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  • The clandestine status of cannabis and its attendant risks are beginning to erode
  • The idea of cannabis as an evil drug is a relatively recent phenomenon
  • Plants have been the historical source of medicine for most of human history, and cannabis is no exception
  • There is a large and growing pharmacological and clinical interest in cannabis as medicine
  • Two distinct legal markets for cannabis are emerging: the tightly regulated pharmaceutical market and the less regulated market of herbal preparations
  • The FDA has approved cannabis-related drugs, which are used for a number of indications
  • There may be a recognizable pathway leading to more cannabis compounds becoming medicine
  • To become accepted as a medicine that doctors prescribe, pharmacists supply and healthcare providers support, cannabis compounds need to demonstrate their biochemical uniformity, stability, safety and efficacy
 
Medical cannabis and modern healthcare

Today, cannabis medicine for most people involves the black market with its attendant risks and lack of quality control. But this is changing to a more desirable alternative. As legal opinion changes, and clinical studies increase; the clandestine nature of cannabis and its attendant risks are beginning to erode, and two distinct legal markets for medical cannabis are emerging. One is the tightly regulated pharmaceutical market where medical cannabis provides safe and effective pharmaceutical solutions, which doctors prescribe, pharmacists’ supply, and healthcare providers support, and the other is the less regulated market of herbal preparations. A report by ArcView Market Research reported that 2016 annual sales of legal cannabis in the US grew by 25%, to US$6.7bn, and projects sales will reach US$21.8bn by 2020. This Commentary focuses on the pharmaceutical market, which relies on randomized clinical studies to demonstrate biochemical consistency, safety and efficacy.
 
The cannabis plant and its main properties

Cannabis is a genus of an annual herbaceous flowering plant, which includes 2 familiar sub-species or chemovars: ‘C sativa’, and ‘C indica’. Modern molecular techniques applied to the taxonomic classification of cannabis have resulted in many more classifications, which, in time, will become increasingly relevant as the plant’s medicinal qualities are increasingly identified. Cannabis is an indigenous plant of central Asia and India, but can be grown in almost any climate in any part of the world, and is increasingly being cultivated by means of indoor hydroponic technology. The cannabis plant contains more than 100 cannabinoids, which are chemical compounds secreted by cannabis flowers. About 60 of these have been identified as pharmacologically active, with the primary active cannabinoids being delta-9-tetrohydro-cannabinol, commonly known as THC, and cannabidiol, which is commonly known as CBD. THC provides the principal mind-altering ingredient, while CBD does not affect the mind or behavior.
 
Cannabis as medicine

Medical cannabis refers to using extracts from the cannabis plant - cannabinoids - to treat a range of conditions or their symptoms. Cannabinoids can be administered orally, sublingually, or topically; they can be smoked, inhaled, mixed with food, or made into tea. When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain and body. Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds with receptors in the brain called CB-1, while CBD has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable. THC is the most active cannabinoid; it has dominated research into medical cannabis and resulted in FDA-approved drugs. Although CBD is one of the least active cannabinoids, it has come to dominate more recent research into medical cannabis as it is considered to have a relatively wide scope of potential medical applications with fewer side effects than THC.
 
Pot-ted history

Plants have been the historical source of medicine for most of human history, and continue to account for the base material of about 25% of modern pharmaceuticals. Approved medicines of botanical origin are relatively common, but require evidence-based randomized clinical studies to demonstrate their biochemical uniformity, stability, safety and efficacy. Medical cannabis is no exception, and the FDA has approved drugs derived from cannabinoids and synthetic cannabinoids. However, regulators have not approved the entire cannabis plant as medicine because there are insufficient clinical studies to demonstrate its benefits against its potential risks to patients it is meant to treat.

For centuries the cannabis plant has been used throughout the world for medicinal purposes. Only in recent history has it acquired the status of a dangerous drug and banned. Its first recorded use is 4000 BC when an extract from the cannabis plant was used in China as an anesthetic during surgery. The Chinese went on to use cannabis compounds extensively for a range of conditions including malaria, constipation, rheumatic pains, "absentmindedness" and "female disorders."
 
From China, cannabis travelled throughout Asia into the Middle East, Africa, Europe, and eventually to the US. Galen, a prominent Greek doctor and scientist in the Roman Empire, noted cannabis as a remedy. In India it was used to lower fevers, quicken the mind, induce sleep, cure dysentery, stimulate appetite, improve digestion, relieve headaches, and cure venereal disease. The Vikings and medieval Germans used cannabis for toothache, and for relieving pain during childbirth. In Africa it was used for a variety of fevers including malaria. Despite its extensive medicinal use in early history, there were warnings against the over-use of cannabis as it was said to result in “seeing demons”.

 
Opinion changing

The idea of cannabis as an evil drug is a relatively recent phenomenon. Despite its contemporary clandestine status, there is a large and growing pharmacological and clinical interest in cannabis as medicine, and a recognizable pathway leading to its return to mainstream medicine. As early as 1985 the FDA approved cannabinoids as medicine. As of June 2016, 25 American states and Washington DC, have legalized cannabis for medical use. Germany is now expected to follow suit. In the UK, more than half of its national parliamentarians, including the former deputy Prime Minister, want to see the legalisation of medical cannabis. In March 2017, Oxford University announced that it is to launch a £10m global centre of excellence in cannabinoid research. The program, which is a partnership between the University and Kingsley Capital Partners, a private equity business based in London, will examine the role of cannabis medicines in treating pain, cancer and inflammatory diseases.
  
FDA approved

The FDA has approved two cannabis-related drugs: dronabinol and nabilone. The former contains the psychoactive compound THC extracted from the resin of C-sativa. The latter contains a synthetic cannabinoid, which mimics THC; the primary psychoactive compound found naturally occurring in cannabis. Both treat chemotherapy-induced nausea and vomiting (CINV), and extreme weight loss caused by HIV/AIDS, among a number of other indications.

Nabiximols, a CBD extract of cannabis, has been approved in 27 countries as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Although it has not yet undergone clinical studies, scientists have recently developed Epidiolex, a CBD-based liquid drug to treat certain forms of childhood epilepsy.

 
Chemotherapy-induced nausea and vomiting
 
Chemotherapy-induced nausea and vomiting (CINV), is one of the most common and feared adverse events that can be experienced by cancer patients. Its occurrence depends on the dose and the type of chemotherapy agent used, but it tends to be more prevalent in anxious woman under 50 who do not drink alcohol, and who have a history of sickness during pregnancy. Despite advances in the prevention and treatment of emesis, of the 70% to 80% of cancer patients who experience CINV, many delay or refuse future chemotherapy treatments, and contemplate stopping all treatments because of fear of further nausea and vomiting. 
 
