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Tagged: cancer genomics

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  • Tobacco is a legacy recreational drug that causes cancers, and kills over 6m people each year
  • No new food, drink, recreational or over the counter drug with a similar adverse health profile would ever be approved in the modern world
  • Smoking causes 150 extra mutations in every lung cell
  • New research demonstrates that smoking causes cancers in organs not exposed to smoke such as the bladder, kidney and pancreas
  • Smoking triggers cell mutations that can cause cancer years after quitting
  • Anti-smoking campaigns have decreased the prevalence of smoking, but incidence rates have increased because of population growth
  • Identifying all the cancer genes will eventually improve treatments
 
 
Smoking is playing Russian roulette with your life
 
Tobacco is the only legal drug that kills millions when used exactly as intended by manufacturers. New research into the root causes of cancer demonstrates how tobacco smoke mutates DNA, and gives rise to more than 17 types of cancers, and surprisingly, causes cancers in organs not directly exposed to tobacco smoke.
 

Cell mutation and the body’s natural resistance
 
A mutation occurs when a DNA gene is damaged or changed in such a way as to alter the genetic message carried by that gene. The more mutations a cell acquires, the more likely it is to turn cancerous.
 
Decreased prevalence, but increased incidence of smoking

Globally, smoking prevalence - the percentage of the population that smokes regularly - has decreased, but the number of cigarette smokers worldwide has increased due to population growth. Today, over 1bn people worldwide smoke tobacco, which each year causes nearly 6m early deaths, many different cancers, pain, misery and grief; not to mention the huge costs to healthcare systems and the loss of productivity.  If current trends continue tobacco use will cause more than 8m deaths annually by 2030. On average, smokers die 10 years earlier than nonsmokers.
 

Cancer and the body’s natural resistance

Cancer is a condition where cells in a specific part of the body mutate and reproduce uncontrollably. There are over 200 different types of cancer. Cancerous cells can invade and destroy surrounding healthy tissue and organs. Cancer sometimes begins in one part of the body before spreading to other areas. This process is known a metastasis. The body has a capacity to naturally resist cancer, through tumor suppressor genes, which function to restrain inappropriate mutations, and stimulate cell death to keep our cells in proper balance.New therapies that boost the body’s own immune system to fight cancer are believed to be a game-changer in cancer treatment.

Cancer and the causes of cancer

Whitfield Growdon, a surgical oncologists from Harvard University Medical School and the Massachusetts General Hospital in Boston, describes cancer and the causes of cancer:
 
What is cancer?



What causes cancer?
 
Epidemiology of smoking

Today, it is widely accepted that tobacco use is the single most important preventable health risk in the developed world, and an important cause of premature death worldwide. The research of the British epidemiologists Richard Doll and Tony Bradford Hill, more than anyone else, is responsible for the link between tobacco use and lung cancer. Following reports of several case-controlled studies in the early 1950’s Doll and Hill published findings of a larger case-controlled study in 1954 in the British Medical Journal, which suggested that smoking was, "a cause, and an important cause" of lung cancer. This was followed by the publication of further research findings in 1956. Doll and Hill’s latter study confirmed their earlier case-controlled findings: that there is a higher mortality rate among smokers than in non-smokers, and a clear dose-response relationship between the quantity of tobacco used, and the death rate from lung cancer. Data also indicated a significant progressive reduction in mortality rates with the length of time following the cessation of smoking.
 
US Surgeon General Report of smoking and lung cancer

The research of Doll and Hill, along with other cohort studies published in the 1950s, formed the basis for the game-changing 1964 report of the US Surgeon General, which concluded that, "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors". This led to groundbreaking research on tobacco use, and investments by governments and nonprofit organizations to reduce tobacco prevalence and cigarette consumption, which in some developed countries has been successful. In 2003, the Framework Convention on Tobacco Control was adopted by the World Health Organization, and has since been ratified by 180 countries.  
 
The best and the worst countries for smoking related lung cancer
 
Between 1980 and 2012 age-standardized smoking prevalence decreased by 42% for women and 25% for men worldwide. Canada, Iceland, Mexico, and Norway have reduced smoking by more than half in both men and women since 1980. The greatest health risks for both men and women are likely to occur in countries where smoking is pervasive and where smokers consume a large quantity of cigarettes. These countries include China, Ireland, Italy, Japan, Kuwait, South Korea, the Philippines, Uruguay, Switzerland, and several countries in Eastern Europe. The number of cigarettes smoked worldwide has grown to more than 6 trillion. In 75 countries: smokers consume an average of more than 20 cigarettes a day.
 
