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  • The burden of breast cancer throughout the world is significant and increasing
  • Research has shown that a cheap pill (anastrozole) halves postmenopausal women’s risk of breast cancer and continues to be effective seven years after women stop taking the drug
  • Anastrozole has less side-effects and is more effective than comparable treatments
  • Government watchdogs both in the UK and US recommend anastrozole
  • But the uptake of the drug in the UK is relatively low
  • Doctors are not prescribing anastrozole and women are not availing themselves of the drug
  • The UK’s NHS should employ new behavioural techniques to influence and change doctors’ and patients’ decisions and increase the uptake of anastrozole to reduce the burden of breast cancer

Will behavioural techniques improve breast cancer outcomes?
 
Being a woman and growing older are two unavoidable risk factors for breast cancer. Indeed, most breast cancers are found in women who are 50 years or older. Despite significant advances in diagnoses and treatments, breast cancer is one of the rapidly increasing cancers among women and a significant cause of cancer-related morbidity and mortality worldwide.  Breast cancer alone accounts for 30% of all new cancer diagnoses among females and has become a major 21st century health challenge.
 
Study shows long term benefits of a cheap breast cancer pill

Research findings reported in the December 2019 edition of The Lancet and also presented at the  December 2019 San Antonio Breast Cancer Symposium in Texas, show that a cheap pill, anastrozole,  if taken once a day for 5 years, not only halves postmenopausal women’s risk of breast cancer, but continues to be effective seven years after stopping treatment, which for the first time, suggests a long-term benefit.
 
Relatively low uptake
 
The UK’s NHS watchdog, the National Institute for Health and Care Excellence (NICE), suggests that hundreds of thousands of healthy older women should take anastrozole to cut their risk of breast cancer and recommends that the drug is offered to postmenopausal women at moderate to high risk of breast cancer unless they have severe osteoporosis. However, evidence suggests that some doctors in the UK are not prescribing anastrozole and some women are not availing themselves of the drug despite its demonstrated clinical benefits and the fact that anastrozole is supported by NICE.
 
Jack Cuzick, the lead author of The Lancet 2019 paper, who is Professor of Epidemiology and the Director of the Wolfson Institute of Preventive Medicine at Queen Mary UniversityLondon, is concerned because although anastrozole is, “An agent that looks really effective with minimal side-effects and is available on the NHS in the UK; its uptake has been quite low with only a tenth of eligible women receiving it”. Cuzick’s concerns are echoed by Delyth Jane Morgan, Chief Executive of the charity Breast Cancer Now, who said: "It is worrying to hear that anastrozole may not be being offered to all that could benefit. We need to understand the extent of this potential issue. It's essential that we raise awareness of this option among doctors and patients".
 
 In this Commentary
 
Part 1 of this Commentary explores some of the reasons for the relatively low uptake of anastrozole. Part 2 describes new behavioural techniques, which could be cheaply and easily employed by health systems to increase the uptake of anastrozole and dent the burden of breast cancer. Also the Commentary: (i) describes breast cancer, (ii) provides some epidemiological facts of the disease, (iii) estimates the cost to treat breast cancer in the UK, (iv) describes hormone receptor positive breast cancer, (v) explains how anastrozole works and (vi) reports the findings of The Lancet 2019 study.

 
Part 1
 
 
Breast cancer
 
Cancer is a group of diseases that cause cells in your body to change and spread out of control. Most types of cancer cells eventually form a lump or mass called a tumour and are named after the part of your body where the tumour originates.

 

Breast cancer is characterized by the presence of cancer cells in the tissue or ducts of your breast. Most breast cancers begin either in the breast tissue made up of glands for milk production, called lobules, or in the ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective and lymphatic tissues. Advanced breast cancer refers to cancer that has spread outside of your breast to lymph nodes and/or distant locations in your body, often invading your vital organs.
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Epidemiology of breast cancer
 
Breast cancer is a common malignancy. Although more and more women are surviving the disease, each year in the UK there are over 55,000 new breast cancer cases: which equates to over 1,000 diagnosed each week. In the US, there are some 250,000 new breast cancer cases diagnosed each year: nearly 5,000 a week. Between 1993 and 2016 the incidence of breast cancer in the UK increased by 24%. Over a similar period, breast cancer incidence in the US declined, but an increasing trend of some 1.1% was observed among American Asians. In China, between 2000 to 2013, breast cancer increased at an annual rate of around 3.5%. Breast cancer rates in China are higher in urban areas than in rural areas: the higher the population density, the higher the rate. It is not altogether clear why breast cancer incidence is increasing. Experts suggest that breast cancer is a complicated disease with a variety of causes. Most cases of the disease are not linked to a family history. Around 5% of people diagnosed with breast cancer have inherited a faulty BRCA1 or BRCA2 gene. However, if you have a faulty gene, it does not mean that you will automatically develop breast cancer, but you are at higher risk. Out of every 100 women with a faulty gene, between 40 and 85 will develop breast cancer in their lifetime. Optimal therapy for breast cancer often requires several different treatment modalities including surgery, radiation, chemotherapy and hormone therapy (see below).
 
Cost of breast cancer treatment in the UK
 
The cost of treating breast cancer in the UK is significant and rising. Findings of research on the treatment costs of breast cancer published in the August 1999 edition of The Breast estimated that the average cost per case of breast cancer in the UK to be £7,247 (US$9,418).  Although the estimate is dated, it provides a guide. With 55,000 new cases of breast cancer diagnosed each year, the annual cost of treating the newly diagnosed alone, would be about £0.4bn (US$0.52bn). According to the UK charity Breast Cancer Now, an estimated 840,000  women  living in the UK have been diagnosed with breast cancer and the charity predicts that this figure will increase to 1.2m over the next decade. Thus, ceteris paribus, we can assume that the current annual cost  of treating breast cancer in the UK is significantly higher than £0.4bn and this figure is expected to increase substantially by 2030.
 
 
Hormones and hormone therapy
 
Hormones are chemical messengers secreted directly into your bloodstream, which carry them to organs and tissues of your body to exercise their functions.  Oestrogen and progesterone are steroid hormones produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women. These hormones play a critical role in regulating reproduction. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.
 
Similar hormones are produced artificially either for use in oral contraceptives or to treat menopausal and menstrual disorders. Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive (or hormone-dependent) breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors, which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes that can stimulate cell growth.
 
Anastrozole is a hormone therapy (also called hormonal therapy and endocrine therapy), which slows or stops the growth of hormone-sensitive tumours by either blocking the body’s ability to produce hormones or by interfering with the effects of hormones on breast cancer cells. Anastrozole blocks a process called aromatisation, which changes sex hormones called androgens into oestrogen. This happens mainly in the fatty tissues, muscle and the skin and needs a particular enzyme called aromatase.
 
 Prescribing anastrozole
 
Anastrozole belongs to a group of drugs called aromatase inhibitors, which are specifically designed to treat postmenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer.  It is most often prescribed as an adjuvant therapy (after surgery) to decrease the risk of your cancer returning but can also be used in the neoadjuvant setting (prior to surgery) to decrease the size of your cancer in the breast. Hormone blocking therapy is also used to treat breast cancer that has recurred or spread. Most hormone blocking therapy drugs such as anastrozole are taken daily in pill form.
 
Anastrozole also may be given to reduce the risk of breast cancer in women who have not had breast cancer but have an increased risk of developing it because of their family history. Most experts suggest that your breast cancer risk should be higher than average for you to consider taking anastrozole as a preventative strategy. If your cancer is hormone receptor negative, then anastrozole will not be of any benefit, because these cancers do not need oestrogen to grow and usually such cancer cells do not stop growing when treated with hormones that block oestrogen from binding.
 
Reasons for the relatively low uptake of anastrozole
 
There are at least three probably reasons for the relatively low uptake of anastrozole. These include: (i) doctors becoming so used to prescribing the gold standard tamoxifen as an adjuvant hormone therapy, (ii) doctors wanting to be convinced about anastrozole’s long term benefits, and (iii) doctors wanting assurance about anastrozole’s minimal side effects.
  
Tamoxifen
 
Tamoxifen is the oldest and most-prescribed aromatase inhibitor and for the past three decades has become the standard of care as the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. The drug reduces the risk of breast cancer returning by 40% to 50% in postmenopausal women and by 30% to 50% in premenopausal women. Notwithstanding, over the past two decades a new generation of aromatase inhibitors have been developed, and anastrozole is one of these. How does anastrozole compare with the gold standard tamoxifen?

Tamoxifen and anastrozole compared
 
Findings of two long-term comparative clinical studies undertaken in North America and Europe involving over 1,000 women with oestrogen receptor positive advanced breast cancer, showed that anastrozole is better than tamoxifen for: (i) increasing the time before the cancer returns in those who experience recurrence, (ii) reducing the risk of the cancer spreading to other parts of the body and (iii) reducing the risk of a new cancer developing in the other breast.

Significantly, studies have shown that anastrozole avoids two of tamoxifen's more serious side-effects: an increased risk of developing a blood-clotting disease and an increased risk of developing womb cancer.  Anastrozole can make bones weaker and so it is not recommended for women with osteoporosis and also it can cause stiff joints, hot flushes and vaginal dryness, which clinicians need to recognize and manage. But overall, the benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. However, anastrozole is not a therapy for  premenopausal women because it blocks the hormone oestrogen and in effect creates a drug-induced menopause.


Part 2

Increasing the uptake of anastrozole
 
For healthcare systems to function effectively and efficiently we expect doctors and patients to behave rationally and make effective and efficient decisions. Traditionally, the rational choice model, which is predicated upon the belief that all human beings (including doctors and patients) act rationally in their own self-interest, has been used to influence people to behave in desirable ways. However, evidence suggests that, despite the well-founded theory and sound evidence to support it, the rational choice approach does not appear to work that well in practice.



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Behavioral scientists not doctors will prevent CVD

 A newer theory to explain peoples’ choices and behaviours
 
A newer approach to influencing behaviour, which builds on decades of research by Nobel prize-winning psychologist Daniel Kahneman, and described in a book published in 2008 entitled Nudge, by Nobel Prize winning economist Richard Thaler and Harvard Law School professor Cass Sunstein, suggests that no choice is ever presented in a neutral way and people - including doctors and patients - are susceptible to biases that can lead them to make suboptimal decisions. The authors suggest that many decisions and consequent behaviours are made automatically rather than after a considered rational decision. And this applies to decisions about your health.
Policymakers have been quick to latch onto the possibilities of these new behavioural techniques. Following the publication of Thaler and Sunstein’s book in 2008, President Obama set up a “Nudge Unit” in the White House and the UK Government, under Prime Minister David Cameron, set up the Behavioural Insights Team, popularly known as the Nudge Unit, in 10 Downing Street, and other governments around the world have since followed suit.

Nudges
 
Nudges are particular types of interventions, which are used to change peoples’ behaviour and improve outcomes at lower cost than traditional tools across a range of policy areas. Nudge techniques have been used in healthcare to influence behaviour and decision making to improve patient outcomes. For instance, the behavioural analysis of the decision-making that leads to a patient taking one drug instead of another. A research paper published in 2015 by the UK’s Health Foundation entitled “Behavioural insights in healthcare” suggests that health messages are often inconsistent and confusing to patients and framing them using social comparison via descriptive social norms (pointing out what is commonly done) or using injunctive norms (pointing out what is approved of) has been demonstrated to change patients’ behaviour and thereby have the potential to improve patient outcomes.
 
Information design
 
Behavioural techniques suggest that more attention should be given to the design of health information because the design and the way information is presented can influence and change doctors' and patients’ behaviour. Clinical guidelines, patients’ checklists and decision aids can all be improved in terms of text and language (e.g. the use of “plain English” and behaviourally specific, concrete statements and presentation of risk) and appearance (e.g. colour, visual stimuli, images etc).
 
HealthPad advocates that health information can have significantly more influence on the choices that doctors and patients make and on their  behaviour simply by presenting critical information in a video format. Over the past few decades people have moved away from consuming information in written and audio formats to consuming information predominantly in a visual format.  
 
Shift to consuming information in video format
 
Consider the following as being indicative of this shift. 82% of Twitter’s 330m average monthly users consume information in video format. The video channel You Tube has over a billion users and more than 500m hours of video are watched on the channel each day. 72 hours of video are uploaded to You Tube every 60 seconds, and more video content is uploaded onto the channel in 30 days than the major US television networks have created in 30 years. To further put things into perspective, in 2017, 56 exabytes (equivalent to 1bn gigabytes) of internet video content was consumed on a monthly basis, and this figure is expected to more than quadruple to 240 exabytes per month by 2022.

Today, almost all industries,  with the exception of healthcare, use video formats to communicate and the overwhelming majority of people who have consumed information in video format say it has influenced their choices and changed their behaviour. With video becoming the most significant influence on consumer decisions, it seems reasonable to suggest that more health information needs to be communicated in a video format if it is to influence and change doctors’ and patients’ behaviours in order to improve medical outcomes, increase the quality of care and slow and prevent chronic lifetime diseases.
 
Prompts cues reminders and audits
 
Prompts, cues and reminders have been demonstrated to be generally effective “nudges” that can successfully change the behaviour of healthcare providers and consumers, as well as being relatively inexpensive and easy to administer. Audit and feedback “nudges” are also effective. A set of best practices derived from systematic review evidence suggests that various nudge-type interventions (notably information design and presentation) may offer new ways to enhance choices and change behaviour.
  
Takeaways
 
The burden of breast cancer is huge and increasing globally. Research has demonstrated that a cheap pill, anastrozole, halves postmenopausal women’s risk of the disease and continues to be effective seven years after women stop taking the drug. We suggest that healthcare systems should consider using new behavioural techniques to influence and change doctors' and patients’ decisions to increase the uptake of anastrozole to help reduce the burden of breast cancer. Evidence suggests that nudge-type interventions, if suitably applied, can influence and change the behaviour of doctors and patients and thereby contribute to the reduction of the burden of breast cancer. However, given the newness of these techniques the quality of evidence available about their impact is relatively thin and patchy. Notwithstanding, this suggests a need for more quality evaluation and synthesised evidence of nudge-type interventions, their behaviour change potential and their impact on reducing the burden of breast cancer and other chronic lifetime diseases.
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  • Bioengineers throughout the world are competing to achieve the Holy Grail: an affordable, point-of-care blood test - liquid biopsy - that detects cancer before any symptoms present
  • Success in achieving this will save millions of lives, substantially reduce healthcare costs and make investors, researchers and organisations billions
  • Despite significant advances no one has yet achieved the Holy Grail and there remains a substantial gap between researchers’ aspirations and reality
  • How close are we?

 
 

Finding the Holy Grail: early detection tests for cancer
 

 

“It’s too soon to even claim that the research is promising," commented Paul Pharoah, a professor at Cambridge University’s Centre for Cancer Genetic Epidemiology, on the research findings of  Daniyah Alfattani, a PhD student in the Centre of Excellence for Autoimmunity in Cancer (CEAC) at Nottingham University’s School of Medicine in the UK.
 
Alfattani was presenting research findings of a small study at the National Cancer Research Institute’s (NCRI) conference in Glasgow, Scotland, in November 2019, which is an international forum for showcasing cancer advances.
 
A September 2019 HealthPad Commentary described another early detection test for breast cancer called CanRisk, which has been developed by researchers from Cambridge University’s Centre for Cancer Genetic Epidemiology and  has the potential to identify women with different levels of risk of breast cancer.
 
Alfattani and bioengineers from the universities of Nottingham and Cambridge are players in a vast and rapidly evolving international army of researchers engaged in an intensely competitive global race to develop an affordable, point-of-care, early detection test (EDT) for cancer based upon a liquid biopsy and next generation sequencing technologies. The Holy Grail is for such a test to detect cancer cells in an asymptomatic patient, locate the tissue of origin and give that person an early diagnosis when treatment is more likely to be successful; and to do all this with 100% accuracy. 

Although Alfattani’s research study is modest, her findings are potentially clinically relevant because they are on the Holy Grail therapeutic pathway, and her preliminary findings suggest that a simple, cheap and easy-to-use blood test - liquid biopsy - could detect breast cancer five years before any symptoms present. If demonstrated to be exquisitely accurate, safe and efficient by a larger study, which already is underway at Nottingham University’s CEAC, Alfattani’s research could be a key to saving thousands of lives and substantial amounts of money.

 


Gold standard breast cancer screening
 
Currently, mammography screening is the gold standard for preventing and controlling breast cancer, which is costly to administer and only has a sensitivity between 72% and 87%.  For every death from breast cancer that is prevented by mammography screening, it is estimated there are three false-positive cases detected and treated unnecessarily. Further, nearly half of all cancer sufferers are diagnosed late, when their tumours have already metastasized. It is estimated that 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
In this Commentary
 
This Commentary provides a partial update of some bioengineering initiatives described in a 2016 HealthPad Commentary, to speed up and improve liquid biopsies, which can simultaneously detect cancer early and identify its tissue of origin. Although there have been significant developments, the challenge for liquid biopsy assays still remains the level of their positive predictive values. This Commentary provides a brief and partial epidemiology of breast cancer, describes Alfattani’s research and its findings and briefly mentions some similar research that is underway. We describe categories of biomarkers employed by researchers and indicate some advances in EDTs made by some giant biopharma companies as well as briefly describing another innovative university-based development. We conclude by suggesting that: (i) despite significant and well supported research endeavours over the past decade to develop EDTs, there still remains a gap between scientific aspirations and reality; and (ii) there appears to be a gap opening between commercially available personalised cancer therapies, which are by-products of EDT research and standard oncological therapies.
 
