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Boubaddi M, Rossi J, Marichez A, Marty M, Amintas S, Laurent C, Dabernat S. Preoperative Prognostic Factors in Resectable Pancreatic Cancer: State of the Art and Prospects. Ann Surg Oncol 2025; 32:4117-4127. [PMID: 40095311 DOI: 10.1245/s10434-025-17062-w] [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: 12/20/2024] [Accepted: 02/09/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Only 15% to 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have access to surgical resection, which represents the only chance of curative treatment. Current resection classifications are almost exclusively anatomic and do not correlate sufficiently with patient survival. It is essential to develop preoperative prognostic factors to distinguish patients at high risk of early postoperative recurrence from those who will have prolonged survival after surgery. In some cases, PDACs may present biomolecular differences reflecting their aggressiveness that are not yet assessable by the current clinical-biologic assessment. This study aimed to assess the preoperative prognostic factors that are already available and the future perspectives being developed. METHOD This study reviewed the literature using the PubMed public database for preoperative prognostic factors for resectable PDAC. CONCLUSION Validated preoperative prognostic factors, whether clinical, biologic, radiologic, or histologic, are very important in anticipating the course of each patient's disease. The identification of potential new prognostic biomarkers such as genomic, transcriptomic, and proteomic analyses and the dosage of circulating tumor DNA are very serious avenues to be developed, but the extraction and analysis techniques as well as the interpretation of their results need to be standardized in prospective studies.
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Affiliation(s)
- Mehdi Boubaddi
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France.
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France.
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital, Bordeaux, France.
| | - Julia Rossi
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Arthur Marichez
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Marion Marty
- Tumor Biology and Tumor Bank Laboratory, CHU Bordeaux, Bordeaux, France
| | - Samuel Amintas
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Christophe Laurent
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
| | - Sandrine Dabernat
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
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Demyan L, Weiss MJ. Personalized Care for Pancreatic Cancer: Harnessing Patient-Derived Organoids. J Gastrointest Cancer 2025; 56:113. [PMID: 40347361 DOI: 10.1007/s12029-025-01164-5] [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] [Accepted: 01/01/2025] [Indexed: 05/12/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers. Surgical resection combined with appropriate chemotherapy currently offers the best chance for long-term survival and potential cure. However, effective treatment is hindered by the limited chemotherapy options and the absence of reliable clinical tools to guide chemotherapy selection. Patient-derived organoids (PDOs) have emerged as a promising technology with the potential in precision medicine for PDAC. This review provides an overview of pancreatic organoid genesis, explores the role of PDOs in elucidating PDAC biology within clinically relevant contexts, and concludes by examining current literature on the utility of PDOs as biomarkers for personalized treatment strategies.
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Affiliation(s)
- L Demyan
- Northwell Health, New Hyde Park, USA.
| | - M J Weiss
- Northwell Health, New Hyde Park, USA.
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, USA.
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3
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Panagopoulou M, Panou T, Gkountakos A, Tarapatzi G, Karaglani M, Tsamardinos I, Chatzaki E. BRCA1 & BRCA2 methylation as a prognostic and predictive biomarker in cancer: Implementation in liquid biopsy in the era of precision medicine. Clin Epigenetics 2024; 16:178. [PMID: 39643918 PMCID: PMC11622545 DOI: 10.1186/s13148-024-01787-8] [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: 09/12/2024] [Accepted: 11/19/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the Homologous Recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed "BRCAness". MAIN TEXT One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters, and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response. CONCLUSIONS We believe that BRCA1/2 methylation alone or combined with other biomarkers in a clinical setting is expected to change the scenery in prognosis and predicting treatment response in multiple cancer types and is worthy of further attention. The quantitative BRCA1 promoter methylation assessment might predict treatment response in PARPi and analysis of BRCA1/2 methylation in liquid biopsy might define patient subgroups at different time points that may benefit from PARPi. Finally, we suggest a pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.
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Grants
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
- TAEDR-0535850 European Union- Next-Generation EU, Greece 2.0 National Recovery and Resilience plan, National Flagship Initiative "Health and Pharmaceuticals"
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Affiliation(s)
- Maria Panagopoulou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece.
- Institute of Agri-Food and Life Sciences, University Research and Innovation Centre, Hellenic Mediterranean University, 71003, Heraklion, Greece.
| | - Theodoros Panou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece
| | - Anastasios Gkountakos
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece
| | - Makrina Karaglani
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, University Research and Innovation Centre, Hellenic Mediterranean University, 71003, Heraklion, Greece
| | - Ioannis Tsamardinos
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 70013, Heraklion, Greece
- Department of Computer Science, University of Crete, Voutes Campus, 70013, Heraklion, Greece
- Institute of Applied and Computational Mathematics, 70013, Heraklion, Greece
- JADBio Gnosis Data Analysis (DA) S.A., Science and Technology Park of Crete (STEPC), 70013, Heraklion, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100, Alexandroupolis, Greece
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 70013, Heraklion, Greece
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Limijadi EKS, Muniroh M, Prajoko YW, Tjandra KC, Respati DRP. The role of germline BRCA1 & BRCA2 mutations in familial pancreatic cancer: A systematic review and meta-analysis. PLoS One 2024; 19:e0299276. [PMID: 38809921 PMCID: PMC11135687 DOI: 10.1371/journal.pone.0299276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/15/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Familial Pancreatic Cancer (FPC) presents a notable risk, with 3-10% of pancreatic adenocarcinoma cases having a family history. Studies link FPC to syndromes like HBOC, suggesting BRCA1/BRCA2 mutations play a role. BRCA gene functions in DNA repair impact FPC management, influencing sensitivity to therapies like PARP inhibitors. Identifying mutations not only aids FPC treatment but also reveals broader cancer risks. However, challenges persist in selectively applying genetic testing due to cost constraints. This Systematic Review focuses on BRCA1/BRCA2 significance in FPC, diagnostic criteria, prognostic value, and limitations. METHOD Original articles published from 2013 to January 2023 were sourced from databases such as Scopus, PubMed, ProQuest, and ScienceDirect. Inclusion criteria comprised observational cohort or diagnostic studies related to the role of BRCA1/2 mutation in correlation to familial pancreatic cancer (FPC), while article reviews, narrative reviews, and non-relevant content were excluded. The assessment of bias used ROBINS-I, and the results were organized using PICOS criteria in a Google spreadsheet table. The systematic review adhered to the PRISMA 2020 checklist. RESULT We analyzed 9 diagnostic studies encompassing 1325 families and 4267 patients from Italy, USA, and Poland. Despite the limitation of limited homogenous PICO studies, our findings effectively present evidence. BRCA1/2 demonstrates benefits in detecting first-degree relatives FPC involvement with 2.26-10 times higher risk. These mutation findings also play an important role since with the BRCA1/2 targeted therapy, Poly-ADP Ribose Polymerase inhibitors (PARP) may give better outcomes of FPC treatment. Analysis of BRCA1 and BRCA2 administration's impact on odds ratio (OR) based on six and five studies respectively. BRCA1 exhibited non-significant effects (OR = 1.26, P = 0.51), while BRCA2 showed significance (OR = 1.68, P = 0.04). No heterogeneity observed, indicating consistent results. Further research on BRCA1 is warranted. CONCLUSION Detecting the BRCA1/2 mutation gene offers numerous advantages, particularly in its correlation with FPC. For diagnostic and prognostic purposes, testing is strongly recommended for first-degree relatives, who face a significantly higher risk (2.26-10 times) of being affected. Additionally, FPC patients with identified BRCA1/2 mutations exhibit a more favorable prognosis compared to the non-mutated population. This is attributed to the availability of targeted BRCA1/2 therapy, which maximizes treatment outcomes.
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Affiliation(s)
- Edward Kurnia Setiawan Limijadi
- Doctoral Study Program of Medical and Health Science, Universitas Diponegoro, Semarang, Indonesia
- Faculty of Medicine, Department of Clinical Pathology, Universitas Diopnegoro, Semarang, Indonesia
| | - Muflihatul Muniroh
- Faculty of Medicine, Department of Physiology, Universitas Diponegoro, Semarang, Indonesia
| | - Yan Wisnu Prajoko
- Faculty of Medicine, Department of Surgical Oncology, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Kevin Christian Tjandra
- Kariadi General Hospital, Semarang, Indonesia
- Faculty of Medicine, Departement of Medicine, Universitas Diponegoro, Semarang, Indonesia
| | - Danendra Rakha Putra Respati
- Kariadi General Hospital, Semarang, Indonesia
- Faculty of Medicine, Departement of Medicine, Universitas Diponegoro, Semarang, Indonesia
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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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Brozos-Vázquez E, Toledano-Fonseca M, Costa-Fraga N, García-Ortiz MV, Díaz-Lagares Á, Rodríguez-Ariza A, Aranda E, López-López R. Pancreatic cancer biomarkers: A pathway to advance in personalized treatment selection. Cancer Treat Rev 2024; 125:102719. [PMID: 38490088 DOI: 10.1016/j.ctrv.2024.102719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/08/2024] [Accepted: 03/10/2024] [Indexed: 03/17/2024]
Abstract
Pancreatic cancer is one of the tumors with the worst prognosis, and unlike other cancers, few advances have been made in recent years. The only curative option is surgery, but only 15-20% of patients are candidates, with a high risk of relapse. In advanced pancreatic cancer there are few first-line treatment options and no validated biomarkers for better treatment selection. The development of targeted therapies in pancreatic cancer is increasingly feasible due to tumor-agnostic treatments, such as PARP inhibitors in patients with BRCA1, BRCA2 or PALB2 alterations or immunotherapies in patients with high microsatellite instability/tumor mutational burden. In addition, other therapeutic molecules have been developed for patients with KRAS G12C mutation or fusions in NTRK or NRG1. Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.