There are several drug classes for the prevention and management of CINV. In 1985 the FDA approved a cannabinoid, dronabinol, for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment. The number of people taking cannabinoids for therapeutic purposes is increasing, but very few medicines based on cannabis have yet been developed on rigorous scientific principles. Ahmed Ahmed, professor of gynaecological oncology at Oxford says, “This field holds great promise for developing novel therapeutic opportunities for cancer patients.
 
The endogenous cannabinoid system is a significant pathway involved in the emetic response. Cannabinoids can reduce or prevent chemotherapy-induced emesis by acting at central CB-1 receptors by preventing the pro-emetic effects of endogenous compounds, such as dopamine and serotonin. In addition, by acting as an agonist to CB-1, cannabinoids used as a treatment result in an antiemetic effect. Notwithstanding, few studies have evaluated medical cannabis alone or in combination to treat CINV. The published studies that have been conducted have mixed results. THC has to be dosed relatively highly, so that resultant adverse effects may occur comparatively frequently. Some investigations suggest that THC in low doses improves the efficacy of other antiemetic drugs if given together.

 
Some additional indications

In addition to its ability to reduce nausea, THC is effective as an appetite stimulant in both healthy and sick individuals, and is used to boost appetite in patients with cancer, HIV-associated wasting syndrome, and patients with anorexia.

Another common use of medical cannabis is as an analgesic. Studies suggest that THC activates pathways in the central nervous system, which work to block pain signals from being sent to the brain. THC has been shown to have some effect against neuropathic, cancer and menstrual pain, headache, and chronic bowel inflammation.

The high, which users get from cannabis THC is also associated with temporary loss of memory. For most people this would be concerning, but for people with post-traumatic stress disorder (PTSD), memory loss can be positive. PTSD is a chronic, disabling mental health condition triggered by a significant event, and results in traumatic flashbacks, nightmares, and emotional instability. A 2013 study published in the journal Molecular Psychiatry reported a correlation between the quantity of cannabinoid CB-1 receptors in the human brain and PTSD, and concluded that oral doses of THC could help relieve PTSD-related symptoms.

Review of clinical studies

In 2015 a systematic review of the pros and cons of cannabinoids was published in the Journal of the American Medical Association. The paper analyzed 79 clinical studies of cannabinoids, involving 6,462 participants, for a number of indications including: CINV, chronic pain, appetite stimulation in HIV/AIDS, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome.

Most studies in the review showed improvement in symptoms that were correlated with cannabinoids, compared with a placebo. However, symptoms positively correlated with cannabinoids did not reach statistical significance in all studies. The review reported that there was an increased risk of short-term adverse effects associated with cannabinoids, some of which were severe. Common among these were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

The review concluded that, “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were correlated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were also correlated with an increased risk of short-term adverse effects.”

 
Clinical studies design challenges

Although cannabis compounds are currently used to treat disease or alleviate symptoms for a number of conditions, their efficacy for some specific indications is not altogether clear. This reflects the relative dearth of clinical studies that have been carried out on cannabinoids. Further, there are several design challenges associated with clinical studies that involve THC. One is whether cannabis components beyond THC contribute to its medicinal effects. Another is connected with the ability of studies to provide adequate blinding for psychoactive compounds such as THC. Clinical studies generally are known to show a degree of subjective improvement associated with the additional attention participants in a study are given, and this is compounded when a clinical study outcome measures subjective responses, such as pain and mood, as in the case of THC.
 
Gold standard
 
To be accepted by doctors, supplied by pharmacists and supported by healthcare providers, a medical cannabis product must be standardized and consistent, and display a quality equal to any recognized pharmacological compound. It must have a secure supply chain, possess an appropriate low-risk delivery system, and have minimal adverse effects. Although there are entities working to bring this about, the fact remains that the overwhelming majority of cannabis available today is unregulated, and this provides significant challenges, which include the biochemical variability of one chemovar to another, the possibility of the presence of bacteria and pesticides, and the variation in potency.
 
Nabiximols
 
A significant success of medical cannabis is nabiximols, an oromucosal spray produced from whole cannabis extracts, which is used to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Currently nabiximols is available in 27 countries, is biochemically uniform and provides an easy-to-use, reliable delivery system with immediate onset, allowing a therapeutic window for control of symptoms without intoxication. This suggests a gold standard benchmark, which other cannabis-based medicines will be required to follow.

 
Takeaways
 
There seems to be a clear pathway for medical cannabis to increase in importance in modern pharmacology. Modern technology, which facilitates advanced cultivation and extraction processes appear to be well positioned to facilitate the creation and development of cannabis products to target specific medical needs for maximum relief of a number of chronic conditions.
 
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  • Each year about 1.7m women are diagnosed with breast cancer worldwide and over 0.5m die from the condition
  • Between 5% and 10% of these breast cancers result from harmful gene mutations
  • BRCA1 and BRCA2 gene mutations are the most common cause of hereditary breast cancer
  • 45% to 85% of women with a BRCA mutation will develop breast cancer in their lifetime compared to 12% of women in the general population
  • Most women do not know if they have a harmful BRCA mutation
  • Testing for the BRCA gene is now affordable, fast and accessible
  • Surgical interventions of women with BRCA mutations can significantly reduce their risk of developing breast cancer and substantially increase cancer survival
  • Genetic test results for breast cancer are fraught with uncertainty because testing reveals the likelihood of developing cancer rather than a certain fate
  • Research suggests that BRCA test results are not being clearly communicated to women
  • Best practice demands that expert counselors discuss genetic testing and help interpret results
 
Breast cancer and harmful BRCA gene mutations


Few things frighten women more than discovering a lump in one of her breasts The standard treatment: surgery, followed by radio- and chemotherapy, can be disfiguring, painful, sometimes unsuccessful, and the impact of the disease is felt by far more individuals than just those who have the diagnosis.The good news is that over the past 30 years breast cancer survival rates in most developed countries have been improving, largely due to screening, earlier diagnosis and improved treatments. The bad new is that in most developed countries it is twice as likely for a woman to be diagnosed with breast cancer than 60 years ago.
 
Harmful BRCA genes mutations

5 to 10% of breast cancers are thought to be due to gene mutations, and harmful BRCA mutations account for 20 to 25% of these. Women who inherit the BRCA1 mutations have a 60 to 90% risk of developing breast cancer in their lifetime, and those who inherit BRCA2 mutations increase their risk of breast cancer by 45 to 85%, compared to 12% of women in the general population. Most women do not know if they carry the harmful BRCA mutation, but if they discover they do, many elect to have a bilateral mastectomy. This is a significant procedure with potential risks and side effects, but can reduce your mortality risk by about 50%.
 
