Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort

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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Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa054 ◽

2020 ◽

Vol 4 (5) ◽

Author(s):

Aser Abrha ◽

Navika D Shukla ◽

Rachel Hodan ◽

Teri Longacre ◽

Shyam Raghavan ◽

...

Keyword(s):

Colorectal Cancer ◽

Pancreatic Cancer ◽

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Gastrointestinal Malignancies ◽

Pathogenic Variants ◽

Repair Deficiency ◽

Common Etiology ◽

Significant Pathway ◽

Tumor Material

Abstract Background In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016. Methods In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available. Results A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%). Conclusions Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.

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A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4122 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4122-4122 ◽

Cited By ~ 2

Author(s):

T. Kuo ◽

A. Fitzgerald ◽

H. Kaiser ◽

B. I. Sikic ◽

G. A. Fisher

Keyword(s):

Pancreatic Cancer ◽

Tyrosine Kinase ◽

Phase I ◽

Tyrosine Kinase Inhibitor ◽

Phase I Study ◽

Kinase Inhibitor ◽

Advanced Pancreatic Cancer ◽

Patient Cohort ◽

Grade 3 ◽

Dose Levels

4122 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib (PTK787/ZK 222584) is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Previous adjuvant chemoradiotherapy with fluorouracil was allowed. Gemcitabine was given by fixed-dose rate infusion weekly x 3 in a 28-day cycle, and vatalanib was given orally daily. Dose-limiting toxicities (DLT) are defined as any grade 3/4 toxicity during the first cycle. The dose levels are as follows: Results: To date, 11 patients are evaluable for toxicity (5M/6F; median age 62 years, range 40–82 years; median KPS 90%). Thus far, 42 cycles have been given, with a median of four cycles per patient. Two patients have experienced DLT. The first patient (cohort 1) experienced grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The second patient (cohort 3) developed grade 3 deep vein thrombosis. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (3), thrombocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Three of eleven patients (27%) did not complete treatment to the first evaluation timepoint (2 cycles); two discontinued due to toxicity and one discontinued due to disease progression. Two of eleven patients (18%) had a partial response by RECIST. Six of eleven patients (55%) had stable disease as the best response ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated with most grade 3/4 toxicities occurring late in the treatment course. Antitumor responses have been observed at initial dose levels and accrual to the final cohort with BID dosing of vatalanib continues. [Table: see text] No significant financial relationships to disclose.

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Germline mutations in Brazilian pancreatic carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16749 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16749-e16749

Author(s):

Livia Munhoz Rodrigues ◽

Simone Maistro ◽

Maria Lucia Hirata Katayama ◽

Luiz A.Senna Leite ◽

Joao Glasberg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Carcinoma ◽

Germline Mutations ◽

Family History Of Cancer ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

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Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00190-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Krithika Murali ◽

Tanya M. Dwarte ◽

Mehrdad Nikfarjam ◽

Katherine M. Tucker ◽

Rhys B. Vaughan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

High Risk ◽

Screening Program ◽

Familial Cancer ◽

Pathogenic Variant ◽

Pathogenic Variants ◽

Pancreatic Cancer Screening ◽

Cancer Services ◽

Cancer Screening Program

Abstract Background The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. Methods Individuals aged 40–80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. Results Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. Conclusion Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

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Soluble gC1qR in Blood and Body Fluids: Examination in a Pancreatic Cancer Patient Cohort

International Journal of Cancer Research and Molecular Mechanisms ◽

10.16966/2381-3318.110 ◽

2015 ◽

Vol 1 (3) ◽

Cited By ~ 2

Author(s):

Peerschke Ellinor IB

Keyword(s):

Pancreatic Cancer ◽

Cancer Patient ◽

Pancreatic Cancer Patient ◽

Body Fluids ◽

Patient Cohort

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Hereditary pancreatic cancer

International Journal of Clinical Oncology ◽

10.1007/s10147-021-02015-6 ◽

2021 ◽

Author(s):

Kodai Abe ◽

Minoru Kitago ◽

Yuko Kitagawa ◽

Akira Hirasawa

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Precision Medicine ◽

Cancer Patients ◽

Genome Wide Association Study ◽

Parp Inhibitor ◽

Cancer Syndrome ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants

AbstractPancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

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