š Events
AI in Healthcare - A Six Part Masterclass
TheĀ Royal Society of MedicineĀ is a world-renowned institution known for its quality programme of educational events and conferences. Donāt miss out on the annual AI in healthcare event in February 2021. Itās a virtual masterclass comprisingĀ six sessions over two afternoons. Expect amazing speakers, top notch panel discussions and CPD certificates. Donāt miss out!
According to the NHS āLong Term Planā, the UK is on a mission to diagnose 75% of cancers at an early stage by 2028.
Itās an admirable but difficult task. Funding, screening and advancements in diagnostics will all be required to help achieve that goal.
Letās learn about one technique that might prove pivotalā¦
š¤·āāļø Problem
In the unhappy realm of cancer, tissue biopsies are the gold standard for the diagnosis and characterisation of solid tumours. Unfortunately theyāre not ideal:
The location and size of a tumour can make tissue sampling difficult. Some parts of the body like the pancreas and brain arenāt very accessible.
The procedure can be expensive and invasive. Think long needles and lots of trained staff on hand.
This limits the frequency of sampling and makes monitoring cancer progression and treatment response more difficult.
š” Solution
In recent years, a new technique has gained traction - the liquid biopsy. It normally involves a simple blood test, and therefore has several advantages:
Itās relatively quick, cheap and less invasive
Because of this, liquid biopsies can be obtained more frequently
The process is less damaging to DNA - making it more amenable to sequencing (weāll see why this is important below)
š Terms
Tissue biopsies. A medical procedure that involves using a needle to take a small sample of tissue. The sample might be analysed under the microscope and subjected to variety of other tests to determine certain characteristics of the tumour.
Liquid biopsies. Described as āliquidā because rather than analysing a piece of tumour, a sample of blood is taken instead. Two main components of the blood are of interest:
Circulating tumour DNA (ctDNA) - fragments of DNA released into the bloodstream by tumour cells as they grow and die. The molecular assays used to detect ctDNA have only recently become sensitive enough to pick up the relatively small quantity found in bodily fluids. Assays used to detect viral or bacterial DNA benefit from much larger quantities.
Intact circulating tumour cells (CTCs) - cancerous cells found in the bloodstream that work to help the cancer spread (metastasize)
Analysis of ctDNA and CTCs can provide a snapshot of the āgenomic landscapeā of the tumour. The analysis is normally carried by one of two methods:
Polymerase chain reaction (PCR) is a relatively fast and cheap tool but can only assess for a few mutations at a time.
Next generation sequencing (NGS) on the other hand is comparatively expensive, slow and more technically difficult but can assess for a much broader range of mutations.
š History
Weāve known about fragments of DNA swimming around in the bloodstream for a while. For a long time however, no-one really caredā¦
1948 - French scientists - Mandel and Metais - are the first to demonstrate the presence of cell free DNA (cfDNA) in blood. Their discovery doesnāt get much attention.
1977 - Scientists identify abnormally high levels of cfDNA in cancer patients relative to healthy individuals. The cfDNA is presumed to mainly reflect ctDNA.
1994 - cfDNA analysis of patients with certain blood cancers identifies mutations on the āRasā gene - a significant mutation for the development of these type of cancers.
1997 - Foetal cfDNA is identified in the blood of pregnant women.
2005 - Researchers carry out the first clinical study for the detection of mutations through cfDNA analysis.
2012 - First attempt is made to screen mutations involved in cancer treatment resistance by analysing ctDNA.
2013 - ctDNA is used to monitor the progression of metastatic breast cancer.
2014 - The first commercially available multi-gene liquid biopsy platform becomes available.
2015 - Merck develop liquid biopsy test for metastatic colon cancer.
2016 - FDA approves Rocheās ācobas EGFR Mutation Testā for use in lung cancer patients.
2020 - FDA grants breakthrough device designation for the āFoundationOne Liquid CDxā test for ovarian, breast and lung cancer, and āGaurdant360 CDxā test for lung cancer.
š¼ Use cases
Liquid biopsies have a range of use cases:
Diagnosis. Identifying ctDNA or CTCs that must have originated from a cancerous tumour.
Treatment planning/tumour profiling. Deciding which treatments will be most effective based on the mutations present.
Treatment monitoring. Finding whether further mutations have made the cancer resistant to treatment.
Cancer recurrence. Based on ctDNA or CTC detection, is there evidence that the cancer has returned?
š„Ā Players
Companies and institutions are doubling down on liquid biopsy research. The global liquid biopsy market is expected to grow by $4.02B between 2020 and 2024. Here are some of the major players.
Companies
Foundation Medicine - US subsidiary of Roche and makers of the āFoundationOne Liquid CDxā test. Can be used in prostate cancer and lung cancer. Utilises NGS.
Guardant - US āprecision oncologyā company and makers of the āGuardant 360 CDxā test. Can be used in lung cancer. Also utilises NGS.
Roche - your favourite Swiss multinational and makers of the ācobas EGFR Mutation Test v2 CDxā. Can be used in lung cancer and only targets a few mutations related to the āEGFRā gene
Qiagen - Euro-US company headquarted in Germany. Make the ātherascreen kitā. Can be used in breast cancer and is able to detect 11 mutations in the āPIK3CAā genes.
Inivata - UK-based developers of the āInVisionā platform for ctDNA analysis.
Creatv Bio - biotech company and developers of the āLifeTracDxā blood test that analyses CTCs to identify a range of solid cancers.
