Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

A family history of pancreatic cancer (PC) is a risk factor of PC, and risk levels increase as affected families grow in number and/or develop PC at younger ages. Familial pancreatic cancer (FPC) is defined as a client having at least two PC cases in a first degree relatives. In the narrow sense, FPC does not include some inherited cancer syndromes that are known to increase the risks of PC, such as Peutz–Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary breast ovarian cancer syndrome (HBOC), and so on. FPC accounts for 5%–10% of total PC diagnoses and is marked by several features in genetic, epidemiological, and clinicopathological findings that are similar to or distinct from conventional PC. Recent advances in genetic medicine have led to an increased ability to identify germline variants of cancer-associated genes. To date, high-risk individuals (HRIs) in many developed countries, including FPC kindreds and inherited cancer syndromes, are screened clinically to detect and treat early-stage PC. This article highlights the concept of FPC and the most recent data on its detection.

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The Hereditary Spectrum of Pancreatic Cancer: The Edmonton Experience

Canadian Journal of Gastroenterology ◽

10.1155/2004/631909 ◽

2004 ◽

Vol 18 (1) ◽

pp. 17-21 ◽

Cited By ~ 5

Author(s):

Margaret Lilley ◽

Dawna Gilchrist

Keyword(s):

Pancreatic Cancer ◽

At Risk ◽

Family History ◽

Hereditary Cancer ◽

Cancer Genetics ◽

Hereditary Cancer Syndrome ◽

Molecular Testing ◽

Cancer Syndrome ◽

History Of ◽

Cancer Syndromes

OBJECTIVE:Pancreatic cancer is known to aggregate in some families and has been associated with a wide variety of cancer syndromes. The authors describe their experience with pancreatic cancer and the range of associated cancer syndromes.METHODS:The charts of all patients seen for concern of a hereditary cancer syndrome in the Cancer Genetics Clinic at the University of Alberta between 1995 and 2002 were reviewed.RESULTS:Forty families reported a personal or family history of pancreatic cancer in the context of a possible hereditary cancer syndrome. Three additional families reported a history of pancreatitis. Twenty-four (56%) of those families were suspected of having a hereditary breast and ovarian cancer syndrome. A further seven (16%) were suspected of having hereditary nonpolyposis colon cancer. Only three (7%) were believed to be at risk for a site-specific pancreatic cancer syndrome. Another three (7%) were suspicious for hereditary pancreatitis. The remaining family histories were suggestive of Li-Fraumeni syndrome, von Hippel-Lindau syndrome or a nonspecific cancer predisposition.CONCLUSIONS:With such a wide variety of hereditary cancer syndromes associated with pancreatic cancer, an accurate assessment of the family history is essential to determine the most appropriate cancer screening for at-risk family members and to guide any molecular testing that may be offered.

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Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00160-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Kodai Abe ◽

Arisa Ueki ◽

Yusaku Urakawa ◽

Minoru Kitago ◽

Tomoko Yoshihama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Genetic Analysis ◽

Pathogenic Variant ◽

Familial Pancreatic Cancer ◽

Case Presentation ◽

Pathogenic Variants ◽

Pancreatic Cancers ◽

Epidemiological Surveys ◽

History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20030561 ◽

2019 ◽

Vol 20 (3) ◽

pp. 561 ◽

Cited By ~ 8

Author(s):

Akihiro Ohmoto ◽

Shinichi Yachida ◽

Chigusa Morizane

Keyword(s):

Pancreatic Cancer ◽

Checkpoint Inhibitors ◽

Susceptibility Gene ◽

Treatment Strategies ◽

Familial Pancreatic Cancer ◽

Cancer Syndrome ◽

Increased Risk ◽

Clinical Benefits ◽

Surveillance Programs ◽

Cancer Syndromes

Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.

