The Liquid Biopsy in Cancer Predisposition Protocol is a discovery and exploratory protocol that will enable us to obtain serial blood samples from patients with cancer predisposition syndromes, and their relatives, who may or may not have been diagnosed with a malignancy.
Cancer predisposition syndromes (CPS), whilst individually rare, are associated with approximately 20% of cancer diagnoses. They span a broad spectrum from those thought of as site specific, such as BRCA1/2, to those associated with a broad range of malignancies, such as Li Fraumeni Syndrome which is associated with cancers of the breast, soft tissue and brain, amongst others. Individuals with a CPS have a higher risk of malignancy than the general population and thus are advised to enrol in screening and surveillance programmes where available. Established protocols exist for breast & colon cancer, and guidance is available for other malignancies. However, most programmes are tumour site specific and therefore patients are required to undergo multiple investigations to remain current with surveillance recommendations.
Liquid biopsy describes broadly the process of analysing a blood sample for cell free DNA (cfDNA), circulating tumour DNA (ctDNA) or circulating tumour cells in lieu of tissue biopsy. It was first characterised in those with a known cancer diagnosis where it provides an opportunity for non-invasive genomic characterisation of a patient’s cancer. Liquid biopsy has demonstrated utility in lung cancer, for example, where the evolution of resistance mutations as detected on liquid biopsy can anticipate clinical or radiological disease progression. Recent work has described the use of liquid biopsy in the early detection of a cancer diagnosis, as an early indicator of disease relapse and as a marker of residual disease and increased risk of relapse following neoadjuvant therapy in triple negative breast cancer.
With this knowledge, there is significant interest in the exploration of liquid biopsy as a screening tool for those patients with a cancer predisposition syndrome. The CCGA consortium recently published their experience of multi-cancer detection and localization utilising methylation profiling of cell free DNA. Velculescu (Our collaborator at John Hopkins) et al demonstrated the utility of genome-wide cell free DNA fragmentation as a novel technique, which, when combined with mutation-based cell free analyses detected 91% of patients with cancer. Utilising digital PCR techniques, it has been proven possible to detect circulating tumour DNA, separate to circulating tumour cells, and also to demonstrate mechanisms of resistance to therapies. (5) Such approaches offer a potential option for those patients with a multi-site CPS as a single surveillance tool.
We will analyze the liquid biopsies collected using genomic liquid biopsy approaches for detection of tumor-derived DNA in blood plasma. Our collaborators at Johns Hopkins have developed genomic liquid biopsy approaches to sensitively and specifically analyze cfDNA in the blood plasma using next-generation sequencing to identify ctDNA and aberrant features of cfDNA as biomarkers for cancer. In this study, we will explore these biomarkers and the evolution thereof in serum samples of individuals with a CPS and their relatives without a CPS. It is anticipated that knowledge generated by this study will be hypothesis generating and lead to further studies.
Grail are a healthcare company focused on saving lives and improving health by pioneering new technologies for early cancer detection. Grail have built a multi-disciplinary organization of scientists, engineers, and physicians and they are using the power of next-generation sequencing (NGS), population-scale clinical studies, and state-of-the-art computer science and data science to overcome one of medicine’s greatest challenges. Their mission is to detect cancer early, when it can be cured. They are working to change the trajectory of cancer mortality and bring stakeholders together to adopt innovative, safe, and effective technologies that can transform cancer care. They have developed a clincal, commercially available test to detect circulating tumour DNA in patient blood samples. In studies, the Galleri test has shown the ability to detect multiple types of cancers through a single blood draw. Most of these cancers cannot be detected through current screening paradigms. When cancer signal was detected, the Galleri test localized the cancer signal with high accuracy, helping inform next steps to diagnosis.
This project compliments project#1. The difference is that the results of project number 2 can be incorporated directly into patient care. Project #1 is a research study with considerable potential to impact on patient care in the future but as the testing is research testing and not of a certified clinical standard the results will not be returned to the patient and the results will not be used in clinical care. In project ~2 we will be used a clinically accredited test and incorporating it into patient care for the first time in Ireland.
Hepatic arterial infusion is a type of cancer treatment in which surgeons implant a special pump to deliver specialized chemotherapy drugs directly to metastatic tumours in the liver. Via the pump, a catheter is connected to the hepatic artery, which supplies blood to tumours within the liver. Because the chemotherapy is delivered directly to the liver, high doses that are effective against tumours can be used without causing damage to the rest of the body. This reduces side effects and makes HAI chemotherapy very effective in treating advanced tumours in the liver. The HAI pump needs to be refilled every 2 to 4 weeks. The pump releases chemotherapy at a set rate and delivers a constant dose of chemotherapy to the liver, which also increases the effectiveness of the treatment. When combined with systemic chemotherapy, hepatic arterial infusion leads to higher response rates compared to systemic chemotherapy alone. There are several major benefits to including HAI chemotherapy in late-stage cancer treatment plans: Higher resection rates of previously unresectable tumours, Lower recurrence rates, Prolonged survival rates. Hepatic arterial infusion is used to treat certain advanced cancers in the liver. It is more effective than systemic chemotherapy because much higher concentrations of chemo can be delivered directly to the liver without causing damage elsewhere in the body. Advanced cancers that may be treated with HAI chemotherapy include metastatic colorectal cancer and bile duct cancers (cholangiocarcinoma). This treatment is currently not available in Ireland. Prof David Gallagher (St. James’s Hospital) and Mr. John Conneally (Mater Misericordiae University Hospital) have developed a clinical collaboration between their respective inner city Dublin hospitals with the goal of bringing this important to Ireland. This will require a specialised team travelling abroad to train.