Partial epidemiology of breast cancer
 
Despite significant advances in the awareness, diagnosis and treatment of breast cancer, it still remains the most common cancer in women worldwide, contributing 25.4% of the total number of new cases of cancer diagnosed in 2018. Each year, more than 0.5m women throughout the world die from the condition.  In the US each year, over 268,000 new cases of invasive breast cancer are diagnosed in women, and over 41,000 women die from breast cancer. Between 1989 and 2016, death rates from female breast cancer in the US dropped by 40%. Over the past decade, death rates from breast cancer in older women in the US continued to decrease but remained steady in women under 50. Such decreases are attributed to increased awareness of the condition, earlier detection through screening and improved treatments. In the UK, there are over 55,000 new breast cancer cases diagnosed each year. In contrast to the US, since the early 1990s, breast cancer incidence rates in the UK have increased by around 19%, but death rates have fallen because of greater awareness, earlier detection and enhanced therapies. Notwithstanding, each year more than 11,000 women in the UK die from breast cancer. Furthermore, each year in the US, there are over 1.7m new diagnoses of all cancers, while in the UK there are over 360,000 new cases. Although recent advances in EDTs have the potential to decrease cancer deaths, as yet there is not a simple and cheap liquid biopsy, which can be used routinely  in clinics to diagnose a range of cancers early. .
 
Alfattani’s research
 
The research pursued by Alfattani and her Nottingham colleagues is predicated upon the fact that cancer cells produce proteins called antigens, which trigger the body to make antibodies against them. These are called “autoantibodies”. Researchers discovered that these tumour-associated antigens (TAAs) are good indicators (biomarkers) of cancer. Alfattani and her colleagues developed panels of TAAs, which are known to be linked with breast cancer as a technique to detect whether or not there are autoantibodies against them in blood samples taken from patients.

The Nottingham researchers took blood samples from 90 breast cancer patients at the time they were diagnosed with the disease and matched them with samples taken from 90 patients without breast cancer (the control group). Researchers employed technology (protein microarray), which allowed them to screen the blood samples for the presence of autoantibodies against 40 TAAs associated with breast cancer and also 27 TAAs not known to be linked with the disease. The accuracy of the test improved in the panels that contained more TAAs.

Findings

A panel of five TAAs correctly detected breast cancer in 29% of the samples from the cancer patients and correctly identified 84% of the control group as being cancer-free. A panel of seven TAAs was able to detect disease in 35% of cases with breast cancer and rule out 79% of patients in the control group. The most successful technique was a panel of nine antigens, which correctly identified the disease in 37% of cancer samples and no cancer in 79% of the controls. “The results of our study showed that breast cancer does induce autoantibodies against panels of specific tumour-associated antigens. . . . . The results are encouraging and indicate that it is possible to detect a signal for early breast cancer. Once we have improved the accuracy of the test, then it opens the possibility of using a simple blood test to improve early detection of the disease”, said Alfattani.

David Crosby, head of early detection at the Cancer Research UK charitysaid, “Diagnosing cancer at the earliest stages before it grows or spreads gives patients the best chance that their treatment will be successful. So, the potential to detect markers in the blood before other signs appear is promising”.
 
Similar studies
 
Nottingham University’s CEAC is also working on similar tests to that used by Alfattani for pancreatic, colorectal and liver cancers. Solid tumours like these, as well as lung and breast cancer, represent around 70% of all cancers. Further, a similar test for lung cancer is currently being tested in a randomised controlled clinical study in Scotland, which is believed to be the largest trial of its kind in the world, involving 12,000 people at high risk of developing lung cancer because they smoke.
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Participants in the study have been randomly assigned to two groups: one is given an autoantibody blood test and the other (the control group ) is not. Participants who test positive for the autoantibodies are then followed up with a CT scan every two years in order to detect lung cancer in its early stages when it is easier to treat. Findings suggest that the test detects lung cancer four years or more before standard clinical diagnosis. In the UK about 85% of lung cancer patients are left undiagnosed until the disease has spread to other parts of the body.

 


Liquid biopsies

 
Liquid biopsies require biomarkers, which are substances, structures, or processes in your body that can be analysed in order to explain the pathogenesis of cancer and other disease states, and thereby inform diagnosis, predict onset and suggest appropriate therapies. Notwithstanding, the multiple types of biomarkers have varying degrees of reliability. Initially, the principal focus of research into EDTs was largely focussed on circulating tumour cells (CTC) and DNA. More recently however, additional biomarkers have become an important focus for such research. Antibodies are just one type of molecular biomarker. Because antibodies function by binding specific antigens, attempts to identify antibody biomarkers have involved using antigens to capture antibodies that are overproduced in cancer. Identifying relevant antigens is critical for discovering antibody biomarkers. Array-based approaches employed by Alfattani and her colleagues depend on exposing serum samples from patients to an ordered array of putative antigens, capturing those antibodies that bind antigens on the arrays and measuring their levels. Antibodies that are present at significantly higher levels in the serum of patients with breast cancer, (compared to control serums from healthy patients) are candidate biomarkers. 
 
Because of the unreliability of such biomarkers, new liquid biopsy tests tend to be predicated upon the levels of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and exosomes. These also pose challenges because of the varying physiological levels of the different biomarker fragments in your bloodstream.
cfDNA refers to DNA molecules that circulate in your blood after cell death. The amount of cfDNA varies significantly depending on the location, type and stage of your cancer. Concentrations of cfDNA can range from 1 to 100,000 fragments per ml of blood.

ctDNA refers to DNA that comes from cancerous cells and is present in your bloodstream. As a tumour grows, your cells die and are replaced by new cells. Your dead cells decompose and their contents, including DNA, are released into your bloodstream. So, ctDNA are small fragments of DNA, the quantity of which varies between individuals and the location, type and stage of your cancerous tumour. Detection of single mutations in ctDNA requires a large volume of blood. The principal challenge of research predicated upon ctDNA is their relatively low abundance in your bloodstream. As a consequence, scientists cannot rely solely on ctDNA, and are forced to search for other genetic and epigenetic mutations in your blood.
Exosomes is another class of biomarker. Cancer related exosomes are nano-size membrane vesicles that play important roles in tumour microenvironment. A 2007 paper in Nature Cell Biology 
suggested that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of a tumour. Since the 2007 Nature paper, research into exosomes has increased and they are now being used as diagnostic and prognostic biomarkers for various cancers. 

 
CancerSEEK

 
An innovative liquid biopsy called CancerSEEK, which has been developed by researchers from the Johns Hopkins Kimmel Cancer Center, in Baltimore, USA, is expected to make early cancer detection a part of routine medical care. Significantly, the test screens for eight common cancers, which account for more than 60% of all cancer deaths in the US. Currently, five of the cancers covered by the test have no screening test. CancerSEEK combines cutting-edge liquid biopsy technology with a machine learning engine, which is expected to improve the test’s accuracy with every person it screens. Findings of a retrospective study of multiple cancer types published in the February 2018 edition of the journal Science suggested that CancerSEEK has a sensitivity between 69% and 98% for ovarian, liver, stomach, pancreatic and oesophageal cancers, a specificity of 99%. Further, the study suggested that the test  has a false-positive rate of less than 1%. In 2019, CancerSEEK received Breakthrough Device designation from the US Food and Drug Administration (FDA) for the detection of genetic mutations and proteins associated with pancreatic and ovarian cancers, and also raised US$110m to launch a start-up company to develop the technology further.
 
FDA approval for a liquid biopsy developed by Roche
 
In June 2016, Roche, a global biopharma, became the first company to receive FDA approval of a liquid biopsy test to detect mutations associated with non-small cell lung cancers (NSCLC). Notwithstanding, the biopsy is not a universal test to detect the presence of NSCLC, but rather a test, which is being used in people with lung cancer to enhance personalised targeted therapies, and to monitor progression of the cancer. Some patients may benefit from the test's accompanying drug erlotinib (Tarceva), which treats NSCLC.
 
In September 2019, Genentech, a member of the Roche Group, announced positive results from the first prospective phase II/III clinical study to use a liquid biopsy and next generation sequencing to select treatment for people with NSCLC, without the need for a tissue biopsy. Next-generation sequencing facilitates the analysis of minute quantities of cfDNA circulating in the blood. In addition, Genentech is using machine learning algorithms on large data sets to characterize the molecular signatures of various cancer types.
 
Guardant and GRAIL
 
Previous HealthPad Commentaries have described research endeavours by Guardant Health  and GRAILwhich are “betting-on” liquid biopsies. Here briefly we update the developments of these two giant biopharma companies.

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In 2014 Guardant launched a next generation sequencing cfDNA assay called Guardant360 for treatment selection in a number of solid tumour cancers. In December 2018, the company launched an assay referred to as LUNAR to detect a range of early stage and recurrent cancers. LUNAR is based on data that Guardant collected from 80,000 advanced cancer patients using its 360 technology. In October 2019, the company launched ECLIPSE, a 10,000-patient clinical study to evaluate the performance of a second generation LUNAR blood test to detect colorectal cancer (CRC) in average-risk adults. The study is intended to improve CRC screening rates by offering a simpler liquid biopsy that overcomes challenges associated with current testing methods described above.
GRAIL has developed a prototype cfDNA sequencing assay to detect a range of cancers, many of which are not screened today and often present at late stages. Significantly, GRAIL has developed a prospective, observational, longitudinal clinical study called the Circulating Cell-free Genome Atlas (CCGA). The study has 15,000 participants across 142 sites in the US and Canada and has been designed to characterize the landscape of genomic cancer biomarkers of people with and without cancer. The company’s STRIVE study is fully enrolled with approximately 115,000 women and another study called SUMMIT also is fully enrolled with approximately 50,000 men and women aged 50 and older who do not have a cancer diagnosis at the time of enrolment.
 
Despite advancing technologies, FDA approvals, ongoing clinical studies and large and increasing investments in the development of liquid biopsies, (see a paper published in the June 2019 edition of Clinical and Translational Science entitled, “The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics”) there remains a substantial gap between scientific aspirations and reality. Liquid biopsies still do not provide physicians with a reliable, point-of-care means to detect cancer early and become a reliable substitute for the more invasive and more expensive gold standard tissue biopsy.
 
Takeaways
 
Liquid biopsies represent a large and rapidly evolving area of bioengineering. There are hundreds of research papers published in peer reviewed medical journals, which describe findings of the latest research in this area. Oncologists involved in EDT research are familiar with genomics, the molecular properties of cancer tumours and commercially available innovative therapies, which are by-products of EDT research, but many oncologists are not. This difference of knowhow seems to be creating another gap  between certain personalised cancer therapies advocated by research oncologists and standard cancer management provided in many clinics. Closing these gaps is partly contingent upon continued and open EDT research and more effective education.
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  • Prime editing devised by researchers at the Broad Institute led by David Liu is a significant advance of the original CRISPR gene editing tool discovered in 2012
  • CRISPR can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of incurable diseases and has revolutionized biomedicine
  • The original CRISPR is fraught with inaccuracies referred to as off target effects
  • Prime editing substantially reduces CRISPR’s off target effects and has the potential to correct up to 89% of known disease-causing genetic variations
  • CRISPR also has the capacity to edit genes in an embryo in such a way that the change is heritable
  • In 2018 Chinese researcher He Jiankui “created” the world’s first CRISPR babies
  • This triggered international criticism from scientists and bioethicists
  • A principal concern is that CRISPR is easy-to-use, cheap, regularly used in thousands of laboratories throughout the world and there is no internationally agreed and enforceable regulatory framework for its use
 
For better or worse we all now live in CRISPR’s world
 
In 2012 the world of biomedicine changed when a revolutionary gene editing technology known as CRISPR-Cas9 (an acronym for Clustered Regularly Interspaced Short Palindromic Repeats) was discovered. The technology harnesses your body’s naturally occurring immune system that bacteria use to fight-off viruses and has the potential to forever change the fundamental nature of humanity. Since its discovery CRISPR has been developing at lightning speed primarily because it is simple and affordable and today is used in thousands of laboratories throughout the world.
 
In this Commentary
 
In this Commentary we describe prime editing, which is the latest advance of the CRISPR's tool box, devised bya team of researchers, led by Andrew Anzalone, a Jane Coffin Childs postdoctoral fellow from the Broad Institute of MIT and Harvard and published in the October 2019 edition of Nature. Prime editing is significant because it provides a means to eliminate the unintentional consequences of CRISPR and therefore bring the technique closer for use in clinics. But this is still a long way off.
 
We also review a case where an ambitious scientist “created” the first CRISPR babies. This immediately triggered international criticism and a call for tighter regulatory control of the technology. Scientists and bioethicists are concerned that CRISPR can easily be used to create heritable DNA changes, which ultimately could lead to ‘designer babies’.
 
These two accounts of CRISPR might seem “opposites” and not sit well together in a single Commentary. Notwithstanding, what prompted putting them together was John Travis, the News Managing Editor of the well-known scientific journal Science, who soon after CRISPR’s discovery in 2012  said, “For better or worse we all now live in CRISPR’s world”
 
CRISPR and your DNA

CRISPR is different to traditional gene therapy, which uses viruses to insert new genes into cells to try and treat diseases and has caused some safety challenges. CRISPR, which avoids the use of viruses, was conceived in 2007 when a yogurt company identified an unexpected defence mechanism that its bacteria used to fight off viruses. Subsequent research made a surprising observation that bacteria could remember viruses. CRISPR has been likened to a pair of microscopic scissors that can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of intractable diseases. The standard picture of DNA is a double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. The fundamental building blocks of DNA are the four bases adenine (A), cytosine (C), guanine (G) and thymine (T). They are commonly known by their respective letters, A, C, G and T. Three billion of these letters form the complete manual for building and maintaining  your body, but tiny errors can cause disease.  For example, a mutation that turned one specific A into a T results in the most common form of sickle cell disease.
 
The original CRISPR
 
The original CRISPR tool, which is the first and most popular gene editing system, uses a guide RNA (principally a messenger carrying instructions from your DNA for controlling the synthesis of proteins) to locate a mutated gene plus an enzyme, like Cas9, to cut the double-stranded gene helix and create space for functioning genes to be inserted. However, a concern about CRISPR is that the editing could go awry and cause unintended changes in DNA that could trigger health problems. Findings of a study published in the July 2018 edition of  the journal Nature Biotechnology found that such inaccuracies, referred to as off-target effects, were substantially higher than originally reported and some were thought to silence genes that should be active and activate genes that should be silent. These off-target effects, such as random insertions, deletions, translocations, or other base-to-base conversions, pose significant challenges for developing policy associated with the technology.

Subsequently however, the paper was retracted, and an error correction was posted on a scientific website. Contrary to their original findings, the authors of the Nature Biotechnology paper restated that the CRISPR-Cas9 gene editing approach, "can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations".

 
Base editing

Notwithstanding, researchers remained concerned about CRISPR’s off target effects and several devised a technique, referred to as base editing, to reduce these. Base editing is described in three research papers published in 2017: one in the November edition of the journalProtein and Cell’, another in the October edition ofSciencethe and a third by researchers from the Broad Institute, in the October edition of the journal Nature’. Base editing takes the original CRISPR-Cas9 and fuses it to proteins that can make four precise DNA changes: it can change the letters C-to-T, T-to-C, A-to-G and G-to-A. The technique genetically transforms base pairs at a target position in the genome of living cells with more than 50% efficiency and virtually no detectable off-target effects. Despite its success, there remained  other types of point mutations that scientists wanted to target for diseases.

 

Prime editing
 
Prime editing is different to previous gene editing systems in that it uses RNA to direct the insertion of new DNA sequences in human cells. According to David Liu,  the senior author of the 2019 Nature paper and a world renowned authority on genetics and next-generation therapeutics, “a major aspiration in the molecular life sciences is the ability to precisely make any change to the genome in any location. We think prime editing brings us closer to that goal”.  Because prime editing provides a means to be more precise and more efficient in editing human cells in a versatile way, which eliminates many of CRISPR’s unintentional errors, it significantly expands the scope of gene editing for biological and therapeutic research.
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There are around 75,000 different mutations that can cause disease in people and prime editing has the potential to correct up to 89% of known disease-causing genetic variations. According to Liu, "Prime editing is the beginning, rather than the end, of a long-standing aspiration in the molecular life-sciences to be able to make any DNA change in any position of a living cell or organism, including potentially human patients with genetic diseases". Liu’s team at the Broad Institute intends to continue optimizing prime editing. In their October 2019 Nature paper researchers reported that they can precisely correct mutant genes, which cause sickle cell anaemia and Tay Sachs disease.
 

Sickle cell anaemia and Tay Sachs
 
Sickle cell anaemia is an inherited form of anaemia. This is when there are not enough healthy red blood cells  (haemoglobin) to carry adequate oxygen throughout your body. The condition is the most common inherited blood disorder in the US, affecting 70,000 to 80,000 and further it is estimated  each year some 300,000 babies are born with the disorder worldwide. Tay-Sachs disease is a rare and fatal nerve condition often caused by the addition of four extra letters of code.  Although anyone can be a carrier of  the disease it is much more common among people of Ashkenazi (Eastern European) Jewish descent. In the Ashkenazi Jewish population, the disease incidence is about 1 in every 3,500 new-borns and the carrier frequency is 1 in every 29 individuals.

 
Some moral and ethical implications of CRISPR
 
Being able to modify your DNA with CRISPR tools has transformed scientific research and is revolutionising medicine although it will be some time before the technology is regularly used in clinics. In addition to its potential benefits there are significant moral and ethical challenges associated with the technology, especially when it is used for germline engineering, which is the process by which your genome is edited in such a way that the change is heritable. Inappropriate use of germline editing could dent the progress of the CRISPR technology.
 
The first CRISPR babies
 
One well publicized  inappropriate use of CRISPR is a team in China, led by He Jiankui of the Southern University of Science and Technology in Shenzhen, which in November 2018 “created” the first gene edited twins, known by their pseudonyms Lulu and Nana. He edited the twins’ cells to be immune to HIV infection when they were embryos, therefore ensuring that every cell in their bodies were changed, including their reproductive ones, which means their edited genomes can be passed on to their children and grandchildren, despite the fact that scientists cannot be sure what the long term effects of such lasting modifications might be. The twins are the first CRISPR babies and the first humans to have every cell in their body genetically modified using the technology.
 
In 2015 Chinese researchers were the first to edit the genes of a human embryo in a laboratory dish. Although the embryos did not go to term, the experiment triggered an international outcry from bioethicists, who argued that CRISPR should not be used to make babies. Notwithstanding, He Jiankui did just this.
 