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Affiliation(s)
- Elena Brozos-Vázquez
- Medical Oncology Department, University Hospital of A Coruña (CHUAC), A Coruña, Spain
| | - Marta Toledano-Fonseca
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
| | - Nicolás Costa-Fraga
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET); Clinical University Hospital & Health Research Institute of Santiago de Compostela. CIBERONC; University of Santiago de Compostela, Santiago de Compostela, Spain
| | - María Victoria García-Ortiz
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
| | - Ángel Díaz-Lagares
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET); Clinical University Hospital & Health Research Institute of Santiago de Compostela. CIBERONC; Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Santiago de Compostela, Spain
| | - Antonio Rodríguez-Ariza
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain.
| | - Enrique Aranda
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain; Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain; Department of Medicine, Faculty of Medicine, University of Córdoba, Córdoba, Spain
| | - Rafael López-López
- Clinical University Hospital & Health Research Institute of Santiago de Compostela. CIBERONC; Medical Oncology Department & Translational Medical Oncology Group-ONCOMET, Spain; Oncology at Santiago de Compostela School of Medicine, Spain
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Szentmartoni G, Mühl D, Csanda R, Szasz AM, Herold Z, Dank M. Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors. Biomedicines 2024; 12:593. [PMID: 38540206 PMCID: PMC10967875 DOI: 10.3390/biomedicines12030593] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 01/11/2025] Open
Abstract
Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.
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Affiliation(s)
- Gyongyver Szentmartoni
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary
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8
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Anbil S, Reiss KA. Targeting BRCA and PALB2 in Pancreatic Cancer. Curr Treat Options Oncol 2024; 25:346-363. [PMID: 38311708 DOI: 10.1007/s11864-023-01174-0] [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] [Accepted: 12/22/2023] [Indexed: 02/06/2024]
Abstract
OPINION STATEMENT An important subgroup of pancreatic ductal adenocarcinomas (PDACs) harbor pathogenic variants in BRCA1, BRCA2, or PALB2. These tumors are exquisitely sensitive to platinum-based chemotherapy and patients may experience deep and durable responses to this treatment. PARP inhibitors offer potential respite from the cumulative toxicities of chemotherapy as they significantly extend progression-free survival compared to a chemotherapy holiday. Given the lack of proven survival benefit, the decision to use a maintenance PARP inhibitor rather than continue chemotherapy should be individualized. Interestingly, in both published clinical trials of maintenance PARP inhibitors, there is a striking range of interpatient benefit: Even in the platinum-sensitive setting, roughly 25% of tumors appear to be PARP inhibitor refractory (progressive disease within 2 months of starting treatment), 50% sustain moderate benefit (up to 2 years), and 25% are hyper-responsive (more than 2 years of benefit). This finding highlights the need to refine our understanding of which patients will respond to maintenance PARP inhibitors, both by being able to identify biallelic loss and by deepening our knowledge of resistance mechanisms and who develops them. Recent data supports that reversion mutations are common in PARP inhibitor refractory patients, but we have little understanding of the mechanisms that drive delayed resistance and long-term responses. Identifying which patients are more prone to certain mechanisms of resistance and tackling them with specific treatment strategies are areas of active investigation. Additionally, given that PARP inhibitors have limited overall efficacy for most patients, upfront combination strategies are an important future strategy.
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Affiliation(s)
- Sriram Anbil
- Abramson Cancer Center, 10th Floor Perelman Center South, The University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19121, USA
| | - Kim A Reiss
- Abramson Cancer Center, 10th Floor Perelman Center South, The University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19121, USA.
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Wang Y, Lin W, Zhuang X, Wang X, He Y, Li L, Lyu G. Advances in artificial intelligence for the diagnosis and treatment of ovarian cancer (Review). Oncol Rep 2024; 51:46. [PMID: 38240090 PMCID: PMC10828921 DOI: 10.3892/or.2024.8705] [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: 07/18/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Artificial intelligence (AI) has emerged as a crucial technique for extracting high‑throughput information from various sources, including medical images, pathological images, and genomics, transcriptomics, proteomics and metabolomics data. AI has been widely used in the field of diagnosis, for the differentiation of benign and malignant ovarian cancer (OC), and for prognostic assessment, with favorable results. Notably, AI‑based radiomics has proven to be a non‑invasive, convenient and economical approach, making it an essential asset in a gynecological setting. The present study reviews the application of AI in the diagnosis, differentiation and prognostic assessment of OC. It is suggested that AI‑based multi‑omics studies have the potential to improve the diagnostic and prognostic predictive ability in patients with OC, thereby facilitating the realization of precision medicine.
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Affiliation(s)
- Yanli Wang
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Weihong Lin
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Xiaoling Zhuang
- Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Xiali Wang
- Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, Fujian 362000, P.R. China
| | - Yifang He
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Luhong Li
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
- Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, Fujian 362000, P.R. China
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10
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Pantaleo A, Forte G, Fasano C, Lepore Signorile M, Sanese P, De Marco K, Di Nicola E, Latrofa M, Grossi V, Disciglio V, Simone C. Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review. Cancers (Basel) 2023; 16:56. [PMID: 38201484 PMCID: PMC10778202 DOI: 10.3390/cancers16010056] [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: 11/09/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance.
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Affiliation(s)
- Antonino Pantaleo
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Elisabetta Di Nicola
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Marialaura Latrofa
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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11
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Hu YF, Hu HJ, Kung HC, Lv TR, Yu J, Li FY. DNA damage repair mutations in pancreatic cancer- prognostic or predictive? Front Oncol 2023; 13:1267577. [PMID: 37954082 PMCID: PMC10634423 DOI: 10.3389/fonc.2023.1267577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/10/2023] [Indexed: 11/14/2023] Open
Abstract
Objective The efficacy of platinum-based chemotherapy (PtCh) for pancreatic cancer (PC) patients with DNA damage repair gene mutations (DDRm) compared to those without DDRm remains uncertain. Methods After a thorough database searching in PubMed, Embase, and Web of Science, a total of 19 studies that met all the inclusion criteria were identified. The primary outcomes were overall survival (OS) and progression-free survival (PFS) for PC patients with DDRm versus those without DDRm after PtCh. Results Patients with advanced-stage PC who have DDRm tend to have longer OS compared to patients without DDRm, regardless of their exposure to PtCh (HR=0.63; I2 = 66%). Further analyses indicated that the effectiveness of PtCh for OS was modified by DDRm (HR=0.48; I2 = 59%). After the first- line PtCh (1L-PtCh), the PFS of advanced-stage PC with DDRm was also significantly improved (HR=0.41; I2 = 0%). For patients with resected PC, regardless of their exposure to PtCh, the OS for patients with DDRm was comparable to those without DDRm (HR=0.82; I2 = 71%). Specifically, for patients with resected PC harboring DDRm who received PtCh (HR=0.85; I2 = 65%) and for those after non-PtCh (HR=0.87; I2 = 0%), the presence of DDRm did not show a significant association with longer OS. Conclusion 1L-PtCh treatment is correlated with favorable survival for advanced-stage PC patients with DDRm. For resected-stage PC harboring DDRm, adjuvant PtCh had limited effectiveness. The prognostic value of DDRm needs to be further verified by prospective randomized controlled trials. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022302275.
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Affiliation(s)
- Ya-Fei Hu
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hai-Jie Hu
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Heng-Chung Kung
- Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, United States
| | - Tian-Run Lv
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jun Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Fu-Yu Li
- Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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12
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Byeon S, du Toit‐Thompson T, Gillson J, Gill AJ, Samra JS, Mittal A, Sahni S. Heterogeneous tumor microenvironment in pancreatic ductal adenocarcinoma: An emerging role of single-cell analysis. Cancer Med 2023; 12:18020-18031. [PMID: 37537839 PMCID: PMC10523961 DOI: 10.1002/cam4.6407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/21/2023] [Accepted: 07/25/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies in the world, for which the mortality is almost as high as the disease incidence and is predicted to be the second-highest cause of cancer-related deaths by 2030. These cancerous tumors consist of diversified gene expressions within the different cellular subpopulations that include neoplastic ductal cells, cancer-associated fibroblasts, and immune cells, all of which collectively facilitate cellular heterogeneity in the PDAC tumor microenvironment (TME). Active intratumoral interaction within the cell populations in TME induces the proliferation of cancerous cells, accounting for tumorigenesis and rapid metastasis. METHODS This review will focus on novel findings uncovering PDAC heterogeneity in different cellular subpopulations using single-cell RNA-sequencing (scRNA-seq) and other single-cell analysis technologies. It will further explore the emerging role of single-cell technologies in assessing the role of different subpopulations of neoplastic ductal cells, cancer-associated fibroblasts, and immune cells in PDAC progression. RESULTS AND CONCLUSION The application of scRNA-seq in PDAC has started to unveil associations between disease progression and heterogeneity in pancreatic TME and could influence future PDAC treatment. Recent advances in scRNA-seq have uncovered comprehensive analyses of heterogeneous ecosystems present within the TME. These emerging findings underpins further need for a more in-depth understanding of intratumoral heterogeneity in the PDAC microenvironment.
