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20th May 2024
With the potential of personalised medicine becoming ever clearer, clinicians are increasingly turning their attention to the various ways in which this can be realised, and genomics is a prime example of where huge progress can be made. Consultant in medical oncology Dr Nirupa Murugaesu discusses how the 100,000 Genomes Project has supported both research and service delivery in the UK and how whole genome sequencing can be harnessed to transform cancer care.
In October 1990, some of the best scientific brains in the world began working on an international programme to sequence an entire human genome. It took 10 years to complete an initial sequence and cost billions of US dollars.
Fast forward to today, and the picture is vastly different. ‘Because of next-generation sequencing and advances in technology we are now able to sequence a genome comprising around 20,000 genes in less than a week, at a fraction of the cost,’ says Dr Nirupa Murugaesu, consultant in medical oncology and cancer genomics lead at London’s Guy’s and St Thomas’ NHS Foundation Trust.
‘We can now see how routine sequencing to understand the mutational landscape of cancers has helped in terms of understanding more how the cancer is likely to behave, and also determining the best treatment approaches for patients.’
Dr Murugaesu is also principal clinician in cancer genomics and clinical studies at Genomics England. The organisation has been collaborating with NHS England, Queen Mary University of London and the University of Westminster on research into how whole genome sequencing can be combined with clinical data from patients to identify changes in in their cancer’s DNA.
The study, published earlier this year in the journal Nature Medicine, involved more than 13,000 participants with solid mass tumours, and examined clinicopathological data – their type of cancer, histological subtype, the behaviour of their tumour, the types of treatment and survival – over a five-year period.
By combining that information with genomic data, the researchers could pinpoint the cancer’s genetic changes and mutations that resulted in different outcomes. Crucially, this can improve precision cancer care, meaning therapies can be better targeted and individualised to each patient.
Participants were recruited as part of the UK’s 100,000 Genomes Project, which has also collected and analysed data on a number of rare diseases. The solid cancer study found that, through whole genome sequencing, clinicians can use a single test to uncover genetic changes in a tumour.
What sets this study apart from other research in genomics is that, for the first time, the information collected could be applied in real-world settings and in real time, Dr Murugaesu explains.
‘The unique selling point was to have a research study that is embedded within a healthcare system. After the genomes were sequenced, the results were in fact returned to the respective hospital trusts and treating clinicians,’ she says.
‘Normally when research is carried out, the results are not necessarily fed back. We have clinical trials and outcomes that do not always reflect what we end up seeing in practice. But here, we have that real-world clinical information linked with patients’ genomic data, so if there were relevant findings that could be acted upon, this could be undertaken by the treating clinical team.’
Currently, this can be applied in healthcare settings and influence how cancer patients are treated. In particular, it may be helpful in knowing which treatments are less likely to work, or which may not be necessary. ‘If we know from the data that a person’s tumour is likely to be less aggressive, we can decide to not overtreat them, and we can give less-toxic therapies,’ Dr Murugaesu says.
In addition, clinicians can provide patients with more information about how their cancer is likely to behave and what their prognosis may be. In the future, as more data are accumulated and genomics research progresses further, they may be used to develop new and improved therapies as well.
Having laid the groundwork for genomic testing in England, the 100,000 Genomes Project has led to a Genomic Medicine Service being developed and rolled out nationwide.
As a result, Dr Murugaesu says there are criteria for ensuring that minimum standards are met for testing different cancer types, and, importantly, that testing is provided equitably across the country, rather than only at larger cancer centres.
Enormous progress has been made from the early shoots of genomics, when sequencing took years and had a hefty price tag, to becoming embedded into routine care. Now, however, training and education must keep pace with the science, Dr Murugaesu explains.
‘It is now about upskilling the workforce – not just oncologists, but the whole multidisciplinary team – so they understand the role of genomics, and that there is a Genomic Medicine Service available to their patients,’ she says.
In addition, infrastructure and pathways must be set up efficiently to ensure that when a patient undergoes genomic sequencing, their results are returned to their treating team in a timely manner. If genomic testing is performed alongside a biopsy to confirm a cancer diagnosis, and taking that as Day 1, the goal is to have the results back by Day 14, Dr Murugaesu says.
‘That is a challenge that’s not consistently being met, but work is ongoing and one of the main focuses over the next year will be to try and understand the bottlenecks so we can streamline these pathways,’ she adds.
Other technology will have a role in supporting enhanced learning about the genomics of cancer, too. A case in point is liquid biopsies, whereby a blood sample can enable the extraction of circulating tumour DNA – which is shed by tumours, especially those that are more advanced – and sequencing of that DNA can then be undertaken, just as you would for a genomic panel. ‘The repertoire is expanding for what is available and possible to fully molecularly profile tumours,’ Dr Murugaesu says.
