Diagnosis of cancer in the UK, and how it might change in future

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1 Diagnosis of cancer in the UK, and how it might change in future The UK has one of the poorest survival rates of cancer in Western Europe. Treatment given in UK NHS hospitals is possibly among the best in the world, so why is the outcome so poor? The most likely reason is the delay in diagnosing the disease soon enough for most cancers, the earlier the diagnosis, the more likely a favourable outcome of treatment. So, what happens now and how might that change in the future? The Present Most people prefer not to think about the possibility that they might have cancer, but one in two of us will be diagnosed with one of the many forms of the disease. How does that happen? It s possible that it will be picked up through a screening test, like a mammogram, or a Pap smear, or a test for blood in your stool, or a colonoscopy. All of these diagnostic tests are associated with some degree of discomfort so in general the take up rate is not particularly high. More likely, the first signs of the disease will be through a symptom: a lump somewhere, a cough that doesn t go away, a headache that doesn t seem the kind we all encounter from time to time, or perhaps abnormal bleeding; you may experience an unexplained weight loss, erectile disfunction, a strange looking mole, or some other slightly worrying symptom. You try to ignore it for a while, but finally your partner says, Why don t you see a doctor about that and after a bit more delay, you do. In the ten minutes GPs allocate to see patients, he or she will take a brief history and probably give you a quick examination. Then they will say one of three things: It s harmless; forget about it I don t think it s anything to worry about but let s keep an eye on it I think this needs to be looked at further; I m going to refer you to the hospital GPs are trained not to refer patients unnecessarily hospitals are overburdened as it so the third option is probably the least likely outcome of your consultation. You go away reassured you don t have cancer after all. But perhaps the worrying symptom doesn t go away, so it s back to the GP. After the second or third visit, you will get the hospital referral. Now you will see a consultant, who

2 takes a more detailed history, gives you a more thorough examination, and orders a blood test, some scans and possibly a biopsy. On your follow up visit, you will get the bad news: it looks like you may have cancer and, following government guidelines it will need to be treated in 62 days from the date of first referral surgery, radiotherapy, chemotherapy, or a combination of all three. Doctors classify cancers in various stages from 1 4 where stage 1 is often curable, but stage 4 has a poor outlook because it has spread beyond the original tumour site. Most cancers in the UK are diagnosed at stage 3 or 4, which is why the UK has among the worst cancer survival rates among European countries. This slightly oversimplified version of the events leading up to a cancer diagnosis points to two critical factors in improving survival: the time between appearance of the cancer and the methods used to reach the diagnosis. The earlier the diagnosis is made, the greater the chance of survival, but early diagnosis requires methodologies capable of detecting cancer at its early stages. When symptoms appear, it is usually too late; imaging methods like x-ray, CT or MRI scans only work when tumours are sufficiently advanced to be visible. Recently, the NHS in the UK, copying a model from Denmark, has trialled several cancer referral centres; the intention is to offer GPs and their patients a one-stop-shop for those presenting with vague but possible cancer symptoms. The diagnostic tests used in these centres are conventional but eliminate the need for patients to be referred from one department to another until a definitive diagnosis is made and treatment can commence. It is expected, and to be hoped, that this will allow diagnosis to be made earlier, thus improving survival rates. Professor Lord Ara Darzi, Imperial College London Kings Fund report The Future is Now (2015)

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5 The Future Can cancer be diagnosed earlier? There is quite a lot of interest in this idea both in the UK and indeed throughout the world. Most of the UK activity is based on better ways to accelerate patient pathways towards diagnosis, and refinements in imaging technology. But is it possible to diagnose cancer much earlier, at the pre-symptomatic or Stage Zero? The answer is probably not now, with existing technology but newer approaches are not too far down the line, with several different methodologies in clinical trial. Pregnancy is diagnosed in the home using a urine dip-stick; diabetics are familiar with daily finger sticks, producing a drop of blood which is applied to a test strip. These devices are biosensors, a device which converts a biochemical substance to a convenient readout. Imagine the benefits of a biosensor for diagnosing cancer: available instantly in the doctors office, or the home, no more biopsies or scans to make an initial diagnosis. Regrettably, it is not quite that simple, cancer is not one but several different diseases. However, there is currently a worldwide effort to develop such devices, with over $1 billion invested, and several clinical trials underway, it can only be a matter of time before cancer biosensors reach the clinic. These new diagnostic methodologies rely on the identification of bio-markers, biological or genetic fragments, or biochemical entities thrown off by developing cancer cells and microtumours. These tiny markers exist in extremely low concentrations, so require exceptionally sensitive analytical methods to detect them in blood, breath, and urine. Cancer grows though genetic mutation of cells, and dying cells shed some of their genetically mutated DNA into the blood stream, which can be sampled though a simple