Smoking-related deaths in the UK and US

19% (10m) of adults in the UK, and 17% (40m), of adults in the US are current cigarette smokers, a figure, which has more than halved since the mid 1970s. Results from a 50-year study shows that half to two thirds of all lifelong cigarette smokers will be eventually killed by their habit. Death is usually due to lung cancer, chronic obstructive lung disease and coronary heart disease. Many who suffer from these diseases experience years of ill health and subsequent loss of productivity. Every year, around 96,000 people in the UK, and 480,000 people in the US, die from diseases caused by smoking. This equates to 226 and 1,300 smoking-related deaths every day in the UK and US respectively.
 
Costs

In addition to death and sickness, tobacco use also imposes a significant economic burden on society. These include direct medical costs of treating tobacco-induced illnesses, indirect costs including loss of productivity, fire damage and environmental harm from cigarette litter and destructive farming practices. Cigarettes sales contribute significant tax revenues to national coffers; the industry employs tens of thousands of people who also pay taxes. Notwithstanding, the total burden caused by tobacco products outweighs any economic benefit from their manufacture and sale.
 
Direct link between the number of cigarettes smoked and cancers

Scientists from the Wellcome Trust Sanger Institute near Cambridge, UK, the Los Alamos National Laboratory in New Mexico, and others have discovered a direct link between the number of cigarettes smoked and the number of mutations in the tumor DNA, and that smoking also causes cancers in organs not exposed to tobacco smoke.

Research published in the Journal Science in 2016 analyzed more than 5,000 cancer tumors from smokers and nonsmokers, and concluded that if you smoke even a few cigarettes a day you will erode the genetic material of most of the cells in your body, and thereby be at a significantly greater risk of cancer. "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking," says Ludmil Alexandrov, a theoretical biologist at Los Alamos National Labroratory and an author of the study.
 
The discovery means that people who smoke a pack of cigarettes a day for a year, develop on average, 150 extra mutations in every lung cell, and nearly 100 more mutations than usual in each cell of the voice box, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver.
 
Smoking causes cancers not exposed to smoke
 
Scientists were surprised to find that tobacco smoke caused mutations in tissues that are not directly exposed to smoke. While more than 70 of the 7,000 chemicals in tobacco smoke have long been known to raise the risk of at least 17 forms of cancer, the precise molecular mechanisms through which these chemicals mutate DNA, and give rise to tumours in different tissues have never been altogether clear, until now. The study showed that some chemicals from tobacco smoke damage DNA directly, but others found their way to different organs and tissues, and ramp up the natural speed at which mutations built up in the tissues in more subtle ways, often by disrupting the way cells function. The more mutations a cell acquires, the more likely it is to turn cancerous.
 
Why some smokers get cancer and others do not

It won’t happen to me. . . . My grandfather started smoking when he was 11, smoked 20 a day, and lived ‘til he was 90”. We have all heard this before. But we now know why some smokers get cancer and others do not. it is because of the way mutations arise. When a person smokes, the chemicals they inhale create mutations at random points in the genome. Many of these changes will be harmless, but others will not be so benign. The more smoke a person is exposed to, the greater the chance that the accumulating mutations will hit specific spots in the DNA that turn cells cancerous. Even decades after people stop smoking, former smokers are at a long-term increased risk of developing cancers.“You can really think of it as playing Russian roulette,” says Alexandrov.
 
Takeaways

Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that do not come into direct contact with smoke.
 
Sir Mark Walport, director of the Wellcome Trust, says that the findings from the research described above: “will feed into knowledge, methods and practice in patient care.” Dr Peter Campbell, from the Wellcome Trust Sanger Institute says: “The knowledge we extract over the next few years will have major implications for treatment. By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes, and work out which patients will benefit from these novel treatments.”
 
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The Future of Healthcare
 
Fahad Aziz
Co-founder of Caremerge, which provides comprehensive web and mobile communications and care-coordination solutions for senior living communities. Fahad is the author of several technical papers, and the recipient of Pakistan’s prestigious Performance Excellence Award.
 
  • How will machine learning, virtual reality, the Human Genome Project, and the Internet of things change healthcare?
  • Will technology result in a healthier future full of empowered patients?
  • Will big data strategies help physicians perform their jobs better?
  • Will 3D printing be used to replace tissue and organs?
  • Will VR allow scientists to experience physical and psychological challenges rather than observe them?

 
Living in Silicon Valley I have a front row seat to the in technology poised to reshape the future of humanity. Machine learning, Virtual Reality, the Human Genome Project and the Internet of things will undoubtedly impact our lives in general, but they can also have a major impact on the Healthcare industry in particular.