Again, performed as soon as there is radiological suspicion of cancer, a simple blood sample can enable genomic sequencing of the tumour’s circulating DNA. If successful, this testing can potentially circumvent problems associated with tissue biopsies, such as not getting enough tissue to yield meaningful results. This has implications for patients – needing to go through the upheaval of a repeat biopsy, for example – and places resource and time pressures on healthcare systems.
A pilot exploring this technology in non-small cell lung cancer is currently under way and has demonstrated promising results in the initial phase.
‘The next phase has now launched and there will be 10,000 tests made available across England for patients with suspected lung cancer, which is exciting because there’s a real opportunity to expand our circulating tumour DNA testing,’ Dr Murugaesu says. ‘There is more and more emerging data about what the role of circulating DNA may be, including screening and earlier detection of cancers.’
There is interesting work in genomic testing across Europe, too. For example, scientists at The Hartwig Medical Foundation in Amsterdam found clinically relevant data from almost 5,000 metastatic solid tumour samples, and supported recruitment to a large-scale trial in the Netherlands – the Drug Rediscovery Protocol (DRUP) trial.
The study is collecting information on the off-label use of registered targeted therapies for patients with incurable cancer who have exhausted standard treatment options, based on their tumour’s molecular profile.
This is one way of embedding genomic testing into cancer care. Dr Murugaesu hopes this becomes routine in the future so that not only will whole genome and genomic panel sequencing help predict the best therapies, but also it could identify whether patients are at increased risk of their cancer reoccurring.
There is enormous potential for genomic medicine to take much of the guesswork out of how tumours are treated, and to be truly transformative in cancer care globally.
17th February 2024
Speaking at Hospital Healthcare Europe’s Clinical Excellence in Cardiovascular Care event, Dr Rebecca Dobson discussed the need and demand for cardio-oncology services, how they’ve developed over time and the current state of play in this evolving field, as well as providing an overview of cardio-toxicity.
A decade or two ago, there was no such thing as cardio-oncology, and Dr Rebecca Dobson, consultant cardiologist specialising in imaging and cardio-oncology at Liverpool Heart and Chest Hospital and the Clatterbridge Cancer Centre, says things have ‘progressed somewhat from the days when all you were interested in was an ejection fraction’.
In fact, specialists like Dr Dobson – who also heads up her regional cardio-oncology service – now combine their wide-ranging cardiology expertise with close multidisciplinary working to allow cancer patients to receive the best possible treatments safely and minimise cancer therapy-related cardio-toxicity across the entire continuum of cancer care.
For a long time, everyone’s known that certain cancer therapies can affect the heart and, traditionally, these patients have been seen in heart failure clinics because we were looking for left ventricular systolic dysfunction.
But as the global burden of cancer has increased, and the treatments that we use to treat these cancers have increased, we’re seeing more and more patients with cancer who are exposed to more and more potentially cardio-toxic therapies, who would then potentially require the input of a cardiologist to maximise their cardiac health.
Previously, if a patient had cancer and was treated with cardio-toxic treatment, unfortunately, their outlook would have been relatively poor and a cardiologist would very rarely have to get involved with that patient’s treatment. Whereas now patients are living a lot longer with the effects of the cancer therapies.
And I think this is a real testament to the advances within oncology – the field is advancing at a really rapid pace, which is great for patients from a cancer point of view but it has important implications from a cardiology point of view.
What we don’t want to do with patients is cure their cancer and forget about their heart because it would be a real tragedy to cure someone’s cancer and then they end up having an avoidable cardio-toxicity.
It’s really important that we think about these patients’ cardiovascular health, and I think in the past, as cardiologists we’ve often almost shied away from patients with cancer. And I think we’ve probably done some of our patients a bit of a disservice because there is a lot we can do, and we need a rapid response service so that we can see these patients quickly.
I think a lot of patients worry that when they come to a cardio-oncology clinic, that we’re going to put up barriers and say, ‘you can’t have your cancer therapy’. And sometimes we do have to do that, but it’s actually quite rare. Far more often, we can facilitate the necessary cancer therapy by optimising the cardiac side of things.
Then at the other end of the spectrum, we look after patients who have been happily cured of their cancer, but who are at risk of late effects. So, these will be, perhaps, children or young adults who’ve had cancer at a young age and had lots of cardio-toxic therapy, but who are living with that increased risk for the rest of their lives.
These are the patients that we really don’t want to lose track of – they need to stay on someone’s radar so that we can screen them at regular intervals and pick up any issues at the earliest possible point.
One of the service fundamentals, I would say, is that we provide prompt cardiology input. At the moment, the way we’ve set our service up means we can see patients within a week to two weeks, so it’s a very responsive service. There’s lots of moving patients around to try and make sure that the most urgent patients get seen most quickly.