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Affiliation(s)
- Sooin Byeon
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Kolling Institute of Medical Research, University of SydneySydneyNew South WalesAustralia
| | - Taymin du Toit‐Thompson
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Kolling Institute of Medical Research, University of SydneySydneyNew South WalesAustralia
| | - Josef Gillson
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Kolling Institute of Medical Research, University of SydneySydneyNew South WalesAustralia
| | - Anthony J. Gill
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Kolling Institute of Medical Research, University of SydneySydneyNew South WalesAustralia
- Australian Pancreatic CentreSydneyNew South WalesAustralia
- Cancer Diagnosis and Pathology GroupKolling Institute of Medical ResearchSt LeonardsNew South WalesAustralia
- NSW Health Pathology, Department of Anatomical PathologyRoyal North Shore HospitalSt LeonardsNew South WalesAustralia
| | - Jaswinder S. Samra
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Australian Pancreatic CentreSydneyNew South WalesAustralia
- Upper GI Surgical UnitRoyal North Shore Hospital and North Shore Private HospitalSt LeonardsNew South WalesAustralia
| | - Anubhav Mittal
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Australian Pancreatic CentreSydneyNew South WalesAustralia
- Upper GI Surgical UnitRoyal North Shore Hospital and North Shore Private HospitalSt LeonardsNew South WalesAustralia
- The University of Notre Dame AustraliaSydneyNew South WalesAustralia
| | - Sumit Sahni
- Northern Clinical School, Faculty of Medicine and HealthUniversity of SydneySydneyNew South WalesAustralia
- Kolling Institute of Medical Research, University of SydneySydneyNew South WalesAustralia
- Australian Pancreatic CentreSydneyNew South WalesAustralia
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13
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Lee PWP, Strum SW, Tsvetkova E. It Is All in the Genes: A Story of Unexpected Survival in a 67-Year-Old Male with Metastatic Pancreatic Cancer. Case Rep Oncol Med 2023; 2023:8751205. [PMID: 37547629 PMCID: PMC10400294 DOI: 10.1155/2023/8751205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/07/2023] [Indexed: 08/08/2023] Open
Abstract
Background We describe a case report of a 67-year-old male with PDAC who experienced an exceptional survival outcome during systemic therapy and its implications in precision medicine. We hypothesize that his outcomes are attributable, in part, to a germline BRCA2 deletion and somatic GNAS substitution. Methods Retrospective single-patient chart review was performed at the London Regional Cancer Program, as well as a structured literature search spanning all years in PubMed of BRCA and GNAS mutations in pancreatic cancer. Results The case described herein represents a 67-year-old male who survived over 27 months after third-line treatment with gemcitabine, docetaxel, and capecitabine (GTX) chemotherapy for metastatic PDAC after progression on gemcitabine and Abraxane and then on FOLFIRINOX. His survival far exceeded the median overall survival metrics. Genetic testing revealed a pathogenic heterozygous germline BRCA2 6643delT p.(Tyr2215Thrfs∗14) frameshift mutation and somatic GNAS 2531G > A p.(Arg844His) mutation. Conclusions This case highlights the urgent need to expand our knowledge of cancer biology to advance personalized cancer treatment and therapy development.
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Affiliation(s)
- Patsy W. P. Lee
- Department of Internal Medicine, Schulich School of Medicine and Dentistry, Western University, Canada
| | - Scott W. Strum
- Department of Medical Oncology, London Regional Cancer Program, Western University, Canada
| | - Elena Tsvetkova
- Department of Medical Oncology, London Regional Cancer Program, Western University, Canada
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14
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Keane F, O’Connor CA, Park W, Seufferlein T, O’Reilly EM. Pancreatic Cancer: BRCA Targeted Therapy and Beyond. Cancers (Basel) 2023; 15:2955. [PMID: 37296917 PMCID: PMC10251879 DOI: 10.3390/cancers15112955] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
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Affiliation(s)
- Fergus Keane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
| | - Catherine A. O’Connor
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Thomas Seufferlein
- Department of Internal Medicine, Ulm University Hospital, 89081 Ulm, Germany;
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
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15
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Ceylan F, Guven DC, Taban H, Aktepe O, Sahin TK, Kilickap S, Turker A, Hamaloglu E, Karakoc D, Isik A, Akyol A, Yalcin S, Dizdar O. Prognostic and predictive value of tumoral DNA damage repair protein expression in patients with resected pancreatic cancer. Clin Res Hepatol Gastroenterol 2023; 47:102091. [PMID: 36738855 DOI: 10.1016/j.clinre.2023.102091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/06/2023]
Abstract
OBJECTIVE DNA damage repair (DDR) gene mutations gained interest in the treatment of metastatic pancreatic cancer (PC) patients, but their relevance in adjuvant setting is not well characterized. We assessed the prognostic and predictive potential of tumoral expression of DDR proteins along with clinical and tumor characteristics in patients with resected PC. PATIENTS AND METHODS Patients with PC who underwent pancreatic resection in our institution between 2005 and 2017 were retrospectively retrieved. Tumoral expression of a panel of DDR proteins including BRCA1, BRCA2, ATM, and p53 with immunohistochemistry was evaluated and association with patient and tumor features as well as prognosis was assessed. RESULTS 130 patients were included in the study. The median age was 61 and 66% were males, 57% had lymph node involvement and 17% had a vascular invasion. 25 patients (19%) had thrombosis at the time of diagnosis. Median overall survival (OS) and disease-free survival (DFS) were 21.6 and 11.8 months, respectively. More advanced disease stage (HR: 3.67 95% CI 1.48-9.12, p = 0.005), presence of thrombosis (HR: 2.01 95% CI 1.04-3.89, p = 0.039), high BRCA1 expression (HR: 2.25, 95% CI 1.13-5.48, p = 0.023) and high post-operative CA 19-9 level (>100 IU/ml) (HR:2.61 95% CI 1.40-4.89, p = 0.003) were associated with shorter DFS. BRCA2, ATM, and p53 expression were not associated with DFS or OS. Adjuvant gemcitabine-cisplatin regimen was not associated with increased DFS or OS in the whole group, neither in low or high expressors of BRCA1, BRCA2, ATM or p53. CONCLUSION Contrary to BRCA2, ATM, and P53, BRCA1 expression may be beneficial for prognosis in resected pancreatic cancer, while no predictive role was observed in terms of adjuvant platinum efficacy.
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Affiliation(s)
- Furkan Ceylan
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey.
| | - Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Hakan Taban
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Oktay Aktepe
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Taha Koray Sahin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Sadettin Kilickap
- Department of Preventive Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Alev Turker
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Erhan Hamaloglu
- Department of General Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Derya Karakoc
- Department of General Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Aynur Isik
- Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey
| | - Aytekin Akyol
- Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey; Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Omer Dizdar
- Department of Preventive Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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16
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de Jesus VHF, Riechelmann RP. Current Treatment of Potentially Resectable Pancreatic Ductal Adenocarcinoma: A Medical Oncologist's Perspective. Cancer Control 2023; 30:10732748231173212. [PMID: 37115533 PMCID: PMC10155028 DOI: 10.1177/10732748231173212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 03/01/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic cancer has traditionally been associated with a dismal prognosis, even in early stages of the disease. In recent years, the introduction of newer generation chemotherapy regimens in the adjuvant setting has improved the survival of patients treated with upfront resection. However, there are multiple theoretical advantages to deliver early systemic therapy in patients with localized pancreatic cancer. So far, the evidence supports the use of neoadjuvant therapy for patients with borderline resectable pancreatic cancer. The benefit of this treatment sequence for patients with resectable disease remains elusive. In this review, we summarize the data on adjuvant therapy for pancreatic cancer and describe which evidence backs the use of neoadjuvant therapy. Additionally, we address important issues faced in clinical practice when treating patients with localized pancreatic cancer.
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17
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Mohindroo C, De Jesus-Acosta A, Yurgelun MB, Maitra A, Mork M, McAllister F. The Evolving Paradigm of Germline Testing in Pancreatic Ductal Adenocarcinoma and Implications for Clinical Practice. Surg Pathol Clin 2022; 15:491-502. [PMID: 36049831 DOI: 10.1016/j.path.2022.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Identification of deleterious germline mutations in pancreatic ductal adenocarcinoma (PDAC) patients can have therapeutic implications for the patients and result in cascade testing and prevention in their relatives. Universal testing for germline mutations is now considered standard of care in patients with PDAC, regardless of family history, personal history, or age. Here, we highlight the commonly identified germline mutations in PDAC patients as well as the impact of multigene panel testing. We further discuss therapeutic implications of germline testing on the index cases, and the impact of cascade testing on cancer early detection and prevention in relatives.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 401 North Broadway, Baltimore, MD 21231, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Anirban Maitra
- Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX 77030, USA
| | - Maureen Mork
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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18
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O'Kane GM, Lowery MA. Moving the Needle on Precision Medicine in Pancreatic Cancer. J Clin Oncol 2022; 40:2693-2705. [PMID: 35839440 DOI: 10.1200/jco.21.02514] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 03/20/2022] [Accepted: 04/18/2022] [Indexed: 12/21/2022] Open
Abstract
The management of pancreatic ductal adenocarcinoma (PDAC) has posed a considerable challenge for decades, with incidence and mortality rates almost mirroring each other. Despite this, a deeper understanding of the complex biology inherent to PDAC has provided a roadmap for a more precise approach to treatment. PDAC deficient in homologous recombination repair and mismatch repair is a subgroup that should be identified in the clinic for a targeted approach. In addition, KRAS wild-type PDAC, occurring in approximately 10% of patients, is enriched in highly actionable alterations including fusions, underscoring the importance of integrative germline and somatic sequencing. Comprehensive sequencing efforts over the past decade have documented genomic- and transcriptomic-based classifiers, with the latter emerging as two main subtypes: the classical and basal-like, which are now being evaluated in clinical trials. Together with promising, innovative strategies to target KRAS mutations and their pleotropic effects, a new era of precision medicine in PDAC is on the horizon.