To visualize the future of healthcare, I took a look at what’s trending in Silicon Valley and applied them to the healthcare industry. If the possibilities seem farfetched today, remember the iPhone is less than a decade old and has spawned countless industries that have shaped our daily existence, and will continue to do so. Technology moves fast and these four trends can potentially disrupt all aspects healthcare.

Machine learning
Artificial Intelligence (AI) is not new to the technology world, but with machine learning, AI has taken on an open-ended form rife with endless opportunities for technology in general and healthcare in particular.

Machine learning enables computers to identify patterns and observe behaviors based on empirical data, and use all that to ‘learn’. In other words, machine learning is a set of self-learning algorithms that can eventually become smarter than any human being on this planet.

In 2012, Vinod Khosla, an American businessman and a co-founder of Sun Microsytems, predicted that in time, “Technology will replace 80% of what doctors do”; sparking outrage and umbrage within the healthcare industry. Physicians overlooked what Khosla was really saying: that big data, properly harnessed and utilized, had the potential to help physicians perform their jobs better. Farfetched at the time, big data and machine learning have come far enough in just four years to provide levity to Khasla’s argument.

When given access to a trillion gigabytes of patient data collected from devices, electronic health records (EHRs), laboratories, and DNA sequencing - alongside surrounding factors such as weather, geo-location, and viral outbursts - computers learn quickly, and they learn everything. The depth of information provided at such a scale suggests patients will not need to consult with various specialities to figure out what’s ailing them in the future. Instead, consolidated data will create and provide a fully coordinated treatment plan.

If you are thinking this sounds crazy, consider the fact that IBM acquired Truven Health for $2.6 Billion in early 2016. Truven delivers information, analytic tools, research, and services to the healthcare industry, and gives IBM access to data of some 200 million patients to feed Watson, which is IBM’s machine learning product that is a powerful question answering computer system capable of answering questions posed by natural language.

I can only imagine what Watson will offer after digesting this massive data, but one thing is for sure: the result is nothing but good news for patients and their care plans.

The Internet of things
Gartner, a US IT research and advisory firm, estimates six billion devices will be “connected” by 2020; collecting data for consumption, analytics and a whole lot more.

Healthcare has historically been a sucker for devices, embracing hardware that captures data, provides diagnostics and even treats patients. Previously, these devices have been in use only at hospitals and other healthcare locations, but in the future this technology has the potential to become a part of every single home; marking a new era in care.


How can the NHS innovate? - Mike Farrar, former NHS Confederation CEO

In the future, doctor’s visits will begin before we even head out the door. Our vitals will be captured at home and sent to our doctor. In some cases, we may even receive treatment in the comfort of our home. Further, once treatment begins, a real-time feed of our vitals and conditions will be shared and analyzed automatically via set protocols, which will trigger alerts if our health declines and requires a change in treatment.
 
The Internet of things has implications elsewhere for the healthcare industry. Pharmaceutical research could bid farewell to clinical trials once they can access millions of patients’ data to accurately analyze behaviors and outcomes.

Challenges facing immunizations could also be solved using simple, digitized solutions. Currently, vaccinations are rendered ineffective by temperature changes during their transport; a simple tracking device with a thermometer could solve that problem. Similar challenges with manufacturing, delivery and tracking of vaccination can also be digitized to make the immunization programs successful globally.

Last but not least, I foresee nano devices embedded within the human body to monitor glucose, blood pressure, temperature, and more; to allow for swifter, more effective decisions to be made so treatments can begin as soon as needed, significantly increasing positive outcomes.

The Human Genome Project
One of the greatest breakthroughs in healthcare this last decade was decoding the human genome to understand the DNA sequencing. It took over 10 years and a staggering US$2.7bn to crack the code of one human being. Just a decade later, it takes US$1,500 and a couple of hours to run the genome for any person.

The more we learn about DNA and its sequencing, the more accurately we can treat patients for their illnesses. There will be no guesswork involved, instead, a complete technical report will show exactly what went wrong since last time, and what can be done to fix it.

The future is closer than we think. I suspect human genome machines will be deployed at healthcare locations in the near term. The appetite for this type of information will grow, and eventually, we may live in an age where small genome devices are installed under your sink or inside your toilet seat to analyze changes in your DNA sequencing several times a day.

Today, researchers in Europe are using 3D printers and DNA sequencing to create human body parts that can potentially replace limbs or ailing organs. Prototypes already exist. DNA sequencing will help people take more control over their bodies, allowing them to make better informed decisions about their lifestyle, illnesses and treatments. This means that doctors’ roles will change, potentially allowing for a complete shift in the healthcare paradigm.