6 blood test a liquid biopsy. Biomarkers also appear in breath or urine, making sampling even less invasive. Analysis of the blood sample allows identification of cells, and other biological and bio-chemical entities to not only diagnose cancer, but to determine the type of cancer and where it is from. Testing now under way can detect up to eight different cancer types. This is a challenge: to identify different cancer types, at exceptionally low concentrations, and at the same time not identify false positivescancers which are not there. Despite a worldwide effort, this screening test is not yet ready for routine clinical application, although several clinical trials suggest they are years, not decades, away. Commercial Cancer Screening Tests in Clinical Trials GRAIL, CA, USA (2016) uses genetic screening technology to identify cancer cells In order to enable the most accurate detection of early-stage cancer, GRAIL is conducting one of the largest clinical study programs ever pursued in genomic medicine Google s LabX, CA, USA (2014) is developing a Nanoparticle Platform technology using a pill containing nanoparticles which attach to cancer markers in the patient s blood and transmit data to a wrist worn device. Freenome, CA, USA (2014) is using Artificial Intelligence to decode the vast complexity of the cell free genome, turning hidden patterns to early screening tools for cancer. Owlstone Medical, Cambridge UK (2016) has developed a sensor chip allowing the detection of volatile organic compounds in breath the Breath Biopsy. Its clinical trials include LuCID, the world s largest breath-based study of lung cancer. Hitachi, Japan (2015) has been working on a urine screening test for cancer for three years, have detected 1300 metabolites and found 30 cancer biomarkers. It is now refining the test on 250 samples and plans clinical use in The test is intended primarily for breast and colon cancer. Inclusion of a company in this table does not imply any endorsement by Captum Capital Limited.

7 It is quite likely that blood, breath and urine testing will emerge in the next few years as viable tests for cancer with the goal of detecting the disease at the very early, Stage Zero, phase. It is highly likely in the immediate future that these tests will be useful for detecting Stage 1 or later cancers or monitoring the progress of already diagnosed cancers. Developments in medicine proceed slowly, but having tests which are faster, less invasive, and suitable for use in a doctor s office or home are all progress along the path to clinical acceptance. Moving to the point where such tests are applicable to most cancers at the pre-symptomatic Stage Zero, would be the greatest humanitarian achievement of biosensor technology elimination of scans and biopsies to reach a rapid, non-invasive definitive diagnosis of cancer. Cancer diagnosis requires more attention worldwide to: 1. Develop sensitive, specific low cost, rapid and selective techniques for early stage cancers 2. Create platform technologies to diagnose multiple cancers from a single liquid biopsy 3. Move diagnostic technologies more quickly from the research lab to the clinic more quickly 4. Work more closely in parallel with developments in cancer therapy: there will be little point in having a Stage Zero diagnostic test without a practical treatment for such early stage cancers. Cancer could become boring, like going to the dentist, you head in twice a year to have your blood tested. They may find you have zero stage cancer, you take a pill and you don t have cancer any more. That is the vision at hand. Vijay Pande, (2017) Head, biotech fund, VC Andreessen Horowitz Michael Brand PhD SM FRSC (mjb@captum.com) Michael is a founding director of Captum Capital Limited. In 2012 he created Sensor100, a global network of people active in the development of biosensors, which has highlighted the importance of that technology in cancer diagnosis. He and Suzanne celebrate their 45 wedding anniversary in Copyright Captum Capital Limited All worldwide rights reserved