Prevalence and molecular etiology of mismatch repair deficiency among gastrointestinal cancers.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 215-215 ◽  
Author(s):  
Navika Shukla ◽  
Aser Abrha ◽  
Teri A. Longacre ◽  
Rachel Koff ◽  
James M. Ford ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Esophageal Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Patient Characteristics ◽  
Gi Cancer ◽  
Fda Approval ◽  
Repair Deficiency ◽  
Common Etiology ◽  
Significant Pathway

215 Background: In light of recent FDA approval of anti-PD-1 therapy for microsatellite unstable (MSI-H) or mismatch repair deficient (dMMR) solid tumors, identifying patients with dMMR tumors has become increasingly important. While screening for dMMR and MSI-H in colorectal cancer (CRC) is recommended, this screening is less commonly done for extracolonic gastrointestinal (GI) tumors. At Stanford Comprehensive Cancer Institute (SCCI), all GI cancer patients have been universally screened for dMMR via immunohistochemistry since January 2016. Methods: In this study, we undertook a retrospective review of all GI cancer patients screened for dMMR between January 2016 to December 2017. Data on patient characteristics, germline and tumor sequencing, and tumor characteristics were collected and reported. Results: A total of 1543 GI malignancies were screened for dMMR at SCCI during the study period. Colorectal (n = 711), pancreatic (n = 264), gastric (n = 159), and gastro-esophageal (n = 137) cancer were amongst the most frequently screened tumors. dMMR was detected in 7.1% of all GI malignancies. We detected the highest prevalence of dMMR in colorectal (69/711, 9.7%), followed by gastric (15/159, 9.4%), pancreatic (18/264, 6.8%), and gastro-esophageal cancer (6/137, 4.4%). Lynch syndrome was the most common etiology for dMMR in CRC patients (39.4%), double somatic (confirmed or possibly) mutations were most common in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation was the most common etiology in gastric (73.3%) and gastro-esophageal cancer (100%). Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we strongly recommend screening all GI malignancies. Of note, we found higher than previously reported rates of dMMR within pancreatic cancer. Our results also suggest that while rare, double somatic mismatch repair mutations may be a significant pathway causing dMMR in pancreatic cancer.

scholarly journals Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford

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.

scholarly journals Venous and Arterial Thromboembolism Related Hospitalizations Among Patients with Gastrointestinal Malignancy in United States - Data from Nationwide Sample

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4993-4993
Author(s):  
Chaitanya Puligondla ◽  
Rachit Kumar ◽  
Sravanthi Parasa
Keyword(s):  
Gastric Cancer ◽  
Pancreatic Cancer ◽  
Esophageal Cancer ◽  
Cancer Patients ◽  
Arterial Embolization ◽  
Discharge Diagnosis ◽  
Vascular Events ◽  
Arterial Embolism ◽  
Gi Cancer ◽  
Increased Risk

Abstract Introduction: Patients with underlying malignancies are at high risk for developing venous thromboembolism (VTE). We sought to characterize the risk and risk factors for developing VTE (both deep vein thrombosis (DVT) and Pulmonary embolism (PE)) and arterial thromboembolism among patients with underlying Gastrointestinal(GI) malignancies. Methods: We used the Nationwide Inpatient Sample (NIS) database to perform a cross-sectional study. The study group was defined as all hospitalized patients with GI malignancies above 18 years included in the NIS 2011 database with a primary discharge diagnosis of thromboembolism (Venous or arterial), as per the International Classification of Diseases - Clinical Modification, 9th revision (ICD-9-CM) codes. This VTE and arterial embolism population's demographics and outcomes were compared to the remainder of inpatient GI cancer patients without the diagnosis. All analyses were performed using STATA MP 12.VTE and Arterial embolism, identified by the ICD-9-CM codes, were studied comprehensively for their association with GI cancers and the risk factors were using multivariate logistic regression analysis. Odds ratios were calculated adjusting for relevant patient comorbidities. Results: Based on the location of GI cancer, there were a total of 37,872 patients hospitalized with underlying diagnosis of esophageal cancer, 97020 patients with pancreatic cancer, 45669 patients with gastric cancer and 267756 patients with colorectal cancer. The rates of VTE were highest among patients with pancreatic cancer (3.3%) followed by esophageal cancer 2.2%; gastric cancer 1.9%; colorectum (1.4%). In multivariate analysis, risk of VTE diagnosis was highest among pancreatic cancer patients, adjusted Odds ratio (aOR) - 2.8; 95% CI (2.53 - 3.09) after adjusting for active chemotherapy status, race, age, gender and comorbidities as determined by Deyo - Charlson comorbidity index. aOR for risk of VTE among Esophageal cancer patients was 1.73 , 95% CI (1.49-2.01) ; Colorectal cancer 1.18; 95% CI (1.09-1.27) and gastric cancer 1.52, 95% CI(1.30-1,78). The risk of PE was higher than DVT among patients with VTE. Underlying GI cancer was not associated with increased risk of arterial embolization, acute cerebro vascular events or acute myocardial infarction. The number of death associated with a principal discharge diagnosis code of VTE were not significantly high. Conclusion: Patients with pancreatic cancer have the highest risk of hospitalization for VTE among patients with underlying GI malignancies. Underlying GI malignancy is not associated with increased risk of arterial embolization, acute cerebro vascular events or acute myocardial infarction. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical features and survival of gastric cancer patients with DNA mismatch repair deficiency