Virtual reality in healthcare
Mark Zuckerberg, chairman, CEO and co-founder of Facebook, takes every opportunity he can to promote his latest US$2bn acquisition, Oculus VR, an American virtual reality company, whose product, Oculus Rift, is a virtual reality (VR) headset. I had the opportunity to try Oculus Rift, and was blown away. Market analysts say Zuckerberg was crazy to bet on this, but I know he has discovered a platform with the potential to be larger than Facebook.

Virtual reality transports you into another world by creating an artificial environment, deceiving your sense of sight and touch, so your mind believes you are part of that environment. At a recent Aging2.0 conference, I watched a man in his 30s struggle to walk while wearing an Oculus Rift headset. A moment after putting it on he experienced the physical shortcomings of someone in there 80s. These types of experiences open up a new world for researchers by providing them with the ability to directly experience physical and psychological challenges rather than rely on observations.


Doctors' resistance to change - Devi Shetty,  founder of Narayana Hrudayala, Bangalore, India

The environment created by VR is artificial and programmed, at least for now. But fast forward three to four years, and you will likely be in a real environment. Consider this: a doctor could be transported to a hospital in Kenya while sitting in the relative comfort of his clinic in San Francisco. VR would allow the user to move around and interact with people enabling participation in treatments, research or even surgery.

I suspect Zuckerberg will combine social networking and virtual reality, allowing people from any part of the world to meet up with one another, to visit places they have previously only dreamed of, and go on adventures their body would never allow in the real world.

In healthcare, innovators are already leveraging VR for treating post-traumatic stress disorder (PTSD), autism, social cognition, meditation, and help with exposure therapy and surgical training. And this is just the beginning.
 
Takeaways
The day is fast approaching when I will be able to virtually go to hospital to meet with doctors and specialists, share my vitals through various devices and a video camera to gain assessment and treatment plans from the comfort of my own home.

Healthcare information and management systems (HIMSS) have never disappointed me in terms of their participation and size, and I am hopeful that innovations will continue to shock, whispering promises of a healthier future full of empowered patients.

 
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Clinical study challenges off-label use of targeted cancer therapies

  • Oncologists increasingly use targeted agents directed at molecular features of cancer cells
  • There is increased off label use of these new targeted agents without evidence to support the practice
  • A landmark study concludes that off label use of targeted agents show no benefit and should be discouraged
  • Professor Gabra, head of cancer at Imperial College, says more research is needed
 

Despite significant progress in cancer care over the past decade, there remain substantial challenges in the treatment of advanced cancers. This has increased off-label use of newer drugs based on molecular studies of tumours, largely without much evidence to support the practice.

A landmark clinical study, known as SHIVA, led by Christophe le Tourneau, a senior medical oncologist at the Institut Curie in Paris, raised expectations among both doctors and patients, because it is one of the first randomized studies to explore molecularly targeted agents applied outside their indicated use (off-label) among those with advanced cancers for whom standard therapies had failed.
 
Findings, published in Lancet Oncology, September 2015, concluded that, “off-label use of molecularly targeted agents should be discouraged,” since the study detected no improvement in survival rates when compared to treatments selected by clinicians that were not based on such sophisticated DNA profiling. 

What are the implications of the study’s negative findings for personalised medicine?

Christophe le Tourneau

In the videos below Le Tourneau describes the SHIVA trail and some of the challenges it faced.

   

   
     (click to play the video) 

 

The context

Cancer is a heterogeneous, complex, and challenging disease to treat. Tumours formerly categorized as a single entity on the basis of microscopic appearance are now known to be diverse in their molecular characteristics. Cancer chemotherapy is on an evolutionary path from non-specific cytotoxic drugs that damage both tumour and normal cells to targeted agents that are directed at unique molecular features of cancer cells, and aims to produce greater effectiveness with less toxicity.
 
Over the past decade our understanding of cancer and the basis of its treatment has been significantly changed by the advent of rapid and cheap DNA sequencing technology. The application of these sophisticated analytic techniques to arrive at a therapy for a particular cancer has been called “personalized oncology.” The idea of personalized cancer care based on molecular characteristics of the tumour promises to expand the boundaries of precision medicine. Numerous case reports and other observations have suggested that therapy targeted at molecular characteristics of a tumour can have significant beneficial effects.
 
These personalized therapeutic strategies have rendered traditional classifications of many cancers redundant, because they have advanced our understanding of the underlying biology and molecular mechanisms of specific cancers. Cancer is no longer considered a single disease entity, and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient's tumour to make therapeutic and treatment decisions has changed the landscapes of both cancer care and cancer research.