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Affiliation(s)
- Grainne M O'Kane
- Trinity St James Cancer Institute, Dublin, Ireland
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto, ON, Canada
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19
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Association Between Family History and Risk of Pancreatic Cancer in Patients With BRCA1 and BRCA2 Pathogenic Variants. Pancreas 2022; 51:733-738. [PMID: 36395396 DOI: 10.1097/mpa.0000000000002104] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Current guidelines limit pancreatic cancer screening to those BRCA1/2 patients who have a family history of pancreatic cancer. We aimed to assess the association between family history and risk of pancreatic neoplasms in BRCA1/2 patients. METHODS We reviewed medical records of BRCA1/2 patients followed at our institution between 1995 and 2020. Family history was defined as those with a first-degree relative with pancreatic cancer. We compared the incidence and prevalence of pancreatic neoplasms between patients with and without family history of pancreatic cancer. RESULTS We identified 56 BRCA1/2 patients with family history and 238 without family history of pancreatic cancer. No difference between these groups was noted in age, race, or sex. Mean follow-up interval for BRCA1/2 patients was 4.6 years (range, 0-19.7 years). There was no significant difference in prevalence (19.6% vs 12.6; P = 0.3) or incidence (29% vs 14.1%; P = 0.08) of branch-duct intraductal papillary mucinous neoplasm between the 2 groups. No association between family history and pancreatic cancer risk was noted. Only 1 of 10 BRCA1/2 patients with pancreatic cancer had a family history. CONCLUSIONS Our results do not support using family history to determine eligibility for pancreatic cancer screening.
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20
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Calderwood AH, Sawhney MS, Thosani NC, Rebbeck TR, Wani S, Canto MI, Fishman DS, Golan T, Hidalgo M, Kwon RS, Riegert-Johnson DL, Sahani DV, Stoffel EM, Vollmer CM, Al-Haddad MA, Amateau SK, Buxbaum JL, DiMaio CJ, Fujii-Lau LL, Jamil LH, Jue TL, Law JK, Lee JK, Naveed M, Pawa S, Storm AC, Qumseya BJ. American Society for Gastrointestinal Endoscopy guideline on screening for pancreatic cancer in individuals with genetic susceptibility: methodology and review of evidence. Gastrointest Endosc 2022; 95:827-854.e3. [PMID: 35183359 DOI: 10.1016/j.gie.2021.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023]
Affiliation(s)
- Audrey H Calderwood
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire, USA
| | - Mandeep S Sawhney
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Nirav C Thosani
- Center for Interventional Gastroenterology at UTHealth, McGovern Medical School, Houston, Texas, USA
| | - Timothy R Rebbeck
- Harvard TH Chan School of Public Health and Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sachin Wani
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Marcia I Canto
- Division of Gastroenterology and Hepatology, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Douglas S Fishman
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | - Talia Golan
- Cancer Center, Sheba Medical Center, Yehuda, Israel
| | - Manuel Hidalgo
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York, USA
| | - Richard S Kwon
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Douglas L Riegert-Johnson
- Department of Clinical Genomics and Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Dushyant V Sahani
- Department of Radiology, University of Washington, Seattle, Washington, USA
| | - Elena M Stoffel
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Charles M Vollmer
- Department of Surgery, Penn Medicine, Philadelphia, Pennsylvania, USA
| | - Mohammad A Al-Haddad
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Stuart K Amateau
- Division of Gastroenterology Hepatology and Nutrition, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - James L Buxbaum
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of University of Southern California, Los Angeles, California, USA
| | - Christopher J DiMaio
- Department of Gastroenterology, Mount Sinai School of Medicine, New York, New York, USA
| | - Larissa L Fujii-Lau
- Department of Gastroenterology, The Queen's Medical Center, Honolulu, Hawaii, USA
| | - Laith H Jamil
- Section of Gastroenterology and Hepatology, Beaumont Health, Royal Oak, Michigan, and Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA
| | - Terry L Jue
- Department of Gastroenterology, The Permanente Medical Group, San Francisco, California, USA
| | - Joanna K Law
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Jeffrey K Lee
- Department of Gastroenterology, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA
| | - Mariam Naveed
- Advent Health Medical Group, Gastroenterology/Hepatology, Advent Health Hospital Altamonte Springs, Altamonte Springs, Florida, USA
| | - Swati Pawa
- Department of Gastroenterology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
| | - Andrew C Storm
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Bashar J Qumseya
- Department of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA
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21
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Sawhney MS, Calderwood AH, Thosani NC, Rebbeck TR, Wani S, Canto MI, Fishman DS, Golan T, Hidalgo M, Kwon RS, Riegert-Johnson DL, Sahani DV, Stoffel EM, Vollmer CM, Qumseya BJ. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc 2022; 95:817-826. [PMID: 35183358 DOI: 10.1016/j.gie.2021.12.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 12/02/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Mandeep S Sawhney
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Audrey H Calderwood
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire, USA
| | - Nirav C Thosani
- Center for Interventional Gastroenterology at UT Health, McGovern Medical School, Houston, Texas, USA
| | - Timothy R Rebbeck
- Harvard TH Chan School of Public Health and Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sachin Wani
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Marcia I Canto
- Division of Gastroenterology and Hepatology, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Douglas S Fishman
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | - Talia Golan
- Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Manuel Hidalgo
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York, USA
| | - Richard S Kwon
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Douglas L Riegert-Johnson
- Department of Clinical Genomics and Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Dushyant V Sahani
- Department of Radiology, University of Washington, Seattle, Washington, USA
| | - Elena M Stoffel
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Charles M Vollmer
- Department of Surgery, Penn Medicine, Philadelphia, Pennsylvania, USA
| | - Bashar J Qumseya
- Department of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA
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22
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Tadehara M, Kato T, Adachi K, Tamaki A, Kesen Y, Sakurai Y, Ichinoe M, Koizumi W, Murakumo Y. Clinicopathological Significance of BRCAness in Resectable Pancreatic Ductal Adenocarcinoma and Its Association With Anticancer Drug Sensitivity in Pancreatic Cancer Cells. Pancreas 2022; 51:183-189. [PMID: 35404895 DOI: 10.1097/mpa.0000000000001975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE The concept of BRCAness has been proposed as a homologous recombination repair dysfunction triggered by a genetic defect in the BRCA pathway including the BRCA1/2 mutations. A certain number of pancreatic ductal adenocarcinoma (PDAC) patients have BRCAness. However, a large-scale analysis of BRCAness in PDAC has not been performed. In addition, no basic studies have examined the significance of BRCAness in PDAC cell lines. METHODS Ninety-two patients who underwent surgery for PDAC were enrolled. Formalin-fixed and paraffin-embedded specimens of resected PDACs were used to analyze BRCAness by multiplex ligation-dependent probe amplification. We also analyzed BRCAness in pancreatic cancer cell lines and the sensitivity to cisplatin and olaparib using a colony formation assay. RESULTS Of the 92 patients with PDAC, 6 were detected to have BRCAness-positive PDAC (6.5%). No significant differences in overall survival and progression-free survival were observed between the BRCAness-positive and BRCAness-negative groups. One PDAC cell line, KP-2, was positive for BRCAness and was more sensitive to cisplatin and olaparib than the BRCAness-negative cell lines. CONCLUSIONS Our results revealed that a considerable number of PDACs are positive for BRCAness, suggesting that BRCAness status could be a useful biomarker for selecting anticancer treatments for advanced or relapsed PDAC.
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Affiliation(s)
| | | | | | | | | | | | | | - Wasaburo Koizumi
- Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan
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23
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Park JH, Jo JH, Jang SI, Chung MJ, Park JY, Bang S, Park SW, Song SY, Lee HS, Cho JH. BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients. Cancers (Basel) 2022; 14:236. [PMID: 35008403 PMCID: PMC8750183 DOI: 10.3390/cancers14010236] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 02/01/2023] Open
Abstract
We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.
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Affiliation(s)
- Ji Hoon Park
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Jung Hyun Jo
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea;
| | - Moon Jae Chung
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Jeong Youp Park
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Seungmin Bang
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Seung Woo Park
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Si Young Song
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Hee Seung Lee
- Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea; (J.H.P.); (J.H.J.); (M.J.C.); (J.Y.P.); (S.B.); (S.W.P.); (S.Y.S.)
| | - Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea;
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24
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Lai E, Ziranu P, Spanu D, Dubois M, Pretta A, Tolu S, Camera S, Liscia N, Mariani S, Persano M, Migliari M, Donisi C, Demurtas L, Pusceddu V, Puzzoni M, Scartozzi M. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer 2021; 125:1321-1332. [PMID: 34262146 PMCID: PMC8575931 DOI: 10.1038/s41416-021-01469-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 05/28/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
- Department of Medical Oncology, Institut Jules Bordet-Université Libre de Bruxelles (ULB), Brussells, Belgium
| | - Simona Tolu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Silvia Camera
- Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Nicole Liscia
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
- Medical Oncology Unit, Sapienza University of Rome, Rome, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
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25
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Hu HF, Ye Z, Qin Y, Xu XW, Yu XJ, Zhuo QF, Ji SR. Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications. Acta Pharmacol Sin 2021; 42:1725-1741. [PMID: 33574569 PMCID: PMC8563973 DOI: 10.1038/s41401-020-00584-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/16/2020] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-of-function mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.