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High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2015.61.4503 ◽

2015 ◽

Vol 33 (31) ◽

pp. 3544-3549 ◽

Cited By ~ 86

Author(s):

Maureen E. Mork ◽

Y. Nancy You ◽

Jun Ying ◽

Sarah A. Bannon ◽

Patrick M. Lynch ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Counseling ◽

Family History ◽

Hereditary Cancer ◽

Hereditary Cancer Syndrome ◽

Hereditary Cancer Syndromes ◽

Cancer Syndrome ◽

History Of ◽

Cancer Syndromes ◽

History Of Cancer

Purpose Established guidelines recommend evaluation for hereditary cancer syndromes in patients younger than 50 years diagnosed with colorectal cancer (CRC). This group has been well described in the literature; however, patients diagnosed as adolescents and young adults are not well represented in CRC studies. Here, we define the clinical profile, including the extent of hereditary cancer syndromes and family history of cancer, in patients diagnosed with CRC at age 35 or younger. Patients and Methods We reviewed patients who underwent genetic counseling at our institution during 5 years (2009 to 2013). Data were collected regarding demographics, clinicopathologic information, tumor and genetic testing, and family history. Patients with an identified hereditary cancer syndrome were compared with those without a syndrome. Results Of the 193 patients with evaluable data, 35% had an identifiable hereditary cancer syndrome, including 23 with Lynch syndrome, 22 with mutation-negative Lynch syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with biallelic MUTYH mutations, and one with Li-Fraumeni syndrome. Patients without a hereditary syndrome more frequently presented with metastatic disease, whereas patients with a syndrome were more likely to present at earlier stages and to have a family history of cancer. Nevertheless, a substantial proportion of the hereditary syndromes (19%) were diagnosed in individuals with no family history of the disease. Conclusion We conclude that patients diagnosed with CRC at age 35 years or younger should receive genetic counseling regardless of their family history and phenotype.

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Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion

Journal of Clinical Oncology ◽

10.1200/jco.18.01489 ◽

2019 ◽

Vol 37 (2) ◽

pp. 153-164 ◽

Cited By ~ 35

Author(s):

Elena M. Stoffel ◽

Shannon E. McKernin ◽

Randall Brand ◽

Marcia Canto ◽

Michael Goggins ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Adenocarcinoma ◽

Health Care Providers ◽

Expert Panel ◽

Familial Pancreatic Cancer ◽

Care Providers ◽

Increased Risk ◽

History Of

Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

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Spanish registry and screening program for families at high risk of pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.192 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 192-192

Author(s):

Carmen Guillen-Ponce ◽

Evelina Mocci ◽

Mirari Marquez ◽

Julie Earl ◽

Carmen T Guerrero ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

High Risk ◽

Screening Program ◽

Familial Aggregation ◽

Molecular Characteristics ◽

High Risk Population ◽

Familial Pancreatic Cancer ◽

Preneoplastic Lesions ◽

History Of

192 Background: 5-10% of pancreatic cancer (PC) cases show familial aggregation. 20% of these correspond to syndromes: Peutz Jeghers, hereditary pancreatitis, familial multiple melanoma, breast and ovarian cancer (HBOC) and others. Familial pancreatic cancer (FPC) is defined as: ≥2 first degree relatives with PC and with no other known syndromes. FPC seems to have autosomal dominant inheritance, but the genetic cause is unknown. Methods: The objectives are: 1) To develop the first FPC Spanish Registry, connecting different groups interested in this disease 2) To study inheritance, phenotypic and molecular characteristics of the FPC, and families with early PC 3) To establish a strategy for early detection of PC in high-risk individuals and to implement it 4) To characterize preneoplastic lesions and diagnosed PC by monitoring high-risk individuals. 16 Spanish hospitals are participating. This study has two components: 1) Cohort to identify families with FPC and hereditary PC. Sources for the families are the PanGen-ES Study, a case-control study of PC which identifies families through a questionnaire on family history of cancer, and Genetic Counseling Units, 2) Cohort of high-risk families. The latter will be followed up by endoscopic ultrasound (EUS) and CT ± abdominal magnetic resonance imaging. In addition, circulating tumor cells (CTC) in peripheral blood will be determined. Results: The assessment of family history of the 421 cases included in the PanGen Study has identified 32 (7.6%) families with FPC and 52 patients with PC ≤ 50 years (12.4%). In addition, the 190 families presenting PC aggregation with other neoplasms are being further evaluated. At this time we have obtained clinical data and blood samples to carry out molecular studies of 23 individuals: 17 belonging to 3 families with FPC, and 6 members of 2 families with an HBOC with some cases of pancreatic cancer. 18 relatives at risk began a follow-up with EUS and CT, with no detection of any suspicious pancreatic lesion; also CTC have not been detected. Conclusions: This initiative will permit to know more about FPC and will serve to evaluate protocols and PC markers in screening the high-risk population, and promote connections with other international groups.