 

The SHIVA study

The SHIVA study, carried out at eight academic centres in France and conducted in 195 patients with metastatic cancer resistant to standard care, was a proof-of-concept, open-label, randomized controlled study. The patients were randomly assigned to receive either molecularly targeted agents (used off-label) chosen on the basis of the molecular profile of the tumour; or therapy based on the clinician's choice. The median follow-up period was 11.3 months. Findings showed a median progression free survival (PFS) of 2.3 months for patients receiving targeted therapy, versus 2.0 months for patients receiving therapy based on the clinician's choice.

"So far, no evidence from our randomised clinical trial supports the use of molecularly targeted agents outside their indications on the basis of tumour molecular profiling . . . . . Our findings suggest that off-label use of molecularly targeted agents outside their indications should be discouraged, and enrolment into clinical trials encouraged," says Le Tourneau and his colleagues.
 

More research required

Hani Gabra, Professor of Medical Oncology and Head of Cancer, Imperial College London says, "SHIVA is important because it is the first randomized study carried out in this complex area of matching drugs to genomic profiles of tumours. Despite the fact that the results are negative we should continue research in this area because personalised medicine is a relatively new area. One thing to note is that the molecularly targeted agents used in SHIVA were single agents, which could increase resistance and reduce the agent’s efficacy. In clinical practice we tend to use several targeted agents in combination in order to counteract drug resistance. SHIVA tested specific agents and specific targets, which resulted in disappointing findings. This doesn’t necessarily negate the overall strategy, but it does suggest that more research is necessary to test the overall strategy, and this might be more challenging.”
 

Takeaways

SHIVA is one of several on going and proposed studies aimed at defining the role of targeting sequencing of tumours in an endeavour to enhance therapy. The SHIVA study did not uncover any new positive evidence to help in the management of advanced cancers. Le Tourneau and his colleagues suggest further studies in a subset of patients that have tumours with molecular alterations in the chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. Oncologists, while disappointed by SHIVA’S results, still hold out hope for their patients and advocate further studies.

 
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Is cancer avoidable?

  • Cancer results when stem cells divide and mutate uncontrollably
  • Whether this is predominantly the result of intrinsic or extrinsic factors is unclear
  • Some experts say 65% of cancers result from intrinsic factors and are unavoidable
  • Other experts say most cancers result from extrinsic factors and are avoidable
  • Cancer strategy should not hide behind ‘bad luck’
  • Resources need to be allocated more smartly to prevent cancer

Is cancer the result of bad luck and unavoidable, or is it self-inflicted and prevented by simple lifestyles choices? Two 2015 studies arrive at strikingly different conclusions.
 
One, carried out by researchers from the John Hopkins Kimmel Cancer Centre and published in January 2015 in the journal Science, suggests that two thirds of cancers result from bad luck. Another, carried out by researchers from the Stony Brook Cancer Centre in New York and published in December 2015 in the journal Nature rebuts the findings of the Science paper, and suggests that 70 to 90% of cancer risk is self-inflicted and therefore can be avoided.

Which is right? And, why should this concern us?
 

Cancer


Cancer is a complex group of diseases characterised by the uncontrolled growth and spread of abnormal cells. If this is not checked it can cause death. Nearly 80% of all cancer diagnoses are in people aged 55 or older. Some facts about cancer In 2015 around 1.7m new cancer cases were diagnosed in the US, and about 330,000 in the UK. Each year, there are some 589,430 cancer deaths in the US, and some 162,000 in the UK. The annual treatment cost of cancer for the US is about $90bn and for the UK about £10bn. The causes of cancer include genetic, and lifestyle factors; certain types of infections; and environmental exposures to different types of chemicals and radiation.  Whitfield Growdon, Oncology Surgeon at Massachusetts General Hospital and professor at the Harvard University Medical School describes cancer and the causes of cancer:


         

         
            (click on the image to play the video) 


 

The Science paper: cancer is unavoidable

The Science paper found that 65% of cancer cases are a result of bad luck: random DNA mutations in tissue cells during the ordinary process of stem cell division; regardless of lifestyle and hereditary factors. The remaining 35% of cancer cases, say the authors, are caused by a combination of similar mutations and some environmental and hereditary factors. One implication of these findings is that preventative strategies will not make a significant difference to the incidence rates of most adult cancers. So accordingly, the optimal way to reduce adult cancers is early detection when they are still curable by surgery.
 
Stem cell division is the normal process of cell renewal, but the extent to which random cell mutations contribute to cancer incidence, compared with hereditary or environmental factors, is not altogether clear. This is what the John Hopkins researchers sought to address with their study. Scientists examined 31 tissue types to discover whether the sheer number of cell divisions increases the number of DNA mutations, and therefore make a given tissue more prone to become cancerous.
 
