatology, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
| | - Pascal Hammel
- Department of Digestive Oncology and Genetic Counselling, Beaujon Hospital (AP-HP) and University Paris Diderot, Clichy, France
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8
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Neuzillet C, Gaujoux S, Williet N, Bachet JB, Bauguion L, Colson Durand L, Conroy T, Dahan L, Gilabert M, Huguet F, Marthey L, Meilleroux J, de Mestier L, Napoléon B, Portales F, Sa Cunha A, Schwarz L, Taieb J, Chibaudel B, Bouché O, Hammel P. Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC). Dig Liver Dis 2018; 50:1257-1271. [PMID: 30219670 DOI: 10.1016/j.dld.2018.08.008] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND This document is a summary of the French intergroup guidelines regarding the management of pancreatic adenocarcinoma (PA), updated in July 2018. DESIGN This collaborative work was produced under the auspices of all French medical and surgical societies involved in the management of PA. It is based on the previous guidelines, recent literature review and expert opinions. Recommendations were graded in three categories, according to the level of evidence. RESULTS Over the last seven years, significant changes in PA management have been implemented in clinical practice. Imaging/staging: diffusion magnetic resonance imaging is useful before surgery to rule out small liver metastases. SURGERY centralization of pancreatic surgery in expert centers is associated with a decreased postoperative mortality. Adjuvant chemotherapy: modified FOLFIRINOX in fit patients, or gemcitabine, or 5-FU, or gemcitabine plus capecitabine, to be discussed on a case-by-case basis. Locally advanced PA: no survival benefit of chemoradiotherapy. Metastatic PA: FOLFIRINOX and gemcitabine plus nab-paclitaxel combination are first-line standards in fit patients; second-line with 5FU/nal-IRI or 5FU/oxaliplatin combination after first-line gemcitabine. CONCLUSION Guidelines for management of PA are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research. However, as each individual case is particular, they cannot substitute to multidisciplinary tumor board discussion.
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Affiliation(s)
- Cindy Neuzillet
- Department of Medical Oncology, Curie Institute, Versailles Saint-Quentin University (UVSQ), Saint-Cloud, France.
| | - Sébastien Gaujoux
- Department of Digestive, Hepato-Biliary and Pancreatic Surgery, Cochin Hospital, AP-HP, Paris Descartes Faculty of Medicine, Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Nicolas Williet
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Jean-Baptiste Bachet
- Hepato-Gastroenterology Department, Pitié Salpétrière University Hospital, AP-HP, Paris Cedex 13, France
| | - Lucile Bauguion
- Hepato-Gastroenterology Department, Departmental Hospital Center, La Roche sur Yon, France
| | - Laurianne Colson Durand
- Department of Radiotherapy, Henri Mondor Hospital, AP-HP, Université Paris Est Creteil, Créteil, France
| | - Thierry Conroy
- Department of Medical Oncology, Lorraine Institute of Oncology and Lorraine University, Vandoeuvre-lès-Nancy Cedex, France
| | - Laetitia Dahan
- Digestive Oncology Department, "DACCORD" (Digestif, Anatomie pathologique, Chirurgie, CISIH, Oncologie, Radiothérapie, Dermatologie) pole, CHU Timone, Marseille Cedex 05, France
| | - Marine Gilabert
- Paoli Calmettes Institute, Department of Medical Oncology and Cancer Research Center of Marseille (CRCM), INSERM U1068 Stress Cell, Aix-Marseille University, Marseille, France
| | - Florence Huguet
- Department of Oncology and Radiotherapy, Tenon Hospital, East Paris University Hospitals, AP-HP, Paris Sorbonne University, Paris, France
| | - Lysiane Marthey
- Gastroenterology Department, Béclère Hospital, AP-HP, Clamart, France
| | - Julie Meilleroux
- Pathology Department, Toulouse University Hospital, Toulouse, France
| | - Louis de Mestier
- Department of Gastroenterology-Pancreatology, Beaujon Hospital, APHP, Paris 7 University, Clichy, France
| | - Bertrand Napoléon
- Jean Mermoz Private Hospital, Ramsay Générale de Santé, Lyon, France
| | - Fabienne Portales
- Digestive Oncology Department, Regional Institute of Cancer, Montpellier, France
| | - Antonio Sa Cunha
- INSERM UMR 935, Paul Brousse Hospital, Hepatobiliary Center, AP-HP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Lilian Schwarz
- Department of Digestive Surgery, Hôpital Charles Nicolle, Rouen University Hospital, Rouen, France and Genomic and Personalized Medicine in Cancer and Neurological Disorders, UMR 1245 INSERM, Rouen University, France
| | - Julien Taieb
- Hepato-Gastroenterology and Digestive Oncology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Olivier Bouché
- Hepato-Gastroenterology and Digestive Oncology Department, Robert Debré University Hospital, Avenue Général Koenig, 51092 Reims Cedex, France
| | - Pascal Hammel
- Department of Digestive Oncology, Beaujon University Hospital (AP-HP), Paris VII Diderot University, Clichy-la-Garenne, France.
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Kardosh A, Lichtensztajn DY, Gubens MA, Kunz PL, Fisher GA, Clarke CA. Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study. Pancreas 2018; 47:958-966. [PMID: 30074526 PMCID: PMC6095724 DOI: 10.1097/mpa.0000000000001133] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 06/09/2018] [Indexed: 01/07/2023]
Abstract
OBJECTIVES Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California. METHODS Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival. RESULTS The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites. CONCLUSIONS Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.
