Implementation of a Video-based Remote Germline Testing for Individuals With Pancreatic Ductal Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Kasliwal S
PROVIDER: S-EPMC9245458 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGermline genetic testing is universally recommended for patients with pancreatic cancer, but testing remains infrequent. In May 2018, we implemented a systematic patient intake workflow featuring an in-clinic genetic testing station (GTS) at the University of California San Francisco (UCSF) to expedite genetic counseling and facilitate sample collection. We sought to determine the impact of this innovation on rates of genetic counseling and testing.MethodsMedical records, patient intake records, and genetic test reports were retrospectively reviewed for new patients with pancreatic cancer eligible for germline testing at UCSF from May 2018 to May 2019. Primary outcomes included the rate of offered genetic counseling and confirmed germline testing. Data were compared for periods before and after GTS implementation. Associations between demographic characteristics and testing rates were assessed.ResultsGenetic counseling/testing was offered to 209 (94%) of 223 eligible patients, and 158 (71%) completed testing (135 at UCSF, 23 elsewhere). Compared with a traditional referral-based genetic counseling model, confirmed testing increased from 19% to 71%, patient attrition between referral and genetics appointment decreased from 36% to 3%, and rate of pathogenic variant detection increased from 20% to 33%. Patients who were younger, identified as non-Hispanic White, and spoke English as a primary language were more likely to complete testing.ConclusionsImplementation of a systematic patient intake workflow and in-clinic GTS resulted in the highest reported real-world rate of germline testing for patients with pancreatic cancer. Health care disparities were identified and will guide future innovation. This report provides a model for other centers to create a similar testing infrastructure.Implications for practiceThis study demonstrates that a systematic patient intake workflow and associated in-clinic genetic testing station improve delivery of genetic counseling and completion of germline testing for patients with pancreatic cancer. This study achieved, to the authors' knowledge, the highest real-world rate of confirmed genetic testing in this patient population. This article describes this innovation in detail to guide replication at other medical centers and facilitate guideline-concordant care for patients with pancreatic cancer. This infrastructure can also be applied to other cancers for which germline testing is recommended.
| S-EPMC8571767 | biostudies-literature
Project description:BACKGROUND:The outcomes of sporadic pancreatic ductal adenocarcinoma (PDAC) patients with germline mutations of BRCA1/BRCA2 remains unclear. The prognostic significance of BRCA1/BRCA2 mutations on survival is not well established. STUDY DESIGN:We performed targeted next-generation sequencing (NGS) to identify BRCA1/BRCA2 germline mutations in resected sporadic PDAC cases from 2000 to 2015. Germline BRCA mutation carriers were matched by age and tumor location to those with BRCA1/BRCA2 wild-type genes from our institutional database. Demographics, clinicopathologic features, overall survival (OS), and disease-free survival (DFS) were abstracted from medical records and compared between the 2 cohorts. RESULTS:Twenty-two patients with sporadic cancer and BRCA1 (n = 4) or BRCA2 (n = 18) germline mutations and 105 wild-type patients were identified for this case-control study. The BRCA1/BRCA2 mutations were associated with inferior median OS (20.2 vs 27.8 months, p = 0.034) and DFS (8.4 vs 16.7 months, p < 0.001) when compared with the matched wild-type controls. On multivariable analyses, a BRCA1/BRCA2 mutation (hazard ratio [HR] 2.10, p < 0.001), positive margin status (HR 1.72, p = 0.021), and lack of adjuvant therapy (HR 2.38, p < 0.001), were all independently associated with worse survival. Within the BRCA1/BRCA2 mutated group, having had platinum-based adjuvant chemotherapy (n = 10) was associated with better survival than alternative chemotherapy (n = 8) or no adjuvant therapy (n = 4) (31.0 vs 17.8 vs 9.3 months, respectively, p < 0.001). CONCLUSIONS:Carriers of BRCA1/BRCA2 mutation with sporadic PDAC had a worse survival after pancreatectomy than their BRCA wild-type counterparts. However, platinum-based chemotherapy regimens were associated with markedly improved survival in patients with BRCA1/BRCA2 mutations, with survival differences no longer appreciated with wild-type patients.