Researchers developed a mathematical model, which suggested that it is incorrect to assume that cancer may be prevented with “good genes” even though we smoke, drink heavily, and carry excess weight. Their study found that, "the majority [of adult cancer risk] is due to bad luck, that is, random mutations arising during DNA replication in normal, noncancerous stem cells."  And, "this is important not only for understanding the disease, but also for designing strategies to limit the mortality it causes," say the researchers.
 
According to the Science paper bad luck mutations account for 22 of 31 adult cancer types, including ovarian, pancreatic, bone and testicular cancers. The remaining nine, including lung, skin and colorectal cancers, occurred more often than the random mutation rate predicted. This suggests that in these cancers, either inherited genes or environmental factors have a significant influence on cases.
 
Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue,” says Bert Vogelstein, Clayton Professor of Oncology at the John Hopkins University School of Medicine, and co-author of the study. One example, he says, is in colon tissue, which in humans, undergoes four times more stem cell divisions than small intestine tissue. Likewise, colon cancer is much more prevalent than small intestinal cancer.
 
In a BBC Radio 4 interview Cristian Tomasetti, co-author of the study said: “Let’s say my parents smoked all their lives, and they never got lung cancer. If I strongly believed cancer was only environment, or the genes that are inherited, then since my parents didn’t get cancer, I may think I must have good genes, and it would be OK to for me to smoke. On the contrary, our study says ‘no’, my parents were just extremely lucky, and played a very dangerous game.


Related Commentaries


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Full circle in cancer research
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Is patient engagement the new blockbuster drug? 
We should give up trying cure cancer



The Nature paper: cancer is avoidable

In a BBC interview, Yusuf Hannun, Director of the Stony Brook Cancer Center, Joel Strum Kenny Professor of Cancer Research and one of the authors of the Nature paper, challenged the findings of the ‘bad luck’ study. He suggests that hiding behind ‘bad luck’ is like playing Russian roulette with one bullet; one in six will get cancer. "What a smoker does is add two or three more bullets to the revolver and pulls the trigger. Although there is still an element of luck, because not every smoker gets cancer, they have stacked the odds against themselves. From a public health point of view, we want to remove as many bullets as possible from the revolver," says Hannun.
 
The Nature paper rebuts the John Hopkins ‘bad luck’ thesis. Its lead author, Song Wu, from the Department of Applied Mathematics and Statistics at Stony Brook University, notes that the Science paper had not conducted an alternative analysis to determine the extent to which external risk factors contribute to cancer development, and it assumes that the two variables: intrinsic stem-cell division rates, and extrinsic factors, are independent. “But what if environmental factors affect stem-cell division rates, as radiation is known to do?” asks Wu.
 
Wu and his colleagues provide an alternative analysis by applying four analytical approaches to the data that were used in the earlier Science paper and arrive at a radically different conclusion: that 70 to 90% of adult cancer cases result from environmental and lifestyle factors, such as smoking, drinking alcohol, sun exposure and air pollution. Wu admits that some rare cancers can result from genetic mutations, but suggest that incidence rates of cancers are far too high to be explained primarily by mutations in cell division.
 
According to the Nature paper, if intrinsic risk factors did play a key role in cancer development, the total number of divisions in tissue stem cells would correlate with lifetime cancer risk, and the incidence rates of the disease would be less than it actually is. Wu and his colleagues analyzed the same 31 cancer types as in the earlier Science paper, and evaluated the number of stem cell divisions in each. They then compared these rates with lifetime cancer incidence among the same cancer types. This allowed them to calculate the contribution of stem cell division to cancer risk.
 
Wu et al also pursued epidemiological evidence to further access the contribution of environmental factors to cancer risk. They analyzed previous cancer studies, which show how immigrants moving from regions of low cancer incidence to regions with high cancer incidence soon develop the same tumor rates, suggesting that the risks are environmental rather than biological or genetic.
 
The researchers’ findings suggest that mutations during cell division rarely accumulate to the point of producing cancer, even in tissues with relatively high rates of cell division. In almost all cases, the Nature paper found that some exposure to carcinogens or other environmental factors would be needed to trigger disease, which again suggested that the risks of the most prevalent adult cancers are due to environmental factors. For example, 75% of the risk of colorectal cancer is due to diet, 86% per cent of the risk of skin cancer is due to sun exposure, and 75% of the risk of developing head and neck cancers is due to tobacco and alcohol.
 
The Nature paper concludes that bad luck, or intrinsic factors, only explain 10 to 30% of cancer cases, while 70 to 90% of adult cancer cases result from environmental and lifestyle factors. "Irrespective of whether a subpopulation or all dividing cells contribute to cancer, these results indicate that intrinsic factors do not play a major causal role," say the authors. This suggests that many adult cancers may be more preventable than previously thought. 
 

