A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study.
<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful b...
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Public Library of Science (PLoS)
2020-12-01
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| Series: | PLoS Medicine |
| Online Access: | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003489&type=printable |
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| author | Silvana Debernardi Harrison O'Brien Asma S Algahmdi Nuria Malats Grant D Stewart Marija Plješa-Ercegovac Eithne Costello William Greenhalf Amina Saad Rhiannon Roberts Alexander Ney Stephen P Pereira Hemant M Kocher Stephen Duffy Oleg Blyuss Tatjana Crnogorac-Jurcevic |
| author_facet | Silvana Debernardi Harrison O'Brien Asma S Algahmdi Nuria Malats Grant D Stewart Marija Plješa-Ercegovac Eithne Costello William Greenhalf Amina Saad Rhiannon Roberts Alexander Ney Stephen P Pereira Hemant M Kocher Stephen Duffy Oleg Blyuss Tatjana Crnogorac-Jurcevic |
| author_sort | Silvana Debernardi |
| collection | DOAJ |
| description | <h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers.<h4>Methods and findings</h4>Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy.<h4>Conclusions</h4>We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc. |
| format | Article |
| id | doaj-art-758ce4bbd92c47ee997f083080f5b0de |
| institution | Kabale University |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2020-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj-art-758ce4bbd92c47ee997f083080f5b0de2025-08-20T03:46:15ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762020-12-011712e100348910.1371/journal.pmed.1003489A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study.Silvana DebernardiHarrison O'BrienAsma S AlgahmdiNuria MalatsGrant D StewartMarija Plješa-ErcegovacEithne CostelloWilliam GreenhalfAmina SaadRhiannon RobertsAlexander NeyStephen P PereiraHemant M KocherStephen DuffyOleg BlyussTatjana Crnogorac-Jurcevic<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers.<h4>Methods and findings</h4>Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy.<h4>Conclusions</h4>We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003489&type=printable |
| spellingShingle | Silvana Debernardi Harrison O'Brien Asma S Algahmdi Nuria Malats Grant D Stewart Marija Plješa-Ercegovac Eithne Costello William Greenhalf Amina Saad Rhiannon Roberts Alexander Ney Stephen P Pereira Hemant M Kocher Stephen Duffy Oleg Blyuss Tatjana Crnogorac-Jurcevic A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. PLoS Medicine |
| title | A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. |
| title_full | A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. |
| title_fullStr | A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. |
| title_full_unstemmed | A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. |
| title_short | A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. |
| title_sort | combination of urinary biomarker panel and pancrisk score for earlier detection of pancreatic cancer a case control study |
| url | https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1003489&type=printable |
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