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Affiliation(s)
- Adel Kardosh
- From the Stanford Cancer Institute
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto
| | | | - Matthew A. Gubens
- Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA
| | - Pamela L. Kunz
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto
| | - George A. Fisher
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto
| | - Christina A. Clarke
- Greater Bay Area Cancer Registry, Cancer Prevention Institute of California, Fremont; and
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10
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Abstract
Pancreatic cancer is the twelfth most common cancer in the United States, representing 3.2% of all new cancer cases. While composing a small percentage of cancer diagnoses, pancreatic cancer is amongst the most lethal carcinomas, with an overall 5-year survival of 8.2% and incidence rates almost equivocal to death rates. By the time of diagnosis, a majority of patients will present with advanced stage disease. For patients with resectable disease, the estimated overall survival (OS) remains low at 20% as most will develop metastatic disease within 5 years. The lethality of this cancer is attributed to several factors including delayed presentation, lack of effective screening, and complex tumor biology and genetics. Data also suggest that even upon early presentation, pancreatic cancer is a systemic disease with micrometastasis present in the early stages. Traditional cytotoxic therapies have not been clinically impactful in pancreatic cancer, especially in advanced stages, and very little headway has been made in the development of new targeted therapies. As such, this review will discuss current advances in standard of care treatments and novel drug targets being researched.
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Affiliation(s)
- Amber Draper
- Emory Winship Cancer Institute, Atlanta, GA, USA
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11
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Neuzillet C, Rousseau B, Kocher H, Bourget P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers Part 1: GI carcinomas. Pharmacol Ther 2017; 174:145-172. [PMID: 28223233 DOI: 10.1016/j.pharmthera.2017.02.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom.
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Hemant Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom
| | - Philippe Bourget
- Department of Clinical Pharmacy, Necker-Enfants Malades University Hospital, 149 Rue de Sèvres, 75015 Paris, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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12
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Vera R, Ferrández A, Ferrer CJ, Flores C, Joaquín C, López S, Martín T, Martín E, Marzo M, Sarrión A, Vaquero E, Zapatero A, Aparicio J. Procedures and recommended times in the care process of the patient with pancreatic cancer: PAN-TIME consensus between scientific societies. Clin Transl Oncol 2017; 19:834-843. [PMID: 28105537 PMCID: PMC5486521 DOI: 10.1007/s12094-016-1609-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 12/29/2016] [Indexed: 01/20/2023]
Abstract
PURPOSE Pancreatic cancer (PC) is a disease with bad prognosis. It is usually diagnosed at advanced stages and its treatment is complex. The aim of this consensus document was to provide recommendations by experts that would ameliorate PC diagnosis, reduce the time to treatment, and optimize PC management by interdisciplinary teams. METHODS As a consensus method, we followed the modified Delphi methodology. A scientific committee of experts provided 40 statements that were submitted in two rounds to a panel of 87 specialists of 12 scientific societies. RESULTS Agreement was reached for 39 of the 40 proposed statements (97.5%). CONCLUSIONS Although a screening of the asymptomatic population is not a feasible option, special attention to potential symptoms during primary care could ameliorate early diagnostic. It is especially important to decrease the period until diagnostic tests are performed. This consensus could improve survival in PC patients by decreasing the time to diagnose and time to treatment and by the implementation of multidisciplinary teams.
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Affiliation(s)
- R Vera
- Spanish Society of Medical Oncology, Madrid, Spain.
| | - A Ferrández
- Spanish Society of Pathological Anatomy, Madrid, Spain
| | - C J Ferrer
- Spanish Society of Radiation Oncology, Madrid, Spain
| | - C Flores
- Spanish Society of General and Family Physicians, Madrid, Spain
| | - C Joaquín
- Spanish Society of Endocrinology and Nutrition, Madrid, Spain
| | - S López
- Spanish Society of Surgical Oncology, Madrid, Spain
| | - T Martín
- Spanish Society of Medical Radiology/Spanish Society of Abdominal Radiology, Madrid, Spain
| | - E Martín
- Spanish Association of Surgeons, Madrid, Spain
| | - M Marzo
- Spanish Society of Family and Community Medicine, Madrid, Spain
| | - A Sarrión
- Spanish Society of Primary Care Physicians, Madrid, Spain
| | - E Vaquero
- Spanish Association of Gastroenterology, Madrid, Spain
| | - A Zapatero
- Spanish Society of Internal Medicine, Madrid, Spain
| | - J Aparicio
- Spanish Society of Medical Oncology, Madrid, Spain
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13
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Foulkes WD, Sugano K. BRCA2: a grown-up cancer susceptibility gene. Endocr Relat Cancer 2016; 23:E1-3. [PMID: 27650115 DOI: 10.1530/erc-16-0354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 08/12/2016] [Indexed: 11/08/2022]
Affiliation(s)
- William D Foulkes
- Departments of Human GeneticsMedicine and Oncology, McGill University, Montreal, Quebec, Canada
| | - Kokichi Sugano
- Oncogene Research Unit/Cancer Prevention UnitTochigi Cancer Center Research Institute, Tochigi, Japan
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14
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Baines A, Martin P, Rorie C. Current and Emerging Targeting Strategies for Treatment of Pancreatic Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:277-320. [DOI: 10.1016/bs.pmbts.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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