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Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.3502 ◽

2017 ◽

Vol 35 (30) ◽

pp. 3382-3390 ◽

Cited By ~ 121

Author(s):

Koji Shindo ◽

Jun Yu ◽

Masaya Suenaga ◽

Shahriar Fesharakizadeh ◽

Christy Cho ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Germline Mutation ◽

Cancer Susceptibility ◽

Germline Mutations ◽

Susceptibility Genes ◽

Familial Pancreatic Cancer ◽

Cancer Susceptibility Genes ◽

Periampullary Neoplasms ◽

History Of

Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

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BRCA mutations and their clinical relevance in unselected pancreatic cancer population.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16240 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16240-e16240

Author(s):

Viola Barucca ◽

Andrea Petricca Mancuso ◽

Salvatore De Marco ◽

Daniela Iacono ◽

Carmelilia De Bernardo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Disease Progression ◽

Personal History ◽

First Line ◽

Brca Mutations ◽

Cancer Family ◽

Cancer Family History ◽

Brca 2 ◽

History Of

e16240 Background: Germline pathogenetic mutations in BRCA1/2 genes are described in pancreatic cancer patients (PCP) in about 5–9% of cases. The purpose of this study was to determine their relevance in an unselected consecutive cohort of PCP describing family and clinical history. Methods: Patients (pts) were recruited at a single cancer center from September 2019 to October 2020. Participants provided blood for DNA analysis; cancer family history and treatment records were reviewed; DNA was analyzed by Next Generation Sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1/2 Results: 69 pts were included, 61 (88,4%) with locally advanced and metastatic pancreatic cancer received first line chemotherapy and 38 (62%) were full eligible for BRCA analysis; 8 out of 69 pts were BRCA screened even if in adjuvant setting, 10 patients are still under evaluation. Out of the 38 first line screened PCP germline BRCA mutations were found in 9 (19%): 4 pts (8,7%) with pathogenetic BRCA-2 variants (subgroup 1 – S1) and 5 pts (10,8%) with variants of unknown significances (VUSs), i.e. c.5339T>C and c.5096G>A in BRCA1 (subgroup 2 – S2). Samples from 29 pts were established as BRCA wild-type (subgroup 3 – S3). Pathogenetic BRCA-2 variants were observed in 2 male and 2 female (median age, 61.5 years, range 48-69), 3 out 4 without family history of breast, ovarian and pancreatic cancer, one patient (pt) had ovarian cancer family history. All pts had a negative personal history of others cancers. All S1 pts received FOLFIRINOX regimen achieving one complete response, 2 partials responses and 1 disease progression with RECIST criteria. The S2 included 2 male and 3 female (median age, 61 years, range 45-70) 2 with family history of pancreatic cancer, no pt had personal history of others cancers; 2 pts had stable disease and 3 disease progression receiving platinum-based regimen (4 pts) and gemcitabine/nabpaclitaxel (1 pt), respectively. Platinum responders were observed only in the well known pathogenetic BRCA-2 variants group with twice a median progression-free survival (PFS, months -ms-) as compared to the one observed in VUSs group. (>6 C.I. 95% 2- >12 ms; vs 3 ms, 95% C.I. 3-12 ms). S3 included 9 male and 20 female, (median age, 66 years, range 42-78); 5 pts had family history of pancreatic or breast cancer, 5 pts had a personal history of other cancers (breast and thyroid). In this group,16 pts received a platinum based regimen and 12 pts have been treated without platinum based regimen. Conclusions: Our results suggest that: 1) BRCA pathogenetic mutations rate (8,7%) is in line with literature data and seems not to be related with family or personal history, and to be associated with a better outcome; 2) No BRCA mutations were detected in patients over 70 years. 3) VUSs subgroup do not seem to benefit from platinum-regimen.

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