The gold standard screening for breast cancer is an x-ray picture of the breast (mammography), but increasingly women are turning to genetic testing as their awareness of the harmful BRCA mutations increase, and genetic testing becomes more accessible and affordable. However, results from these tests are not straightforward, and often not communicated well. This can increase the anxiety in women with suspected breast cancer, and make them elect to have unnecessary interventions and procedures.
 
This Commentary describes how advanced genetic testing together with expert counselling help women improve their management of breast cancer.
 

Breast Cancer
 
Cancer is a group of diseases that cause cells in your body to change and grow out of control: they mutate. Most types of cancer cells eventually form a lump or mass called a tumor, and are named after the part of the body where the tumor originates, e.g. “breast cancer”, although this convention is changing with the development of targeted personalized medicine. The exact cause of breast cancer is unknown, but the overwhelming majority result from some combination of environment, lifestyle, and genes. Breast cancer affects about 1 in 8 women at some point during their life, usually after the menopause, and is the most common cancer in women.  The majority of breast cancers begin in the parts of the breast tissue that are made up of glands for milk production, called lobules, and ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective, and lymphatic tissue. Most invasive breast cancers (those that have spread from where they started) are found in women 55 and older. Women with a family history of the disease have an increased risk of getting breast cancer. Each year about 1.7m women are diagnosed with breast cancer worldwide, and over 0.5m die from the condition. However in developed economies more and more women survive the disease. In the US, for instance, the average 5-year survival rate for people with breast cancer is 89%. The 10-year rate is 83%, and the 15-year rate is 78%. Other developed countries have similar success rates. What makes breast cancer fatal is if it spreads to the bones, lungs, liver and other organs. Early detection in order to improve breast cancer outcomes remains the cornerstone of the condition’s management. Although breast cancer is thought to be a disease of the developed world, it is increasing rapidly in emerging countries where the majority of cases present later and die earlier than women in developed countries: almost 50% of breast cancer cases and 58% of deaths occur in emerging economies. This is because women generally have relatively poor knowledge of the risk factors, symptoms and methods for early detection. Also, they experience cancer fatalism, believe in alternative medicine, and lack of autonomy in decision making, which often results in delays in seeking or avoidance of evidence-based medicine.
 
Mammography
 
Mammography, which has long been the mainstay of breast cancer detection, is a specific type of breast imaging that uses low-dose x-rays to detect small changes in the breast before there are any other signs or symptoms of the disease when it is most treatable. Mammography is noninvasive, relatively inexpensive, and has reasonable sensitivity (72–88%), which increases with age. It can also be used to detect and diagnose breast disease in women experiencing symptoms such as a lump, pain, or nipple discharge. If breast cancer is found at an early stage, there is an increased chance for breast-conserving surgery and a better prognosis for long-term survival. Most developed countries operate breast-screening programs, which regularly provides mammography for women between certain ages.
 
Advances in mammography

In recent years, mammography has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dosage, cost and patient anxiety. In response to these challenges, new forms of mammography screening have been developed, including; low dose mammography, digital mammography, computer-aided detection, tomosynthesis, which is also called 3-D mammography, automated whole breast ultrasound, molecular imaging and MRI. Notwithstanding, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. More recently, women have turned to genetic testing to gain a better understanding of their risk of inherited breast cancer.
 
Genes

Every cell in your body contains genes. These contain the genetic code for your body, which not only determines the color of your eyes and hair etc., but also provides information that affects how the cells in your body behave: for example, how they grow, divide and die. Information in your genes is inherited from both parents, and you pass on this information to your children. A change in your genetic code that affects the function of a gene is called a mutation. Many inherited gene mutations do not have any effect on your health, but some do; the BRCA1 and BRCA2 mutations account for 20 to 25% of all inheritable female breast cancers and 15% of ovarian cancers.
  
BRCA genes

In normal cells, BRCA genes are tumor suppressor genes that assist in preventing cancer developing by making proteins that help to keep cells from growing abnormally. Mutated versions of BRCA genes cannot stop abnormal growth, and this can lead to cancer. Mutated BRCA genes have a higher prevalence in certain ethnic groups, such as those of Ashkenazi Jewish descent.

In the video below Professor Robert Leonard, a medical oncologist and an authority on breast cancer, describes how BRCA genes are influential in breast and ovarian cancer risk. BRCA1 runs in families and may also increase a woman’s risk of developing fallopian tube and peritoneal cancers. BRCA2 also runs in families, and is more breast cancer-specific, but a less commonly inherited abnormality. Both or either of these genes may not be detectably abnormal even in a family with a strong inherited pattern of breast cancer, but there is a significant possibility that you will find them in people with a family history of breast and ovarian cancer. Breast and ovarian cancers associated with BRCA mutations tend to develop at younger ages than their non-hereditary counterparts.

 
 
Enhanced risk when family members have cancer
 
In December 2013, the US Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a familial history that is associated with an increased risk of a harmful mutation in one of the BRCA genes. Compared to women without a family history of cancer, risk of breast cancer is about 2 times higher for women with a close female relative who has been diagnosed with cancer; nearly 3 times higher for women with two relatives, and nearly 4 times higher for women with three or more relatives. Risk is further increased when the affected relative was diagnosed at a young age. Notwithstanding, the Preventive Services Task Force recommends against BRCA testing for women with no family history of cancer.
  
The Angelina Jolie effect

The Hollywood actress and filmmaker Angelina Jolie lost her grandmother and aunt to breast cancer and her mother to ovarian cancer. After discovering that she carried a maternally inherited pathogenic BRCA1 mutation, and being told that she had an 87% chance of developing breast cancer, and a 50% chance of ovarian cancer, Jolie elected to have her breasts, ovaries and fallopian tubes removed. After surgery her risk of developing breast cancer in later life fell to 5%.
 
In May 2013, Jolie described her decision in a New York Times (NYT) article,  “I am writing about it now because I hope that other women can benefit from my experience . . . . . Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”
 
Over testing of by low-risk women
 
Findings published in December 2016 in the British Medical Journal suggest that tests for the BRCA genes shot up by 64% following Jolie’s article. Researchers analysed data on US health insurance claims from more than 9m women between 18 and 64, and suggested that in just 2 weeks following Jolie’s NYT disclosure, 4,500 additional BRCA tests were carried out, which cost the US healthcare system some US$13.5m. Interestingly, increased testing rates were not accompanied by a corresponding increase in mastectomy rates, which suggests that additional testing did not identify new BRCA mutations. Thus, the Angela Jolie effect might have encouraged over-testing among low-risk women.
 