Preventing cancer 

Even the Science study concedes that extrinsic factors play a role in 35% of the most common adult cancers, including lung, skin and colorectal cancers. This, together with the Nature study, and the rising incidence of avoidable cancers, should be a wake-up call because a substantial proportion of cancers can be prevented.
 
Hannun is right! Whatever the causes of cancer, we should not ‘hide behind bad luck’.  We should act on evidence, which suggests that it is within everyone’s capabilities to make simple lifestyle changes that can prevent common adult cancers.  Although maintaining a healthy lifestyle is no guarantee of not getting cancer, the Nature paper underlines the fact that a healthy lifestyle stacks the odds in your favor.  The paper supports preventative cancer strategies.
 
In 2015, tobacco smoking caused about 171,000 of the estimated 589,430 cancer deaths in the US. The Nature paper suggests that the overwhelming majority of these could have been prevented. In addition, the World Cancer Research Fund has estimated that up to 33% of the cancer cases that occur in developed countries are related to being overweight or to obesity, physical inactivity, and/or poor nutrition, and thus could also be prevented.
 
It seems reasonable to suggest that the risk of cancer can be significantly reduced by: (i) a cessation of smoking, (ii) drinking less alcohol, (iii) protecting your skin from the sun, (iv) eating healthily, (v) maintaining a healthy weight, and (vi) exercising regularly.
 

The UK Position

Everyone understands the enormity of the burden of cancer, and what to do to reduce its risk. In the UK, as in other wealthy countries, there is no lack of money, no lack of resources, and no lack of expertise for cancer care. The annual spend on cancer diagnosis and treatment alone in the UK is about £10 billion. The UK also has a government appointed Cancer Czar charged with producing a national cancer plan to bring Britain's cancer survival rates up to those of European levels. Despite our understanding and all these resources, a 2014 study published in the Lancet suggests that cancer survival rates in the UK still lag more than 20 years behind many other European countries, and that people are dying needlessly.  Why is this?
 

Fear of preventative medicine 

Writing in The Times in January 2016, Sir Liam Donaldson, a former UK Chief Medical Officer, suggested that although preventative healthcare strategies are vital “to provide safe, high quality care without running out of money”, governments avoid helping the public to mitigate the risks of modern living, which can cause cancer, because of  “two primal political forces: the mortal dread of being labeled a ‘nanny state’, and a fear of removing people’s perceived pleasures.
 
During Donaldson’s tenure between 1998 and 2010, the government rejected his recommendation for a minimum unit price for alcohol, and for the same reasons in 2014, the government rejected a tax on sugar recommended by Public Health England. Excess sugar increases the risk of cancer, heart disease and diabetes. According to Donaldson, without effective government action to lower the vast and escalating burden of cancer, and other chronic diseases, the NHS is unsustainable.
 
The missing link in preventative strategies is behavioral techniques that engage people who are at risk and help them change their behaviors. Such techniques have been demonstrated to be successful in both the UK and US. They explain how people behave, and encourage them to reduce unhelpful influences on their health, and change the way they think and act about important health-related issues such as diets, lifestyles, screenings and medication-management. See: Behavioral Science provides the key to reducing diabetes
 

Takeaway 

It is crucial that the UK government now embraces behavioral techniques to curb the curse of cancer.  Donaldson is right: if cancer, and other chronic diseases, which together consume the overwhelming percentage of healthcare expenditure, are not prevented the NHS will become unsustainable.

 
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Full circle in cancer research 

  • The scientific framework for understanding cancer has gone full circle

  • Cancer research is back where it began 60 years ago

  • Cancer mutations outsmart the smartest scientists

  • Challenges for cancer treatment go beyond biological complexity 

 

After sixty years of cancer research we’re back where we started. That’s according to MIT cancer scientist Professor Robert Weinberg, known for his discoveries of the first human oncogene (a gene that causes normal cells to form tumors), and the first tumor suppressor gene.

Writing in the journal Cell in 2014, Weinberg argues that, in the 1950s scientists viewed cancer as, “An extremely complicated process that needed to be described in thousands of different ways.” Then, scientists believed viruses caused cancer, which was proved wrong. In the 1980s cancer scientists developed the notion that the disease was caused by mutant genes. “This gave . . . the illusion . . . that we would be able to understand the laws of cancer formation the way we understand, with some simplicity, the laws of physics," says Weinberg. This was not the case. Over the past decade, scientists have returned to where they started in the 1950s, and view cancer as an extremely complex disease, “We are once again caught in this quandary: how can we understand this complexity in terms of a small number of underlying basic principles?", asks Weinberg.

