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New clinical prediction tools for myeloma

Myeloma is a cancer of the bone marrow that caused 117,077 deaths worldwide in 2020 (International Agency for Research on Cancer). Earlier diagnosis improves the rate of survival but unfortunately, delays in myeloma diagnosis are common and result in poorer patient outcomes.

One of the reasons for the diagnostic delay is that myeloma symptoms are non-specific and relatively common in people without cancer. For example, back pain is associated with myeloma yet there are many other non-myeloma causes of this symptom. Additional measures are therefore needed to highlight the possibility of myeloma in patients where GPs do not originally suspect this disease.

GPs frequently order simple laboratory tests, such as the full blood count, to investigate patients presenting with non-specific symptoms. Previous work by Dr Constantinos Koshiaris, Dr Jason Oke, Dr Brian Nicholson and colleagues from Oxford’s Nuffield Department of Primary Care Health Sciences and the University of Exeter identified certain abnormalities in blood test results that indicate a higher risk of myeloma, such as low haemoglobin which can be observed up to 2 years before a myeloma diagnosis.

In this paper published recently in the British Journal of General Practice, the Oxford researchers have developed new clinical prediction models for myeloma that incorporate both symptoms and blood test results. Using the Clinical Practice Research Datalink (GOLD version), a primary care database containing electronic health records for more than 11 million patients in the UK, the team identified the most common symptoms and full blood count results recorded for patients with myeloma. The most predictive of these were included in the models they developed and the new tools were validated against a set of test data. Decisions made using their prediction models resulted in fewer false positives and more true positives when compared to single tests or symptoms alone.

By identifying patients at highest risk of myeloma in primary care, these new prediction rules have the potential to reduce diagnostic delays by a substantial amount. Further research is now needed to understand more about the feasibility and implementation of this tool in the primary care setting and the impact it will have on the diagnostic pathway and patient outcomes.

Early Detection Award for research into the clinical application of single cell genomics

Myelodysplastic syndromes (MDS) are a group of blood cancers in which the bone marrow fails to make normal levels of blood cells. MDS can be broadly classified into two major groups: high-risk MDS, in which patients progress to acute myeloid leukaemia with a very poor survival rate; and low-risk MDS, in which the disease is less aggressive but patients still suffer from a huge burden of symptoms, often the result of anaemia.

There are a number of exciting new targeted treatment options for low-risk MDS. However, these do not work in all patients and, particularly given the high economic cost of newer treatments, current biomarkers are not sufficiently predictive of treatment response. There is a need to more precisely categorise MDS to predict the disease trajectory and the response to therapy so that the most effective treatment can be given to each patient.

Large investments in sequencing technology in clinical laboratory services are enabling precision medicine in certain cancers and revolutionising patient care. Dr Onima Chowdhury, MRC Clinical Academic Research Fellow and Consultant Haematologist (MRC Weatherall Institute of Molecular Medicine and Oxford University Hospitals) is working with Professor Adam Mead, Dr Supat Thongjuea and Dr Lynn Quek at the MRC WIMM to explore the use of single-cell genomics in the clinical diagnosis and management of MDS. Funded by a Cancer Research UK Early Detection and Diagnosis Primer Award, the team will seek to develop a simple, clinically applicable processing and analysis pipeline, as well as identifying biomarkers that correlate and can perhaps supersede current diagnostic modalities.

Long-term, the team hope that this approach will be able to improve outcomes of patients through improved diagnosis, risk prediction and targeted treatment in MDS and other haematological malignancies.

Higher testosterone levels in men linked to greater melanoma risk

1 in 36 UK males and one in 47 UK females will be diagnosed with melanoma skin cancer in their lifetime. However, 86% of melanoma cases were preventable, as many cases are caused by UV ray exposure, but other factors can also play a role in who is most at risk, such as age and genetics.