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Affiliation(s)
- Hai-Feng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xiao-Wu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Qi-Feng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Shun-Rong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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26
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Zimmer K, Kocher F, Puccini A, Seeber A. Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives. Front Oncol 2021; 11:662055. [PMID: 34707985 PMCID: PMC8542868 DOI: 10.3389/fonc.2021.662055] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Mutated germline alleles in the DNA damage repair (DDR) genes “breast cancer gene 1” (BRCA1) and BRCA2 have originally been identified as major susceptibility genes in breast and ovarian cancers. With the establishment and approval of more cost-effective gene sequencing methods, germline and somatic BRCA mutations have been detected in several cancers. Since the approval of poly (ADP)-ribose polymerase inhibitors (PARPi) for BRCA-mutated cancers, BRCA mutations gained rising therapeutic implications. The impact and significance of BRCA mutations have been evaluated extensively in the last decades. Moreover, other genes involved in the DDR pathway, such as ATM, ATR, or CHK1, have emerged as potential new treatment targets, as inhibitors of these proteins are currently under clinical investigation. This review gives a concise overview on the emerging clinical implications of mutations in the DDR genes in gastrointestinal cancers with a focus on BRCA mutations.
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Affiliation(s)
- Kai Zimmer
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Kocher
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Alberto Puccini
- Medical Oncology Unit 1, Ospedale Policlinico San Martino Istituto di ricovero e cura a carattere scientifico (IRCCS), University of Genoa, Genoa, Italy
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
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Xiong A, Ma N, Wei G, Li C, Li K, Wang B. Genomic alterations in tumor tissue and ctDNA from Chinese pancreatic cancer patients. Am J Cancer Res 2021; 11:4551-4567. [PMID: 34659905 PMCID: PMC8493393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 05/21/2021] [Indexed: 06/13/2023] Open
Abstract
Though the genomic feature of pancreatic cancer has been comprehensively studied in western patients, the genetic feature of Chinese patients is poorly clarified. In this study, a total of 225 pancreatic cancer patients were enrolled, mainly pancreatic ductal adenocarcinoma (PDAC, 97.33%). 140 patients (62.22%) provided sufficient tumor tissues for genomic analysis, and the rest (37.78%) were provided serum instead. Utilizing target next-generation sequencing (NGS), we analyzed genomic alterations of 618 selected genes. Corresponding data in the TCGA database were also analyzed here. In total, 26 (11.61%) patients had pathogenic or likely pathogenic germline variants, mainly (84.62%) involved genes in the DNA damage repair (DDR) pathway. The mean and median counts of somatic alterations per sample were 6.28 and 5, respectively. The most frequently mutated genes in our cohort were KRAS, TP53, CDKN2A, SMAD4, FBXW7 and ARID1A, revealing a significantly different prevalence of genes including KRAS, CDKN2A, ARID1A, NOTCH1, ARID1B than the corresponding data in the TCGA database. 39.11% of patients were identified with actionable alteration and the ratio was not significantly different between tissue and serum samples. 22.67% of patients harbored DDR gene alterations, which were associated with a higher tumor mutation burden. We also found that all the DDR alterations were not correlated with the overall survival and immune and stroma score, but the changes in NK cells and follicular T cells were identified in samples with DDR changes according to TCGA database. In summary, we identified a distinct genomic feature of Chinese pancreatic cancer patients by comparing with the data in TCGA database, and suggested the role for genetic testing using tissue or ctDNA samples in decision-making process. DDR alterations were associated with a higher tumor mutation burden and the significantly higher counts of NK cells in DDR altered samples may raise the attention in future related drugs development.
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Affiliation(s)
- Anwen Xiong
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai 200438, P. R. China
| | - Ning Ma
- Department of Clinical Laboratory, 905th Hospital of PLA1328 Huashan Road, Shanghai 200050, P. R. China
| | - Guo Wei
- Department of General Surgical, Changhai Hospital, Second Military Medical University168 Changhai Road, Shanghai 200433, P. R. China
| | - Chunhua Li
- Department of Oncology, The Second Affiliated Hospital of Shandong University of Traditional Chinese MedicineJingba Road #1, Jinan 250001, Shandong, P. R. China
| | - Kainan Li
- Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University11 Wuyingshan Middle Road, Jinan 250031, Shandong, P. R. China
| | - Bin Wang
- Department of Oncology, Changhai Hospital, Second Military Medical University168 Changhai Road, Shanghai 200433, P. R. China
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28
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Perkhofer L, Golan T, Cuyle PJ, Matysiak-Budnik T, Van Laethem JL, Macarulla T, Cauchin E, Kleger A, Beutel AK, Gout J, Stenzinger A, Van Cutsem E, Bellmunt J, Hammel P, O’Reilly EM, Seufferlein T. Targeting DNA Damage Repair Mechanisms in Pancreas Cancer. Cancers (Basel) 2021; 13:4259. [PMID: 34503069 PMCID: PMC8428219 DOI: 10.3390/cancers13174259] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.
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Affiliation(s)
- Lukas Perkhofer
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Talia Golan
- Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv 52621, Israel;
| | - Pieter-Jan Cuyle
- Digestive Oncology Department, Imelda General Hospital, 2820 Bonheiden, Belgium;
- University Hospitals Gasthuisberg Leuven and KU Leuven, 3000 Leuven, Belgium;
| | - Tamara Matysiak-Budnik
- IMAD, Department of Gastroenterology and Digestive Oncology, Hôtel Dieu, CHU de Nantes, 44000 Nantes, France; (T.M.-B.); (E.C.)
| | - Jean-Luc Van Laethem
- GI Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Teresa Macarulla
- Vall d’Hebrón University Hospital and Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain;
| | - Estelle Cauchin
- IMAD, Department of Gastroenterology and Digestive Oncology, Hôtel Dieu, CHU de Nantes, 44000 Nantes, France; (T.M.-B.); (E.C.)
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Alica K. Beutel
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Johann Gout
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg Leuven and KU Leuven, 3000 Leuven, Belgium;
| | - Joaquim Bellmunt
- Medical Oncology, University Hospital del Mar, 08003 Barcelona, Spain;
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | | | - Eileen M. O’Reilly
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Medicine, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas Seufferlein
- Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany; (L.P.); (A.K.); (A.K.B.); (J.G.)
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Macchini M, Centonze F, Peretti U, Orsi G, Militello AM, Valente MM, Cascinu S, Reni M. Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants. Cancer Treat Rev 2021; 100:102262. [PMID: 34418781 DOI: 10.1016/j.ctrv.2021.102262] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 01/07/2023]
Abstract
Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking. Recently germline mutations in BRCA 1 and 2 genes, leading to homologous repair deficiency, have emerged as new targets for more specific and effective therapies, exploiting the increased susceptibility to platinum salts and PARP inhibitors. In addition to BRCA, pathogenic variants in PALB2 and in other genes involved in the DNA damage response pathway (DDR) represent potential targets, as well as their respective somatic alterations. This enlarged molecularly-selected population sharing the BRCAness phenotype, is expected to show a higher sensibility to a number of DNA damaging agents and DDR inhibitors. However, the possibility of new therapeutic opportunities for DDR defective PDAC patients has to face the lack of solid evidence about the proper type and timing of targeted-treatments, the potential combination strategies and most importantly, the lack of informations on the functional impact of each specific pathogenic variant on the DDR pathway. This review summarizes the current and near-future options for the clinical management of PDAC patients harboring a DDR deficiency, analyzing the state of the art of the indications of platinum salts and other cytotoxic agents in the advanced and early stage PDAC, the development of PARP inhibitors and the rational for new combinations with immunotherapy and cycle checkpoint inhibitors, as well as the strategy to overcome the development of resistance over treatments.
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Affiliation(s)
- Marina Macchini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Federico Centonze
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Umberto Peretti
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Orsi
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Maria Militello
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Maria Maddalena Valente
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy.
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Li MR, Liu MZ, Ge YQ, Zhou Y, Wei W. Assistance by Routine CT Features Combined With 3D Texture Analysis in the Diagnosis of BRCA Gene Mutation Status in Advanced Epithelial Ovarian Cancer. Front Oncol 2021; 11:696780. [PMID: 34381719 PMCID: PMC8350445 DOI: 10.3389/fonc.2021.696780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/08/2021] [Indexed: 12/02/2022] Open
Abstract
Purpose To evaluate the predictive value of routine CT features combined with 3D texture analysis for prediction of BRCA gene mutation status in advanced epithelial ovarian cancer. Method Retrospective analysis was performed on patients with masses occupying the pelvic space confirmed by pathology and complete preoperative images in our hospital, including 37 and 58 cases with mutant type and wild type BRCA, respectively (total: 95 cases). The enrolled patients’ routine CT features were analyzed by two radiologists. Then, ROIs were jointly determined through negotiation, and the ITK-SNAP software package was used for 3D outlining of the third-stage images of the primary tumor lesions and obtaining texture features. For routine CT features and texture features, Mann-Whitney U tests, single-factor logistic regression analysis, minimum redundancy, and maximum correlation were used for feature screening, and the performance of individual features was evaluated by ROC curves. Multivariate logistic regression analysis was used to further screen features, find independent predictors, and establish the prediction model. The established model’s diagnostic efficiency was evaluated by ROC curve analysis, and the histogram was obtained to conduct visual analysis of the prediction model. Results Among the routine CT features, the type of peritoneal metastasis, mesenteric involvement, and supradiaphragmatic lymph node enlargement were correlated with BRCA gene mutation (P < 0.05), whereas the location of the peritoneal metastasis (in the gastrohepatic ligament) was not significantly correlated with BRCA gene mutation (P > 0.05). Multivariate logistic regression analysis retained six features, including one routine CT feature and five texture features. Among them, the type of peritoneal metastasis was used as an independent predictor (P < 0.05), which had the highest diagnostic efficiency. Its AUC, accuracy, specificity, and sensitivity were 0.74, 0.79, 0.90, and 0.62, respectively. The prediction model based on the combination of routine CT features and texture features had an AUC of 0.86 (95% CI: 0.79–0.94) and accuracy, specificity, and sensitivity of 0.80, 0.76, and 0.81, respectively, indicating a better performance than that of any single feature. Conclusions Both routine CT features and texture features had value for predicting the mutation state of the BRCA gene, but their predictive efficiency was low. When the two types of features were combined to establish a predictive model, the model’s predictive efficiency was significantly higher than that of independent features.