 

Each cancer is unique

Victor Velculescu, Professor of Oncology at Johns Hopkins University, and internationally known for his discoveries in cancer genomics, stresses the uniqueness of cancer. “Between everybody that has cancer today, to everybody that's probably ever had cancer since the beginning of humankind, [each person] has had different molecular alterations in this disease,” he says. Adding to cancers complexity is the fact that the disease mutates over time, which means that people become resistant to specific drugs, and clinicians are obliged to search for other treatments. Professor Axel Walther, Consultant Medical Oncologists and Director for Research in Oncology at University Hospitals, Bristol describes the challenges of drug resistance for cancer patients:

     

 

Pathways

A significant advance in cancer treatment is the notion that random “errors” in our genes, which cause cancer could be simplified into specific pathways, which are the “rail tracks” within cells along which chemicals flow that keep cells alive and functioning. Genes are “stations” along these pathways. There are thousands of pathways, some known and others, unknown, and their breakdown causes cancer. Discovering these pathways provides an opportunity to block the progress of cancer, with appropriate drugs.

Professor William Nelson, a recognized leader in cancer research, and Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, says, the complexity of cancer means that, “Only rarely can a single drug block a single pathway.” Most cancers require a combination of drugs. Walther describes the challenges that the complexity of cancer pose for personalised medicine:

   

 

Cost factor

Challenges in cancer treatment go far beyond biological complexity. Increasingly, the cost of drugs is an important factor. Dr. Richard Pazdur, the FDA’s Cancer Czar, questions how much longer the FDA can remain blind to drug prices, and the growing debate over how to place an appropriate value on cancer drugs, which can cost US$100,000 or more a year. Earlier this year NHS England withdrew funding for 25 cancer drugs because the costs were too high.
 

Takeaways

Weinberg is not defeated by the notion that the scientific framework for understanding cancer has come full circle. Over the past 60 years of cancer research, many ideas have flowed from laboratories, and led to incremental advances in treating cancer, and this will continue.

 

 
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In July 2014 the European Translational Research Network in Ovarian Cancer (EUTROC), held its annual conference in London. High on its agenda was cancer’s resistance to established drugs.

Cancer is a complex disease. It arises from random “errors” in our genes, which regulate the growth of cells that make-up our bodies. Error-laden cells either die or survive, and multiply as a result of complex changes that scientists don’t fully understood.

Translational medicine
Translational medicine is a rapidly growing discipline in biomedical research, which benefits from a recent technological revolution that allows scientists to monitor the behaviour of everyone of our 25,000 genes, identify almost every protein in an individual cell, and work to improve cancer therapies.

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Austin Smith

Medical Director, Theradex

Dr Smith is a Medical Director for Europe having joined Theradex® in February 2010.

He has background training in Medical Oncology with 15 years’ clinical practice experience. He is a graduate of the Royal College of Surgeons in Ireland and completed his postgraduate training in St Bartholomew and the Royal Marsden hospital. 

Dr Smith joined the industry with PPD as Lead Medical Director for Oncology (ex-US). His responsibilities at Theradex® include evaluation of the clinical, commercial feasibility and project strategy with clients; protocol development; and selecting and liaising with clinical investigators during the clinical trial progress. He is also responsible for assessing AE and SAEs for selected European studies, commenting and preparing narrative reports for onward reporting to clients, regulatory agencies, investigators and ethics committees as necessary.

Dr Smith is also responsible for medical review of data emerging from clients’ clinical trials and for advising clients on appropriate action to be taken based on the emerging data and to advise on risk management especially risk mitigation.

Dr Smith also has experience in early access patient schemes and advising on integrating market access programs in the product lifecycle development.

Dr Smith is a member of both American Society of Clinical Oncologists and European Society of Medical Oncology.

 

 


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David Bowtell

Head, Cancer Genomics and Genetics Program, Peter MacCallum Cancer Centre, Melbourne, Australia

Professor Bowtell is the Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre and PI for the Australian Ovarian Cancer Study (AOCS).

Professor Bowtell is one of Australia’s leading ovarian cancer and human molecular genetics researchers.

He was Director of Research at Peter Mac for the last decade, returning to fulltime research in 2010 to lead the ovarian cancer arm of the National Health and Medical Research Council’s (NHMRC) $27 million involvement in the International Cancer Genomics Consortium, a world-wide effort aimed at mapping all the significant mutations in common cancers.

 Professor Bowtell heads the Australian Ovarian Cancer Study, a nationally collaborative project involving over 2000 women with ovarian cancer and one of the largest cohort studies of ovarian cancer in the world.

He is a molecular biologist and his lab focuses on the genomic analysis of ovarian cancer, with a focus on primary and acquired drug resistance. His lab is also funded from Cancer Australia and the US DoD to investigate high-risk BRCA mutations in women with ovarian cancer.


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