He  employed CRISPR to alter a gene in IVF embryos to disable the production of an immune cell surface protein, CCR5, which HIV uses to establish an infection before insemination. CCR5 is a well-studied genetic mutation, and there is scientific and medical value in understanding how CRISPR can be used to disable and prevent HIV/AIDS. He believed that the use of CRISPR technology was medically appropriate and expected his experiment, “to produce an IVF baby naturally immunized against AIDS”. But more contentiously, He created twins who could pass the protective mutation to future generations. It is CRISPR’s ability to easily and cheaply edit human embryos, eggs, or sperm in order to create irrevocable changes and the potential for designer babies, which raises concerns.  
 
He defended his work at a Hong Kong genomics conference in late November 2018, but there was immediate and significant international criticism about the scientific and ethical legitimacy of his experiments, which broached China’s guidelines as well as international ethical and regulatory norms. A Chinese government investigation found He to have violated state law in pursuit of “personal fame and fortune”.  His endeavours cost him his university position and the leadership of a biotech company he founded, which had successfully raised US$43m start-up capital and was advised by Craig Melloprofessor  of the University of Massachusetts Medical School and Nobel Laureate for medicine in 2006 for his genetics research.
 
Opacity and scientific competition
 
Some scientists are reluctant to be critical of He and suggest his studies, which resulted in the first CRISPR babies,  simply signal the “next chapter in the technology’s story”. He Jiankui appears to be an ambitious scientist desperate to become the first to conduct the gene editing experiment on humans, but who made some significant errors of judgement by initiating his study prematurely and by withholding information from regulatory authorities and his university. A generous interpretation might suggest that He was motivated by science and humanity. Through a Beijing-based organization, which helps Chinese people with HIV, he recruited couples for his experiment where only the fathers were living with HIV infections, which they managed by antiviral drugs. Eight couples agreed to participate, although one subsequently withdrew.
 
Since He’s statement at the Hong Kong conference he has disappeared, but the background to his studies has been well documented. In late 2017, He, who specialized in sequencing DNA, began his efforts to produce human babies from gene edited embryos and before and during his study it is reported that he sought advice from international experts in the field and communicated openly with international colleagues about his plans. Notwithstanding, it is alleged that He faked a blood test for one of the fathers in the study, aware that in China the HIV status of the father would disqualify him from participating in fertility treatments. Also, He failed to appropriately inform the hospital where the twins were edited and implanted of the status of his experiments.

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Fierce competition among scientists is not uncommon and competition fuels opacity among scientists in their battle to become the first to make a discovery. Indeed, it is not uncommon for scientists to shield their ideas and research. This does not condone He’s actions, but it might help to explain them. Generally speaking, scientific opacity is not created by ambitious scientists alone, but it is partly created by scientific funding bodies and research institutions. Such opacity is a significant obstacle to open collaboration. In addition to wanting to be the first, He’s intentions might also have been an attempt to spare children of parents with HIV/AIDS  from inheriting the disease.
CRISPR is not yet safe
 
Be that as it may, many scientists agree that CRISPR is not yet safe and precise enough to be used in human embryos. In the March 2019 edition of Nature a group of 18 prominent CRISPR scientists and bioethicists from seven countries called for a global moratorium on heritable genome editing until the establishment of an international framework that would compel countries to establish both scientific safety and broad societal agreement before allowing the technology to progress.  "We call for a global moratorium on all clinical uses of human germline editing; that is, changing heritable DNA (in sperm, eggs or embryos) to make genetically modified children" , the scientists wrote.

Opposition to germline editing is mixed
 
However, opposition to germline editing is mixed. In February 2017 the US National Academies of Sciences, Engineering, and Medicine (NASEM) published a report, which did not call for an international ban of germline editing, but instead suggested that it "might be permitted" if strict criteria were met. In July 2018, the UK’s Nuffield Council of Bioethics published a report on heritable genome editing and suggested that under certain circumstances it could be morally permissible, even in cases of human enhancement. 

Given that CRISPR is cheap, easy-to-use and already an effective tool in thousands of laboratories throughout the world, it seems reasonable to assume that standards and laws are unlikely to prevent a determined scientist and desperate patients from using the technology prematurely. Indeed, science and medicine have a history of researchers attracting public criticism for undertaking experiments prematurely only to have those experiments become common medical practices: in-vitro fertilization  (IVF) is one such example. Although IVF has a chequered history today it accounts for millions of births worldwide and  1% to 3% of all births every year in the US and Europe.
 
Germline engineering and somatic genetic modification
 
Here we describe the difference between germline and somatic adjustments. The former uses CRISPR to modify DNA in such a way that the change is heritable. The latter uses CRISPR to modify the DNA of people with incurable diseases in a way that such modifications are limited to the people treated and not passed on to future generations. Broadly speaking, your body has two kinds of cells: somatic and germ cells. The vast majority are somatic. These cells make up your body and are responsible for forming all your familiar structures: such as your skin, blood, muscles and organs etc. Your somatic cells die when you die so there is no chance of them creating a new organism. However, germ cells are different. Early in your development your germ cells  are sequestered: they divide more slowly and under restricted circumstances. Germ cells cannot become a physical feature such as an ear or a finger, but they do make the only bits of you, which can form a new person: your eggs and your sperm. Every cell in your body holds your DNA in an unbroken lineage stretching back millions of years and thousands of generations, but only the germline has a chance to go forward. Human germline modification means deliberately changing the genes passed on to children and future generations and thereby creating genetically modified people. Somatic genetic modification is different. It adds, cuts, or changes the genes in some of your cells, typically to alleviate a medical condition. The use of human genome editing to make edits in somatic cells for purposes of treating genetically inherited diseases is already in clinical studies. If perfected, somatic gene editing (gene therapy) holds promise for helping people who are sick, affecting only an individual consenting patient. With the exception of He’s studies, human clinical studies with CRISPR have been limited to somatic cells. In effect, this renders CRISPR no more consequential than any other experimental drug or treatment. Any CRISPR-made somatic cell changes are a genetic dead-end and are not heritable. However, germline cells have the possibility of immortality, with the potential to affect thousands of people over the course of several generations. Tampering with germline cells is therefore a much more serious proposition.
 
Clinical studies of gene therapies
 
Gene therapy is primarily available in a research setting. The US Food and Drug Administration (FDA) has approved only a limited number of gene therapy products for sale in the US.According to the US National Institutes of Health, which serves as a clearinghouse for biomedical research worldwide, there are over 800 clinical studies currently underway to test gene therapy as a treatment for genetic conditions. The list includes a relatively small number of CRISPR studies as a treatment for cancers of the lung, bladder, cervix and prostate, the majority of which are in China where doctors appear to be leading the race to treat cancer by editing genes. For the past two decades China has been investing heavily in biomedicine. It is one way that China is able to compete with the West and demonstrate its technological prowess in the 21st century. Also, it is important for China to keep its vast population healthy in the 21st century. Given the somewhat ambiguous state of CRISPR technology it seems reasonable to assume that the first therapeutic applications of CRISPR will be in diseases where cells can be taken out of your body, edited, checked to ensure they are safe and then reintroduced. This suggests blood disorders such as sickle cell or thalassemia.
 
Takeaways
 
Bioethicist Henry T (Hank) Greely, professor at Stanford University, California, US, compares CRISPR to the Model T Ford, which was not the first automobile, but because of its simplicity of production, dependability and affordability it transformed society. CRISPR is not the first gene editing technology, but it is cheap and easy to use and is on the cusp of transforming biomedicine. A significant challenge is getting CRISPR tools, which are capable of performing gene edits, into the right place and to ensure they are safe. Prime editing is a smart, innovative and a substantial step forward in achieving this. Indeed, David Liu and his colleagues from the Broad Institute  have expanded the gene editing toolbox to facilitate ever-more precise editing ability and efficiency. Significantly, the overwhelming majority of human genetic disorders are due to the types of mutation that prime editing is able to correct, which stands the technique in good stead to be useful in therapies for intractable diseases. Notwithstanding, it is one thing to cut out sequences of DNA that cause genetic diseases and another to make genetic changes that are passed down to all later generations. Because CRISPR is cheap, easy-to-use, in the hands of scientists throughout the world, and already has been used to create babies with heritable traits, the technology provokes deep ethical and societal debate about what is, and what is not acceptable in efforts to prevent disease. Given that CRISPR has the potential to change the nature of humanity, it is incumbent on all citizens, not just scientists, bioethicists and regulators, to call for open and inclusive processes associated with all aspects of CRISPR.
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  • Diabetic foot ulcers (DFUs) are a result of diabetes complications and can lead to amputations and death
  • Scientists and clinicians struggle to reduce the vast and escalating burden of DFUs
  • In wealthy countries like the UK there are specialist multidisciplinary diabetic foot clinics
  • New and innovative therapies are beginning to emerge, which accelerates the rate of complete wound closure for DFUs
  • Notwithstanding new products coming to market, the best therapy is prevention
  
The vast and rapidly growing burden of diabetic foot ulcers and amniotic tissue
 
This Commentary discusses diabetic foot ulcers (DFUs) within the context of chronic wounds. Although chronic wounds tend to be an overlooked area of medicine and do not feature prominently in the popular media; NHS England, spends £5bn a year treating 2m patients with chronic wounds. The incidence rates of people affected with wounds are rising fast and some experts suggest that nearly 60% of all wounds become chronic. According to Una Adderley, a wound expert and Director of NHS England’s National Wound Care Strategy Programme, therapy in England for chronic wounds is patchy and suboptimal, “leading to non-healing or delayed healing (which) increases the number of people living with chronic wounds. Too many people are receiving care for which there is little evidence that it works and too few are receiving care for which there is strong evidence that it works”.
 
According to a 2019 report by the consulting firm MarketsandMarkets the global wound care market in 2019 is estimated to be US$20bn and projected to reach US$25bn by 2024. Market drivers include the vast and fast-growing incidence rates of hard-to-heal chronic wounds, a large proportion of which are associated with diabetes, increasing R&D spending, technological developments, the growing use of regenerative medicine in wound care, recent advances in molecular data that have contributed to genome sequencing, and the increasing use of AI in the management of wound care solutions. The chronic wound care markets of North America and Europe are expected to grow at a CAGR of ~4.5% for the next 5 years, but the highest CAGR is expected in Asia where the vast pool of patients is increasing significantly, and favourable reimbursement policies are expected to persist in the region for the next decade. 

When accompanied by an underlying condition such as diabetes, chronic wounds in the form of DFUs, are challenging to heal and have a deleterious effect on your quality of life: you experience pain, suffering, disfigurement, anxiety impaired mobility, malodour and social isolation. Because the prevalence of diabetes is increasing worldwide, DFUs have become a large, severe and growing public health issue as described in two research papers published in 2019.
 
One, published in the May 2019 edition of Diabetic Medicine, reports findings of an 18 year study of DFUs, and suggests that although current therapies in the UK result in better than previously reported survival in persons < 65 years (10 year survival is 85%), treatments fail to, “reduce recurrent incidence (of DFUs and) cumulative prevalence of all ulcers continues to increase”; from 20.7 to 33.1 per 1,000 persons between 2003 to 2017. The second paper, published in the January-March 2019 edition of the International Journal of Applied Basic Research, report sfindings of a prospective Indian study of 63 patients >18 with DFUs and shows the increase in the severity of DFUs and the consequent increase in the rate of hospital readmissions, amputations and mortality.
 
In this Commentary
 
This Commentary briefly describes the increasing prevalence of diabetes and its complications, the causes and symptoms of DFUs, which benefit from specialist multidisciplinary clinics and strategies to prevent them deteriorating to the point where the only therapy is amputation. We complete the Commentary by briefly mentioning how human amniotic membrane is being used in the current standard of care as a therapy for DFUs and describe the findings of two amniotic membrane studies. Notwithstanding these and other new product offerings coming to market, which accelerate the closure of DFUs, the most efficacious therapy for DFUs is prevention.
 
Diabetes and DFUs
 
Diabetes is a chronic disease that occurs either when your pancreas does not produce enough insulin or when your body cannot effectively use the insulin it produces. Insulin is a hormone that regulates your blood sugar level. High blood sugar levels (hyperglycaemia) is a common effect of uncontrolled diabetes and can lead to serious complications, which include blindness, kidney failure, heart attacks, stroke, diabetic foot ulcers (DFUs), and lower limb amputations. According to the World Health Organization, the global prevalence of diabetes among people >18 has risen from 4.7% in 1980 to 8.5% in 2014. Today, some 422m people worldwide have diabetes, which has increased from 108m in 1980. There is expected to be some 642m people >18 living with diabetes by 2040.
 
If you have diabetes you are prone to ulcers because your increased blood sugar levels create thick, sticky blood, which can lead to  peripheral artery disease (PAD), neuropathy (a loss of sensation due to nerve damage), and/or problems with circulation due to damage to your small blood vessels, which reduce your body’s ability to heal injuries.
 
Signs and symptoms of DFUs include numbness in your toes and a loss of feeling in your feet, painful tingling sensations, blisters, minor abrasions and cuts without pain that do not heal, skin discoloration and temperature changes  With a loss of sensation, a minor injury to your foot can go unnoticed and untreated, and quickly lead to an ulcer. If you are living with diabetes, ulceration is an ongoing challenge. Only about 66% of DFUs eventually heal without surgery. If you have had a foot ulcer you are at increased risk of further ulceration. Studies suggest that around 25% of people living with diabetes who become ulcer-free have developed new ulcers within 3 months, and 34% to 41% within 12 months. Some foot ulcers are painful, and treatment often requires that you spend a significant amount of time visiting clinics to frequently change your wound dressings. The poor prognosis of DFUs is often attributed to other complications of diabetes such as peripheral neuropathy, peripheral vascular disease and persistent hyperglycaemia. Managing diabetic foot ulcers is a major challenge for healthcare systems globally and the main cause of more than half of nontraumatic lower limb amputations: every 30 seconds in the world, a lower limb is amputated due to diabetes. Amputations have life-altering repercussions for patients and represent a significant burden for the healthcare industry as a whole. Between 0.03% and 1.5% of people with DFUs require an amputation and most amputations start with ulcers.

 
Major amputations and mortality rates
 
For major amputations, the prognosis is poor because your other limb is at risk.  Research suggests that only around 50% of patients survive for two years after major diabetes related amputations. The one-year mortality rate has been estimated at 32.7% after major amputation and 18.3% after minor amputation if you have diabetes. Five-year cumulative mortality for patients with diabetes undergoing a first major amputation has been estimated at 68% to 78.7%. Thus, if you have diabetes and a DFU you have almost a 50% chance of being dead within five years, which is significantly higher than for people with either breast (18%) or prostate (8%) cancers.

 
The UK
 
In the UK some 70,000 to 90,000 people living with diabetes have DFUs at any one time. If you have diabetes you are about 23 times more likely to experience an amputation than someone without diabetes. In England, diabetes leads to more than 9,000 lower limb amputations each year. Each week in England some 169 people undergo an amputation procedure as a result of diabetes. Analysis by the charity Diabetes UK found that between 2014 and 2017, 26,378 people had lower limb amputations linked to diabetes, which represented a 19% rise from 2010 to 2013. Diabetes affects almost 3.7m people in the UK. In 2017 NHS England launched a special transformation fund aimed at improving patients with diabetes access to specialist multidiscipline foot care clinics to help avoid amputations.

 
Specialist multidisciplinary treatment centres
 
In the video below Hisham Rashid, Consultant Vascular Surgeon at King’s College Hospital, London, describes a DFU and explains why they benefit from specialist multidisciplinary treatment centres. “DFUs have similar features to other ulcers, and often present in the toes and heal areas of the foot with the loss of skin and an exposed base with infection and necrosis. The significant difference is that a DFU usually comes with multiple pathologies, which, in addition to infection, include neuropathy and peripheral vascular disease. DFUs do not heal quickly and often require vascular surgeons working closely with radiologists, orthopaedic surgeons to correct any deformity and a microbiology unit to manage infection,” says Rashid.

 
What are diabetic foot ulcers?
 
Why does therapy for diabetic foot ulcers complications require a special center?

Rashid also explains that different therapies are used to heal DFUs. “If the patient has peripheral artery disease (ischaemia) then this has to be treated first with an angioplasty or a bypass or both to improve blood circulation into the foot. Once this is achieved, the ulcer is debrided and dressed. There are different dressings, which include negative pressure dressing, which sucks the blood into the tissues and thereby promotes healing. Sometimes skin graphs are necessary to get the tissue to heal faster. This can be done as a day surgery using local anaesthetic,” says Rashid.
 

How do diabetic foot ulcers heal?

Prevention of DFUs
 
Given the severity of DFUs and their vast and rapidly increasing burden on individuals with diabetes and healthcare systems, increasing attention is being devoted to prevention,  which involves adequate glycaemic control and modification of risk factors. While education is an obligation of healthcare professionals, it is crucial that people living with diabetes themselves increase their awareness and understanding of the condition and integrate regular feet examination and care into their daily lives.  In the video below, Roni Sharvanu Saha, Consultant in Acute Medicine, Diabetes and Endocrinology, St George’s Hospital, London, suggests that, “We’re getting better at understanding why DFUs occur, and better at examining peoples’ feet. In England, if you have diabetes you are entitled to a clinical examination of your feet at least twice a year. Checks include whether you have any minor abrasions, or whether you can distinguish hot and cold water with your feet, and  signs that you might have problems with your circulation and nervous system. Ensuring that people living with diabetes receive regular checks means that if you have reduced or poor circulation, you’re referred to the correct specialty team in order to protect you from developing DFUs. Prevention is better that cure. If we can get better at examining feet, outcomes will improve. If diabetes is not controlled complications will occur”.
 
 
New therapies and amniotic membrane
 
With the well-being of millions of people living with diabetes at stake, there is a pressing need for therapies that bring DFUs to closure as quickly as possible. The current standard of care (SOC) regimen for DFUs involves maintaining a moist wound environment, debriding nonviable tissue, relieving pressure with an offloading boot and preventing or managing wound infection. Even with a good SOC, DFUs are notoriously slow to close, creating a demand for new and innovative medicines and techniques to enhance closure. Increasingly, there are advanced therapies to facilitate healing DFUs when traditional approaches fail.
 