Mindful of her influence on women’s decisions, in 2015 Jolie wrote another NYT article in which she attempted to correct her earlier support for radical risk reduction surgery for women carriers of BRCA mutations. She said that because surgery worked for her, it is not necessarily the optimal therapeutic pathway for all women, and stressed that non-surgical treatments could be more appropriate.
 
Traditional genetic testing for breast cancer risk was slow and expensive

Genetic testing to detect BRCA mutations has been available since 1996, but for many years it was under-used because of its scarcity, high cost, and the length of time it took to produce a result. The rapid development and plummeting costs of genetic testing, and a 2013 US Supreme Court ruling, which invalidated the patents held by Myriad Genetics Inc., which restricted BRCA testing, have resulted in the growth and accessibility of genetic testing.
 
BRCA testing is not straightforward

There are hundreds of mutations in the BRCA1 and BRCA2 genes that can cause cancer. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member), and tests that check for all possible mutations in both genes. Commercial laboratories usually charge between US$450 and US$5,000 to carry out BRCA testing, depending on whether you are being tested for only a specific area(s) of a gene known to be abnormal or if hundreds of areas are being examined within multiple genes. Tests that use traditional technology take several months to report findings. This means that even if a woman is tested at the time of diagnosis, she might not know the results before she has to decide on treatment.
 
Importance of regulated testing laboratories

Testing for the BRCA genes usually involves a blood sample taken in a doctor’s clinic and sent to a commercial laboratory. In 1988, the US Congress passed the Clinical Laboratory Improvement Amendments (CLIA) to ensure quality standards, and the accuracy and reliability of results across all testing laboratories. Since then, all legitimate genetic testing in the US is undertaken in CLIA-approved facilities. During testing for BRCA mutations, the genes are separated from the rest of the DNA, and then scanned for abnormalities. Unlike other clinical screening such as HIV tests and colonoscopies, which provide a simple positive or negative result; genetic testing is fraught with uncertainty because it reveals the likelihood of developing cancer rather than a certain fate.
 
BRCA1 and BRCA2 genetic test results
 
A positive BRCA test result indicates that you have inherited a known harmful mutation in the BRCA1 or BRCA2 gene. This means that you have an increased risk of developing breast and ovarian cancers, but it does not mean that you will actually develop cancer. Some women who inherit a harmful BRCA mutation will never develop cancer. A positive test result may create anxiety and compel clinicians to perform further tests and women to undergo premature and unnecessary clinical interventions, other women in a similar situation will opt for regular screening.
 
The potential benefits of a true negative result include a sense of relief regarding your future risk of cancer, learning that your children are not at risk of inheriting the family's cancer susceptibility, and that a range of interventions may not be required. However, a negative result sometimes can be difficult to interpret because its meaning partly depends on your family’s history of cancer, and whether a BRCA mutation has been identified in a blood relative. Further, scientists continue to discover new BRCA1 and BRCA2 mutations, and have not yet identified all potentially harmful ones. Therefore, it is possible that although you have a “negative” test result you might have a harmful BRCA1 or BRCA2 mutation, which has not been identified.
 
Counselling
 
Because of these uncertainties and the agonising choices women with suspected breast cancer face, health providers in most developed countries recommend counselling as part of breast cancer treatment pathways. In the video below Dr John Green, a medical oncologist knowledgeable about the influence of inherited BRCA gene mutations on treatment options underlines the importance of expert genetic counselling to help women navigate their therapeutic pathways. Counselling is performed by a health professional experienced in cancer genetics, and usually includes the psychological risks and benefits of genetic tests, a hereditary cancer risk assessment based on a person’s personal and family medical history; a description of the tests, their technical accuracy and appropriateness, medical implications of a positive or a negative test result, the possibility of uncertain or ambiguous test results, cancer risk-reducing treatment options, and the risk of passing on a mutation to children. Because people are more aware of the genetic mutations linked to breast cancer, the demand for genetic testing and counselling have increased, and in some instances it is challenging for genetic counsellors to keep pace with demand.
 
 
The context in which genetic tests are carried out

A 2017 study published in the Journal of Clinical Oncology suggests that genetic test results for breast cancer are not being clearly communicated to women, and this could cause them to opt for treatments that are more aggressive than they actually need. To reduce this possibility the Royal Marsden NHS Trust Hospital in London has introduced the Mainstreaming Cancer Genetics programme. Since 2014 the Marsden has employed genetic counseling and used laboratories with enhanced genetic testing capabilities. This reduces processing time and costs, helps to meet the increased demand for rapid, accurate and affordable BRCA testing, and helps women make critical decisions about their treatment options.
 
There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex,” says Nazneen Rahman, Professor and Head of Cancer Genetics at the UK’s Institute for Cancer Research in London. “We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital,” says Rahman.

The Marsden is now offering tests to three times more patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.”

 
Takeaways

The history of cancer is punctuated with overzealous interventions, many of which have had to be modified once it has been demonstrated that they could cause more harm than good.

As advanced genetic testing becomes affordable and more accessible it is important that their results are interpreted with the help of genetic counsellors in a broader familial context in order to help women make painfully difficult decisions about their treatment.
 
Migration to next generation genetic testing technologies has many benefits, but it also introduces challenges, which arise from, the choice of platform and software, and the need for enhanced bio-informatics analysts, which are in scarce supply. An efficient, cost-effective accurate mutation detection strategy and a standardized, systematic approach to the reporting of BRCA test results are central for diagnostic laboratories wishing to provide a service during a time of increasing demand and downward pressure on costs.
 
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  • 3m men in the US and 330,000 men in the UK are living with prostate cancer
  • The standard test used to diagnose prostate cancer is inaccurate
  • This inaccuracy causes anxiety in men and leads to unnecessary treatments
  • Standard therapies for prostate cancer can result in incontinence and impotence
  • Two new studies describe procedures that promise significant improvements in diagnosis and treatment
 
New developments in the management of prostate cancer
 
A vicious circle

There is general agreement on two issues concerning the management of prostate cancer: one, over-diagnosis and overtreatment rates are high; and two, there is a need to refine the standard prostate-specific antigen (PSA) diagnostic test.
 
The test does not provide information to allow doctors to determine which early-stage prostate tumors pose a risk of being aggressive and need treatment, and which should be left alone. Therefore, efforts to reduce the prevalence of prostate cancer by early detection using the PSA test can lead to over-diagnosis, which in turn can result in overtreatment, which in the case of prostate cancer, can result in incontinence and impotence.
 
