Liquid biopsy for early cancer detection in children and adults with hereditary cancer syndromes across Canada
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction:
People with hereditary cancer syndromes (HCS) are born with a genetic change that puts them at high risk for developing multiple cancers throughout their lifetime. They undergo extensive lifelong surveillance; however, there are important gaps in current clinical cancer screening programs, including accessibility of screening tests, and inability of current screening methods to detect all cancer types early. Our community, known as the CHARM Consortium (cfDNA in Hereditary And High-Risk Malignancies) was founded in 2018 to explore the possibility of using less invasive and more accessible testing of blood cell-free DNA (cfDNA) to detect cancers at the earliest stages and to pinpoint where in the body they are developing. By bringing together seven genetics clinics from five Canadian provinces, the CHARM community created a richly annotated biobank of just under 3,000 longitudinal blood samples collected from people with over 20 types of HCS. Analysis of these samples led to new advancements in cfDNA sequencing, which we are now putting into clinical practice.
Methods:
We have launched a prospective randomized control trial, to compare whether cancer can be detected with cfDNA sequencing at the same time, or earlier, than current cancer screening programs. We are specifically focused on people with a genetic diagnosis of one of five HCS: Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome (LS), Li-Fraumeni syndrome (LFS), Neurofibromatosis Type 1 (NF1), and Hereditary Diffuse Gastric Cancer (HDGC). We are enrolling 1000 people; all are continuing to receive standard of care surveillance according to current guidelines. Half of the participants are randomized to the experimental cohort and additionally receive cfDNA sequencing every 4 months, for 4 years.
All blood samples are subject to clinical cfDNA sequencing in a CAP-accredited laboratory using: 1) targeted deep sequencing of a core set of genes frequently mutated in HCS tumours to detect somatic mutations, and 2) shallow whole genome sequencing to detect cancer associated copy number changes. If an abnormality is identified, reflex methylation testing is done to try to identify a tissue of cancer origin. Results of the cfDNA sequencing are returned to managing physicians who follow-up on any abnormal cfDNA findings with targeted imaging for any suspected malignancies.
We are also administering questionnaires to both study cohorts, assessing anxiety, quality of life, and risk perception, among other emotional outcomes. We will compare psychological distress of receiving or not receiving the blood test results and evaluate its effect in patients’ engagement and adherence to screening protocols.
Results:
During the period spanning April 2024 to November 2024, we enrolled 239 cancer-free participants (119 HBOC, 107 LS and 13 LFS). 118 participants have been randomized to receive cfDNA sequencing tri-annually. A total of 104 samples have been collected (97 baseline collections, 7 follow-up collections), on which cfDNA sequencing has been completed or is in progress. 54 negative test results have been returned to participants. The average time from the date of sample collection to the date results were disclosed to the participant was 52 days.
Conclusion:
Standard clinical screening programs can pose many challenges for this high-risk population. As our trial continues, we will establish the cancer detection rate of cfDNA sequencing. We hope to demonstrate the utility and clinical benefit gained by following up on detection of early cancer using cfDNA. Early recruitment into our trial has shown great enthusiasm from both providers and patients. Our CHARM community hopes that in the future, cfDNA sequencing can be incorporated into high-risk screening programs across Canada, to transform cancer detection and increase access to timely and effective medical treatment.
People with hereditary cancer syndromes (HCS) are born with a genetic change that puts them at high risk for developing multiple cancers throughout their lifetime. They undergo extensive lifelong surveillance; however, there are important gaps in current clinical cancer screening programs, including accessibility of screening tests, and inability of current screening methods to detect all cancer types early. Our community, known as the CHARM Consortium (cfDNA in Hereditary And High-Risk Malignancies) was founded in 2018 to explore the possibility of using less invasive and more accessible testing of blood cell-free DNA (cfDNA) to detect cancers at the earliest stages and to pinpoint where in the body they are developing. By bringing together seven genetics clinics from five Canadian provinces, the CHARM community created a richly annotated biobank of just under 3,000 longitudinal blood samples collected from people with over 20 types of HCS. Analysis of these samples led to new advancements in cfDNA sequencing, which we are now putting into clinical practice.
Methods:
We have launched a prospective randomized control trial, to compare whether cancer can be detected with cfDNA sequencing at the same time, or earlier, than current cancer screening programs. We are specifically focused on people with a genetic diagnosis of one of five HCS: Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome (LS), Li-Fraumeni syndrome (LFS), Neurofibromatosis Type 1 (NF1), and Hereditary Diffuse Gastric Cancer (HDGC). We are enrolling 1000 people; all are continuing to receive standard of care surveillance according to current guidelines. Half of the participants are randomized to the experimental cohort and additionally receive cfDNA sequencing every 4 months, for 4 years.
All blood samples are subject to clinical cfDNA sequencing in a CAP-accredited laboratory using: 1) targeted deep sequencing of a core set of genes frequently mutated in HCS tumours to detect somatic mutations, and 2) shallow whole genome sequencing to detect cancer associated copy number changes. If an abnormality is identified, reflex methylation testing is done to try to identify a tissue of cancer origin. Results of the cfDNA sequencing are returned to managing physicians who follow-up on any abnormal cfDNA findings with targeted imaging for any suspected malignancies.
We are also administering questionnaires to both study cohorts, assessing anxiety, quality of life, and risk perception, among other emotional outcomes. We will compare psychological distress of receiving or not receiving the blood test results and evaluate its effect in patients’ engagement and adherence to screening protocols.
Results:
During the period spanning April 2024 to November 2024, we enrolled 239 cancer-free participants (119 HBOC, 107 LS and 13 LFS). 118 participants have been randomized to receive cfDNA sequencing tri-annually. A total of 104 samples have been collected (97 baseline collections, 7 follow-up collections), on which cfDNA sequencing has been completed or is in progress. 54 negative test results have been returned to participants. The average time from the date of sample collection to the date results were disclosed to the participant was 52 days.
Conclusion:
Standard clinical screening programs can pose many challenges for this high-risk population. As our trial continues, we will establish the cancer detection rate of cfDNA sequencing. We hope to demonstrate the utility and clinical benefit gained by following up on detection of early cancer using cfDNA. Early recruitment into our trial has shown great enthusiasm from both providers and patients. Our CHARM community hopes that in the future, cfDNA sequencing can be incorporated into high-risk screening programs across Canada, to transform cancer detection and increase access to timely and effective medical treatment.