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Affiliation(s)
- Meng-Ru Li
- Department of Radiology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Ming-Zhu Liu
- Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ya-Qiong Ge
- General Electric (GE) Healthcare China, Shanghai, China
| | - Ying Zhou
- Department of Gynecological Oncology, The First Affiliated Hospital of USTC, Hefei, China
| | - Wei Wei
- Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Hayashi H, Higashi T, Miyata T, Yamashita Y, Baba H. Recent advances in precision medicine for pancreatic ductal adenocarcinoma. Ann Gastroenterol Surg 2021; 5:457-466. [PMID: 34337294 PMCID: PMC8316748 DOI: 10.1002/ags3.12436] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum-based anti-cancer agents and poly-ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Takaaki Higashi
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Tatsunori Miyata
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Yo‐ichi Yamashita
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Life SciencesKumamoto UniversityKumamotoJapan
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Rosen MN, Goodwin RA, Vickers MM. BRCA mutated pancreatic cancer: A change is coming. World J Gastroenterol 2021; 27:1943-1958. [PMID: 34007132 PMCID: PMC8108028 DOI: 10.3748/wjg.v27.i17.1943] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/04/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.
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Affiliation(s)
- Michael N Rosen
- Faculty of Medicine, The University of Ottawa, Ottawa K1H 8L6, Ontario, Canada
| | - Rachel A Goodwin
- Faculty of Medicine, The University of Ottawa, Ottawa K1H 8L6, Ontario, Canada
| | - Michael M Vickers
- The Ottawa Hospital Cancer Center, The University of Ottawa, Ottawa K1H 8L6, Ontario, Canada
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Chang AE, Radke MR, Zhen DB, Baker KK, Coveler AL, Wong KM, Pillarisetty VG, Reddi D, Redman MW, Swisher E, Chiorean EG. DNA Damage Repair Defects and Survival Outcomes for Patients With Resected Pancreatic Ductal Adenocarcinoma. Pancreas 2021; 50:e50-e52. [PMID: 34106577 PMCID: PMC8585585 DOI: 10.1097/mpa.0000000000001819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Kim SH, Hwang HK, Lee WJ, Kang CM. Biologic behavior of resected BRCA-mutated pancreatic cancer: Comparison with sporadic pancreatic cancer and other BRCA-related cancers. Pancreatology 2021; 21:544-549. [PMID: 33612442 DOI: 10.1016/j.pan.2021.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/23/2021] [Accepted: 02/09/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Since margin-negative resection is essential for the cure of pancreatic cancer (PC), early detection of PC is important. Although PC is the third most common cancer associated with BRCA1/2 mutations, clinical research regarding BRCA mutations in resected PC are rare. In this study, we investigated the oncologic characteristics of resected PC with BRCA mutation to suggest management strategies. METHODS We retrospectively reviewed data from 493 patients who were confirmed to be pathogenic BRCA1/2 mutation carriers between January 2007 and December 2019. We investigated the oncologic characteristics of PC patients by comparing them with resected sporadic PC and other BRCA-related cancer groups (breast cancer, ovarian cancer, and others). RESULTS Ten BRCA mutation carriers (2.0%) experienced PC, and PC onset was significantly later than that of BRCA-related breast cancer (age: breast vs. pancreas, 45.0 vs. 53.5 years, p = 0.050). Six patients underwent pancreatectomy and their long-term survival outcomes did not differ from those of sporadic PC patients (disease free survival: BRCA1/2 vs. sporadic, 10.0 months vs. 9.0 months, p = 0.504; overall survival: BRCA1/2 vs. sporadic, 29.0 months vs. 35.0 months, p = 0.520). CONCLUSION BRCA-mutated PC occurs later than BRCA-mutated breast cancer. Active genetic testing to identify BRCA1/2 mutation carriers at the onset of breast cancer and continuous long-term surveillance of these patients can provide opportunities to detect BRCA-mutated PC at a resectable stage.
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Affiliation(s)
- Sung Hyun Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea.
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Rainone M, Singh I, Salo-Mullen EE, Stadler ZK, O'Reilly EM. An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice: A Review. JAMA Oncol 2021; 6:764-771. [PMID: 32053139 DOI: 10.1001/jamaoncol.2019.5963] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Importance Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm with a rising incidence and is a leading public health challenge. Pancreatic ductal adenocarcinoma has been well characterized genomically, with findings of therapeutic actionability that have substantive implications for clinical practice based on recent high-level evidence. Observations Pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, as evidenced in multiple recent data sets, with a frequency of approximately 10%. The most common PGAs are in BRCA1, BRCA2, and ATM and more rarely in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, with an aggregate frequency of 3.8% to 9.7%. These PGAs are of key interest owing to therapeutic actionability and the downstream identification of at-risk family members and possible hereditary cancer syndromes. Approximately 3% to 7% of individuals with PDAC harbor a BRCA1 or BRCA2 mutation, which are among the most frequently mutated genes in PDAC. Recent updates to the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend risk assessment for all individuals with PDAC irrespective of personal or family history or ethnicity. Treatment implications include the use of checkpoint inhibitor therapy for mismatch repair-deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC. Conclusions and Relevance With increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine. Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.
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Affiliation(s)
- Michael Rainone
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Mount Sinai St Luke's and Mount Sinai West Hospitals, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Isha Singh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Mount Sinai St Luke's and Mount Sinai West Hospitals, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Erin E Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Weill Cornell Medicine, New York, New York
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Yadav S, Kasi PM, Bamlet WR, Ho TP, Polley EC, Hu C, Hart SN, Rabe KG, Boddicker NJ, Gnanaolivu RD, Lee KY, Lindstrom TH, Petersen GM, Couch FJ, McWilliams RR. Effect of Germline Mutations in Homologous Recombination Repair Genes on Overall Survival of Patients with Pancreatic Adenocarcinoma. Clin Cancer Res 2020; 26:6505-6512. [PMID: 33028596 PMCID: PMC9063708 DOI: 10.1158/1078-0432.ccr-20-1788] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/20/2020] [Accepted: 09/28/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes. RESULTS The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70-0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55-0.94; P = 0.01). CONCLUSIONS This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.
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Affiliation(s)
| | - Pashtoon M Kasi
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa
| | - William R Bamlet
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Thanh P Ho
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Eric C Polley
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Chunling Hu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Steven N Hart
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Kari G Rabe
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | | | - Rohan D Gnanaolivu
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Kun Y Lee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Tricia H Lindstrom
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Molinaro E, Andrikou K, Casadei-Gardini A, Rovesti G. BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives. Cancers (Basel) 2020; 12:E3346. [PMID: 33198203 PMCID: PMC7697442 DOI: 10.3390/cancers12113346] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 10/26/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
A strong association between pancreatic cancer and BRCA1 and BRCA2 mutations is documented. Based on promising results of breast and ovarian cancers, several clinical trials with poly (ADP-ribose) polymerase inhibitors (PARPi) are ongoing for gastrointestinal (GI) malignancies, especially for pancreatic cancer. Indeed, the POLO trial results provide promising and awaited changes for the pancreatic cancer therapeutic landscape. Contrariwise, for other gastrointestinal tumors, the rationale is currently only alleged. The role of BRCA mutation in gastrointestinal cancers is the subject of this review. In particular, we aim to provide the latest updates about novel therapeutic strategies that, exploiting DNA repair defects, promise to shape the future therapeutic scenario of GI cancers.
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Affiliation(s)
| | | | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy; (E.M.); (K.A.); (G.R.)
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Pishvaian MJ, Wang H, He AR, Hwang JJ, Smaglo BG, Kim SS, Weinberg BA, Weiner LM, Marshall JL, Brody JR. A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer. Clin Cancer Res 2020; 26:5092-5101. [PMID: 32669374 PMCID: PMC10184025 DOI: 10.1158/1078-0432.ccr-20-1301] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/08/2020] [Accepted: 07/13/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined. PATIENTS AND METHODS We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1-7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations. RESULTS The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%. CONCLUSIONS The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.