2017 ◽  
Vol 117 (4) ◽  
pp. 707-709
Author(s):  
Naruhiko Ikoma ◽  
Jordan Cloyd ◽  
Brian D. Badgwell ◽  
Annamaria Agnes ◽  
Miguel Rodriguez-Bigas ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Clinical Features ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Gastric Cancer Patients ◽  
Dna Mismatch Repair Deficiency

Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320730 ◽  
Author(s):  
Robert C Grant ◽  
Robert Denroche ◽  
Gun Ho Jang ◽  
Klaudia M Nowak ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mismatch Repair ◽  
Exact Matching ◽  
Driver Genes ◽  
Cancer Driver ◽  
Dna Mismatch ◽  
Clinical Cohort ◽  
Pancreatic Cancers ◽  
Repair Deficiency ◽  
Basket Trials

ObjectiveTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).DesignWe identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).Results12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.ConclusionsMMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.

DNA repair deficiency association with prognosis in pancreatic cancer: A single-institution experience.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15798-e15798
Author(s):  
Suhaib Bajwa ◽  
Thomas A Odeny ◽  
Anwaar Saeed ◽  
Anup Kasi
Keyword(s):  
Pancreatic Cancer ◽  
Dna Repair ◽  
Cancer Patients ◽  
Parp Inhibitor ◽  
Survival Outcomes ◽  
Dna Repair Genes ◽  
Repair Deficiency ◽  
Dna Repair Deficiency ◽  
Baseline Characteristics ◽  
Repair Genes

e15798 Background: Understanding survival outcomes of various pathogenic mutations helps guide treatment decision making for patients. Classic pancreatic cancer mutations such as KRAS and TP53 have well documented survival outcomes while other mutations leading to DNA repair deficiency do not have well understood survival outcomes. Methods: We retrospectively evaluated survival outcomes of 70 pancreatic cancer patients who had their cancers genetically profiled by NGS methods. Patients with DNA repair deficiency harbored mutations in genes such as BRCA1 (1 Pts), BRCA2 (8 Pts), ATM (5 Pts), NBN (1 Pt), and BRIP1 (1 Pt). We compared baseline characteristics, tumor stage and clinical outcomes between patients with DNA repair deficiency versus DNA repair proficient cancer patients. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods. Results: Baseline characteristics for all patients are recorded in (Table). Median OS is 24 months for DNA repair proficient group and 20 months for DNA repair deficient group. A comparison of Kaplan-Meir survival curves between the two groups yielded a p-value of 0.72. This is most likely due to sample size and different chemotherapy regimens which make it hard to retrospectively compare patient groups. Conclusions: Patients with mutated DNA repair genes did not have significantly worse survival. We are designing a clinical trial utilizing a PARP inhibitor, for these patients in order to better control for all factors in order to better ascertain any survival differences between the two groups. PARP inhibitor will create multiple single strand breaks which cancer cells deficient in DNA repair genes cannot repair and thus trigger cancer cell death[Table: see text]

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