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Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms

. 2018 Oct 1;110(10):1067-1074. doi: 10.1093/jnci/djy024. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms Winston Wong^{1 3}, Emmet J Jordan¹, Jonathan W Lee¹, Yelena Kemel⁴, Joseph Vijai^{4 5}, Diana Mandelker⁶, Ahmet Zehir^{4 5}, Marinela Capanu⁷, Erin Salo-Mullen⁴, Angela G Arnold⁴, Kenneth H Yu^{1 2 3}, Anna M Varghese^{1 2 3}, David P Kelsen^{1 2 3}, Robin Brenner^{1 2}, Erica Kaufmann^{1 2}, Vignesh Ravichandran^{4 5}, Semanti Mukherjee⁴, Michael F Berger^{5 6}, David M Hyman^{1 5 3}, David S Klimstra⁶, Ghassan K Abou-Alfa^{1 3}, Catherine Tjan¹, Christina Covington¹, Hannah Maynard¹, Peter J Allen^{2 8}, Gokce Askan^{2 6}, Steven D Leach^{2 8}, Christine A Iacobuzio-Donahue², Mark E Robson^{1 4}, Kenneth Offit^{1 4}, Zsofia K Stadler^{1 4 3}, Eileen M O'Reilly^{1 2 3}

Affiliations

¹ Department of Medicine.
² David M. Rubenstein Center for Pancreatic Cancer Research.
³ Department of Medicine, Weill Cornell.
⁴ Robert and Kate Niehaus Center for Inherited Genomics.
⁵ Center for Molecular Oncology.
⁶ Department of Pathology.
⁷ Department of Epidemiology and Biostatistics.
⁸ Department of Surgery.

PMID: 29506128
PMCID: PMC6186514
DOI: 10.1093/jnci/djy024

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Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms

Maeve A Lowery et al. J Natl Cancer Inst. 2018.

. 2018 Oct 1;110(10):1067-1074. doi: 10.1093/jnci/djy024. Authors Maeve A Lowery^{1 2}, Winston Wong^{1 3}, Emmet J Jordan¹, Jonathan W Lee¹, Yelena Kemel⁴, Joseph Vijai^{4 5}, Diana Mandelker⁶, Ahmet Zehir^{4 5}, Marinela Capanu⁷, Erin Salo-Mullen⁴, Angela G Arnold⁴, Kenneth H Yu^{1 2 3}, Anna M Varghese^{1 2 3}, David P Kelsen^{1 2 3}, Robin Brenner^{1 2}, Erica Kaufmann^{1 2}, Vignesh Ravichandran^{4 5}, Semanti Mukherjee⁴, Michael F Berger^{5 6}, David M Hyman^{1 5 3}, David S Klimstra⁶, Ghassan K Abou-Alfa^{1 3}, Catherine Tjan¹, Christina Covington¹, Hannah Maynard¹, Peter J Allen^{2 8}, Gokce Askan^{2 6}, Steven D Leach^{2 8}, Christine A Iacobuzio-Donahue², Mark E Robson^{1 4}, Kenneth Offit^{1 4}, Zsofia K Stadler^{1 4 3}, Eileen M O'Reilly^{1 2 3} Affiliations

¹ Department of Medicine.
² David M. Rubenstein Center for Pancreatic Cancer Research.
³ Department of Medicine, Weill Cornell.
⁴ Robert and Kate Niehaus Center for Inherited Genomics.
⁵ Center for Molecular Oncology.
⁶ Department of Pathology.
⁷ Department of Epidemiology and Biostatistics.
⁸ Department of Surgery.

PMID: 29506128
PMCID: PMC6186514
DOI: 10.1093/jnci/djy024

Item in Clipboard

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures
Figure 1.

Kaplan-Meier curve for patients who…

Figure 1.

Kaplan-Meier curve for patients who consented to germline testing with and without pathogenic…

Figure 1.

Kaplan-Meier curve for patients who consented to germline testing with and without pathogenic germline mutations from diagnosis date. Data from 356 patients were analyzed, 281 without pathogenic germline alterations (PGAs) and 75 with PGAs. PGA = pathogenic germline alteration.

Figure 2.

Kaplan-Meier curve for patients with…

Figure 2.

Kaplan-Meier curve for patients with and without pathogenic germline mutations, restricted to those…

Figure 2.

Kaplan-Meier curve for patients with and without pathogenic germline mutations, restricted to those with metastatic or recurrent disease who consented to germline testing. Data from 292 patients were analyzed, 229 without pathogenic germline alterations (PGAs) and 63 without PGAs. PGA = pathogenic germline alteration.