A recent study lead by Dr Eleanor Watts at the Nuffield Department of Population Health has now found that testosterone is one of these risk factors. Published in the International Journal of Cancer, the team found that men with high levels of testosterone have an increased risk of developing a potentially deadly type of skin cancer. This was a result of studying blood samples hormone data. collected by the UK Biobank from 182,600 men and 122,100 postmenopausal women aged 40 to 69.

The researchers looked both the total level of testosterone in the blood samples, as well as levels that were freely circulating. They then used national registries and NHS records to explore whether participants went on to develop or die from cancer.

The results show that by 2015-16, after being followed for an average of seven years, 9,519 men and 5,632 postmenopausal women – 5.2% and 4.6% of participants respectively – had been diagnosed with a malignant cancer. By excluding other, non-melanoma diagnoses and accounting for other factors, they found that for men, higher levels of testosterone, whether freely or in total, were associated with a greater risk of developing malignant melanoma.

Specifically, each 50 pmol/L increase in free testosterone was found to raise the chance of developing this cancer by 35%. 90% of men included in the study had free testosterone concentrations of between 130 pmol/L and 310 pmol/L.

Among other findings, higher levels of freely circulating testosterone were associated with a greater risk of prostate cancer in men, while in post-menopausal women, higher levels of testosterone, whether freely circulating or in total, were associated with a greater chance of endometrial and breast cancer.

Dr Eleanor Watts, the first author of the research from the University of Oxford, says:

“There has been indirect evidence for testosterone and melanoma before, but this is the first time we have been able to look directly at the hormones in the blood

“Although we have seen associations of prostate, breast and endometrial cancer with testosterone before, this is the first time we have seen an association with risk of melanoma in men.”

 

About Eleanor

Eleanor is an Early Career Research Fellow in the Cancer Epidemiology Unit (CEU), part of the Nuffield Department of Population Health. Her research examines the role of endogenous hormones on prostate cancer risk using UK Biobank.

New funding for early diagnosis research using platelets

It is known that the earlier a cancer is detected, the more likely a cancer patient is to have better outcomes. One of the challenges for achieving early detection is to develop a minimally invasive test to detect the signs of early cancer in the body.

Because blood tests are simple to carry out in the clinic, a lot of effort has been focused on detecting molecules released from cancer cells in blood samples – so-called ‘liquid biopsies’. However, the majority of techniques that are used currently have a low sensitivity for early-stage cancers, due to low levels of cancer cell-derived molecules being present in blood plasma.

Dr Bethan Psaila, Cancer Research UK (CRUK) Advanced Clinician Scientist, Group Leader at the Medical Research Council Weatherall Institute of Molecular Medicine (MRC WIMM) and principal investigator at the Radcliffe Department of Medicine at Oxford University, is pioneering an approach that might be able to enrich for cancer-derived molecules in the blood. Working with Professor Chris Gregory (University of Edinburgh), Professor Paul Rees (University of Swansea) and Dr Henkjan Gersen (University of Bristol), Beth is leading a multi-disciplinary team that brings together cancer cell biologists, and imaging and engineering expertise to explore the use of platelets for early cancer diagnosis.

Platelets perfuse tumours and take up cancer cell-derived biomolecules. Isolating platelets from the blood and analysing their contents will hopefully be a more sensitive method for detecting cancer-specific molecules in the blood.

In this newly funded project, the team will use state-of-the-art pre-clinical models as well as samples from patients with colorectal cancer, pancreatic cancer and oesophageal cancer as exemplar cancers to assess the utility of ‘tumour-educated’ platelets (TEPs) for early cancer diagnosis. They will use detailed imaging and biomechanical techniques to assess whether TEPs can be reliably distinguished from platelets in healthy people or those with non-malignant disorders.

This multi-institutional project is funded by a Cancer Research UK Early Detection and Diagnosis Project Award and builds on a successful CRUK Innovation Award the team received after a workshop on liquid biopsy technologies in 2018. The ~£650,000 award will run for four years and will support two DPhil studentships, a postdoctoral research scientist and a research assistant.

