Implementation of cfDNA Pancreatic Cancer Test in High-Risk Patients with Genetic and/or Family History of Cancer in a Clinical Setting
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Pancreatic Cancer (PaC) is the 3rd leading cause of cancer mortality and is predicted to be the 2nd-leading cause by 2030. Survival expectations are predicted to improve dramatically by implementing effective early detection test modalities.
Genetic predisposition and/or family history can strongly influence the risk of pancreatic cancer. Pathogenic variants in ATM, BRCA1, BRCA2, FAMMM, CDKN2A, STK11 (Peutz-Jeghers), and MLH1, MSH2, MSH6, EPCAM (Lynch syndrome) genes, among others, are known to increase the risk of pancreatic cancer.
Methods:
ClearNote Health has validated a non-invasive, blood-based, cell-free DNA epigenomic early-detection pancreatic cancer test (Avantect). The test has been validated in a large case-control study, including patients with genetic predisposition or family history risk of pancreatic cancer. A pilot program to deploy the test in a clinical setting of high-risk patients was conducted to assess the feasibility and integration of the test into a clinical workflow.
Twenty patients who were part of the Providence Pancreatic High-Risk Program received the Avantect test from ClearNote Health. The test results were delivered to the clinical site for post-test follow-up. The clinical impact of the testing and logistics were reviewed after testing.
Results:
The cohort comprised six males and 14 females. The average patient age was 67 years (range 51-79). All patients were under high-risk pancreatic surveillance (with most meeting CAPS/NCCN criteria for surveillance); 6/20 patients carried P/LP variants in known pancreatic cancer risk genes, and 14/20 were surveillance due to significant family history of pancreatic cancer. Of the 14, 1/20 carried P/LP variants in genes not known to increase risk, and 6 carried variants of uncertain significance (VUS).
Mutation in Gene (Classification) N (%)
N/A 7 (35%)
ATM (1 P/LP, 1 VUS) 2 (10%)
BRCA1 (P/LP) 2 (10%)
BRCA2 (P/LP) 2 (10%)
CDKN2A (reduced penetrance) 1 (5%)
CHEK2 (P/LP) 1 (5%)
DICER1 (VUS) 1 (5%)
KIF1B (VUS) 1 (5%)
MRE11A (VUS) 1 (5%)
PALB2 (VUS) 1 (5%)
STK11 (VUS) 1 (5%)
Conclusion:
These results complimented physician guided management and care aiding in the early detection of pancreatic cancer or cysts and led to appropriate changes in surveillance intervals and therapeutic intervention. The implementation of a cfDNA blood test (Avantect; sensitivity—66.7 %; specificity—96.9%), for patients at a high risk of developing pancreatic cancer has the potential to enhance current guideline directed surveillance, adherence and patient access to care.
Pancreatic Cancer (PaC) is the 3rd leading cause of cancer mortality and is predicted to be the 2nd-leading cause by 2030. Survival expectations are predicted to improve dramatically by implementing effective early detection test modalities.
Genetic predisposition and/or family history can strongly influence the risk of pancreatic cancer. Pathogenic variants in ATM, BRCA1, BRCA2, FAMMM, CDKN2A, STK11 (Peutz-Jeghers), and MLH1, MSH2, MSH6, EPCAM (Lynch syndrome) genes, among others, are known to increase the risk of pancreatic cancer.
Methods:
ClearNote Health has validated a non-invasive, blood-based, cell-free DNA epigenomic early-detection pancreatic cancer test (Avantect). The test has been validated in a large case-control study, including patients with genetic predisposition or family history risk of pancreatic cancer. A pilot program to deploy the test in a clinical setting of high-risk patients was conducted to assess the feasibility and integration of the test into a clinical workflow.
Twenty patients who were part of the Providence Pancreatic High-Risk Program received the Avantect test from ClearNote Health. The test results were delivered to the clinical site for post-test follow-up. The clinical impact of the testing and logistics were reviewed after testing.
Results:
The cohort comprised six males and 14 females. The average patient age was 67 years (range 51-79). All patients were under high-risk pancreatic surveillance (with most meeting CAPS/NCCN criteria for surveillance); 6/20 patients carried P/LP variants in known pancreatic cancer risk genes, and 14/20 were surveillance due to significant family history of pancreatic cancer. Of the 14, 1/20 carried P/LP variants in genes not known to increase risk, and 6 carried variants of uncertain significance (VUS).
Mutation in Gene (Classification) N (%)
N/A 7 (35%)
ATM (1 P/LP, 1 VUS) 2 (10%)
BRCA1 (P/LP) 2 (10%)
BRCA2 (P/LP) 2 (10%)
CDKN2A (reduced penetrance) 1 (5%)
CHEK2 (P/LP) 1 (5%)
DICER1 (VUS) 1 (5%)
KIF1B (VUS) 1 (5%)
MRE11A (VUS) 1 (5%)
PALB2 (VUS) 1 (5%)
STK11 (VUS) 1 (5%)
Of the 20 total test results, 18 patients had no cancer signal detected (90%), and two patients detected a cancer signal (10%). One positive test in a BRCA2 carrier was histologically confirmed as pancreatic adenocarcinoma (Stage 3a by imaging) and patient given neo adjuvant chemotherapy. The second positive signal test, in a patient with family history of multiple pancreatic cancers, was followed by MRI/MRCP; imaging revealed numerous pancreatic cyst lesions of up to 6 mm. EUS revealed three ‘simple’ pancreatic cysts of up to 8 mm. The patient is now on shorter interval, 6-month surveillance. Although this is a small pilot, the 10% positivity rate in this high-risk cohort was higher than in clinical testing from the broader cohort from this program that included an additional 270 patients (positive rate of 2%) that focused on testing patients over the age of 50 with a diagnosis of new onset diabetes. Those with negative results continued prior recommendation for annual surveillance MRCP alternating with EUS if in surveillance arm of program or usual care (no routine surveillance) in non-surveillance (research only) arm.
Conclusion:
These results complimented physician guided management and care aiding in the early detection of pancreatic cancer or cysts and led to appropriate changes in surveillance intervals and therapeutic intervention. The implementation of a cfDNA blood test (Avantect; sensitivity—66.7 %; specificity—96.9%), for patients at a high risk of developing pancreatic cancer has the potential to enhance current guideline directed surveillance, adherence and patient access to care.
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