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Affiliation(s)
- Michael J Pishvaian
- Department of Oncology, Johns Hopkins University School of Medicine, SKCC, Washington, DC.
| | - Hongkun Wang
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Jimmy J Hwang
- Levine Cancer Center, Carolinas Medical Center, Charlotte, North Carolina
| | - Brandon G Smaglo
- Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Sunnie S Kim
- The University of Colorado Cancer Center, Aurora, Colorado
| | | | - Louis M Weiner
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Jonathan R Brody
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, and the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
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Pokataev I, Fedyanin M, Polyanskaya E, Popova A, Agafonova J, Menshikova S, Tryakin A, Rumyantsev A, Tjulandin S. Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies. ESMO Open 2020; 5:e000578. [PMID: 33551067 PMCID: PMC7003386 DOI: 10.1136/esmoopen-2019-000578] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/10/2019] [Accepted: 01/29/2020] [Indexed: 12/18/2022] Open
Abstract
The aim of our study was to determine the effect of homologous recombination deficiency (HRD) on prognosis and efficacy of platinum-based chemotherapy in patients with pancreatic cancer (PC). We performed PubMed and Embase database queries. We included 4 studies into the meta-analysis and 16 studies in the systematic review. Our systematic analysis showed that the average weighted median overall survival (OS) in patients with HRD with advanced PC was 19.8 and 15.6 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 23.8 and 17.1 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 8.3 and 12.0 months in patients without HRD. For resected PC, our meta-analysis demonstrated that HRD status did not affect the prognosis (HR 1.03, 95% CI 0.46 to 2.33), but results were rather heterogeneous (I2=83%, p=0.003). Our systematic analysis showed that the average weighted median OS in patients with HRD was 34.6 and 27.0 months in patients without HRD. With platinum-based chemotherapy, the average weighted median OS in patients with HRD was 46.1 and 36.3 months in patients without HRD. Without platinum-based chemotherapy, the average weighted median OS in patients with HRD was 24.2 and 42.9 months in patients without HRD. Results of our meta-analysis and systematic review support the idea of platinum use in patients with HRD both in resected and metastatic PCs, although a randomised trial is warranted to make a more reliable conclusion. PROSPERO REGISTRATION NUMBER: CRD42019121914.
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Affiliation(s)
- Ilya Pokataev
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Mikhail Fedyanin
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation.
| | - Elizaveta Polyanskaya
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Anna Popova
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Julia Agafonova
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Sophia Menshikova
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Alexey Tryakin
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Alexey Rumyantsev
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
| | - Sergei Tjulandin
- Department of Clinical Pharmacology and Chemotherapy, FBGU National Medical Research Center of Oncology named after N N Blokhin, Moskva, Russian Federation
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Marin JJG, Prete MG, Lamarca A, Tavolari S, Landa-Magdalena A, Brandi G, Segatto O, Vogel A, Macias RIR, Rodrigues PM, Casta AL, Mertens J, Rodrigues CMP, Fernandez-Barrena MG, Da Silva Ruivo A, Marzioni M, Mentrasti G, Acedo P, Munoz-Garrido P, Cardinale V, Banales JM, Valle JW, Bridgewater J, Braconi C. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer 2020; 123:1047-1059. [PMID: 32694694 PMCID: PMC7525457 DOI: 10.1038/s41416-020-0987-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/22/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.
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Affiliation(s)
- José J G Marin
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Maria Giuseppina Prete
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS -, Rozzano (MI), Italy
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Simona Tavolari
- Medical Oncology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Ana Landa-Magdalena
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Oreste Segatto
- Unit of Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rocío I R Macias
- IBSAL, University of Salamanca, Salamanca, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cecilia M P Rodrigues
- Research Insitute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | | | - Marco Marzioni
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Giulia Mentrasti
- Università Politecnica delle Marche/Ospedali Riuniti di Ancona, Ancona, Italy
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Patricia Munoz-Garrido
- Biotech Research & Innovation Centre (BRIC), University of Copenhaghen, Copenhagen, Denmark
| | | | - Jesus M Banales
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Health Institute, Madrid, ES, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | | | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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Macklin-Mantia SK, Hines SL, Kasi PM. Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer. Hered Cancer Clin Pract 2020; 18:17. [PMID: 32793315 PMCID: PMC7419180 DOI: 10.1186/s13053-020-00148-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/24/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. METHODS Pancreas cancer patients with a germline pathogenic variant in BRCA1/2 or other DDR gene were identified retrospectively through review of medical records (medical genetics/oncology) and genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. RESULTS A total of 11 patients with pancreas cancer were identified to carry a pathogenic DDR-variant: BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Four out of 11 patients were still alive at time of data review. Survival in the 7 patients who had died was 13.7, 140.0, 20.5, 22.3, 23.5, 25.8, and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. CONCLUSIONS Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.
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Affiliation(s)
| | - Stephanie L. Hines
- Department of Diagnostic and Consultative Medicine, Mayo Clinic, Jacksonville, FL 32224 USA
| | - Pashtoon M. Kasi
- Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242 USA
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Hu H, Zhu Y, Pu N, Burkhart RA, Burns W, Laheru D, Zheng L, He J, Goggins MG, Yu J. Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma. J Am Coll Surg 2020; 231:527-535.e14. [PMID: 32659497 DOI: 10.1016/j.jamcollsurg.2020.06.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/28/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC). Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC. STUDY DESIGN We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS), and overall survival (OS). RESULTS Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs 11.9 months, p = 0.012) and OS (median, 29.7 months vs 20.2 months, p = 0.034), as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs wild-type patients DFS (median 36.3 months vs 13.1 months, p = 0.006) and OS (median 43.7 months vs 24.3 months, p = 0.045), VUS variant carriers vs wild-type patients DFS (16.5 months vs 13.1 months, p = 0.007). CONCLUSIONS Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Haijie Hu
- Department of Biliary Surgery, West China Hospital of Sichuan University, Sichuan, China; Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD
| | - Yayun Zhu
- Department of Surgery, Baltimore, MD; Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ning Pu
- Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD
| | - Richard A Burkhart
- Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - William Burns
- Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Daniel Laheru
- Department Pathology, Baltimore, MD; Department Oncology, Baltimore, MD; Department Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Lei Zheng
- Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD
| | - Jin He
- Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Michael G Goggins
- Department Pathology, Baltimore, MD; Department Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD
| | - Jun Yu
- Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.
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Alteration of Transforming Growth Factor β Signaling Pathway Predicts Worse Prognosis in Pancreatic Ductal Adenocarcinoma. Pancreas 2020; 49:534-542. [PMID: 32282767 DOI: 10.1097/mpa.0000000000001522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Transforming growth factor β (TGF-β) signaling pathway is one of the core pathways in pancreatic ductal adenocarcinoma (PDAC). Prognostic value of TGF-β pathway genes as a functionally related group in PDAC is rarely studied. METHODS Seventy-two PDAC patients who underwent surgery between November 30, 2015, and September 13, 2017, in West China Hospital, Sichuan University, were identified and included in this study. Whole-exome sequencing or targeted next-generation sequencing was performed with tumor tissue. Clinicopathologic characteristics and survival data were retrospectively collected and analyzed. RESULTS Genetic alterations were detected in 71 patients (98.6%). Although 1 patient (1.4%) had one genetic alteration, 33 patients (45.8%) had 2 to 4 alterations and 37 patients (51.4%) had 5 or more alterations. Twenty-five patients with TGF-β pathway alteration were identified as TGF-βm+ group. Other 47 patients were TGF-βm- group. Mutation of TGF-β pathway was independently associated with inferior survival (hazard ratio, 2.22, 95% confidence interval, 1.05-4.70, P = 0.04), especially in patients accepting radical surgery (hazard ratio, 3.25, 95% confidence interval, 1.01-10.49, P = 0.04). CONCLUSIONS Inferior prognosis was observed in PDACs with mutations of TGF-β pathway. Genomic information could help screen out patients at risk after surgery, and adjuvant therapy might benefit this subgroup of PDACs.
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Llach J, Carballal S, Moreira L. Familial Pancreatic Cancer: Current Perspectives. Cancer Manag Res 2020; 12:743-758. [PMID: 32099470 PMCID: PMC6999545 DOI: 10.2147/cmar.s172421] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 01/15/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer (PC) is a highly lethal disease, mostly incurable when detected. Thus, despite advances in PC treatments, only around 7% of patients survive 5-years after diagnosis. This morbid outcome is secondary to multifactorial reasons, such as late-stage diagnosis, rapid progression and minimal response to chemotherapy. Based on these factors, it is of special relevance to identify PC high-risk individuals in order to establish preventive and early detection measures. Although most PC are sporadic, approximately 10% cases have a familial basis. No main causative gene of PC has been identified but several known germline pathogenic mutations are related with an increased risk of this tumor. These inherited cancer syndromes represent 3% of all PC. On the other hand, in 7% of cases of PC, there is a strong family history without a causative germline mutation, a situation known as familial pancreatic cancer (FPC). In recent years, there is increasing evidence supporting the benefit of genetic germline analysis in PC patients, and periodic pancreatic screening in PC high-risk patients (mainly those with a lifetime risk greater than 5%), although there is no general agreement in the group of patients and individuals to study and screen. In the present review, we expose an update in the field of hereditary and FPC, with the aim of describing the current strategies and implications in genetic counseling, surveillance and therapeutic interventions.