ANGLE - UK-Canadian company providing specialist CTC enrichment and analysis services.
Biocept - molecular oncology diagnostics company focusing on isolating CTCs and ctDNA.
Institutions
European Liquid Biopsy Society - promote research around liquid biopsy and its use in clinical practice.
Institute of Cancer Research - one of the worldās most influential cancer research institutes. World leadersĀ inĀ identifying cancer genes,Ā discovering cancer drugsĀ andĀ developing precision radiotherapy.
BloodPAC - have a mandate to accelerate the development, validation, and clinical use of liquid biopsy assays.
š Impact
The evidence-base is emerging for liquid biopsies, but here are some of the higher profile trials that are ongoing or recently reported:
Trials
STIC CTC METABREAST (ongoing) - randomised trial using CTCs to determine if hormone therapy or chemotherapy should be administered to breast cancer patients. Aims to show that using CTCs versus the standard treatment pathway doesnāt lower survival rates.
PROLIPSY (ongoing) - early detection of prostate cancer by analysing circulating blood-based biomarkers. Primarily aim to assess the validity of CTCs and tumour cell products circulating in blood for early prostate cancer detection.
PlasmaMatch (completed) - cohort study with 1034 patients with advanced breast cancer. ctDNA testing was able to drive mutation-directed therapies with sufficient clinical validity for adoption into routine clinical practice.
PREVAIL ctDNA (ongoing) - pilot study for patients presenting with symptoms of pancreatic, lung, bladder and colorectal cancers will aim to replace invasive tissue biopsies with a liquid biopsy.
IDx-LUNG (ongoing) - prospective cohort study to determine whether adding blood or tissue biomarkers to low-dose CT scanning improves diagnosis in population screening for lung cancer.
š® Predictions
Broader scope. Many liquid biopsy products are authorised to guide the use of a particular drug for a specific cancer (known as a companion diagnostic). As more trials report on the results of liquid biopsies, their treatment guiding ability will likely broaden.
Precision medicine. Liquid biopsy will be the archetype of precision medicine. Targeted treatments based on the unique characteristics of someoneās cancer with a strong (albeit emerging) evidence base.
Next generation sequencing. Basically PCR on steroids. Many of the early products in liquid biopsy can only identify a handful of gene mutations in selected genes. The ānext generationā tests will be much more extensive - think multiple mutations, multiple genes.
Improved accuracy. The challenge in collecting clinically meaningful information from CTCs can't be overstated. A blood sample might have 10 CTCs in a background of 10^6Ā white blood cells and 10^9Ā red blood cells.Ā Definitely needle in a haystack territory. ctDNA can also be ācontaminatedā with non tumour DNA fragments that are present in the blood. Extraction of CTCs and ctDNA will improve, leading to improved accuracy in the analysis stage.
Tissue biopsies. Although harder to collect, tissue biopsies are tried, tested, and still able to identify more cancer mutations. They will likely remain the gold standard for many years to come.
Screening and diagnosis. Early stage tumours donāt release that much DNA. This might limit the role of ctDNA in early stage diagnosis in asymptomatic individuals. The benefit of earlier diagnosis will need to be balanced against the cost and patient suffering associated with false positive results. Routine blood tests in order to detect 'cancerā might not be on the cards any time soon.
Move over DNA. ctDNA and CTCs are great, but researchers are already exploring other cancer related biomarkers that can be found in blood, including exosomes, miRNA, RNA and tumour-educated platelets. Not sure what tumours are teaching platelets, but it canāt be goodā¦
š Opportunities
Build the evidence base. A lot of the liquid biopsy trials to date have been observational in nature. Not bad, but more randomised interventional trials are required to determine if liquid biopsies are better than the established treatment pathways.
Standardisation. Thereās a huge research effort underway in liquid biopsy. But the array of different technologies and pursuits runs the risk of confounding the field and obscuring important progress. The International Liquid Biopsy Standardization Alliance (ILSA) is working to develop a coordinated effort.
Infectious disease. The covid pandemic has highlighted how infectious disease can disrupt the normal functioning of the healthcare system. Tissue biopsies have been delayed because they require specialist staff in specialist centres who have been diverted elsewhere in the pandemic. The relative ease of carrying out liquid biopsies may ensure continuity in cancer care despite the presence of global pandemics.
Stronger together. Rather than viewing liquid biopsy as the heir-in-waiting for tissue biopsy, thereās a huge opportunity in utilising them concurrently to build detailed genomic profiles of cancers that can guide treatments. Itās worth noting that sampling the mutations from just one piece of tumour might not reflect all the mutations present, which is why reviewing the ctDNA alongside is important.
Treatment optimisation. Cancers can develop resistance to treatments through further mutations. Establishing regular liquid biopsies throughout the treatment can ensure that patients can remain on the optimum treatment throughout the course of their treatment.
Treatment tracking. Immumotherapy involves repurposing an individualās immune cells to fight cancer. However it doesnāt work for all patients and itās difficult to know how long the treatment should last. Liquid biopsy to monitor the levels of ctDNA compared to the patientās ctDNA baseline might have an emerging role in guiding immunotherapy treatments.
š Links
This Nature Paper by one of the leading researchers in the field about what is required to further develop liquid biopsy and cement its use in routine clinical practice.
This Lancet editorial exploring how far we are from a universal blood test for asymptomatic screening of several cancers (and what financial and ethical questions remain unanswered).
Thatās it for this week - catch ya next time š