An example of a relatively new product to help close DFUs is human amniotic membrane.  Amniotic membrane has been used for wound healing purposes since the early 20th century, but it represents a relatively recent and promising advanced therapy to accelerate healing in DFUs. Amniotic membrane is derived from the human placental sac that supports the foetus by forming the inner lining of the amniotic cavity. Functions of amniotic membrane include the exchange of water-soluble molecules and the production of cytokines and growth factors  to facilitate the development of the foetes. The anatomic makeup of amniotic membrane dictates its functionality, and a significant characteristic is its ability to produce a wide variety of regenerative growth factors that facilitate foetal development. These growth factors, in combination with various other cytokines, have substantial potential benefits in wound healing, which include creating a structural scaffold for tissue proliferation, modulating the immune response, reducing inflammation, stimulating angiogenesis and facilitating tissue re-modelling.

 
Two studies of human amniotic membrane products used in wound healing

Two small but significant prospective cohort studies on the effectiveness of human amniotic tissue to treat DFUs were reported in the journal Wounds. One in the March 2016 edition and another in the November 2017 edition. The first is a prospective, randomized, multicentre, controlled study and the second a retrospective cohort study of 20 patients. In both studies amniotic membrane is used in combination with SOC, including debridement, well-controlled offloading, management of bacterial burden, and adequate perfusion.
 
Both studies suggested that the use of amniotic membrane is more likely to: (i) lead to complete wound closure, (ii) accelerate the rate of wound closure, and (iii) present no additional safety risks when compared to SOC alone in the treatment of DFUs. The first study demonstrated a statistically significant advantage of an amniotic membrane as compared to SOC in facilitating closure of chronic DFUs. 45% of participants achieved complete wound closure, while 0% of SOC participants alone achieved complete wound closure within 6 weeks. Further, there appears to be no increased rate of adverse events associated with the use of amniotic membrane in these wounds. The second study was a retrospective cohort study using a human amniotic membrane on 20 patients presenting with DFUs and venous leg ulcers. Patients underwent a 2-week ‘run-in’ period with good SOC; and if upon their return the ulcer had closed ≥ 30% in area, the subject was excluded from participation in the study. All wounds were effectively closed in approximately 10 weeks, DFUs in 12 weeks and venous leg ulcers in 9 weeks, and no adverse events were noted, suggesting that the therapy using human amniotic membrane is safe.
 
Discussion
 
The most significant limitation of both studies is their small sample size, which decreases the generalizability of their findings. Notwithstanding, the studies suggest that amniotic tissue products are efficacious options for DFUs when used in conjunction with the current SOC, which includes aggressive sharp debridement, adequate offloading and the application of sterile dressings. Further, amniotic membrane, like most biologic tissue products, requires significant processing and therefore its cost is relatively high: on average between US$500 to US$1,000 per application. Notwithstanding, these costs are significantly less than the average annual therapy cost of US$28,000 per patient for SOC for a DFU. And therefore, using amniotic tissue in the therapy for DFUs could result in significant savings for healthcare systems. Tissue storage as well as the time and skill required to apply amniotic membranes also represent challenges inherent to these products.
 
Takeaways
 
Millions of people are living with diabetes, which, if not managed appropriately can lead to life-changing complications. A DFU is one such complication, which often starts with a minor abrasion on your ankle or toe that you do not feel and therefore tend not to perceive to be important, until that is, it quickly escalates into a chronic wound that does not heal and eventually leads to a lower limb amputation. In most wealthy nations, health providers are aware of the dangers of DFUs and have set up multi-disciplinary diabetic foot clinics to treat and manage the condition. However, access to such clinics is patchy and the prevalence of DFUs continues to increase, and the eye-watering costs of treating and managing DFUs continue to escalate. In recent years, the therapy for DFUs has been improved by technological advances. We describe one of these: the use of amniotic tissue in conjunction with standard of care protocols. Recent research findings suggest that the use of amniotic tissue holds out the possibility not only of significant therapeutic benefits, but also of substantial cost savings for healthcare systems. Notwithstanding, perhaps the most efficacious therapy for DFUs is prevention. This means investing in effective education and awareness programs, good glycaemic control and appropriate footwear; encouraging people living with diabetes to participate in regular foot examinations and screening for peripheral neuropathy and peripheral arterial disease, and insisting that early telltale signs of foot wounds, no matter how minor, should be immediately referred to a specialist clinic.
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  • Hydrocephalus is a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles and increases pressure inside your head
  • Failure to treat the condition can lead to morbidity and death
  • First line therapy is the surgical insertion of a ventriculoperitoneal shunt (VPS) to restore your CSF circulation
  • A significant risk with the procedure is infection
  • To reduce infection manufacturers’ impregnate standard shunts with either silver or antibiotics and market the impregnated shunts at higher prices
  • Which VPS (standard, silver or antibiotic) provides patients with the most protection from infection?
  • Which VPS is most cost effective for healthcare systems?

 

Standard, silver or antibiotic?

 

It” affects people in all walks of life and from every socioeconomic background throughout the world. “It” is as common as Down's Syndrome and more common than Spina Bifida. One out of every 1,000 babies are born with “it”. “It” affects about 1m people in the US  and “it” is the most common reason for brain surgery in children.
 
It” is Hydrocephalus; a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles, (fluid-filled areas). CSF disperses from your ventricles around your brain and spinal cord. Too much CSF may result in an accumulation of fluid, which can cause the pressure inside of your head to increase. In a child, this causes the bones of an immature skull to expand and separate to a larger-than-normal appearance.

There are no medical therapies to effectively treat hydrocephalus. The only viable treatment is surgical. The gold standard therapy is the insertion of a ventriculoperitoneal shunt (VPS), which is a common surgical procedure to restore your CSF circulation, regulate its flow and allow you to have a normal daily life. Notwithstanding, a significant challenge is infection at the site of the surgical wound, the shunt or in the cerebrospinal fluid itself (meningitis). This effects about 15% of hydrocephalus patients and may result in further surgeries, extended hospital stays, a reduction in your quality of life and a significant hike in healthcare costs.

To reduce potential infection manufacturers’ impregnate standard shunts with either silver (silver has benefits in reducing or preventing infection) or antibiotics and market the impregnated shunts at higher prices.
 
In this Commentary

 

This Commentary describes hydrocephalus and reports findings of a clinical study designed to determine, which ventriculoperitoneal shunt (standard, silver or antibiotic) provides patients with the most protection against infection and which type of shunt is most cost effective for healthcare systems. For completeness the Commentary briefly describes the causes of hydrocephalus, its signs and symptoms and how the condition is diagnosed.  Also, the Commentary briefly describes the procedure to insert a ventriculoperitoneal shunt.

 

Hydrocephalus
 
Hydrocephalus is a condition that occurs when excess CSF collects in your brain’s ventricles. CSF cushions your brain and protects it from injury inside your skull. Also, the fluid acts as a delivery system for nutrients that your brain needs and takes away waste products. Normally, CSF flows through these ventricles to the base of the brain. The fluid then bathes your brain and spinal cord before it is reabsorbed into your blood. When this normal flow is disrupted, the build-up of fluid can create harmful pressure on your brain’s tissues, which can damage your brain.
 
There are two principal classifications for hydrocephalus: (i) communicating and (ii) non-communicating hydrocephali. Both can be subdivided into congenital (present at birth) and acquired (occurs following birth). Communicating hydrocephalus can also be subdivided into normal pressure hydrocephalus (NPH) and hydrocephalus ex-vacuo, which occurs when there is damage to your brain caused by stroke or injury. It is generally understood that congenital hydrocephalus can be caused by genetic defects, which can be passed from one or both parents to a child, but the direct hereditary links are still being investigated. Notwithstanding, experts have found a connection between a rare genetic disorder called L1 syndrome and hydrocephalus. L1 syndrome is a group of conditions that mainly affects the nervous system and occurs almost exclusively in males.
 
Most babies born with hydrocephalus or who develop hydrocephalus as infants will have a normal lifespan, and approximately 40 to 50% will have normal intelligence. Seizure disorders have been diagnosed in about 10% of children with hydrocephalus and the mortality rate for infants is approximately 5%.
 
In the video below Sanj Bassi, a Consultant Neurosurgeon at King’s College Hospital, London and a member of the London Neurosurgery Partnership, describes hydrocephalus:

 

Causes
 
Some premature babies have bleeding in the brain, which can block the flow of CSF and cause hydrocephalus. Other possible causes of the condition include: X-linked hydrocephalus, which is caused by a mutation of the X chromosome and rare genetic disorders such as Dandy Walker malformation. This  is  a congenital (present at birth) defect, which affects the back part of the brain (the cerebellum) that controls movement, behaviour and cognitive ability. The most common cause of congenital hydrocephalus is an obstruction called aqueductal stenosis, which occurs when the long, narrow passageway between your third and fourth ventricles (the aqueduct of Sylvius) is narrowed or blocked, perhaps because of infection, haemorrhage, or a tumour. Other conditions, such as neural tube defects (like spina bifida), are also associated with hydrocephalus.

Signs and symptoms
 
Early signs of hydrocephalus in infants include bulging fontanel, which is the soft membranous gaps between the cranial bones on the surface of the infant skull; a rapid increase in head circumference; eyes that are fixed downward and poor feeding. In both infants and adults, symptoms include seizures; fuzzy vision, nausea, vomiting and excessive sleepiness. 

Diagnosing hydrocephalus
 
The diagnosis of hydrocephalus may be made before birth by an antenatal ultrasound. However, in many cases, hydrocephalus does not develop until the third trimester of a pregnancy and, therefore, may not be detected on an antenatal ultrasound. Congenital hydrocephalus may be diagnosed at birth. Important considerations include antenatal and birth history of your baby and whether there is a family history of hydrocephalus. Physical examination at birth can also detect hydrocephalus. A measurement of the circumference of your baby’s head is taken and compared to a graph that can identify normal and abnormal ranges for a baby’s age. Of interest to an early diagnosis for hydrocephalus are the developmental milestones in older babies since the condition may be associated with developmental delay, which might require further medical investigations for potential underlying problems. Other tests that may be performed to confirm a diagnosis of hydrocephalus include magnetic resonance imaging (MRI) and a computed tomography (CT) scan. MRI or CT images can reveal swellings of your brain or another condition that might be causing your symptoms, such as a tumour.
 
 In the video below Bassi describes how hydrocephalus is diagnosed:
 
 

 
 
Insertion of a ventriculoperitoneal shunt 
 
Although currently there is no known way to prevent or cure hydrocephalus, with early detection and appropriate intervention, the future for many patients with the condition is promising. The  gold standard treatment option available today is the surgical insertion of a ventriculoperitoneal shunt.

A shunt consists of two thin, long flexible hollow tubes, called catheters, with a valve that keeps fluid from your brain flowing in the right direction and at the proper rate and thereby reduces brain pressure to a safe level. To install a shunt a surgeon will make a small insertion behind your ear and also drill a small borehole in your scull. One catheter is then threaded into one of your brain’s ventricles through the hole in your scull, and the other is inserted behind your ear and threaded subcutaneously down to your chest and into your abdomen where excess CSF can drain safely, and your body can reabsorb it. Your surgeon may attach a tiny pump to both catheters and place it under the skin behind your ear. The pump will automatically activate to remove fluid when the pressure in your skull increases. Shunts can be programmable (externally adjustable by a magnetic device) to activate when the fluid increases to a certain volume, or non-programmable. Most surgeons tend to choose a programmable model, despite the fact that in clinical studies both types perform comparably.
 
In the video below Sanj Bassi describes both VPS therapy and some temporary treatment options for hydrocephalus. The latter includes medicines, which decrease the production of CFS, draining fluid from the spine via a lumbar puncture and draining fluid directly from your head into a bag via an external drainage system.

 
 
 
The Lancet study
 

To determine the relative clinical benefits and cost-effectiveness of the three different ventriculoperitoneal shunts (standard, silver or antibiotic) following their de novo insertions, the UK’s National Institute for Health Research funded a large prospective multi-centre randomised controlled clinical study - The British Antibiotic and Silver Impregnated Catheters for Ventriculoperitoneal Shunts Study - (BASICS). Findings were published in the September 2019 edition of The LancetThese concluded that shunts impregnated with antibiotics significantly reduce the risk of infection and also healthcare costs compared to both standard shunts and those impregnated with silver. Conor Mallucci, Consultant Paediatric Neurosurgeon at Alder Hey Children’s Hospital, Liverpool, UK, and lead author of the study, suggests that shunts impregnated with antibiotics should be, “the first choice for patients with hydrocephalus undergoing insertion of their first ventriculoperitoneal shunt”.

 

The Study’s clinical findings
 
Patient recruitment for the study took place between 2013 and 2017. Principal investigators assessed 3,505 patients and recruited 1,605 (children and adults) from 19 specialist neurosurgical centres across the UK & Ireland. Participants presented with hydrocephalus of any aetiology [including idiopathic intracranial hypertension (IIH), which is a condition with an unknown cause or causes and associated with raised fluid pressure around the brain]. All required an insertion of their first ventriculoperitoneal shunt.
 
All shunts used in the study were CE marked medical devices intended for the condition. Participants were randomly assigned to three groups: one group of 536 received a standard shunt, another of 531 received a silver impregnated shunt, and a third group of 538 received an antibiotic impregnated shunt. The minimum patient follow-up period was six months and the maximum two years. Six per cent of evaluable patients in both the standard and silver groups presented with infections and required a shunt revision. This compared to only 2% in the antibiotic impregnated shunt group that became infected and needed revising. The difference is significant.
 
The Study’s economic findings
 
The study’s clinical significance is enhanced by the fact that it provides the first health economic analysis of different VPS therapies from a UK perspective. Findings suggest that using an antibiotic impregnated VPS rather than either a standard shunt or those impregnated with silver, would result in annual savings to NHS England of approximately £135,753 (US$166,795) per infection avoided, which amounts to annual savings of some £7m (US$8.6m).
 
The research has a further significance because, despite the high medical costs of treating hydrocephalus, the annual spend  on hydrocephalus research is relatively low. For example, the US National Institutes of Health (NIH) invests less than US$8m per year in hydrocephalus research. This means that there is a dearth of clinical studies associated with the condition and no long-term follow-up research over the lifetime of patients.
 
Although BASICS is a significant study it should be mentioned that it is restricted by the relatively low proportion of patient-reported outcomes: 32, 31 and 12 reported infections after insertion of the standard, silver and antibiotic VPS’s respectively. 
 
Takeaways
 
This Commentary describes the findings of an important, well-conceived and well-executed clinical study of hydrocephalus. Its importance is derived from the fact that there’s a dearth of large prospective multi-centre randomised controlled clinical studies on hydrocephalus. The study’s findings are significant because they unequivocally suggest that, not only are antibiotic impregnated ventriculoperitoneal shunts more likely to deliver better clinical outcomes, but using them, instead of standard or silver impregnated ventriculoperitoneal shunts, would result in a substantial reduction in healthcare costs.
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  • CanRisk is a new online gene-based health-risk evaluation algorithm for detecting breast cancer
  • It identifies people with different levels of risk of breast cancer, not just those at high risk
  • As the infotech and biotech revolutions merge expect authority in medicine to be transferred to algorithms
  • CanRisk has the potential to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnosis before symptoms present
  • Breast cancer is the most common cancer in women worldwide and is the 5th most common cause of death from cancer in women
  • Currently mammography screening, which has a sensitivity between 72% and 87%, is the gold standard for preventing and controlling breast cancer
  • For every death from breast cancer that is prevented by screening, it is estimated there will be three false-positive cases that are detected and treated unnecessarily
  • Lack of resources do not support breast cancer screening in many regions of the world where the incidence rates of the disease are rapidly increasing
  • In the near-term expect interest in the CanRisk algorithm to increase
 
 A new comprehensive gene-based breast cancer prediction device

 
A new online gene-based health-risk evaluation device called CanRisk has the potential to identify women with different levels of risk of breast cancer; not just women who are at high risk. Predicated on a comprehensive algorithm, CanRisk is one of several innovations currently in development, which include novel methods for predicting the recurrence of breast cancer, a new class of molecules that aim to halt or destroy breast cancer, and liquid biopsies, which determine the presence and recurrent risk of the disease through the detection of tumour cells in peoples’ blood.
 
Although over the past two decades there have been significant improvements in the detection and treatment of breast cancer, the disease remains the most common cancer in women worldwide, with some 1.7m new cases diagnosed each year, which account for about 25% of all cancers in women and it is the fifth most common cause of death from cancer in women, with over 0.52m deaths each year.
 
Game changer for breast cancer
 
Findings of CanRisk were reported in the January 2019 edition of Genetics in Medicine. Findings of a less comprehensive version of the device’s algorithm were published in the July 2016 edition of the same journal. Commenting on the 2019 study, Antonis Antoniou, Professor of Cancer Risk Prediction at the University of Cambridge and lead author of the two studies said: "This is the first time that anyone has combined so many elements into one breast cancer prediction tool. It could be a game changer for breast cancer and help doctors to tailor the care they provide depending on their patients' level of risk”.
 
When fully developed and approved, CanRisk will be well positioned to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnostic test to detect breast cancer early in people with diverse levels of risk. This might be expected to provide an alternative to the current gold standard population-based mammography screening and assist in making a significant dent in the vast and escalating global burden of the disease.
 
In this Commentary
 
This Commentary describes the algorithm that drives CanRisk, which benefits from the increasing availability of vast and growing amounts of genomic and other personal data and significant advances in genomic sequencing technologies. The confluence of these two phenomena facilitates and enhances the quality and speed of data analysis and drives the development of new and innovative diagnostic and prognostic cancer technologies. The fact that CanRisk is based on UK data and its algorithm is available to researchers globally, presents a potential  opportunity for medical research organizations in emerging regions of the world where the burden of breast cancer is increasing. The Commentary briefly describes the heterogeneous nature of breast cancer and highlights some of its complexities and risk factors. Originally perceived as a Western disease, breast cancer is growing rapidly in Asia and other regions of the world where it tends to be detected late and managed less effectively. Developed economies prevent and manage breast cancer through well-established population-based mammography screening programs. Because of  the lack of resources,  such screening programs are not widely available in low to middle income countries (LMIC). As the infotech and biotech revolutions merge expect authority in medicine to be transferred to Big Data algorithms such as CanRisk. This not only could provide an alternative to gold standard mammography screening, but also provide a cheap and effective device for use in developing nations where the burden of breast cancer is significant and increasing.
 