Current official advice to UK GPs says: “The PSA test is available free to any well man aged 50 and over who requests it.” But, “GPs should not proactively raise the issue of PSA testing with asymptomatic men”. And, “GPs should use their clinical judgment to manage symptomatic men and those aged under 50 who are considered to have higher risk for prostate cancer”. In 2014 the National Institute for Health and Care Excellence (NICE) updated its guidelines and suggested that prostate cancer patients should avoid immediate treatment and keep their disease under “surveillance”.
 
A killer disease on the increase
 
Prostate cancer is increasing in significance worldwide. In many industrialized countries such as the US and the UK, it is one of the most common cancers and among the leading causes of cancer deaths. In developing countries it may be less common, but its incidence and mortality rates have been on the rise. In the US there are some 3m men living with the disease.  It is expected that in 2017, 161,000 new cases of prostate cancer will be diagnosed in the US, and 27,000 men will die from it. In the UK, there are some 330,000 men living with prostate cancer; each year around 47,000 men are diagnosed with the disease, and each year some 11,000 die from it, which equates to one every hour. Worldwide, there are an estimated 1.6m new cases of prostate cancer, and 366,000 prostate cancer deaths annually, making it the most commonly diagnosed cancer in men and the seventh leading cause of male cancer death.
 
The prostate and prostate cancer

The prostate is a small gland in men, which is located below the bladder and above the rectum. The urethra, which is the tube that carries urine and semen out of the body through the penis, goes through the centre of the prostate. In younger men the prostate is about the size of a walnut, but in older men it can be much larger. Symptoms of prostate cancer include persistent burning, difficult, frequent, uncontrolled or bloody urination in the absence of any infection. The average age of onset is 65 to 69. It is particularly prevalent in African-Caribbean men: affecting I in 4, and killing I in 12, which is double the rate for that of Caucasian men. The main risk factor is age: 80% of all men diagnosed with prostate cancer are over 65. Between 5% and 9% of cases occur in men with a family history of prostate, breast or ovarian cancer. Environmental factors are unclear, but rates of prostate cancer are lower in less urbanised societies, and rates rise when people move to a more westernised diet and lifestyle.
 
The prostate-specific antigen (PSA) test

In the 1980s a simple and cheap blood test was introduced to detect prostate cancer in its earliest, most curable, stage. In the video below Professor Karol Sikora, a cancer expert, describes the PSA test. Although used to detect prostate cancer, it is not a test for prostate cancer, and as a consequence, it has unresolved challenges. The most significant arises because the test is not accurate enough to either rule out or confirm the presence of cancer. Indeed, it is possible for PSA levels to be elevated when cancer is not present, and not to be elevated when it is present. More than 65% of men with elevated PSA levels do not have cancer. Excessive reliance on the test may lead to unnecessary interventions, while insufficient reliance may cause cancers to be missed.
 
 
Biopsies
 
A biopsy will often be recommended if a PSA test is high. It may also be recommended if a digital rectal examination (DRE) reveals a lump or some other abnormality in the prostate. The most commonly used biopsy for diagnosing prostate cancer is the trans-rectal ultrasound-guided prostate biopsy (TRUS-biopsy). This is a surgical procedure, in which tissue is removed from the prostate for microscopic examination. Each year, over 100,000 prostate biopsies are carried out in the UK and 1m in Europe.
 
75 to 80% of men who have TRUS-biopsies have no cancerous cells, and therefore did not need the biopsy. 20 to 25% do have cancerous cells, but a large percentage of these do not need any treatment because the cancers are slow growing.  A 2014 paper by the Harvard School of Public Health estimates that only 3% of men suspected of prostate cancer have an aggressive tumor requiring immediate intervention.
 
Further, doctors cannot tell from a biopsy whether cancerous cells are aggressive and need treatment, or whether they are developing slowly and do not require treatment. This creates confusion and anxiety among men, which prompts a percentage to opt for treatment even though the overwhelming majority do not need it. 25% of older men who elect to have treatment will become incontinent or impotent as a result, despite the fact that they did not need the treatment.
 
Active surveillance
 
In a significant proportion of men, prostate cancer cells grow slowly and never pose a serious risk to health and longevity. Evidence suggests that early treatment with either surgery or radiation does not reduce mortality rates, but leaves a significant percentage of men with urinary or erectile problems and other adverse effects. As a result, more men are willing to manage their condition by active surveillance, in which doctors monitor low-risk cancers closely and consider treatment only when the condition appears to make threatening moves toward growing and spreading. These men choose to live with prostate cancer until it advances, sometimes avoiding potentially life-altering side effects for several years. Active surveillance is a powerful solution to the problem of over-diagnosis and overtreatment.
 
New studies promise significantly improved management

Prostate cancer lags behind other cancers in diagnosis, treatment and research funding. But this is beginning to change. Over the past year, findings of two clinical studies promise significant improvements in the management of the condition.

The first, published in 2017 in the Lancet, describes a process, which uses MRI-guided biopsies to improve the accuracy of prostate cancer diagnosis, and spares those who do not have aggressive cancers from undergoing an unnecessary biopsy, so reducing the confusion and anxiety which prostate patients often experience.

The second, published in 2016 in the Lancet Oncology, describes findings of a laser-activated drug derived from bacteria found at the bottom of the sea that attacks and kills prostate cancer cells without either removing or destroying the prostate gland. This is significant because it avoids the potential adverse effects of surgery and radiotherapy, which can render patients incontinent and/or impotent. 

 
The multi-parametric MRI

The 2017 Lancet study used an advanced type of MRI scan, known as a multi-parametric MRI (MP-MRI), which in addition to recording the shape and size of the prostate, also assesses the blood flow through the gland. Led by Dr Hashim Ahmed of University College London, the study was comprised of more than 500 British men with suspected prostate cancer. Results suggest that using the MP-MRI to triage men would safely reduce the number needing a primary biopsy by about 27%, and substantially improve the detection of clinically significant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancers might be detected compared with the standard pathway of TRUS-biopsy for all.
 
A paradigm shift in prostate cancer treatment

The second study compared the safety and effectiveness of a new therapy called vascular-targeted photodynamic therapy (VTP, also known as TOOKAD), with active surveillance in men with low-risk prostate cancer. It funded by STEBA Biotech, which holds the commercial licence for the therapy. Photodynamic therapy (PDT) is not new, and has been used to treat skin and other cancers where light can easily penetrate.  VTP therapy, however, is viewed as a paradigm shift in prostate cancer care. It involves injecting a light-sensitive drug (padeliporfin or WST11) into the bloodstream, and then activating it with a laser to destroy cancerous tissue.  The benefit of this approach is damage to healthy prostate tissue is minimised, reducing the risk of side effects.
 