Oxford spin out influencing patient care world wide

Optellum, a lung health company aiming to redefine early diagnosis and treatment of lung disease, today announced it received FDA clearance for its “Virtual Nodule Clinic”.

Optellum was co-founded by Oxford cancer researcher Prof. Sir Michael Brady with the mission of seeing every lung disease patient diagnosed and treated at the earliest possible stage, and cured.

Optellum’s initial product is the Virtual Nodule Clinic, the first AI-powered Clinical Decision Support software for lung cancer management. Their platform helps clinicians identify and track at-risk patients and speed up decisions for those with cancer while reducing unnecessary procedures.

Lung cancer kills more people than any other cancer. The current five-year survival rate is an abysmal 20%, primarily due to the majority of patients being diagnosed after symptoms have appeared and the disease has progressed to an advanced stage. This much-needed platform is the first such application of AI decision support for early lung cancer diagnosis cleared by the FDA.

Physician use of Virtual Nodule Clinic is shown to improve diagnostic accuracy and clinical decision-making. A clinical study, which underpinned the FDA clearance for the Virtual Nodule Clinic, engaged pulmonologists and radiologists to assess the accuracy for diagnosing lung nodules when using the Optellum software.

Dr Václav Potěšil, co-founder and CEO of Optellum says:

“This clearance will ensure clinicians have the clinical decision support they need to diagnose and treat lung cancer at the earliest possible stage, harnessing the power of physicians and AI working together – to the benefit of patients.

Our goal at Optellum is to redefine early diagnosis and treatment of lung cancer, and this FDA clearance is the first step on that journey. We look forward to empowering clinicians in every hospital, from our current customers at academic medical centers to local community hospitals, to offer patients with lung cancer and other deadly lung diseases the most optimal diagnosis and treatment.”

Funding to improve childhood, teenage and young adult cancer detection

Cancer is the commonest cause of death among children and young people in the UK and is associated with significant long-term morbidity. Unfortunately, the UK lags behind other high-income countries in the time it takes to diagnose childhood, teenage and young adult (TYA) cancer and this delay worsens patient outcomes.

One of the challenges in diagnosing childhood and TYA cancer is its relative rarity and non-specific presentation, and awareness campaigns have been run in an effort to improve recognition of cancer signs among health professionals. Although this resulted in improvements for certain types of cancers in children and TYA, the national time-to-diagnosis targets have still not been reached in all cancers for all age groups.

Dr Defne Saatci and Professor Julia Hippisley-Cox (Nuffield Department of Primary Care Health Sciences) have successfully applied for a Cancer Research UK Early Detection and Diagnosis Project Award to accelerate diagnosis of childhood and TYA cancer. They will use the QResearch database, the UK’s largest GP electronic health record database, covering 20% of the UK population and linked to national cancer, hospital and mortality registries. QResearch data will be explored to identify the early symptoms and signs associated with a subsequent diagnosis of the commonest childhood and TYA cancers (acute lymphoblastic leukaemia, lymphomas and central nervous system tumours) and this information will be used to develop a risk prediction tool for GP use.

By increasing the understanding about the clinical features associated with childhood and TYA cancers and developing this risk prediction tool for use in primary care, this study aims to make significant advancements in childhood and TYA cancer diagnosis and outcomes.

If you are an Oxford-based researcher thinking of applying for external early detection funding, please get in touch with the OxCODE Scientific Coordinator who can help to coordinate your application.

 

DeLIVER clinical research study underway as recruitment opens

DeLIVER is a five-year Cancer Research UK-funded research programme led by Professor Ellie Barnes (Nuffield Department of Medicine) that aims to detect liver cancer earlier. Liver cancer is the fastest rising cause of cancer death in the UK, with more than 5,000 deaths per year. To improve survival, it is crucial to diagnose liver cancer earlier, when current treatments are more likely to be successful. However, this is challenging because symptoms are vague and late-presenting, and are frequently masked by co-occurring liver disease, such as cirrhosis.

