Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma

Brand, Randall E.; Borazanci, Erkut; Speare, Virginia; Dudley, Beth; Karloski, Eve; Peters, Mary Linton B.; Stobie, Lindsey; Bahary, Nathan; Zeh, Herbert J.; Zureikat, Amer H.; Hogg, Melissa E.; Lee, Kenneth; Tsung, Allan; Rhee, John C.; Ohr, James; Sun, Weijing; Lee, James; Moser, A. James; DeLeonardis, Kim; Krejdovsky, Jill; Dalton, Emily; LaDuca, Holly; Dolinsky, Jill S.; Colvin, Arlene; Lim, Cynthia; Black, Mary Helen; Tung, Nadine

doi:10.1002/cncr.31628

Cited by 75 publications

(66 citation statements)

References 27 publications

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“…We and others have reported that deleterious germline mutations in pancreatic cancer susceptibility genes are commonly (5% to 10%) identified in patients with pancreatic cancer. 14,[19][20][21] Patients with a family history of pancreatic cancer are approximately twice as likely to have such a germline mutation as those without a family history, although most germline mutation carriers who develop pancreatic cancer do not report a family history of pancreatic cancer and do not have family histories that suggest an inherited cancer syndrome. 14,19 Some patients who undergo pancreatic surveillance because of their family history may carry a germline mutation in a pancreatic cancer susceptibility gene.…”

Section: Introductionmentioning

confidence: 99%

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Abe

Blackford

Tamura

et al. 2019

JCO

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PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

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Section: Introductionmentioning

confidence: 99%

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Abe

Blackford

Tamura

et al. 2019

JCO

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“…Germline pathogenic variants have been identified in 4% to 19% of patients with pancreatic ductal adenocarcinoma (PDAC) . This finding has sparked robust discussion regarding the potential role of more frequent germline genetic testing in this population, and the National Comprehensive Cancer Network recently updated its BRCA1/2 testing criteria to include any individual diagnosed with pancreatic cancer, regardless of personal or family history .…”

Section: Introductionmentioning

confidence: 99%

“…We undertook a prospective study to determine the prevalence of germline pathogenic variants in a population of patients newly diagnosed with PDAC; the results of variant prevalence have been reported previously . As part of the study, we wanted to understand the impact of genetic testing in this population and assess the communication of results to family members.…”

Section: Introductionmentioning

confidence: 99%

“…Germline pathogenic variants have been identified in 4% to 19% of patients with pancreatic ductal adenocarcinoma (PDAC). [1][2][3][4][5][6][7] This finding has sparked robust discussion regarding the potential role of more frequent germline genetic testing in this population, and the National Comprehensive Cancer Network recently updated its BRCA1/2 testing criteria to include any individual diagnosed with pancreatic cancer, regardless of personal or family history. [8][9][10] The American Society of Clinical Oncology recently published a provisional clinical guideline recommending the assessment of hereditary risk for all patients newly diagnosed with pancreatic cancer, a discussion of germline testing even for patients with an unremarkable family history, and panel testing for those individuals who choose to undertake germline testing.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24] We undertook a prospective study to determine the prevalence of germline pathogenic variants in a population of patients newly diagnosed with PDAC; the results of variant prevalence have been reported previously. 7 As part of the study, we wanted to understand the impact of genetic testing in this population and assess the communication of results to family members. Given the morbidity of a PDAC diagnosis, we also wanted to evaluate whether it is acceptable to patients to undergo genetic testing at the time of diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma

Peters

Stobie

Dudley

et al. 2019

Cancer

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Background Germline genetic testing currently is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). In the current study, the authors assessed how often results are communicated to first‐degree relatives within 3 months and the emotional impact of testing on patients. Methods A total of 148 patients who were newly diagnosed with PDAC and who had undergone testing of 32 cancer susceptibility genes at 3 academic centers were selected; 71% participated. Subjects completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) and a family communication survey. The results of both surveys were assessed at 3 months according to the genetic test result (positive, negative, or variant of unknown significance [VUS]) and whether a patient met criteria for genetic testing. Results A total of 99 patients completed the MICRA survey and 104 completed the family communication survey. The average age of the patients was 67 years, 47% were female, 29% had stage III/IV (AJCC 8th edition) disease, and 42% met genetic testing criteria. Approximately 80% of patients told at least 1 first‐degree relative about their result. There was a trend toward greater disclosure among patients who tested positive (93% vs 77% for those with a VUS result [P = .149] and 74% for those who tested negative [P = .069]). Patients not meeting genetic testing criteria were less likely to disclose results (69% vs 93%; P = .003). MICRA scores did not differ by test result, age, stage of disease, or sex. Conclusions The rate of result communication was high, although it was lower among patients who did not meet genetic testing criteria, those who tested negative, or those who had a VUS result. Testing‐associated distress was similar across patient groups, and was comparable to that reported by other patients with cancer. Improved communication for all patients is crucial given the prognosis of PDAC, which limits time for disclosure.

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An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice

et al. 2020

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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 RELEVANCEWith 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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Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma

Abstract: These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

Cited by 75 publications

References 27 publications

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma

An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice

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