Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms

Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association...

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Vydané v:JNCI : Journal of the National Cancer Institute Ročník 110; číslo 10; s. 1067
Hlavní autori: Lowery, Maeve A, Wong, Winston, Jordan, Emmet J, Lee, Jonathan W, Kemel, Yelena, Vijai, Joseph, Mandelker, Diana, Zehir, Ahmet, Capanu, Marinela, Salo-Mullen, Erin, Arnold, Angela G, Yu, Kenneth H, Varghese, Anna M, Kelsen, David P, Brenner, Robin, Kaufmann, Erica, Ravichandran, Vignesh, Mukherjee, Semanti, Berger, Michael F, Hyman, David M, Klimstra, David S, Abou-Alfa, Ghassan K, Tjan, Catherine, Covington, Christina, Maynard, Hannah, Allen, Peter J, Askan, Gokce, Leach, Steven D, Iacobuzio-Donahue, Christine A, Robson, Mark E, Offit, Kenneth, Stadler, Zsofia K, O'Reilly, Eileen M
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.10.2018
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ISSN:1460-2105, 1460-2105
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Abstract Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
AbstractList Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.BackgroundIdentification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.MethodsSix hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.ResultsPGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.ConclusionsPGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
Author Wong, Winston
Capanu, Marinela
Ravichandran, Vignesh
Offit, Kenneth
Abou-Alfa, Ghassan K
Askan, Gokce
Kelsen, David P
Hyman, David M
O'Reilly, Eileen M
Vijai, Joseph
Yu, Kenneth H
Salo-Mullen, Erin
Zehir, Ahmet
Robson, Mark E
Lowery, Maeve A
Varghese, Anna M
Maynard, Hannah
Tjan, Catherine
Berger, Michael F
Allen, Peter J
Lee, Jonathan W
Kemel, Yelena
Arnold, Angela G
Kaufmann, Erica
Covington, Christina
Leach, Steven D
Brenner, Robin
Mandelker, Diana
Jordan, Emmet J
Klimstra, David S
Mukherjee, Semanti
Stadler, Zsofia K
Iacobuzio-Donahue, Christine A
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/29506128$$D View this record in MEDLINE/PubMed
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PMID 29506128
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PublicationTitle JNCI : Journal of the National Cancer Institute
PublicationTitleAlternate J Natl Cancer Inst
PublicationYear 2018
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Snippet Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive...
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SubjectTerms Adult
Aged
Aged, 80 and over
Alleles
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biomarkers, Tumor
Female
Genetic Association Studies
Genetic Predisposition to Disease
Germ-Line Mutation
Heterozygote
Humans
Kaplan-Meier Estimate
Loss of Heterozygosity
Male
Middle Aged
Pancreas, Exocrine - pathology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - mortality
Pancreatic Neoplasms - pathology
Pancreatic Neoplasms - therapy
Title Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms
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