CanRisk: a world first
 
CanRisk, developed by members of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, UK, takes advantage of discoveries in both cancer genomics and epidemiology and aims to become a popular device used by primary care physicians, in consultation with their patients, to effectively assess patients’ diverse levels of risk of developing breast cancer. The device is predicated on an algorithm called BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm). This is the world’s first polygenic breast cancer risk model and the only one to-date, which is available to the international research community. Also, it is the first breast cancer risk model to incorporate pathology data and population-specific cancer incidences in risk calculations. The algorithm accounts for over 300 genetic risk factors, including BRCA1, [BReast CAncer gene] BRCA2PALB2CHEK2, and ATM, which are genes that have been found to impact a person’s chances of developing breast cancer. The device uses a Polygenic Risk Score (PRS) based on 313 single-nucleotide polymorphisms (SNPs), [SNPs, pronounced ‘snips’, are the most common types of genetic variation in people. Each SNP represents a difference in a single DNA building block and is called a nucleotide] which explains 20% of breast cancer polygenic variance. CanRisk also includes a residual polygenic component, which accounts for other genetic/familial effects; known lifestyle/hormonal/reproductive risk factors and mammographic density [Dense breast tissue can make it harder to evaluate mammographic results and may also be associated with an increased risk of breast cancer].

 

Authority increasingly being transferred to algorithms
 
Over the past two decades we have increasingly learnt to accept the authority of Big Data algorithms. For example, without question we expect algorithms to give us directions, tell us what movies to watch, who to date, what clothes to wear, where to go on holiday, what flight to take, what hotel to stay in and where to eat. We are  comfortable with algorithms assigning us our credit rating, limiting our overdraft and capping our payments. Furthermore, we are beginning to accept the authority of algorithms in medicine. For example, we are gradually replacing the authority of primary care doctors with algorithms that can diagnose common diseases more accurately and more cost effectively.


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In December 2018, for the first time in history, the US FDA approved an algorithm to diagnose patients without a doctor’s interpretation. The algorithm, called IDx-DR, detects diabetic retinopathy by analysing images of the back of the eye. Indeed, we are living on the cusp of history when the twin revolutions of information technology and biotechnology are merging and providing the basis for us to transfer authority in medicine to algorithms. In the next two decades, it seems reasonable to assume that it will become common practice to accept the authority of algorithms such as CanRisk, which will inform us that we are suffering from a medical condition long before we present any signs or symptoms.
 
Increasing supply of data
 
CanRisk takes advantage of the fact that genetic and other risk factor data are becoming more easily available in clinical practice through electronic health records, biometric sensors that convert biological processes into electronic information, which computers can store and analyse, cost-effective high speed, high capacity genomic sequencing technologies, and efforts such as the 100,000 Genomes ProjectA UK Government sponsored initiative completed in December 2018, which collected, stored and analysed data from the genomes and medical records of 85,000 NHS England patients affected by cancer or rare disease. Genomics Englandwhich is wholly owned by the UK’s Department of Health, was set up in 2003 to deliver the project. Because CanRisk solely is based on UK population data, its findings are likely to be more applicable to similarly developed Western populations, and less so to populations in other regions of the world. This provides a potential opportunity for international organizations interested in early breast cancer diagnosis. 
 
International sequencing projects
 
The UK’s genomes project is part of a much larger rapidly growing and dynamic global genomics market comprised of data and gene sequencing technologies. 100,000 genomes have been the goal of several other nations interested in improving their healthcare - and lowering costs  - by carrying out precision medicine based on insights from sequencing data. Currently the global genomics market is estimated to be about US$19bn and projected to reach US$41bn by 2025. The market is driven by increasing government funding, the consequent rise  in the number of genomics projects, decreasing gene sequencing costs, growing application areas of genomics and the entry and fast growth of commercial players.

China has become the world’s leader in genomic sequencing. In 2010, the Beijing Genomics Institute (BGI) in Shenzhen was understood to be hosting a higher sequencing capacity than that of the entire US. While most government projects aim to sequence 100,000 genomes, China’s sequencing program is set to sequence 1m human genomes, which include subgroups of 50,000 people, each with specific conditions such as cancer or metabolic disease. The data will also include cohorts from different regions of China, which will facilitate “the analysis of different genetic backgrounds of subpopulations”.
 

Revolution in genome sequencing
 
The first human genome project began in 1990, took 13 years and about US$1bn to complete. The last two decades have seen a revolution in genome sequencing with dramatic increases in its speed and efficiency coupled with massive reductions in cost. Genomic sequencing has proved its usefulness as a diagnostic and prognostic tool. Today it is possible to get your genome sequenced for around US$1,000 in a few days and delivered by  post from firms such as Dante Labs and 24 Genetics in Europe, and Veritas Genetics and Sure Genomics in the US.
 
Breast cancer
 
Returning to breast cancer. It is important to note that the disease is not one, but  a group of conditions that manifest themselves with maladies in the same organ. Breasts are comprised of three main parts: lobules, which produce milk; ducts, which carry milk to the nipples; and fibrous and fatty connective tissue, which hold everything together. The type of breast cancer depends on which cells in the breast mutate, but most breast cancers begin in the ducts or lobules. Some mutated cells in the breast may never spread, however, most breast cancers tend to be invasive and may present with a number of different characteristics in terms of hardness and shape, which can provide some indication of their likely progression. Breast cancer can spread outside the breast through blood and lymph vessels. Further, there are significant differences in breast cancer at the genetic level. A study published in the April 2012 edition of Nature compared the genetic makeup of breast cancer tumour samples with their other characteristics for some 2,000 women, for whom information about the tumour characteristics had been meticulously recorded; and identified at least 10 distinct sub-types of breast cancer, each with its own unique characteristics. Although the study contributed to how breast cancer is diagnosed, classified and treated, in practice certain characteristics of these tumours were already known and tested for: most notably cellular receptors for estrogen, and progesterone, which are the two most significant steroid hormones responsible for various female characteristics. Their presence or absence generally suggests the potential utility of additional medication to accompany surgery, radiotherapy and chemotherapy.

 
Despite population screening and advanced therapies breast cancer remains a killer disease
 
Let us briefly consider breast cancer in the world’s most advanced and wealthiest nation: the US. Although there have been significant improvements in the detection and treatment of breast cancer in the US; still about 1 in 8 American women will develop an invasive type of the disease over the course of her lifetime. In 2019, an estimated 268,600 new cases of invasive breast cancer are expected to be diagnosed in the US, along with 62,930 new cases of non-invasive (in situ) breast cancer. Breast cancer death rates for women in the US are higher than those for any other cancer, besides lung cancer. As of January 2019, there were more than 3.1m women with a history of breast cancer in the US. Although breast cancer death rates in the US have been decreasing over the past three decades and women under 50 have experienced larger decreases, still some 41,760 are expected to die in 2019 from the disease. About 2,670 new cases of invasive breast cancer are expected to be diagnosed in men in the US in 2019 where a man’s lifetime risk of breast cancer is about 1 in 883.
 
Breast cancer challenges in Singapore
 
There are also breast cancer challenges in wealthy non-Western developed economies such as Singapore. Over the past four decades, the incidence of breast cancer in Singapore has more than doubled: from 25 to 65 per 100,000 women. Breast cancer is not just the most common cancer for Singaporean women, accounting for one in three cancers in women, but it is also the top killer. Data reported in the country’s Cancer Registry showed that 2,105 women died of the disease between 2011 and 2015. Notwithstanding, Singapore has extensive awareness-raising programs; population-wide mammography screening; excellent, multi-disciplinary primary and long-term care and improving palliative care, which have contributed to a significant increase in the survival rates of breast cancer patients. However, a substantial proportion of Singaporean women still appear to have a patchy knowledge of aspects of the disease, which leads to comparatively low participation rates in the nation’s breast cancer screening services, and this contributes to late presentation of the disease when it is more difficult to cure and more challenging to treat.

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Breast cancer growing rapidly in Asia
 
Breast cancer was once largely confined to developed Western countries and Australasia, but it has now become the most common cancer in Asia. Although Asian data on breast cancer are patchy, an Economist Intelligence Unit report, suggests that, “since the 1990s, increases in the incidence of breast cancer in Asia, as measured by age-standardised rates (ASRs), is four to eight times that of the global average”. Indeed, as younger cohorts of Asian women age and adopt Western diets and lifestyles (particularly fertility patterns, such as later first childbirth and shorter breast feeding), breast cancer incidence rates in Asia look set to converge with the much higher ones in the West.
 Further, in LMIC breast cancer is increasing at a more rapid rate than in the West and has become a significant healthcare challenge: 50% of breast cancer cases and 58% of deaths from the disease occur in LMIC.
 The significance of early detection
 
The good news is that if caught in its early stages, breast cancer can be treated effectively, with high survival rates. The average 5-year survival rate for women with invasive breast cancer is 90%. The average 10-year survival rate is 83%. If the cancer is located only in the breast, the 5-year survival rate of women with breast cancer is 99%. In all types of the disease early detection is the cornerstone of breast cancer control.
 
 Gold standard breast cancer mammography screening
 
The current gold standard for preventing and controlling breast cancer is population-based mammography screening. This is a non-invasive process that uses an x-ray of the breast to look for disease in women who do not have symptoms. The method has reasonable sensitivity (72%–87%) that increases with age and allows for the early detection of breast cancer, which helps increase survival, especially in women between 50 and 70. Notwithstanding, mammograms are not pleasant as the breast is squashed between two metal plates and further some women may find mammograms embarrassing.
 
Success of population-based mammography screening
 
Following a landmark Swedish study that began in 1977 mammography screening has been adopted in more than 26 developed countries worldwide. Findings of the study, reported in a 1989 edition of the Journal of Epidemiology and Community Health, suggested that mortality from breast cancer dropped 31% after screening of women aged 39 to 74. More recent findings of the UK screening program published in the June 2013 edition of the British Journal of Cancer, suggested mortality rates from breast cancer were reduced by 20% in the screened group compared to the unscreened group across all age groups. A study published in 2018 in Cancer, which tracked 52,438 Swedish women aged 40-69 from 1977 to 2015, suggested that regular mammograms contributed to a 60% decrease in breast cancer death during the first 10-years of diagnosis, and a 47% reduced risk within 20-years. Research has shown that mammography has relatively little benefit for women under 50.
 
Diverging views about mammography screening
 
Despite evidence to support the benefits of population-based mammography screening, there are diverging views among healthcare professionals about the impact of several decades of high levels of screening. Some argue that traditional mammography screening stretches finite resources and is not cost-effective because the majority of people who undergo screening do not have cancer and may never go on to develop it. Others suggest that there are significant uncertainties about the magnitude of the harms from mammography screening especially associated with false positives (a test result, which wrongly indicates that breast cancer is present).

Challenges of mammography screening
 
The sensitivity of mammography is between 72% and 87%, but is higher in women over 50 and in women with fatty rather than dense breasts. Dense breast tissue can make it harder to evaluate results of a mammogram. According to the Marmot review, for every death from breast cancer that is prevented by screening, it is estimated there will be three over-diagnosed or false-positive cases that are detected and treated unnecessarily. The chance of having a false positive result after one mammogram ranges from 7% to 12%, depending on age (younger women are more likely to have false positive results). After 10 yearly mammograms, the chance of having a false positive is about 50-60%. The more mammograms a woman has, the more likely it is she will have a false positive result. This makes it difficult for doctors to weigh and communicate the benefits and risks of mammography screening programs and fuels interest in innovations such as CanRisk.
 
Takeaways
 
Mammography screening for breast cancer is not 100% accurate. Further, knowhow, trained healthcare professionals and significant resources are required to effectively implement and manage a well-organized and sustainable breast cancer screening program that targets the right population group and ensures effective coordination and quality of actions across the whole continuum of care. These attributes tend to exist only in developed wealthy countries. CanRisk, and other innovative breast cancer early diagnostic devices under development, offer the potential for cheap, rapid, reliable and exquisitely accurate diagnosis that can be easily used in primary care settings throughout the world. In time, as authority in medicine passes to algorithms, expect these new and innovative devices to replace mammography screening in wealthy countries and quickly become devices of choice in developing economies and significantly dent the vast and rapidly growing global burden of breast cancer.
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  • Over the past decade MedTech valuations  have outperformed the market without changing its business model
  • The healthcare ecosystem is rapidly changing and MedTech is facing significant headwinds which require change
  • MedTech’s future growth and value will be derived from data and smart analytics rather than manufacturing
  • MedTech leaders will be required to leverage both physical and digital assets

 

Increasing MedTech’s future growth and value
 
 
Over the past decade, the medical device (MedTech) industry has enjoyed relatively high valuations and outperformed broader market indices without changing its manufacturing business model. Some MedTech leaders suggest that because the industry’s product offerings are essential, demand for them is increasing as populations grow and age, so unlike other industries, MedTech is immune to market swings and its asset value will continue to increase. As a consequence of this mindset, MedTech has been reluctant to change and slow to develop digitization strategies. Notwithstanding, digitization is an in-coming tide and positioned to impose a step-change on the industry. Future MedTech leaders will need to derive increased growth and value from digitization and emerging markets while improving the efficiency of their legacy manufacturing business and meeting quarterly earnings’ targets.

According to a 2018 report by the consulting firm Ernst & Young,Stagnant R&D investment, low revenue growth and slow adoption of digital and data technologies suggest that entrenched MedTech companies are overly focused on short-term growth, even as the threat of large tech conglomerates entering the space grows larger, which, in addition to the changing global healthcare ecosystem, threatens future revenue growth".

 
In this Commentary
 
This Commentary suggests that to create future growth and value, MedTech will have to (i) leverage data generated by medical devices, patients, payers and healthcare providers to develop clinical insights and trend analysis, which are expected to significantly improve patient outcomes and reduce costs, and (ii) substantially increase its share of the large and rapidly growing emerging markets. We suggest that there is a significant relationship between MedTech’s digital capacity and competences and its ability to increase its share of emerging Asian markets. But first we briefly describe the MedTech industry and its traditional markets and draw attention to some concerns, which include the relative low rates of top-line growth, stagnant R&D and share buybacks, M&A slowdown, giant tech companies entering the healthcare market, and challenges to recruit and retain millennials with natural digital skills and abilities.
 

The medical device industry
 
The MedTech industry designs, manufactures and markets more than 0.5m different products to diagnose, monitor and treat patients. These include wearable devices such as insulin pumps and blood glucose monitors, implanted devices such as pacemakers and metal plates, and stationary devices that range from instruments to sophisticated scanning machines. Medical devices can be instrumental in helping healthcare providers achieve enhanced patient outcomes, reduced healthcare costs, improved efficiency and new ways of engaging and empowering patients. The principal business model employed by the industry is to manufacture innovative products relatively cheaply and sell them expensively in wealthy developed regions of the world; predominantly North America, Europe and Japan; which although representing only 13% of the world’s population account for 86% of the global MedTech market share. This premium pricing model is predicated upon doctors’ and health providers’ belief that MedTech products are of superior quality and safety. Notwithstanding, as eye-watering healthcare costs escalate, providers and regulators demand better evidence of clinical and economic value to justify the pricing and use of MedTech products.  Over the next five years, the global MedTech industry is expected to grow at a compound annual growth rate of between 4% and 5.6% and reach global sales of some US$595bn by 2024.
 
Concern # 1: Reduced growth rates
 
Since the worse post-war recession ended in 2009, MedTech asset valuations have outperformed the market. Notwithstanding, of increasing concern is the slowdown of the industry’s revenue growth rates to single digits. The industry's aggregate revenue grew to US$379bn in 2017, an annual average industry growth rate of 4%, which now appears to be the new normal, and is significantly lower than the average annual growth rate of 15%, which the industry enjoyed between 2000-2007. The reduction in top-line growth rates is largely attributed to the world’s growing and aging population and the consequent growth in the incidence rates of chronic conditions, which increases the burden on overstretched healthcare budgets and intensifies pressure on MedTech’s to reduce their prices.
 
Population growth and aging
 
The aging population is driven by improvements in life expectancy. People are living longer and reaching older ages as fertility decreases and quality healthcare increases. People are having fewer children later in life. Some 8.5% of the global population (617m) have ages 65 and over. This is projected to rise to nearly 17% by 2050 (1.6bn). The number of Americans aged 65 and older is projected to more than double from 46m today to over 98m by 2060 – from 15% to 24% of the total US population. Around 18% of the UK population were aged 65 years or over in 2017, compared with 16% in 2007. This is projected to grow to 21% by 2027.
 
 Concern # 2: Stagnate R&D spend and share buybacks
 
In addition to relatively low revenue growth rates, MedTech R&D spend has stagnated over the past decade despite the need for companies to develop new and innovative product offerings, which drive top-line sales. Over the same period, MedTech returned more cash to shareholders in the form of share buybacks and dividends (US$16.4bn) than it spent on R&D.

To the extent that share buybacks extract, rather than create value why are they popular? One suggestion is that because share incentive plans represent a significant portion of executive compensation, share buybacks make it easier for executives to meet earning-per-share (eps) targets by reducing the number of shares, in the 1970s, share buybacks were effectively banned in the US amid concerns that executives might use them to manipulate share prices. However, in 1982 the US Securities and Exchange Commission (SEC) lightened its definition of stock manipulation, and share buybacks became popular again.
 

 

Concern # 3: High asset values slow M&A activity

Over the past decade, as markets became more uncertain, monetary policy tightened, technologies advanced and global economic growth slowed MedTech’s, buoyed by the dramatic fall in the cost of capital, increased their mergers and acquisitions (M&A) activity. This optimised portfolios, increased scale, reduced competition and improved profits. Notwithstanding, MedTech’s current high asset valuations make M&A transactions challenging to underwrite, and so, M&A activity has slowed.
 