A major goal of the DeLIVER programme is to learn more about the biology of liver cancer development and to use this information to design more sensitive detection tests. Because many people being tested for liver cancer have the high-risk condition cirrhosis, these tests need to be specific enough to detect liver cancer on top of other changes in the liver caused by cirrhosis. In order to identify the defining characteristics of early liver cancer, researchers need to perform a detailed molecular analysis of tissue from tumours and the background liver in people with liver cancer and cirrhosis and compare this to liver tissue from people with cirrhosis alone.

The DELPHI (Deep Liver Phenotyping and Immunology) study will recruit 100 participants at Oxford University Hospitals NHS Trust. 80 of these recruited participants will have cirrhosis (caused by hepatitis virus B or C, fatty liver disease or alcohol) and 20-30 participants will have liver cancer in addition to cirrhosis. After giving consent, the participants will undergo fine-needle aspiration to collect tissue from the liver. This is a safe technique established in Oxford as one of only a few centres in the UK. Blood samples will also be taken.

Cancer Research UK Clinical Research Fellow Dr Rory Peters is leading the study. He said,

“We are very pleased to have started the recruitment for the DELPHI study. The in-depth analysis of samples from the DELPHI participants will be critical for increasing our understanding of how liver cancer develops and will give insights into how this cancer can be detected earlier.”

The researchers will look at individual cells to understand the cellular make-up of the tumour and surrounding tissue, including infiltrating immune cells, and how this may influence cancer development. By comparing the tissue from participants with and without cancer, they will also look for changes in protein or metabolite levels and alterations in the levels of chemical modification of DNA by methylation using the TAPS assay developed in Oxford by Dr Chunxiao Song. They will investigate whether the changes that they observe from the tissue analysis can also be detected in the blood, which would provide evidence that a blood-based assay could be developed as a less invasive diagnostic test.

Professor Ellie Barnes, Chief Investigator for DeLIVER said,

“The DELPHI study is one of three clinical projects within the DeLIVER programme. Together, these studies will inform us which of our diagnostic technologies perform best at detecting liver cancer at the earliest stages. We hope this work will lead to a step-change in earlier liver cancer diagnosis and improved patient survival.”

 

Read more about the DeLIVER programme in the OxCODE liver cancer early detection research showcase.

Registration open for Cancer Early Detection and Epigenetics Symposium

Join us and our co-hosts for this free virtual event on 28-29th April 2021 to hear the latest developments from international leaders in these fields

Drinking alcohol regularly increases cancer risk in Chinese populations

A new study demonstrates that reducing alcohol consumption in China could be an important cancer prevention strategy. Full story on the NDPH website.

For Western populations, there is a well-established association between regular alcohol consumption and a greater risk of various types of cancer. However, it was unknown whether these increased risks were the same for Eastern populations, which have very different drinking patterns and alcohol tolerance. Cancer rates are rising rapidly in China, and this may be partly due to more frequent alcohol consumption as citizens become more affluent. A new study led by NDPH on the large China Kadoorie Biobank has investigated this, with the findings published today in the International Journal of Cancer.

The study assessed over half a million adults recruited across ten diverse regions in China between 2004 and 2008. Each participant was questioned about their drinking habits, then followed up for a median period of 10 years. By the end of the study, almost 27,000 individuals had developed cancer (13,342 men, 13,619 women).

About a third of the men in the study drank regularly (at least once every week). Compared with those who abstained from alcohol, regular drinkers had a 26% higher risk for cancers previously associated with alcohol (ie, mouth/throat, oesophagus, colon-rectum and liver) and a 7% higher risk for all types of cancer. The risks were greater in those who drank daily or drank outside of meals.