It also has to be based upon collaborative, multidisciplinary working. There is no point me sitting in my hospital at Liverpool Heart and Chest doing my cardiac thing with the patients and not talking to the oncologist who’s three miles up the road. It’s all about efficient communication with the oncologists, with the surgeons, anaesthetists, whoever it is who’s involved in that patient’s care. It is a truly multidisciplinary specialty, and I think it has to be because these are complicated patients and the last thing we want to do is make a decision that denies someone that a potentially life-saving cancer therapy.
I’d like to think that we offer a really holistic approach to patient care. And I say that with a smile on my face as a cardiologist because I know we’re not known for that – cardiologists will often focus on the heart and nothing but the heart. And I think these patients have such a lot going on with them, it’s really important that we recognise that within the service and work with other specialties to make sure we treat all of the patient and not just their heart.
Traditionally, cardiologists and oncologists have not worked closely together; we speak different languages. Certainly, when I when I first started in this subspecialty, I had no idea what a TKI was or what CHOP meant. And similarly, cardiologists have their own language talking about DAPT and TAVI and GLS. It’s really important that we try and understand where each other is coming from, understand clinical priorities, and have that collaborative approach to bridge the gap between the two specialties.
I’d recommend reading the 2022 ESC guidelines on cardio-oncology. It’s a really comprehensive document that covers lots of different types of cardio-toxicity.
It also includes a diagram that illustrates quite nicely the role of cardio-oncology care pathway. It’s important that we see patients at the beginning of their diagnosis, we follow them through their treatment, and we follow them up in the long term.
The diagram really illustrates the importance of risk stratifying patients at baseline and tailoring their cardio-oncology input accordingly.
I set up the service in 2019 and at that point, we were doing two cardio-oncology clinics a month. Now we’re running two and a half clinics a week and are looking to increase that further because the demand is there.
I also do a weekly ward round at Clatterbridge Cancer Centre, our local cancer hospital, which provides really useful input to the oncologists and radiotherapists there for inpatients with cancer who have a cardiac issue like atrial fibrillation or high blood pressure.
We run four weekly cardio-oncology echo lists and a weekly cardio-oncology MDT, which we do virtually and that’s probably the most important part of the service. Any patient who is particularly complex, where we’ve got important clinical decisions to make, will come through our MDT, and that will always have oncology, cardiology, radiology and usually cardiothoracic surgical representation.
We’ve recently taken over surveillance and management of all the region’s carcinoid heart disease patients. We’ve set up immunotherapy baseline screening programme so we can try and detect cardio-toxicity at an early stage. And we’ve worked with the radiotherapists at Clatterbridge to educate them and enable them to do their own cardiac monitoring for patients with cardiac devices when they’re receiving radiotherapy.
We’re quite busy, and we’re getting busier all the time, which is why we’re looking to bring in a cardio-oncology nurse specialist as soon as possible. We’re going to be running a physiologist-led echo clinic for those patients that don’t need to see a cardiologist. And we are also looking to improve our baseline ECG review for patients who are receiving immunotherapy.
I could talk for days about this! In the past, we’ve always thought about left ventricular systolic dysfunction being what we mean when we say ‘cardio-toxicity’. Certainly, a lot of what I deal with is cardiac dysfunction or heart failure, but it’s not the only thing I deal with.
It’s a real broad church of different manifestations of cardio-toxicity, which I think is probably another reason why I really enjoy my job – it keeps me on my toes. The more I do in this field, the more I realise that I’ve got a lot to learn and I’m always coming across another cardio-toxicity with a different type of drug.
From a cardiac dysfunction point of view, the drugs that we worry about the most are anthracyclines, the anti-HER2 therapies like herceptin.
From an arrhythmia point of view, oncologists do use arsenic to treat some types of cancers, and arsenic and tyrosine kinase inhibitors (TKIs) are very good at causing atrial fibrillation and arrhythmias. And TKIs and mTOR inhibitors are the main offenders for causing hypertension.
For vascular toxicity, it’s usually the drugs that we use to treat bowel cancer so 5FU, which can cause coronary artery spasm, which can be incredibly dramatic. We’ve seen patients who’ve presented with the peri-arrest with ST elevation that’s all settled down as that spasm is released.
And myocarditis is usually caused by checkpoint inhibitors or immunotherapies, but there are other drugs that can do it as well.
Cardio-toxicity does not always occur at the beginning when someone has commenced on systemic anti-cancer therapy. Patients who present very acutely within hours or days of commencing their therapy, although they tend to have a very dramatic presentation, ironically, they seem to have the best prognosis. Everything usually settles down with some treatment and is reversible.
It’s the patients who present months to years after having their treatment, who can be most challenging. This is why it’s so important to take a proper medical history for all patients and think outside the box.
Keep an open mind and remember that cardio-toxicity has lots of manifestations but also has a very variable timescale. If you’ve got a patient with any of these cardiovascular problems, always think: are they a cancer patient? Have they had treatment? When was the treatment?