| S-EPMC6178809 | biostudies-literature
Project description:Background and aimsPancreatic intraepithelial neoplasia is associated with chronic pancreatitis (CP) changes on EUS. The objective of this study was to determine whether CP changes were more common in high-risk individuals (HRIs) than in control subjects and whether these changes differed among higher-risk subsets of HRIs.MethodsHRIs and control subjects were identified from an endoscopy database. HRIs were defined as having predisposing mutations or a family history (FH) of pancreatic ductal adenocarcinoma. HRIs were classified as vHRIs who met Cancer of the Pancreas Screening (CAPS) criteria for high risk and mHRIs who did not. Multivariable logistic regression was used to adjust for confounders and CP risk factors.ResultsSixty-five HRIs (44 vHRIs, 21 mHRIs) and 118 control subjects were included. HRIs were included for FH (25), Lynch syndrome (5), Peutz-Jeghers syndrome (2), and mutations in BRCA1/2 (26), PALB2 (3), ATM (3), and CDKN2A (1). After adjustment for relevant variables, HRIs were 16 times more likely to exhibit 3 or more CP changes than control subjects (95% confidence interval, 2.6-97.0; P = .003). HRIs were also more likely to have hypoechoic foci (odds ratio, 8.0; 95% confidence interval, 1.9-32.9; P = .004). vHRIs and mHRIs did not differ in frequency of 3 or more CP changes on EUS.ConclusionsHRIs were more likely to exhibit CP changes and hypoechoic foci on EUS compared with control subjects. HRIs with these findings may require closer surveillance. HRIs who did or did not meet CAPS criteria did not differ with regard to CP findings, supporting a more inclusive approach to screening.
| S-EPMC6589432 | biostudies-literature
Project description:To bridge the translational gap between recent discoveries of distinct molecular phenotypes of pancreatic cancer and tangible improvements in patient outcome, there is an urgent need to develop strategies and tools informing and improving the clinical decision process. Radiomics and machine learning approaches can offer non-invasive whole tumor analytics for clinical imaging data-based classification. The retrospective study assessed baseline computed tomography (CT) from 207 patients with proven pancreatic ductal adenocarcinoma (PDAC). Following expert level manual annotation, Pyradiomics was used for the extraction of 1474 radiomic features. The molecular tumor subtype was defined by immunohistochemical staining for KRT81 and HNF1a as quasi-mesenchymal (QM) vs. non-quasi-mesenchymal (non-QM). A Random Forest machine learning algorithm was developed to predict the molecular subtype from the radiomic features. The algorithm was then applied to an independent cohort of histopathologically unclassifiable tumors with distinct clinical outcomes. The classification algorithm achieved a sensitivity, specificity and ROC-AUC (area under the receiver operating characteristic curve) of 0.84 ± 0.05, 0.92 ± 0.01 and 0.93 ± 0.01, respectively. The median overall survival for predicted QM and non-QM tumors was 16.1 and 20.9 months, respectively, log-rank-test p = 0.02, harzard ratio (HR) 1.59. The application of the algorithm to histopathologically unclassifiable tumors revealed two groups with significantly different survival (8.9 and 39.8 months, log-rank-test p < 0.001, HR 4.33). The machine learning-based analysis of preoperative (CT) imaging allows the prediction of molecular PDAC subtypes highly relevant for patient survival, allowing advanced pre-operative patient stratification for precision medicine applications.
| S-EPMC7141256 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma
| PRJNA432344 | ENA
Project description:Cell-free DNA (cfDNA) testing currently does not have a significant role in PDA management: it is insufficient to diagnose PDA, and its use is primarily restricted to identifying targetable mutations (if tissue is insufficient or unavailable). cfDNA testing has the potential to address critical needs in PDA management, such as pre-operative risk stratification (POR), prognostication, and predicting (and monitoring) treatment response. Prior studies have focused primarily on somatic mutations, specifically KRAS variants, and have shown limited success in addressing prognosis and POR. Recent studies have demonstrated the importance of other less prevalent mutations (ERBB2 and TP53), but no studies have provided reliable mutation panels for clinical use. Methylation aberrations in cfDNA (epigenetic markers) in PDA have been relatively less explored. However, early evidence has suggested they offer diagnostic and, to some extent, prognostic value. The inclusion of epigenetic markers of cfDNA adds another dimension to genomic testing and may open new therapeutic avenues beyond addressing critical areas of need in PDA treatment. For cfDNA to substantially influence PDA management, concerted efforts are required to include less frequent mutations and epigenetic markers. Furthermore, relying on KRAS mutations for PDA management will always be inadequate.
| S-EPMC9322623 | biostudies-literature
Project description:Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.
| S-EPMC4912945 | biostudies-literature
Project description:Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.
| S-EPMC7996579 | biostudies-literature
Project description:Over the last decade, many of the major solid organ cancers have seen improvements in survival due to development of novel therapeutics and corresponding biomarkers that predict treatment efficacy or resistance. In contrast, favorable outcomes remain challenging in pancreatic ductal adenocarcinoma (PDAC), in part related to the lack of validated biomarkers for patient and treatment selection and thus optimal clinical decision-making. Increasingly, however, therapeutic development for PDAC is accompanied by bioassays to evaluate response and to study mechanism of actions with a corresponding increase in the number of trials in mid to late stage with integrated biomarkers. In addition, blood-based biomarkers that provide a measure of disease activity and allow for minimally invasive tumor analyses are emerging, including circulating tumor DNA, exosomes, and circulating tumor cells. In this article, we review potential biomarkers for currently approved therapies as well as emerging biomarkers for therapeutics under development. Clin Cancer Res; 24(10); 2241-50. ©2017 AACR.
| S-EPMC5955785 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.
| S-EPMC8301364 | biostudies-literature