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Concern # 4: Giant techs entering market
 
Giant technology companies such as Apple, Amazon, Google and Microsoft, have entered the healthcare market by providing direct-to-customer innovative services, which leverage data, artificial intelligence (AI) and machine learning and define new points of value along the value chain, which is changing the traditional notion of “product vendor. Such innovations and services result in raising the expectations of stakeholders who are beginning to insist that healthcare is as convenient and personalized as every other good or service they purchase. Notwithstanding, leveraging data generated by devices, patients, healthcare providers  and payers is challenging for traditional MedTech’s who tend to view IT as an isolated cost centre often constrained by legacy systems, aging infrastructures, complexity and skills’ shortages rather than as a key strategic asset.
 
It seems reasonable to assume that over the next five years MedTech’s will be forced to rethink their role as product manufactures and forced to find new and innovative ways to deliver value in a rapidly evolving healthcare ecosystem. Failure of MedTech’s to accelerate their digital agendas will benefit giant technology companies who have entered the market and well positioned to take advantage of the digital transformation of the 4th Industrial Revolution: characterized by the marriage of physical and digital technologies and an ability to change the nature of work to the extent where a significant proportion of future enterprise value will be predicated upon analytics, artificial intelligence and cognitive computing.

 
Concern # 5: The dearth of millennials
 
An obstacle for MedTech to develop digital strategies and keep up with the pace of innovation is its inability to recruit, develop and retain millennials. This is significant because millennials are “digital natives” and crucial to MedTech’s shift to increase their service offerings.  Millennials have been raised in a digital, media-saturated world and are well positioned to opine on and contribute to digital initiatives. Also, millennials have a natural ability to understand, adopt and implement new technologies, use digital platforms and analyse data, which enable them to make informed decisions.
 
Unlike most C-suite executives, millennials inhabit a world unconstrained by precedent, where processes are digitized, and tasks automated to create seamless offline-to-online experiences. It seems reasonable to assume that with a dearth of such capabilities MedTech will lag other industries in defining and developing positive online interactions. This is important because effective digital strategies involve significantly more than simply providing online customer services. They involve leveraging social media and evolving technologies to create memorable experiences from content to customer support.

Millennials have a distinct ethical orientation and “sense of purpose”, which makes them difficult for traditional MedTech’s to recruit and retain. According to a 2018 survey by Deloitte’s, millennials tend to be pessimistic about the prospects for political and social progress and have concerns about social equality, safety and environmental sustainability. While they believe that business should consider stakeholders’ interests as well as profits, millennials’ perception of employers tend to be that they prioritize the bottom line above workers, society and the environment. This leaves millennials with little sense of loyalty to traditional business enterprises and thereby difficult to recruit and retain. According to Larry Fink, CEO, Black Rock, “To prosper over time, every company must not only deliver financial performance, but also show how it makes a positive contribution to society. Companies must benefit all of their stakeholders, including shareholders, employees, customers and the communities in which they operate”.

Given MedTech’s dearth of expertise in digital skills, it might be obliged to develop dedicated teams and processes to source and execute value-added partnerships in a similar way big pharma has.
 

Smartphone penetration driving digitization strategies
 
Digital healthcare strategies are driven by the increased penetration of smartphones and the plummeting costs of wireless communications. Smartphones are powerful multipurpose devices capable of performing a number of tasks beyond their primary purpose of communication. These range from using the mobile’s SMS function to send alerts and reminders, to leveraging inbuilt mobile sensors or apps to capture and interpret clinical data.  Over the past decade, smartphones have fuelled the rapid uptake of internet access and transformed life for developed market consumers in terms of convenience and simplicity. In the US and UK smartphone penetration is about 84% and 80% respectively with the older age groups (55+) recording the highest growth. Smartphones have served an even more pivotal role for emerging market consumers by placing the internet into the hands of millions of consumers. In 2018, 98% of the global population had access to a mobile network with 75% having access to the fast 4th generation networks. Smartphones, together with other wireless technologies, (mHealth), are increasingly used in healthcare by patients, healthcare providers and payers, to improve health outcomes, increase efficiencies and reduce large and escalating healthcare costs. It is anticipated that by 2020, global smartphone subscriptions will be about 6bn and growing rapidly especially in emerging economies such as China, India, Egypt, Turkey, and the United Arab Emirates. In the past three years health apps have doubled and have reached over 140,000. The global mHealth market is expected to grow at a CAGR of 45% over the next six years and reach US$236bn by 2026.
 
 Concern # 6: Healthcare in emerging economies is predicated upon digital strategies
 
The relative high levels of healthcare demand and spending are expected to increase in emerging markets as populations grow, household spending rises and smartphone penetration increases. This is important to MedTech because emerging economies represent about 85% of the world’s population, 90% of which is under 30, and this cohort is expected to grow at three times the rate of the similar cohort in developed economies. Further, over the past decade, the number of high-income households have risen globally by about 30% to nearly 570m, with over 50% of this growth coming from emerging economies in Asia. Asia is comprised of 48 countries and represents roughly 60% of the global population, and its stake in world markets has grown dramatically in the last half-century. Today, Asian countries rank as some of the world’s top producers, which has brought them significant wealth.
 
According to Euromonitor International more than 50% of the world’s (3.6bn) internet users reside in Asia. Between 2013 and 2018, Asia accounted for 60% of new users coming online and the region has become an economic powerhouse, populated by young, digitally savvy consumers.  China is the largest mobile market in the world with close to 1.2bn subscribers. Significantly, in 2018, China’s rate of growth in mobile internet penetration reached 58% and the number of smartphone connections surpassed 1bn. Similarly, in India, the number of smartphone users is expected to double to 859m by 2022 from 468m in 2017; growing at a compound annual growth rate (CAGR) of 12.9% and expected to reach 859m by 2022.
 
Digitized services are replacing traditional distributors in China
 
Western MedTech operations in China have tended to replicate the Western commercial model, which relies heavily on distributor networks. But this is changing.
 
China has a land mass similar to that of the US and a population 1.4bn organised by 34 provincial administrative units, which are comprised of 23 provinces, four municipalities, five autonomous regions and two special administrative regions. Healthcare in China consists of both public and private medical institutions and insurance programs. About 95% of the population has at least basic health insurance coverage and is served by over 31,000 hospitals, primary care is patchy and there is a shortage of doctors.  Because of China’s large number of dispersed healthcare providers, traditional distribution models employed by western MedTech companies tend to be inefficient and costly.
 
In recent years, MedTech’s operating in China, supported by Beijing policy makers, have been gaining back control over customers from distributors. The reason for this is because, in the vast bureaucratic Chinese healthcare system, distributors evolved far beyond their core capabilities and controlled most commercial activities. For instance, the value Chinese distributors capture, as opposed to manufacturers, is disproportionately high and has led to restrictive policies. This has caught the attention of  policy makers who are seeking to correct these practices by promoting direct to customer digitized healthcare services. Beijing is minded that effective healthcare services for the nation’s vast and dispersed population cannot be achieved with traditional healthcare delivery models and has to be predicated upon appropriate digitized direct-to-customer operations. Similarly, this is true of other large emerging economies, particularly India.
 
The future is Asia and digitization
 
The reason we suggest that digitization is likely to help MedTech’s increase their market share in China is because digitization has become an essential part of everyday life in China including mobile payments, online-to-offline services, the sharing economy, smart retail, digital ID cards and healthcare services. WeDoctor and WeChat, are at the centre of this digitized society and only show signs of increasing their influence over Chinese healthcare and lifestyle.

WeDoctor is just one example of several Chinese start-ups that has leveraged data and digital strategies to re-engineer the nation’s healthcare system. Founded in 2010, the company has grown into a US$6bn enterprise and not only has increased access to healthcare, improved diagnoses, enhanced patient outcomes and lowered costs, but has disintermediated traditional distributors by simplifying and centralizing the procurement processes of medical devices.
 
It is sometimes hard for people based outside of China to grasp just how fully digitized Chinese society has become. WeChat, known in China as Weixin, is a multi-purpose messaging, social media and mobile payment app first released in 2011. By 2018 it had become one of the world's largest standalone mobile super-apps and controls life in modern China. For most Chinese citizens, especially those living in cities, it is possible to get through an entire day using WeChat for your every need. Millions of businesses have chosen to create mini-apps within WeChat instead of developing their own standalone apps. These allow businesses to send promotional messages directly to their customers via WeChat, as well as tap into the WeChat’s broader user base. With 1bn active monthly users, WeChat has reached the ceiling of its growth within China and its future will be about developing more services, which includes connecting people to businesses and products offerings.
 
Takeaways
 
Over the past decade, while the MedTech industry has increased its asset value, leaders focussed on, (i) short-term growth, (ii) portfolio optimization and (iii) returning cash to shareholders. Also, they allowed R&D to stagnate and were slow to appreciate the strategic significance of digitization. Data and smart analytics are positioned to play an increasing role in future MedTech growth and value creation. They are the key to creating new and innovative service offerings for healthcare providers, patients and payers and critical to MedTech increasing its share in large fast-growing emerging markets. Future  MedTech leaders will be required to leverage both physical and digital assets. Significantly, they will need to enhance the efficiency of legacy manufacturing systems while developing and marketing new innovative offerings derived from data and smart analytics.
 
Postscriptum
 
A concern not mentioned in the above discussion is ‘recession, which although mooted since the sharp fall in markets in December 2018 has not materialized. Indeed, the S&P 500 continues to rally, rising from 2,351 in 24th December 2018, to 3,026 in 26th July 2019. However, a reason for bullish US stock markets is low interest rates: the lower the interest rate, the higher the multiple the market applies to earnings. One indicator of recession is the J.P. Morgan Global Manufacturing Purchasing Managers’ Index (PMI), which has been declining since January 2018. In May 2019, it fell below 50, which is the number that suggests a recession has started. Another indicator of a recession is the yield curve, which is a chart showing the interest rate paid on bonds of different maturity. As a forecasting tool, the difference between long- and short-term interest rates has proved to be a reliable indicator of future recessions. Currently, the difference between the yield on the US 10-year bond and the US 3-month T-Bill is negative. This means the yield curve is inverted, which indicates recession. However, the yield curve is only an indicator of a recession and is neither definitive nor causal.
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  • Experts have called for the worldwide eradication of cervical cancer, but this is not likely to happen for a long time
  • Significant progress has been made to eliminate cervical cancer in developed countries
  • The overwhelming burden of cervical cancer falls disproportionately on women in low- to middle-income countries (LMIC)
  • LMIC have relatively low levels of awareness of cervical cancer, patchy prevent programs and limited treatment options
  • Over 80% of cervical cancer cases and deaths occur in LMIC
  • Cervical cancer is the fourth most common cancer in women worldwide
  • In 2018 there were an estimated 680,000 new cases and 311,000 deaths from the disease worldwide
  • Cervical cancer is caused by sexually acquired infection from high-risk strains of the human papilloma virus (HPV)
  • The majority of women will be infected with HPV at some point in their life
  • HPV also causes genital warts and cancers of the head and neck and is also linked to cancers of the anus, vulva, vagina, penis and oropharynx
  • HPV vaccines protect against 70% of cervical cancers and about 90% of genital warts
  • Regular screening is also recommended to reduce the incidence of cervical cancer
 
Challenges to eradicate cervical cancer globally

Cervical cancer is a killer disease, which only affects women. It affects women of all ages from schoolgirls to grandmothers, but it is significantly more prevalent between the ages of 30 and 45.
 
The cervix, also known as the neck of the womb, connects a woman's womb and her vagina.
 
Lancet study raises hope of eradicating cervical cancer
 
Research findings published in the June 2019 edition of The Lancet suggest that HPV vaccination, which has been available to adolescent girls in wealthy developed countries since 2007, has led to a dramatic reduction in the number of HPV infections, precancerous cervical lesions and anogenital warts and provides hope of eradicating cervical cancer. Marc Brisson, Professor in the Department of Social and Preventative Medicine, Laval UniversityCanada, who led the research - a meta-analysis of over 65 former studies covering 60m people - said: "We will see reductions [in cervical cancer] in women aged 20-30 within the next 10 years, and eradication  of the disease [defined as <4 cases per 100,000] might be possible if sufficiently high vaccination coverage can be achieved and maintained". Over the past two decades, the incidence rates of cervical cancer in developed countries have fallen significantly, and between 1955 and 1992, the incidence rate of the disease decreased 70% in the US. These falls are attributed to effective nationwide screening.
 
Epidemiology

Cervical cancer is the fourth most common cancer in women worldwide and second for women between 15 and 44. In 2018 there were an estimated 680,000 new cases and 311,000 deaths from the disease worldwide. The overwhelming majority of cases are caused by two specific strains of the human papilloma virus (HPV). HPV infection and early cervical cancer typically do not present noticeable symptoms, and cervical cancer may take 20 years or longer to develop after an HPV infection. The overwhelming global burden of the disease falls disproportionately on women in low- to middle income countries (LMIC). There is a significant and growing gap in the incidence and mortality rates of cervical cancer between developed nations and LMIC. Despite international efforts, it seems unlikely that this gap will be narrowed in the medium term.
 
In this Commentary
 
This Commentary describes the spread of HPV, the vaccines developed to prevent infection from specific high-risk strains of the virus and recommended vaccination regimens. We describe the nature and significance of complementary screening programs and present evidence to suggest that women who fail to get screened are more likely to contract cervical cancer in later life than women who are screened. HPV vaccination programs are more prevalent in developed economies and are associated with a significant reduction in the incidence rates of cervical cancer. This suggests that the battle to eliminate cervical cancer is being won in some wealthy developed nations. Australia is positioned to become the first country in the world to eliminate cervical cancer. Despite substantial global efforts to reduce the incidence rates of cervical cancer, the gap in preventing, diagnosing and treating the disease between wealthy nations and LMIC is significant and growing. We conclude by suggesting that to eradicate cervical cancer, screening and prevention programs must be linked to easily accessible and effective treatment.
 
The spread of HPV
 
Over 70% of cervical cancer is caused by two high-risk strains of HPV. Most women will contract HPV at some stage during their life, but this usually clears-up on its own without the need for any treatment. HPV is most commonly spread during vaginal, anal or oral sex. The virus can be passed even when an infected person has no signs or symptoms. If you are sexually active you can get HPV, even if you only have sex with one partner. Notwithstanding, the risk increases with the number of new sexual partners and their sexual histories. You also can develop symptoms years after you have sex with someone who is infected. This makes it hard to know when you first became infected.
  
HPV vaccines
 
The US Food and Drug Administration (FDA) has approved three vaccines, which prevent infection with disease-causing HPV types. These are Gardasil, Gardasil 9 and Cervarix. All three vaccines prevent infection with HPV types 16 and 18 in women who have not already been infected by these types. These are two high-risk HPV’s that cause about 70% of cervical cancers and an even higher percentage of some of the other HPV-caused cancers. Gardasil also prevents infection with HPV types 6 and 11, which cause 90% of genital warts. Gardasil 9 prevents infection with the same four HPV types, plus five additional cancer-causing types.
 
About 79m Americans are currently infected with HPV, with roughly 14m people becoming newly infected in the US each year. In the UK, HPV is present in one in three people and 90% of individuals will come into contact with some form of the virus in their lifetime. About 80% of sexually active people are infected with HPV at some point in their lives, but most people never know they have the virus. Whitfield Growdon, a surgical oncologist at the Massachusetts General Hospital and professor at the Harvard University Medical School describes the HPV vaccination as, “one of the most meaningful interventions for reducing cervical cancer”; see video below.

 
 
Who should get vaccinated?

All girls and boys aged between 11 and 12 should get the HPV vaccination. Every year in the US, over 13,000 males contract cancers caused by HPV. Catch-up HPV vaccines are recommended for girls and women through the age of 26, and for boys and men through the age of 21, if they did not get vaccinated when they were younger. HPV vaccination is also recommended for the following people, if they did not get vaccinated when they were younger: (i) young men who have sex with men through the age of 26, (ii) young adults who are transgender through the age of 26 and (iii) young adults with certain immunocompromising conditions (including HIV) through the age of 26.
 
Early cervical cancer is asymptomatic
 
Because early cervical cancer is asymptomatic, it is important for women to have regular Papanicolaou (Pap) smears - also called Pap tests - to detect any precancerous changes in the cervix that might lead to cancer. This is in addition to the HPV vaccination. In England women are invited to have Pap smears every three years between the ages of 25 and 49, when rates of cervical cancer are at their peak, and every five years between 50 and 65. Other international screening guidelines recommend that women aged 21 to 29 have a Pap smear every three years. Women aged 30 to 65 are advised to continue having a Pap test every three years, or every five years if they also combine it with an HPV DNA test. Women over 65 can stop testing if they have had three consecutive normal Pap tests, or two HPV DNA and Pap tests with no abnormal results.
 
The HPV DNA test determines the most likely cause of cervical cancer by looking for pieces of DNA in cervical cells and is recommended for women over 30 and not for women under 30. This is because women in their 20s tend to be more sexually active and therefore are more likely (than older women) to have an HPV infection that will go away on its own. Results of an HPV DNA test carried out on a woman in her 20s is not as significant as in and older woman and also may be confusing. The HPV DNA test can also be used in women who have slightly abnormal Pap test results to find out if they might need more testing or treatment.
 

The Pap smear/test
 
The Pap smear or Pap test is a method of cervical screening used to detect potentially precancerous and cancerous processes in your cervix. During the routine procedure, cells from your cervix are gently scraped away and then examined for abnormal growth. Abnormal findings are often followed-up by more sensitive diagnostic procedures and if warranted, by interventions that aim to prevent progression to cervical cancer. Detecting cervical cancer early with a Pap smear significantly increases the chances of a cure. A Pap smear can also detect changes in your cervical cells, which suggest you might develop cancer in the future. In the two videos below Growdon describes the Pap smear and other tests for diagnosing cervical cancer.
 

What is a Pap smear test?
 