Findings

The study was comprised of 413 men at low risk of prostate cancer, and carried out across 47 treatment sites in 10 European countries, most of which were performing VTP therapy for the first time. Only men classified with low-risk cancer were included in this study. Participants were randomly assigned either to VTP therapy or active surveillance. At the end of two years, of the 196 men who received the VTP treatment, about half showed no signs of the disease, compared with 13.5% of those given standard care. Only 6% of the VTP group later needed radical treatment, compared with 30% of active surveillance patients. VTP treatment also doubled the average time of cancer progression from 14 to 28 months. Findings suggest that 49% of patients treated with VTP therapy went into complete remission compared with 13.5% in the control group.

A third of the VTP group experienced side effects compared to only 10 of the active surveillance group. Notwithstanding, the study concluded that, “VTP therapy is a safe, effective treatment for low-risk, localised prostate cancer, which might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy”. Patient monitoring will continue in order to ascertain whether the cancer stays away. Further studies should help to understand better which cancers VTP  treatment is most appropriate for so that men can make more informed treatment decisions.

Study enhanced by MRI scanning
 
The study was conducted with people at low risk of prostate cancer. Those at very low risk are better off with no treatment and no adverse-effects. Professor Mark Emberton of University College London, the lead author of the study, believes the therapy will be most useful in patients in the “grey zone”, between low and high risk. “The fact that the treatment was performed so successfully by non-specialist centres in various health systems is really remarkable”, says Emberton because the lack of complication suggests that the treatment protocol is safe, and relatively easy to scale.

At the beginning of the study MRI scans were not universally available, and Emberton believes MRI scanning as suggested by the Ahmed 2017 study will have a significant positive effect on prostate cancer treatment in the future. When carrying out biopsies without guidance from MRI scans researchers had to guess where in the prostate the cancer was; so biopsies were sub-optimal. “If they were to do the study now, with the help of MRI scans, they could hit the cancerous parts of the prostate rather than going in blind and the results would be much better,” says Emberton.

 
Takeaways
 
These two recent studies are potential “game changers”. They promise to significantly enhance the management of prostate cancer and substantially reduce the uncertainty and anxiety, as well as the risks of the life altering side effects of treatment, experienced by millions of men living with the disease.
 
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  • Each year cancer kills 8m people worldwide and cost billions
  • 40% of cancer deaths could be prevented by early detection
  • Nearly half of all cancer sufferers are diagnosed late when the tumors have already spread
  • Victims and doctors often miss early warning signs of cancer
  • Traditional tissue biopsies used to diagnose cancer are invasive, slow, costly, and often yield insufficient tissue
  • New blood tests are being devised that simultaneously detect cancer early and inform where the cancer is in the body
  • Such tests - liquid biopsies - are positioned to end the late diagnosis of cancer
  • But before liquid biopsies become common practice they need to overcome a number of significant challenges
  
World’s first blood tests that detect and locate cancer
 
Just as there is a global race among immunotherapists to enhance cancer treatment, so there is a parallel race among bioengineers to speed up and improve the detection of cancer. Such races are important because nearly half of all cancer sufferers are diagnosed late, when their tumors have already metastasized: 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
Here we describe advances in blood tests - “liquid biopsies” - which can simultaneously detect cancer early, and identify its tissue of origin. We also, describe the growing commercialization of the technology, and some significant hurdles it still has to be overcome.
 
A costly killer disease

Each year cancer kills more than 8m people worldwide, 0.6m in the US and nearly 0.17m in the UK. Survival rates for pancreatic, liver, lung, ovarian, stomach, uterine and oesophageal cancers are particularly low. A large proportion of people do not know they have cancer, and many primary care doctors fail to detect its early warning signs. According to The Journal of Clinical Oncology, a staggering 44% of some types of cancers are misdiagnosed. A significant proportion of people discover that they have cancer only after presenting a different condition at A&E. Each year, the total cost of cancer to the UK’s exchequer is nearly £20bn. In the US, national spending on cancer is expected to reach US$156bn by 2020. And as populations age so some cancer prevalence rates increase, despite substantial endeavours to reduce the burden of the disease.
  
The UK: a stereotypical case

The UK is indicative of what is happening elsewhere in the developed world with regard to cancer diagnosis and treatment. Epidemiological trends suggest that although progress is being made to fight the disease, much work is still required. Death rates for a number of individual cancer types have declined, but rates for a few cancers have increased.

Recently, the UK’s Department of Health invested £450m to improve diagnosis, including giving primary care doctors better access to tests such as CT and MRI scans. But each year there are still some 0.17m cancer deaths in the UK, and 1 in 4 British cancer patients are unlikely to live longer than 6 months after diagnosis because they and their doctors have missed early signs of the disease. For example, in the UK only 23% of lung cancer cases are diagnosed early, as are 32% of cases of non-Hodgkin lymphoma, and 44% of ovarian cancer.

Not only does late detection increase morbidity and mortality, it significantly increases treatment costs. According to the UK’s NHS National Intelligence Network, a case of ovarian cancer detected early costs an average of £5,000 to treat, whereas one detected late at stage three or four costs £15,000. Similarly, a colon cancer patient detected early typically costs £3,000, while one not identified until a later stage would cost some £13,000.

 
Traditional tissue biopsies

Currently, oncologists look to pathologists for assistance in tumor diagnosis. Indeed, oncologists cannot proceed with therapy without a tissue diagnosis, nor are they able to discuss prognosis with the patient. After detecting a tumor through a physical examination or imaging, doctors use traditional tissue biopsies to gather information on the attributes of a patient’s cancer.
 
These pinpoint a cancer’s mutations and malignancy, but solid tissue biopsies are not always straightforward. While some cancers are easily accessed, others are hidden deep inside the body or buried in critical organs. Beyond the physical challenge, sampling from such tumors can be dangerous to patients, and once achieved, they do not always inform on current tumor dynamics. Further, traditional solid tissue biopsies are costly and time consuming to perform; they can yield insufficient tissue to obtain a good understanding of the tumor, and they can be hampered by a patient’s comorbidities, and lack of compliance.

 
Two significant studies
 
Although solid tumor tissue is still the gold standard source for clinical molecular analyses, cancer-derived material circulating in the bloodstream has become an appealing alternative showing potential to overcome some of the challenges of solid tissue biopsies.