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Affiliation(s)
- Joan Llach
- Departmento de Gastroenterología, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - Sabela Carballal
- Departmento de Gastroenterología, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - Leticia Moreira
- Departmento de Gastroenterología, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d' Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
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Razi E, Radak M, Mahjoubin-Tehran M, Talebi S, Shafiee A, Hajighadimi S, Moradizarmehri S, Sharifi H, Mousavi N, Sarvizadeh M, Nejati M, Taghizadeh M, Ghasemi F. Cancer stem cells as therapeutic targets of pancreatic cancer. Fundam Clin Pharmacol 2019; 34:202-212. [PMID: 31709581 DOI: 10.1111/fcp.12521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 11/02/2019] [Accepted: 11/06/2019] [Indexed: 12/11/2022]
Abstract
The discovery of stem cells and their potential abilities in self-renewal and differentiation has opened a new horizon in medicine. Scientists have found a small population of stem cells in some types of cancers with the same functions as normal stem cells. There are two models for tumor progression: clonal (stochastic) and cancer stem cell (CSCs) models. According to the first model, all transformed cells in the tumor have carcinogenic potential and are able to proliferate and produce the same cells. The latter model, which has received more attention recently, considers the role of CSCs in drug resistance and tumor metastasis. Following the model, researchers have found that targeting CSCs may be a promising way in cancer therapy. This review describes CSC characteristics in general, while also focusing on CSC properties in the context of pancreatic cancer.
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Affiliation(s)
- Ebrahim Razi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Mehran Radak
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | - Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Talebi
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Sarah Hajighadimi
- Division of General Internal Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Sanaz Moradizarmehri
- Division of General Internal Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Hossein Sharifi
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Nousin Mousavi
- Department of Surgery, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mostafa Sarvizadeh
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Faezeh Ghasemi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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Yu S, Agarwal P, Mamtani R, Symecko H, Spielman K, O’Hara M, O’Dwyer PJ, Schneider C, Teitelbaum U, Nathanson KL, Domchek SM, Reiss KA. Retrospective Survival Analysis of Patients With Resected Pancreatic Ductal Adenocarcinoma and a Germline BRCA or PALB2 Mutation. JCO Precis Oncol 2019; 3:1-11. [PMID: 35100679 DOI: 10.1200/po.18.00271] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Germline mutations in the homologous recombination genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in homologous recombination genes are sensitive to DNA-damaging agents. We retrospectively studied patients with resected PDAC and a pathogenic germline mutation in one of these three genes. The planned analyses included overall survival (OS) and changes therein when platinum chemotherapy was used in the perioperative setting. MATERIALS AND METHODS Thirty-two individuals with pathogenic germline mutations in BRCA1, BRCA2, or PALB2 and resected PDAC (mutation positive) were matched in a 1:2 fashion to patients who were noncarriers or untested (mutation negative) by age, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at University of Pennsylvania: the Basser Center for BRCA Registry or the electronic medical record. The primary outcome was OS. RESULTS Patients in the mutation-positive group had a median OS (mOS) of 46.6 months; those in the mutation-negative group had an mOS of 23.2 months (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.88). With platinum exposure in the perioperative setting, mOS in the mutation-positive group had not yet been met versus a mOS of 23.1 months in the mutation-negative group (HR, 0.12; 95% CI, 0.01 to 1.00). When neither group was treated with platinum, there was no significant OS difference between groups (HR, 0.52; 95% CI 0.12 to 2.24). Patients in the mutation-positive group who received perioperative treatment with platinum had a trend toward improved mOS compared with those who did not (HR, 0.15; 95% CI, 0.02 to 1.23; P = .07). CONCLUSION Platinum-based chemotherapy may confer a survival benefit in patients with resected PDAC and a pathogenic germline BRCA1, BRCA2, or PALB2 mutation. Knowledge of a germline mutation may be important to determine best choice of perioperative chemotherapy.
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Affiliation(s)
- Shun Yu
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | | | - Ronac Mamtani
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Heather Symecko
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Kelsey Spielman
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Mark O’Hara
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Peter J. O’Dwyer
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Charles Schneider
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Ursina Teitelbaum
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Katherine L. Nathanson
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Susan M. Domchek
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
| | - Kim A. Reiss
- University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, West Chester, PA
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Palacio S, McMurry HS, Ali R, Donenberg T, Silva-Smith R, Wideroff G, Sussman DA, Rocha Lima CMS, Hosein PJ. DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer. J Gastrointest Oncol 2019; 10:1133-1139. [PMID: 31949930 DOI: 10.21037/jgo.2019.09.12] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.
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Affiliation(s)
- Sofia Palacio
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Hannah S McMurry
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Robert Ali
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Talia Donenberg
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Rachel Silva-Smith
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Gina Wideroff
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Daniel A Sussman
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | | | - Peter J Hosein
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
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Pishvaian MJ, Blais EM, Brody JR, Rahib L, Lyons E, De Arbeloa P, Hendifar A, Mikhail S, Chung V, Sohal DP, Leslie S, Mason K, Tibbets L, Madhavan S, Matrisian LM, Petricoin E. Outcomes in Patients With Pancreatic Adenocarcinoma With Genetic Mutations in DNA Damage Response Pathways: Results From the Know Your Tumor Program. JCO Precis Oncol 2019; 3:1-10. [DOI: 10.1200/po.19.00115] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Up to 25% of pancreatic adenocarcinomas (PDACs) harbor mutations in the homologous recombination DNA damage response (HR-DDR) pathway. Although known to affect responsiveness to DNA-damaging chemotherapy, the prognostic relevance of these mutations is unclear and outcomes in patients with PDAC who harbor HR-DDR mutations beyond BRCA1/2 remain unexplored. METHODS We evaluated 820 patients with PDAC enrolled in the Know Your Tumor program for whom we had collected comprehensive genomic testing results and longitudinal clinical outcomes. Patients were categorized as having resected versus advanced disease, and as having received platinum-based therapy versus being platinum naïve. Tumor genomic profiles were categorized as HR-DDR mutated (HR-DDRmut) or proficient (pHR-DDR) on the basis of the presence of pathogenic mutations of somatic or germline origin in BRCA1/2 or PALB2 (group 1); ATM/ATR/ATRX (group 2); or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (group 3). Overall survival was measured from the date of diagnosis until death. RESULTS Median overall survival (mOS) was similar in all resected patients irrespective of exposure to platinum-based therapy, whereas for platinum-treated patients with advanced disease, mOS was significantly longer for HR-DDRmut versus pHR-DDR (2.37 years v 1.45 years, respectively). Of importance, no difference was identified in platinum-naïve patients. mOS in patients with mutations in all three HR-DDRmut groups was greater than that for pHR-DDR patients, but this difference was lost in platinum-naïve patients. CONCLUSION Patients with advanced HR-DDRmut have improved mOS when treated with platinum-based therapy compared with pHR-DDR patients. In platinum-naïve patients, there is no mOS difference, which suggests that HR-DDR status has no pure prognostic value. These findings support the need to test all patients with advanced PDAC to ensure that HR-DDRmut patients receive the benefit of treatment with platinum-based therapy.
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Affiliation(s)
| | | | | | - Lola Rahib
- The Pancreatic Cancer Action Network, Manhattan Beach, CA
| | - Emily Lyons
- The Pancreatic Cancer Action Network, Manhattan Beach, CA
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Rebelatto TF, Falavigna M, Pozzari M, Spada F, Cella CA, Laffi A, Pellicori S, Fazio N. Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis. Cancer Treat Rev 2019; 80:101895. [PMID: 31542591 DOI: 10.1016/j.ctrv.2019.101895] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.
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Affiliation(s)
- Taiane F Rebelatto
- Department of Medical Oncology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Maicon Falavigna
- National Institute for Heath Technology Assessment, Postgraduate Program in Epidemiology, Porto Alegre, Brazil
| | - Marta Pozzari
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Chiara A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Stefania Pellicori
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
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Navarro EB, López EV, Quijano Y, Caruso R, Ferri V, Durand H, Cabrera IF, Reques ED, Ielpo B, Glagolieva AY, Plaza C. Impact of BRCA1/2 gene mutations on survival of patients with pancreatic cancer: A case-series analysis. Ann Hepatobiliary Pancreat Surg 2019; 23:200-205. [PMID: 31225426 PMCID: PMC6558134 DOI: 10.14701/ahbps.2019.23.2.200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 12/19/2022] Open
Abstract
BRCA gene mutations are found in up to 10% of pancreatic adenocarcinoma cases. We present a description of 4 cases along with a review of the current literature regarding pathogenesis, target treatment, response and survival rates in these types of malignancies. We describe four cases of pancreatic adenocarcinoma, in three of which the BRCA2 mutation was identified, in one - BRCA1 gene alteration. Two patients underwent surgery following the neoadjuvant treatment with Folfirinox and radiotherapy; in the first case, a distal pancreatectomy with splenectomy was performed and in the second one - the Whipple's procedure. In both cases, a complete pathological response was reported. Other 2 patients were treated with Folfirinox after BRCA mutation identification and acceptable life expectancy was obtained. The association of pathologic complete response (PCR) with lower rates of local recurrence and better survival in patients with various types of adenocarcinomas is well known. Identification of such patients carrying BRCA mutations could provide an application of better personalized treatment. In some patients with pancreatic cancer, especially when there is clinical or demographic reason to suspect a genetic predisposition, a confirmation of the presence of BRCA mutations could provide an opportunity to use target treatment with beneficial outcomes regarding survival.
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Affiliation(s)
- Ernesto Barzola Navarro
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Emilio Vicente López
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Yolanda Quijano
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Riccardo Caruso
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Valentina Ferri
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Hipolito Durand
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Isabel Fabra Cabrera
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Eduardo Diaz Reques
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Benedetto Ielpo
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | | | - Carlos Plaza
- Department of Pathology, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
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