 
Diagnostic tests for cervical cancer
 
 Women failing to have the Pap test are 6-times at greater risk of cervical cancer
 
There is evidence to suggest that women over 50 who fail to have a regular Pap smear have a much higher risk of developing cervical cancer compared with other women the same age who have a history of regular screening. Research carried out by Cancer Research UK and reported in 2014 investigated the utility of regular cervical cancer screening after 50, and whether 64 was an appropriate age to stop screening and concluded “yes” and “yes”. The study compared the screening history of 1,341 women between 65 and 83 in England and Wales who were diagnosed with cervical cancer over a five-year period, with 2,646 women of the same age without the disease. Findings suggest that women who did not attend screening tests were six times more likely to develop cervical cancer between 65 and 83 compared with women that did. 
 
Australian the first country to eradicate cervical cancer
 
Australia is well positioned to become the first country in the world to eradicate cervical cancer. This is largely due to national vaccination and screening programs, which could see the disease effectively eliminated as a public health issue within the next two decades. In 2007, Australia launched a national publicly-funded school immunisation program to reduce HPV, which complemented a national  cervical cancer screening program that was launched in the 1990s. These have been shown to reduce the incidence of cervical cancer and significantly increase early diagnosis when the disease is curable.
 
A research paper about the Australian initiative published in the January 2019 edition of The Lancet Public Health concludes that, “the annual incidence of cervical cancer in Australia is likely to decrease to fewer than six new cases per 100 000 women by 2020 (range 2018–22) and to fewer than four cases per 100 000 women by 2028 (2021–35). The annual incidence of cervical cancer could decrease to one new case per 100 000 by 2066 (2054–77) if the existing HPV-based screening program continues in cohorts who are offered the nonavalent vaccine”; [a nonavalent vaccine works by stimulating an immune response against nine different antigens, such as nine different viruses or other microorganisms]. According to Suzanne Garland, Professor and Clinical Director of Microbiology and Infectious Diseases at the Royal Women’s Hospital, Melbourne, Australia, who led the research, “within 40 years the number of new cases of cervical cancer [in Australia] is projected to drop to just a few”.
 
The two worlds of cervical cancer
 
Global efforts to reduce the incidence rates of cervical cancer have focused on HPV vaccination  and the Pap test. Although experts are optimistic about eliminating cervical cancer in developed nations, which have advanced healthcare systems and extensive HPV vaccination, screening and treatment programs, they are significantly less sanguine about eradicating the disease in LMIC where there are relatively low levels of awareness of cervical cancer, a dearth of  preventative strategies, limited expertise and a narrow band of treatment options. This results in the disease being identified late when it is at an advanced stage, which leads to higher rates of morbidity and death. Indeed, 85% of all cases and cervical cancer deaths occur in LMIC, where the death rate is 18 times higher than in wealthy nations.
 
Cervical cancer a challenge for LMIC
 
The gap in preventing, diagnosing and treating cervical cancer between wealthy nations and LMIC is  described in a paper published in the November 2017 edition of Gynecologic Oncology Reports and suggests that, “Developing countries continue to bear a disproportionate percentage of the global cervical cancer burden. Investigations into the growing gap in incidence and mortality between developed nations and LMIC have cited persistent financial, infrastructural and educational limitations as key drivers. Pervasive lack of access to both preventative and definitive care has left a substantial portion of cervical cancer patients with minimal options for disease management”.
 
WHO strategy to eliminate cervical cancer
 
Recognising this disparity, in 2018, the Director-General of the World Health Organization (WHO) announced a call to action for the eradication of cervical cancer as a public health problem. In January 2019, the Executive Board of the WHO requested the Director General to develop a draft strategy to accelerate cervical cancer elimination, with clear targets for the period 2020 - 2030.
 
Vaccination and screening must be linked to effective therapies
 
The expansion of screening programs for cervical cancer in LMIC is only part of the answer to closing the gap with developed nations and eradicating cervical cancer globally. It is imperative that screening is linked to increased access to effective treatment for women with cervical cancer, particularly in its early stages when it is still curable.  In LMIC there is often not only reduced access to preventive HPV vaccines and screening, but limited access to treatment and trained personnel. Notwithstanding, there is evidence to suggest that, in LMIC less-invasive and less–resource-intensive treatment options can be effective and are increasingly being made available.
 
Late presentation of cervical cancer in LMIC
 
Women from LMIC generally seek treatment for cervical cancer only after the presentation of symptoms when the disease is advanced and challenging to treat. Also, they often lack awareness of the disease and ways to prevent it. Further, in some regions of the world, cultural norms and myths about cervical cancer pose additional barriers to prevention. Despite such obstacles, the disease can be prevented at low cost by healthcare providers employing relatively simple techniques to screen women for precancerous conditions and treat abnormal tissue early. Among the most promising low cost and low-tech screening alternatives to the Pap smear, is visual screening, which only requires either simple vinegar or iodine solutions and the eye of a trained healthcare provider to spot abnormal tissue.
 
Screening linked to effective therapy
 
Increasingly, these simply tests are being linked with effective treatment. Increasingly, in LMIC relatively cheap and simple therapies are being used to either destroy or remove abnormal cervical tissue, depending on the severity, location and size of the affected area. Two such procedures include cryotherapy and loop electrosurgical excision procedure (LEEP). The former uses extremely low temperatures to destroy abnormal tissue and requires no electricity. The latter involves using a thin wire to remove lesions in the affected area. While this procedure requires more medical equipment than cryotherapy, it allows tissue to be removed for analysis, reducing the possibility that advanced cancer will go unnoticed. Although many LMIC have had cervical cancer prevention programs and simple treatment strategies in place for some time, some have failed to reduce death rates of the disease.
 
Radiotherapy and cervical cancer in LMIC
 
Research findings published in the May 2019 online edition of The Lancet Oncology suggest that the availability of radiotherapy in LMIC (where gross national income is <US$12,000 a year) would generate millions of productive life years and billions of dollars in economic benefits for the patients' families and communities. The study suggests that implementing a 20-year strategy for radiotherapy to treat cervical cancer in LMIC between 2015 and 2035, in parallel with an HPV vaccination program, would save the lives of some 9.4m women and provide a net benefit to economies of US$151.5bn as a direct result of women living longer and more productive lives.

According to Danielle Rodin, lead author and Radiation Oncologist at the Princess Margaret Cancer Centre, University of Toronto, Canada, "Vaccination is hugely important, but we can't neglect the millions of women who are contracting cervical cancer and dying in pain without access to treatment. These are women who have curable cancers: even advanced cervical cancer can be cured with radiotherapy. The possibility exists to make this treatment universally available". Radiation therapy makes small breaks in the DNA inside cells. This stops cancer cells from growing and dividing and causes them to die. Unlike cisplatin therapy, [an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy], which usually exposes the whole body to cancer-fighting drugs, radiation therapy is usually a local treatment.

 
According to the 2019 Lancet Oncology study, HPV vaccination would result in a 3.9% reduction in cervical cancer incidence over the 20-year study period; assuming a best-case scenario of vaccinating every 12-year-old girl in the world starting in 2014. By 2072, when the first vaccinated cohort reaches 70, there would be a 22.9% reduction in incidence, still leaving 41.6m in need for therapy over that time period.

We know that when administered together (chemoradiation) you can give lower doses of both and get a better kill-rate on the tumour. This is now the backbone of cervical cancer therapy”, says Growdon; see video below.

 
 
Abu Dhabi’s endeavours to reduce cervical cancer
 
For some years, experts have discussed religious and cultural barriers to cervical cancer screening and drew attention to the relatively low levels of cervical cancer awareness and screening for women in Middle Eastern Arab countries. Meta-analysis of cervical cancer studies conducted in Arab countries between January 2002 and January 2017 and published in the December 2017 edition of Nursing & Health Sciences, suggest that in Arab speaking countries there tends to be, “low knowledge of and perceptions about cervical screening among Arab women, the majority of whom are Muslim. Factors affecting the uptake of cervical cancer screening practices were the absence of organized, systematic programs, low screening knowledge among women, healthcare professionals' attitudes toward screening, pain and embarrassment, stigma, and sociocultural beliefs”.
 
The success of HPV vaccination in Abu Dhabi and the UAE
 
Notwithstanding, there are signs that this is changing. Leading such changes is Abu Dhabi of the United Arab Emirates (UAE). Over a decade ago, a mandatory free HPV vaccination program for school girls was introduced by Abu Dhabi’s Ministry of Health and Prevention and extended in 2013 to include women between 18 and 26. Also, the Ministry recommends that woman aged 25 to 65 years get a Pap smear every three to five years. Since 2018, HPV vaccinations have been provided free and compulsory for all school girls in Dubai and the Northern Emirates following a campaign to raise awareness.
 
Although the UAE is among the few countries to have relatively low incidence rates of cervical cancer, the disease still ranks as the third most frequent cancer among women in the UAE and the third most frequent cancer among women between 15 and 44. Estimates suggest that every year, 93 women are diagnosed with cervical cancer and 28 die from the disease in the UAE. Although Abu Dhabi is successfully leading the fight against cervical cancer and provides a roadmap for others to follow, the incidence of cervical cancer in the Middle East generally is expected to more than double by 2035 (>33,000 cases) and be responsible for more than 18,000 deaths. In some countries including Morocco and Saudi Arabia, low societal awareness and relatively low levels of screening results in about one in four women with HPV.
 
 Takeaways
 
As cervical cancer screening and prevention programs have been growing and extending their reach, so increases the need to provide access to effective treatment. Despite growing awareness of the disease and global efforts to increase availability of appropriate resources, cervical cancer remains prevalent particularly in LMIC where effective treatment has not become widespread. In many LMIC, the default option is often to do nothing, which results in certain death. Researchers and policy makers should consider focusing their activities on how to best to reconcile the use of existing resources with the expected impact on the quantity and quality of life. Although gaps in oncological resources and barriers to treatment still exist, the good news is that there is increased political will and international attention to improve access to safe and effective treatment of cervical cancer. Notwithstanding, eradicating the disease globally appears to be more of a theoretical possibility than a medium term reality.
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  • AstraZeneca has turned traditional biopharma R&D on its head and is targeting early stage cancer
  • This strategy benefits from  some of AstraZeneca’s R&D endeavours
  • But the strategy faces strong headwinds, which include significant technological and market challenges and substantial Competition from at least two unicorns
  
AstraZeneca’s strategy to target early cancer

 
Will José Baselga’s gamble pay off?
 
Baselga is AstraZeneca's new cancer research chief who has turned traditional biopharmaceutical drug development on its head by announcing AstraZeneca’s intention to target early- rather than late-stage cancer. “We need to spend our resources on those places where we can cure more people and that’s in early disease”, says Baselga, who knows that early detection can significantly improve patient survival rates and quality of life, as well as substantially reducing the cost and complexity of cancer treatment. Baselga also must know his strategy is high risk. Will it work?
 
In this Commentary
 
In this Commentary we discuss the drivers and headwinds of AstraZeneca’s strategy to increase its R&D focus on early stage cancer. But first we briefly describe cancer, the UK’s situation with regard to the disease and explain why big pharma targets advanced cancers. Also, we provide a brief description of AstraZeneca’s recent history.  
 
What is cancer?

Cancer occurs when a normal cell’s DNA changes and multiplies to form a mass of abnormal cells, which we refer to as a tumour. If not controlled and managed appropriately the tumour can spread and invade other tissues and organs. In the video below Whitfield Growdon, a surgical oncologist at the Massachusetts General Hospital in Boston US, and a Professor at the Harvard University Medical School explains.
 
 
The UK’s record of cancer treatment
 
In the UK cancer survival rates vary between types of the disease, ranging from 98% for testicular cancer to just 1% for pancreatic cancer. Although the UK’s cancer survival rates lag those of other European countries, the nation’s overall cancer survival rate is improving. Several cancers are showing significant increases in five-year survival, including breast (80% to 86%), prostate (82% to 89%), rectum (55% to 63%) and colon (52% to 60%). Many of the most commonly diagnosed cancers in the UK have ten-year survival of 50% or more. With regard to cancer spending, compared with most Western European countries, including France, Denmark, Austria and Ireland, the UK spends less on cancer per person, with Germany spending almost twice as much per head.
 
Why big pharma targets advanced cancers?
 
Most cancers are detected late when symptoms have manifested themselves, which renders treatment less effective and more costly. When cancer is caught early, as in some cases of breast and prostate cancer, tumours tend to be removed surgically or killed by chemoradiation therapy (CRT) and this, for many people, provides a “cure”, although in some cases the cancer returns.
 
Studies in developed economies suggest that treatment costs for early-diagnosed cancer patients are two to four times less expensive than treating those diagnosed with advanced-stage cancer. Notwithstanding, there are physical, psychological, socio-economic and technical challenges to accessing early cancer diagnosis and these conspire to delay cancer detection. Thus, big pharma companies have traditionally aimed their new cancer drugs at patients with advanced forms of the disease. This provides pharma companies access to patients who are willing to try unproven therapies, which significantly helps in their clinical studies. And further, big pharma is advantaged because regulators tend to support medicines that slow tumour growth and prolong life, albeit by a few months.
 
Imfinzi: the only immunotherapy to demonstrate survival at three years
 
A good example of this is AstraZeneca’s immunotherapy drug called Imfinzi (durvalumab) used in unresectable stage-III non-small cell lung cancer (NSCLC), which has not spread outside the chest and has responded to initial chemoradiation therapy. Imfinzi works by binding to and blocking a protein called PD-L1, which acts to disguise cancer cells from your immune system. Imfinzi removes the disguise so that your immune system is better able to find and attack your cancer cells.
 
Findings presented at the June 2019 meeting of the American Society of Clinical Oncology (ASCO), build on a clinical study of Imfinzi reported  in the September 2018 edition of The New England Journal of Medicineand suggest that Imfinzi is the only immunotherapy to demonstrate survival at three years in unresectable stage-III NSCLC. AstraZeneca has begun a phase-3 clinical study of the PD-L1 inhibitor protein in stage II NSCLC patients.
 

 

Some information about AstraZeneca
 
AstraZeneca is a British-Swedish multinational biopharmaceutical company with a market cap of US$107bn and annual revenues of US$22bn. The company operates in over 100 countries, employs more than 61,000, has its headquarters in Cambridge, UK, and is recovering after patents expired on some of its best-selling drugs and a failed takeover bid in 2014 by Pfizer.
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A paradigm shift in cancer diagnosis
Patents, legacy drugs and new biologics
 
When pharma companies develop a new drug, they can apply for a patent that stops other companies from making the same thing. A patent lasts for 20 years, after which point other producers can replicate the drug and its selling price plummets. This happened to AstraZeneca’s when the patents expired on two of its best-selling drugs: Crestor (rosuvastatin), and Nexium (esomeprazole). The former is a statin  that slows the production of cholesterol by your body, lowers cholesterol and fats in your blood and is used to reduce your chances of heart disease and strokes. The latter is a drug used to treat symptoms of gastroesophageal reflux disease (GERD) and other conditions involving excessive stomach acid. Unlike some of its rivals, these were oral medicines based on small molecules that are easy for generic manufacturers to copy, which made AstraZeneca vulnerable to cut-price competition immediately after the legal protection of the drugs had expired. Notwithstanding, AstraZeneca’s new generation of biologic medicines, which it launched in the first decade of this century, are protected to some degree by the fact that they are difficult to copy as they are manufactured using cells, instead of big chemistry sets used to make conventional drugs.
 
AstraZeneca’s history with early stage cancer therapies
 
Baselga’s gamble benefits from the fact that AstraZeneca developed an interest in the detection of early stage cancer before his appointment. Today, AstraZeneca is active in clinical studies with other biopharma companies and leading academic institutions targeting earlier-stage therapies.

Working with collaborators over the past two decades, AstraZeneca has tested a number of drugs including Iressa (Gefitinib) and Tagrisso (Osimertinib) in cancers from stage-I onward, in some cases to try to shrink tumours before they are removed surgically. Tagrisso is a potential star-drug for AstraZeneca. It  was originally developed to treat a group of lung cancer patients whose cancer had become resistant to established tyrosine kinase inhibitor therapies such as Iressa  and Roche’s Tarceva (erlotinib). Tagrisso surprised AstraZeneca as it turned out to be better than Iressa and Tarceva when used in untreated patients with epithelial growth factor receptor (EGFR) mutations. EGFR is a protein present on the surface of both normal cells and cancer cells, and are most common in people with lung adenocarcinoma (a form of NSCLC), more common with lung-cancer in  non-smokers, and are more common in women.

 
Epithelial growth factor receptor (EGFR)
 
Think of EGFR as a light switch. When growth factors (in this case tyrosine kinases) attach to EGFR on the outside of the cell, it results in a signal being sent to the nucleus of the cell telling it to grow and divide. In some cancer cells, this protein is overexpressed. The result is analogous to a light switch being left in the "on" position, telling a cell to continue to grow and divide even when it should otherwise stop. In this way, an EGFR mutation is sometimes referred to as an "activating mutation". Tagrisso "targets" this protein and blocks the signals that travel to the inside of the cell and growth of the cell stops. In 2003, when AstraZeneca received regulatory approval of Iressa we had little understanding about EGFR. Today however about 50% of drugs approved for the treatment of lung cancer address this particular molecular profile.

Technological challenges
 
Baselga’s gamble is assisted by advances in  liquid biopsies, which work by detecting fragments of malignant tumour DNA in the bloodstream to identify oncogenic drivers, which help treatment selection. The challenge of this approach is that tumours shed meniscal amounts of circulating tumour DNA (ctDNA), which significantly raises the difficulty of detecting the genetic signals that oncologists need to identify specific cancers and select treatments. ctDNA should not be confused with circulating free DNA (cfDNA), which is a broader term that describes DNA that is freely circulating in the bloodstream but is not necessarily of tumour origin.
 
The good news for Baselga is that in recent years looking for ctDNA has become a viable proposition because of improvements in DNA sequencing technologies, (see below) which make it possible to scan fragments and find those few with alterations that may indicate cancer. While other blood-based biomarkers are being investigated, the advantage of ctDNA is that it has a direct link to a tumour and can be very specific at identifying cancer.  ctDNA also provides a means to profile and monitor advanced stage cancers to inform treatments.
 