For most of the cancers investigated, there was a clear dose-response relationship. Each 280 g/week higher alcohol intake was associated with an increased risk of 98% for oesophageal cancer; 74% for mouth/throat cancer; 52% for liver cancer and 19% for colon-rectum cancer. The study also found that each 280 g/week higher alcohol intake increased the risk of lung cancer (25%) and gallbladder cancer (60%), even though these cancers had not previously been clearly linked with alcohol.

In East Asia, many people cannot metabolise alcohol effectively due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2. This causes the carcinogenic compound acetaldehyde to accumulate, which can lead to facial flushing. In this study, those who experienced flushing after drinking had stronger associations between alcohol intake and cancer risk, particularly for oesophageal and lung cancer. This suggests that the risk of developing cancer is greater for those with low alcohol tolerability.

The associations remained strong when the researchers controlled for potential confounding variables including age, region, education, income, body mass index, physical activity, and fresh fruit intake. The association between alcohol and lung cancer was similar for regular smokers and those who had never smoked regularly. Nevertheless, large-scale genetic studies are needed to determine if the associations between alcohol and cancer are likely to be causal.

Very few women in the study drank alcohol regularly, hence the study was unable to assess whether the association between alcohol and cancer risk was the same for women.

Lead author Dr Pek Kei Im said: ‘Our study has clearly shown that among Chinese men, alcohol consumption is associated with increased risks of several types of cancer, including some that were less clearly established to be alcohol-related previously. This suggests that lowering population levels of alcohol consumption is an important strategy for cancer prevention in China.’

Developing a system to simultaneously detect genetic and epigenetic information

Many diseases are associated with changes to the DNA sequence, most notably cancer. Also altered in disease is the way that the DNA is decorated with chemical modifications such as methylation (epigenetic modifications). Being able to extract genetic and epigenetic information using DNA sequencing has revolutionised biomedical research and has led to new ways to diagnose diseases. A particular interest currently is in using genetic and epigenetic characteristics of tumour DNA circulating in the blood or other bodily fluids as a strategy for detecting cancer earlier. However, despite the potential utility of combining genetic and epigenetic information to enhance disease detection, no methods currently exist that can efficiently simultaneously extract this information from the same DNA sequencing data.

Up until now, DNA methylation has predominantly been detected using methods that rely on a process called bisulphite conversion. Bisulphite is a harsh chemical that damages DNA, resulting in decreased sensitivity and a high error rate in the sequencing data. Because it is not known whether any changes in the DNA compared to a reference genome are introduced by bisulphite or real mutations, it is very challenging to simultaneously detect methylation and mutation data using these methods.

Recently, a new bisulphite-free method for detecting DNA methylation called TET-assisted pyridine borane sequencing (TAPS) has been developed by Ludwig Oxford’s Dr Chunxiao Song and Dr Benjamin Schuster-Böckler. This method is both cheaper than bisulphite sequencing and importantly produces data of higher quality, similar to that of standard DNA sequencing.

In this project, funded by an MRC Methodology Research Grant, Dr Benjamin Schuster-Böckler will collaborate with Professor Gerton Lunter (Visiting Professor, Radcliffe Department of Medicine) to develop algorithms that simultaneously detect mutations and DNA methylation from TAPS data.  Experimental data will be provided in collaboration with Ludwig Oxford’s Dr Chunxiao Song and Professor Xin Lu, and Professor Ellie Barnes (Nuffield Department of Medicine). Test data will be used to train machine-learning algorithms to optimise the accuracy of the sequencing method and to establish the best possible experimental parameters for this technique.

The resulting method will greatly increase the utility of the TAPS technique and will make it possible to routinely query a patient’s genetic background, while simultaneously measuring their epigenetic state. This will lead to a much broader understanding of the role of epigenetics in disease and would raise the possibility of using combined genetic and epigenetic information from sequencing data to aid earlier detection of cancer.

Image attribution: Darryl Leja, National Human Genome Research Institute (NHGRI) from Bethesda, MD, USA, CC BY 2.0 https://creativecommons.org/licenses/by/2.0, via Wikimedia Commons