Findings of two significant studies of liquid biopsies published in 2017 promise a more effective and patient-friendly method for diagnosing cancer: one in the journal Genome Biology, and the other in the journal Nature Genetics. Both studies are on the cusp of developing the world’s first simple blood test, which can both detect early stage cancer, and identify where in the body the cancer is located.

.
The Genome Biology study
 
​The study, reported in Genome Biology, describes findings of a blood test, referred to as the CancerLocator, which has been developed by Jasmine Zhou, Professor of Biological and Computer Sciences and her team at the University of California, Los Angeles (UCLA). The  Locator detected early stage cancer in 80% of breast, lung and liver cases.
 
Zhou and her colleagues devised a computer program that uses genetic data to detect circulating tumor DNA (ctDNA) in blood samples. Once identified, the ctDNA is compared to a database of genetic information from hundreds of people to identify where the tumor is located.  Zhou’s team discovered that tumors, which arise in different parts of the body, have different signatures, which a computer can spot. “The technology is in its infancy and requires further validation, but the potential benefits to patients are huge  . . . . . Non-invasive diagnosis of cancer is important, as it allows the early detection of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease,” says Zhou.
 
The Nature Genetics study

Researchers led by Kun Zhang, Professor of Bioengineering at the University of California, San Diego (UCSD), are responsible for the study published in the journal Nature Genetics. Zhang developed a test that examined ctDNA in blood from cancer patients and, like Zhou, discovered that not only could it detect cancer early, but could also locate where the tumor is growing in the body. When a tumor starts to take over a part of the body, it competes with normal cells for nutrients and space, killing them off in the process. As normal cells die, they release their DNA into the bloodstream; and that DNA can identify the affected tissue.
 
There are many technical differences on how each approach works . . . The work by the UCLA group is a computer program that uses data published previously by other groups, and has reduced the cancer detection error from roughly 60% to 26.5%. In contrast, we developed a new theoretical framework, generated our own data from over 100 patients and healthy people, and our accuracy of locating cancer in an organ is around 90%,” says Zhang, but he adds, “Major medical challenges don’t get solved by one team working alone”.
 
Confluence and advances in computing and biology

The research endeavors of Professors Zhou and Zhang have been made possible by the confluence and advances in computing and molecular biology. Over the past 20 years, there has been a paradigm shift in biology, a substantial increase in computing power, huge advances in artificial intelligence (AI), and the costs of data storage have plummeted. It took 13 years, US$3bn, and help from 7 governments to produce the first map of the human genome, which was completed in 2003. Soon it will be possible to sequence an entire genome in less than an hour for US$100.
 
The end of traditional in vitro diagnostics

Liquid biopsies are a sequencing-based technology used to detect microscopic fragments of DNA in just a few drops of blood, and hold out the potential to diagnose cancers before the onset of symptoms. Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry for his work in understanding how DNA is converted into RNA, “which gives a voice to genetic information that, on its own, is silent,” describes how advances in molecular science are fueling the replacement of traditional in vitro diagnostics with virtually instantaneous, point-of-care diagnostics without resort to complex processes or elaborate and expensive infrastructure. Liquid biopsies, such as those developed by Zhou and Zhang, have the potential to provide clinicians with a rapid and cheap means to detect cancer early, thereby enabling immediate treatment closely tailored to each patient’s disease state.

 
 
FDA approval of liquid biopsy
 
In 2016, the US Food and Drug Administration (FDA) granted Swiss pharmaceutical and biotech firm Roche approval for a liquid biopsy, which can detect gene mutations in the most common type of lung cancer, and thereby predict whether certain types of drugs can help treat it. 

The clinical implementations of such a test are not widespread, and there has been no regulatory approval of liquid biopsies for diagnosing cancer generally. Notwithstanding, ctDNA is now being extensively studied, as it is a non-invasive “real-time” biomarker that can provide diagnostic and prognostic information before and during treatment; and at progression.
 

cfDNA and ctDNA

Cell-free DNA (cfDNA) is a broad term that describes DNA, which is freely circulating in the bloodstream, but does not necessarily originate from a tumor. Circulating tumor DNA (ctDNA) is fragmented DNA, which is derived directly from a tumor or from circulating tumor cells (CTCs).
 
Commercialization of the liquid biopsy race
 
Bill Gates, Jeff Bezos and leading venture capitalists have poured hundreds of millions into the goal of developing liquid biopsies. The US market alone is projected at US$29bn, according to a 2015 report from investment bank Piper Jaffray. Currently, there are about 40 companies in the US analyzing blood for fragments of DNA shed by dying cancer cells. Notwithstanding, only a few companies have successfully marketed liquid biopsies, and these are limited to identifying the best treatments for certain cancers, and to update treatments as the cancer mutates. So far, no one has been successful in diagnosing incipient cancer from a vial of blood drawn from a patient who looks and feels perfectly healthy.
 
Some US companies in the liquid biopsy race

At the 2016 meeting of the American Society of Clinical Oncology (ASCO), a Silicon Valley start-up, Guardant Health, which has raised some US$200m, presented findings from a large study involving over 15,000 participants, which demonstrated the accuracy of its liquid biopsy test, Guardant360, for patients with advanced solid tumors. The study found the same patterns of genomic changes in cfDNA reported by the Guardant360 test as those found in 398 patients with matching tissue samples between 94% and 100% of the time.

The 70-gene test is the first comprehensive, non-invasive genomic cancer-sequencing test to market, and according to the company, about 2,000 physicians worldwide have used it. Guardant expects to continue to develop its technology, and maintain a commercial lead in the cfDNA liquid biopsy space. The next step for Guardant is to go beyond sequencing, which matches patients to targeted oncology drugs to the early detection of cancer itself. 
 
Also in 2016 Gates and Bezos teamed up with San Diego's Illumina, which makes most of the DNA sequencing machines that pick appropriate treatments for cancer patients, to launch another liquid biopsy start-up called Grail. In 2017, Grail raised US$900m to help it develop blood-based diagnostics to enable routine, early detection of cancer. The company aims to refine and validate its liquid biopsy technology by running a number of large-scale clinical studies where it expects to sequence hundreds of thousands of patients. Another Californian-based biotech start-up, Freemome,  raised US$65m to validate its liquid biopsy technology for the early detection of cancer.
 