Notwithstanding, a paper published in the June 2018 edition of the Journal of Clinical Oncology  suggests that, “there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer”, and therefore it is still early to adopt cfDNA analysis for routine clinical use.
 

Next generation genome sequencing
 
DNA sequencing is the process of determining the sequence of nucleotides in a section of DNA. The first commercialised method was “Sanger Sequencing”, which was developed in 1977 by Frederick Sanger, a British biochemist and double Nobel Laureate for Chemistry. Sanger sequencing was first commercialized by Applied Biosystems, and became the most widely used sequencing method for approximately 40 years. More recently, higher volume Sanger sequencing has been replaced by next-generation sequencing (NGS) methods, which cater for large-scale, automated genome analyses. NGS, also known as high-throughput sequencing, is a general term used to describe a number of different state-of-the-art sequencing technologies such as Illumina’s Solexa sequencing. These allow for sequencing of DNA and RNA significantly more quickly and cheaply than the previously used Sanger sequencing and has revolutionised the study of genomics and molecular biology.
 
Can AstraZeneca acquire success?
 
Baselgo’s gamble is not helped by the relative dearth of biotech companies engaged in clinical studies of early stage cancers. This significantly narrows AstraZeneca’s options if it wants to buy-in clinical-phase assets to fit with Baselga’s strategy.
 
Notwithstanding, there are at least two biotech companies of potential interest to AstraZeneca. One is Klus Pharma, founded in 2014, based in Monmouth Junction, New Jersey, US, and acquired for US$13m in October 2016 by the Sichuan Kelun Parmaceutical Co., a Chinese group based in Chengdu. Another is Dendreon, a biotech company based in Seal Beach, California, US. In 2014 Dendreon filed for chapter 11 bankruptcy. In 2015 its assets were acquired by Valeant Pharmaceuticals. In 2017, the Sanpower Group, a Chinese conglomerate, acquired Dendreon from Valeant for US$820m.  
 
Klus is recruiting patients with stage-I rectal cancer for a phase 1/2 clinical study of its anti-HER2 antibody drug, and is also working to extend its flagship product, Provenge (sipuleucel-T) as an option for patients with low-risk prostate cancer. Provenge is an autologous cellular immunotherapy. It was the first FDA-approved immunotherapy made from a patient’s own immune cells. Since its approval in 2010, nearly 30,000 men with advanced prostate cancer have been prescribed the therapy.  
 
Unicorns threaten AstraZeneca’s strategy for early cancer
 
Perhaps the biggest threat to Baselga’s gamble is competition from unicorns, which include  Grail, and Guardant Health.  
 
Grail
Grail was spun-out of the gene sequencing giant Illumina in 2016 and backed by more than US$1.5bn in funding, including money from Microsoft cofounder Bill Gates and Amazon founder Jeff Bezos. Grail is on a quest to detect multiple types of cancer before symptoms manifest themselves by way of a single, simple and cheap blood test to find fragments of ctDNA. Grail has made significant progress in its quest to develop highly sensitive blood tests for the early detection of many types of cancer, but it still has to engage in further large-scale clinical studies. At the 2018 ASCO conference, the company presented data from its Circulating Cell-free Genome Atlas (CCGA) project, which showed detection rates ranging from 59% to 92% in patients with adenocarcinoma, squamous cell and small cell lung cancers. The rate of false positives - a major concern for the oncology community - was under 2%.
 
In an effort to improve its technology and its outcomes, Grail has been working with researchers from the Memorial Sloan Kettering Cancer CenterMD Anderson Cancer Center and the Dana-Farber Cancer Institute, to develop a new assay. According to results published in the March 2019 edition of the journal Annals of Oncology, this joint venture has successfully come up with a method, which can detect mutations in NSCLC patients’ blood with high sensitivity. In some cases, the technology was useful when tissue biopsies were inadequate for analysis. The new tool uses Illumina’sultradeep next-generation sequencing", which involves reading a region of DNA 50,000 times, on average, to detect low-frequency variants. White blood cells were also sequenced to filter out "clonal hematopoiesis", which are noncancerous signals that can come from bone marrow. The sequencing information was then fed to a machine learning algorithm developed by Grail to determine mutation readouts.
 
Guardant Health
The other unicorn for AstraZeneca to watch is liquid biopsy developer Guardant Health. Founded in 2013, it is now an US$8bn precision oncology company based in Redwood City, California US. In April 2019 Guardant presented data of its oncology platform at the American Association of Cancer Research (AACR) in Atlanta, US. The platform leverages Guardant’scapabilities in technology, clinical development, regulatory and reimbursement to drive commercial adoption, improve patient clinical outcomes and lower healthcare costs.  In pursuit of its goal to manage cancer across all stages of the disease, Guardant has launched two next-generation sequencing liquid biopsy-based Guardant360 and GuardantOMNI tests for advanced stage cancer patients, for minimal residual disease/recurrence monitoring and for early detection screening, respectively.
 
The Guardant360 test is used to track patients’ responses to drugs and select most effective future therapies. It can identify alterations in 73 genes from cfDNA and has been used by more than 6,000 oncologists, over 50 biopharmaceutical companies and all 28 of the National Comprehensive Cancer Network Centers. 
 
Further, Guardant has launched a new liquid biopsy called Lunar.  At the April 2019 AACR meeting the company presented data of Lunar’s use as a screen for early-stage colorectal cancer. The assay was used to test plasma samples taken from 105 patients with colorectal cancer and 124 age-matched cancer-free controls. It is the test’s utility as a screen for early-stage disease that should interest AstraZeneca most. Guardant expects to position Lunar as something approaching a true diagnostic: a screening test to identify solid tumours in the healthy population. Wider clinical studies of Lunar are expected to start soon and Guardant believes that Lunar’s market opportunity as a cancer screen is some US$18bn and sees a US$15bn market opportunity in recurrence monitoring.
 
Also, in April 2019 Guardant acquired Bellwether Bio,  a privately held company founded in 2015, for an undisclosed sum. Bellwether is focused on improving oncology patient care through its pioneering research into the epigenomic content of cfDNA. This could aid  Guardant in its efforts to develop a cancer screen and further advance its research into cancer detection at earlier stages of the disease.
 
Guardant is well positioned to develop individual early indications of cancer. Grail, on the other hand,  is well positioned to develop a pan-cancer test. Notwithstanding, both companies need to engage in further lengthy, large-scale clinical studies before it will become clear which of these strategies will be more successful. However, both unicorns and other start-ups are potential competitors to AstraZeneca’s endeavours to target early cancer.
 
Takeaways

AstraZeneca’sproposed bold and risky shift in its R&D strategy is to be welcomed since the early detection and treatment of cancer should significantly enhance the chances of a cure, which would radically improve the quality of life for millions and substantially reduce the vast and escalating costs associated with the disease. AstraZeneca has some advantages since over the past two decade it has significantly enhanced its technology and been developing a platform of therapies for early stage cancer. Notwithstanding, for its strategy to target early stage cancer to be successful the company will have to overcome intense, fast growing, well-resourced competition and substantial technical and markets challenges.  
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  • People are living longer, the prevalence of age-related degenerative disc disease is increasing and sufferers are more and more turning to spinal implant surgery as a solution
  • As this significantly raises the burden on over-stretched healthcare systems, so is spine surgery increasingly becoming a key target for cost reduction within healthcare systems
  • This intensifies the pressure on manufacturers to innovate and make spinal implants more cost effective

Can 3D printing and the use of new alloys reduce the high costs of producing and marketing spinal implants?
 
On January 8th 2019 surgeons at Joseph Spinea specialist surgery centre based in Tampa Bay Florida, were the first in the US to implant a 3D printed interbody fusion device, which was produced  by Osseus Fusion SystemsThe company uses its proprietary 3D printing technology, also known as additive manufacturing,  to build spinal implants from titanium material that is optimized for bone fusion and biological fixation. In August 2018, a suite of Osseus’s devices received clearance from the US Food and Drug Administration (FDA) for a  range of heights and lordotic (inward spinal curvature) angles, which make them adaptable for a variety of patient anatomies. The interbody fusion devices work by being packed with biomaterials and bone grafts and inserted in between two vertebrae, where they fuse with the spine and work to prevent back pain.
 
In this Commentary
 
This Commentary explores whether 3D printing and the use of new alloys could be an appropriate strategy to help spine companies reduce  their production and sales costs and enhance their market positions. Our suggestions here complement a strategy, described in a previous Commentary, for MedTech companies to develop and implement digital strategies to enhance their go-to-market activities, strengthen the value propositions of products and services and streamline internal processes. The reasons spine companies might consider both strategies are because spinal implant markets, which are segmented  by type of surgery, product and geography, are experiencing significant competitive, regulatory, pricing and technological challenges as well as mounting consumer pressure for improved outcomes; and the business model, which served as an accelerator of their financial success over the past decade is unlikely to be effective over the next decade.
 
3D printing
3D printing is a process, which creates a three-dimensional (3D) object by building successive layers of raw material. Each new layer is attached to the previous one until the object is complete. In the healthcare industry, 3D printing is used in a wide range of applications, such as producing dental crowns and bridges; developing prototypes; and manufacturing surgical guides and hearing aid devices. Increasingly, 3D printing is being used for the production of spinal implants.

 
Spine surgery increasing significantly
 
An estimated US$90bn is spent each year in the US on the diagnosis and management of low back pain (LBP). LBP, caused by age related degenerative disc disease, is one of the most common and widespread public health challenges facing the industrialized world. It is estimated that the condition affects over 80% of the global population and inflicts a heavy and escalating burden on healthcare systems. Also, LBP affects  economies more generally in terms of lost production due to absenteeism, early retirement and the psychosocial impact caused by the withdrawal of otherwise active people from their daily activities. According to the American Association of Neurological Surgeons, more than 65m Americans suffer from LBP annually and the Chicago Institute of Neurosurgery and Neuroresearch suggests that by the age of fifty, 85% of the US population is likely to show evidence of disc degeneration. It is estimated that 10% of all cases of LBP will develop chronic back pain, which is one of the main reasons for people to seek surgical solutions and this significantly raises the burden on over-stretched healthcare systems.
 
Findings of a study published in the March 2019 edition of Spine, entitled, “Trends in Lumbar Fusion Procedure Rates and Associated Hospital Costs for Degenerative Spinal Diseases in the United States 2004 to 2015”, report that the rate of elective lumbar fusion surgeries in the US has increased substantially over the past decade. Such trends are indicative of most advanced industrial societies, which  are changing and ageing, primarily driven by improvements in life expectancy and by a decrease in fertility. This results in people living longer, reaching older ages and having fewer children later in life. Over the next decade, these market drivers are expected to make spine surgery a key target for cost reduction within healthcare systems and this, in turn, is likely to increase pressure on manufacturers of spinal implants to make spine surgery more cost effective.

 

The first surgery using a 3D printed spinal implant
 
The first surgery to implant a 3D printed interbody fusion device was carried out in China in August 2014, when surgeon Liu Zhongjun from Peking University Hospital successfully implanted an artificial 3D printed vertebra into a 12-year-old bone cancer patient to help him walk again. Liu first removed a tumour located in the second vertebra of the boy's neck before replacing it with the 3D printed implant between the first and third vertebrae to allow him to lift his head. “The customized 3D printed technology made the disc replacement stronger and more convenient than normal procedures”, said Liu.

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Age of the aged and low back pain
 
In July 2017, a team of doctors, led by Xiao Jianru, Professor of Orthopaedic Surgery at Shanghai Changzheng Hospital, China, treated a 28-year-old woman with a massive, rare neck tumour, by giving her a 3D printed spine. The patient had to have six consecutive cervical vertebrae replaced because they had been affected by the cancer, which was challenging to treat with chemotherapy. Cervical vertebrae, seven in total, which form your spine column in the neck are the most delicate bones in your body. The patient was discharged from the hospital after the operation. Reports suggest that she was able to walk, but had some difficulties turning her head.
 
First US company to receive FDA approval for 3D printed spinal implants
 
The first US  company to receive a 510(k) FDA approval for a 3D printed spinal implant was 4WEB Medical, in 2012. The company was founded in 2008 and since then has become a leader in 3D printed implant technology. Following FDA clearance, the company launched its proprietary and patented Truss Implant platform, which features a unique open architecture that allows for up to 75% of the implant to be filled with graft material and includes an anterior spine Truss System, a cervical spine Truss System, an osteotomy Truss System and a posterior spine Truss System. In April 2018,  at the annual meeting of the International Society for the Advancement of Spine Surgery (ISASS) 4Web announced that it has surpassed 30,000 implants worldwide of its proprietary Truss Implant Technology.
 
There is a plethora of established MedTech companies entering the 3D printing spinal implant market, which include Stryker, K2M, DePuy Synthes, Camber Spine, CoreLink, Medicrea, Renovis, NuVasive and Zimmer Biomet. With Stryker’s acquisition of K2M and DePuy Synthes’ acquisition of Emerging Implant Technologies GmbH (EIT), both in September 2018, the market for 3D printed spinal implants is positioned to grow rapidly over the next few years.
 
Increasing FDA approvals for 3D printed spinal implants
 
Significantly, spinal implants have become one of the most common cases of the FDA-cleared 3D printed medical devices. For instance, in 2018 Zimmer Biomet received FDA clearance for the company’s first 3D printed titanium spinal implantEIT received FDA approval in 2018 for its 3D printed multilevel cervical cage, which can treat multiple injuries in both the middle and top parts of the spine. Centinel Spine Inc, a US company based in Pennsylvania, which develops, manufactures and markets spinal devices used to treat degenerative disc disease, also received FDA clearance in 2018 for its 3D printed spinal implants called FLX devices, which are titanium fusion implants that work to stabilize vertebrae from the front of the spine in order to increase the healing process for patients.

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MedTech must digitize to remain relevant

 
3D printing medical devices market
 
The 3D printing medical devices market is projected to grow at a CAGR of 17.5% and reach US$2bn by 2022. Currently, the market is dominated by North America, followed by Europe, Asia Pacific and the rest of the world. Over the next decade, the Asia Pacific 3D printing medical devices market is expected to grow at the highest CAGR. Emerging markets are attractive for spine companies as they have large patient populations, which are growing fast, rising government healthcare expenditure, vast and rapidly increasing middle classes, rising income levels and rising obesity cases.
One example is India, with a middle class about twice the size of the US population, an economy growing at a rate of 7% year-on-year and a pro-business Prime Minister who has established himself as the country’s most formidable politician in decades and is committed to increasing healthcare spending. According to the World Bank’s March 2018 India Development Update the GDP of India had surpassed that of France and was on track to overtake the UK economy to make India the 5th largest economy in the world. Significantly, India’s GDP per capita has reached US$2,000, which is generally recognised by economists as a “tipping point”: when a country’s economic prospects improve, peoples’ confidence increases, and investment momentum remains at a desirable level for a long period. For instance, when the GDP per capita of China and South Korea reached US$2,000 their respective economies witnessed more than a decade of high growth with an average growth rate of about 10%. India appears to be on the cusp of something similar.
 
3D printing's competitive advantages
 
3D printing, although in its infancy, has the capacity to manufacture products of any complexity anywhere, at any time, which gives it a significant competitive-advantage over traditional manufacturing. Further, 3D printing is cheaper and quicker than traditional production methods because there is less machine, material, labour and inventory costs and less materials' waste. Complex designs can be created as a computer added design (CAD) model and then transformed into a reality in just a few hours. By contrast, traditional manufacturing methods can take weeks or even months to go from the design stage to a prototype and then onto the production process. Also, 3D printing is cost-effective in low production quantities and more environmentally friendly as the place of manufacture can be the same as the place of the product’s application.

The benefits of 3D printing specifically for spinal surgery include; (i) implants can be shaped to custom-fit patients, (ii) porosity and pore size can be personalized to a specific patient’s bone quality, which may improve integration. But perhaps the most significant potential advantage is bioprinting, where cells, growth factors and biomaterials are used to create living tissue.

 
Thinking beyond traditional metals used for spinal implants
 
Some spine companies are complementing their 3D printing endeavours by experimenting with new and stronger alloys. For the past two decades metals used for spinal implants have been mostly composed of cobalt chrome, titanium and stainless steel. The physical properties of these have prevented producers to reduce the size of spinal implants. But this is changing with the introduction of new alloys such as molybdenum-rhenium (MoRe), which is stronger than the traditional metals used for spine implants and has the potential to use less metal to achieve stronger, more durable constructs, while allowing for smaller sized products.

Already, MoRe is used for stents in cardiology and findings of a small animal study presented at the 2018 North American Spine Society meeting in Los Angeles suggested that MoRe is significantly more hydrophilic (having strong affinity to water) and therefore friendlier to bone when compared with cobalt chrome, titanium and stainless steel. This suggests MoRe might provide smaller rods with smaller pedicle screw heads, which decrease the prevalence of protruding, painful hardware in patients with wasting of the body due to severe chronic illness. Further, smaller spinal implants would be beneficial in minimally invasive spine surgery.

Another added benefit of MoRe is that it potentially decreases biofilm formations, which are typically caused by chronic medical device-related infections and allergenicity when compared to the traditional metals used in spine surgery. Bacteria are tougher to kill when they attach to the surface of a spinal implant, even before they form a biofilm. Research findings published in the December 2018 edition of Heliyon draws attention to the prevalence of the  antibiotic-resistant nature of bacterial biofilm infections on implantable medical devices and describes current state-of-the-art therapeutic approaches for preventing and treating biofilms. As the range of materials for spinal implants with improved biocompatibility, biodegradability and load bearing properties increase, so are biofilm infections expected to decrease.

 
Takeaways
 
Spine surgery is positioned to become a key target for cost reduction within healthcare systems over the next decade. This is because low back pain, caused by age related degenerative disc disease, is a common condition affecting most individuals at some point in their lives and increasingly people are turning to surgical solutions. As a consequence, we can expect increased pressure on stakeholders, including spinal implant manufacturers, to innovate to make spine surgery more cost effective. 3D printing and the use of new alloys, while in their infancy, are possible strategies to reduce the costs of producing spinal implants while improving patient outcomes.
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