Demand for collaborative cardio-oncology services is only going to go in one direction and it’s not just for cardio-oncologists, either. All clinical cardiologists are going to see patients with cancer in their clinics, whether that’s valve clinics, percutaneous coronary intervention clinics, heart rhythm clinics or hypertension clinics, because, as I’ve said, cardio-toxicity is much broader than left ventricular systolic dysfunction.
ESC’s position paper on baseline cardiovascular risk assessment in cancer patients from a few years ago is a really useful document.
If we can identify patients at high risk of cardio-toxicity from the beginning, we can optimise things as much as possible. It’s really important that we work with the oncologist to persuade them to take a blood pressure, to do an ECG and to take a history at the beginning of cancer therapy so that we can focus our energies and resources on those that probably need us most.
The ESC guideline published in 2022 comes with a risk calculator. You can download the app onto your phone, and then you put in the patient’s variables: age, troponin, previous history, whatever it might be. Then it will tell you whether they’re low, medium, high or very high risk.
In terms of what that means for their cancer therapy, we will sometimes make a decision with the oncologist and the patient that their risk is too high to proceed with cancer therapy. These are usually patients who are not due to receive curative chemo. If the chemotherapy makes the difference between life and death and is potentially lifesaving then it would be unusual for us to say we can’t give it.
Usually, we will do everything in our power to enable the oncologist to give what they need. But there are certain circumstances where that wouldn’t be the case. For example, I’d be very reluctant for patients who’ve had coronary artery spasm with cardiac arrest to have more of the same chemo because we know that the risk of recurrence is significant. But that would be quite extreme and, as I say, we would work hard to enable the chemo or other treatment to continue.
Sometimes there might be two different treatment options with different risks and benefits. We’ll always bring the patient into that conversation and say, ‘look, we’ve got two different options from a cancer point of view, one is associated with a risk to your heart, the other isn’t’, and we’ll talk a bit about the risk and benefit from the cancer and cardiology sided, and then make that decision together.
Nobody should be making unilateral decisions about these patients; it should be a real collaborative, multidisciplinary approach.
The spring 2024 Clinical Excellence in Cardiovascular Care event will take place on 19 March, with Dr Rebecca Dobson as chair. Registrations for all members of the multidisciplinary team are now open.
17th August 2023
A breakthrough in understanding nutrient ‘addictions’ in chronic myeloid leukaemia (CML) cancer cells has led to the discovery of a potential new treatment option for the condition.
Published in the journal Nature Communications, the study, led by the University of Glasgow, focused on identifying the role glucose plays in the behaviour of treatment-resistant CML stem cells.
The researchers found that these cells use glucose to fuel their mitochondria, which protects them from cancer treatments.
To combat this, the researchers successfully targeted the CML stem cells using an investigational drug that prevents them from absorbing glucose, weakening them and potentially making them more susceptible to cancer treatments.
The same drug, MSDC-0160, has been tested in other clinical trials for the treatment of type 2 diabetes and Alzheimer’s disease.
The research team is now exploring the possibility of pursuing a clinical trial to see if combining this drug with current CML treatments would benefit patients.
Professor Vignir Helgason, lead author of the study from the University of Glasgow, said: ‘Research has shown that cancer cells often rely on increased uptake of specific nutrients – sugar, proteins or fats – to survive. This suggests that if we can use drugs to target that nutrient uptake, it may in turn improve cancer treatments.
‘Our study investigated specific nutrient “addictions” in CML cancer cells. We were able to reveal that CML cancer cells use an increased amount of glucose to support their nutritional needs. Encouragingly, we were also able to show that the same cancer cells were sensitive to a newly developed anti-diabetic drug that prevents a normal breakdown of glucose, blocking the cells’ ability to absorb it.’
Dr Kevin Rattigan, co-author of the study, from the University of Glasgow’s School of Cancer Sciences, added: ‘Our study has revealed that the addiction to glucose is an Achilles heel for the CML stem cells that are resistant to current therapies. We were also able to show that a newly developed drug can prevent CML stem cells using glucose for energy. This breakthrough may lead to improved therapy options and outcomes for patients.’
Currently, CML is treated with tyrosine kinase inhibitors (TKIs), which limit the advancement of the disease but do not target the CML stem cells directly. Patients must remain on TKIs for the rest of their lives, with associated side effects and the risk of developing resistance to the drugs.
Commenting on the study results, Sarah McDonald, Blood Cancer UK’s deputy director of research, said: ‘Blood cancer is the UK’s third biggest cancer killer and receiving a blood cancer diagnosis can be life changing. While there is currently no cure for this form of blood cancer… research findings like these give the 750 people diagnosed with CML each year in the UK hope. ‘Looking at how existing drugs can be used in other conditions maximises their potential and provides insight into where future research can help those with CML.’
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