Takeaways

Despite findings of the two 2017 studies reported in the journals Genome Biology and Nature genetics, FDA approval of Roche’s liquid biopsy, massive increase in investment, and significant commercial biotech activity, there is a gap between reality and aspirations for liquid biopsies. To provide doctors with a reliable, point-of-care means to detect cancer early, liquid biopsies will have to overcome several significant challenges. The major one is assay sensitivity and specificity for analysis of ctDNA and cfDNA. To compete with the gold standard solid tissue biopsy, and to ensure that patients receive early diagnosis and appropriate treatment, a successful liquid biopsy assay will have to demonstrate a high positive predictive value. Concomitantly, good sensitivity and excellent specificity will be required to yield acceptable rates of false positives and false negatives. Notwithstanding, the race among bioengineers to develop a non-invasive “real-time” liquid biopsy to detect cancer early is gaining momentum.
 

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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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  • Stem cell study aims to improve prospects for lung cancer sufferers
  • Professor Sikora suggests that lung cancer is associated with poverty
  • Current therapies for lung cancer extend life by only a few months
  • Lung cancer kills more people than any other cancer

Lung cancer and cutting edge stem cell therapy

In 2015 a combined stem cell and gene therapy for lung cancer started its first clinical study in the UK. Professor Sam Janes of University College London, the study’s leader, said: “This will be the first UK cell therapy for lung cancer, and the biggest manufacturing of cells of its kind.” 

Dr Chris Watkins, director of translational research at the Medical Research Council, which is funding the study, said: “Lung cancer kills more men and women than any other cancer, and improving the outcome for patients with this terrible disease is one of the biggest challenges we face. This new therapy, which uses modified stem cells to target the tumour directly is truly at the cutting edge.”

 
Few studies
 
The use of stem cells for treating lung diseases has increasing appeal, but as yet, little is known about the effects of administering stem cell therapy to patients with lung diseases. Currently, there are only a small number of approved clinical studies in the US and Canada investigating cell therapy approaches for lung diseases. Patrick O’Brien a consultant obstetrician and gynaecologist at University College Hospital, London describes an initiative to create a national stem cell bank in the UK: 
 
       
 
Lung cancer
 
Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. This year, an estimated 224,210 adults in the US, 40,000 in the UK, and 169,000 in India will be diagnosed with lung cancer, 90% of which are and caused by smoking. Of those diagnosed, 95% will die within ten years, although early stage lung cancer has a much better survival rate. Professor Karol Sikora, a world respected oncologist, and campaigner for better universal cancer treatment, suggests that lung cancer is associated with poverty:
 
    

Traditional therapies
 
Cell-gene therapy holds out new hope. “Lung cancer is very difficult to treat because the vast majority of patients are not diagnosed until the cancer has spread to other parts of the body. One therapy option for these patients is chemotherapy, but even if successful this treatment can normally only extend lives by a handful of months,” says JanesCurrent therapeutic strategies of chemotherapy, radiation therapy, and clinical studies with new-targeted therapies have only demonstrated, at best, extension in survival by a few months.
 
Innovative approach
 
“We aim to improve prospects for lung cancer patients by using a highly targeted therapy using stem cells, which have an innate tendency to home in on tumours when they’re injected into the body. Once there, they switch on a ‘kill’ pathway in the cancer cells, leaving healthy surrounding cells untouched,” says Janes. His study will test the treatment in human volunteers, firstly to check that the treatment is safe, and then in 56 lung cancer patients to see how effective the gene-cell therapy compares with standard care. Each patient in the study will receive three infusions comprised of billions of cells in parallel with chemotherapy.
 
Takeaways

A key advantage of Janes’ proposed treatment is that the cells do not have to be closely matched to a person’s tissue type or genetic profile. They are simply taken “off the shelf” from existing bone marrow supplies. This is because the cells have relatively few proteins on their surface, and do not induce an immune response in the recipient.
 
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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.


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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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Liquid biopsies to detect pancreatic cancer are near

  • Detecting pancreatic cancer early is a significant advance
  • 80% of people with pancreatic cancer are diagnosed late
  • Only 3% of pancreatic cancer patients survive 5 years after diagnosis
  • 12% of pancreatic cancer is associated with obesity
  • MD Anderson blood test is 100% accurate at detecting pancreatic cancer
  • Urine test 90% accurate at detecting pancreatic cancer
  • Both tests could be in the clinic in a few years


Liquid biopsies are poised to detect pancreatic cancer early, which is a significant advance.

This is important because the clinical symptoms arise late in people with this cancer. Eighty per cent of people with the disease are diagnosed when it has already spread, so they are not eligible for surgery to remove the tumour, which currently is the only potential cure. Only about 3% of patients diagnosed with pancreatic cancer survive five years after diagnosis.
 


The pancreas is an organ that sits close behind the stomach, and has two main functions: (i) producing digestive enzymes, which break down food so that it can be absorbed, and (ii) producing insulin, which regulates blood sugar levels. Pancreatic cancer occurs when cells are produced in the pancreas in an uncontrolled fashion. This can lead to a number of health risks. Almost half of all new cases of cancer of the pancreas are diagnosed in people aged 75 and over, and is uncommon in people under 40. This year, an estimated 48,960 adults in the US and some 9,000 in the UK will be diagnosed with pancreatic cancer. It is estimated that 40,560 US deaths, and about 9,000 deaths in the UK from this disease also will occur this year. Those at higher risk include people with a family history of the cancer, heavy smokers, and obese people. There is some suggestion that pancreatic cancer is a risk for people over 50 who are newly diagnosed with diabetes.
 



Pancreatic cancer and diabetes

Type-2 diabetes is considered to be associated with pancreatic cancer, but it is not altogether clear whether diabetes is a risk factor or a symptom. Two studies published in 2011; one in the British Journal of Cancer, and the other in the Annals of Oncology confirm the hypothesis that, “increased BMI and abdominal obesity are associated with increased pancreatic cancer risk.” One of the studies estimates that about 12% of all pancreatic cancers in the UK are attributable to overweight and obesity. Fatty tissue in overweight people produces more hormones and growth factors than those in people of a healthy weight. High levels of some of these hormones, including insulin, which is produced in the pancreas, can increase the risk of pancreatic cancer.

Dr Roni Sharvanu Saha, a consultant in acute medicine, diabetes and endocrinology at St George's Hospital, London, opines on the possible relationship between diabetes treatment and pancreatic cancer, and says that, “the jury is out” about the link. 


            
               (click on the image to play the video) 
 

Blood test for pancreatic cancer 

Pancreatic cancer is devastating, it usually shows no signs or symptoms, and presents late. Being able to detect the disease early is considered life enhancing for patients. Scientists from the University of Texas MD Anderson Cancer Center believe they are close to developing a blood test to detect pancreatic cancer, which they describe as "a major advance". Early results, published in 2015 in the journal Nature, showed the test was 100% accurate. Experts said the findings were striking and ingenious, but required refinement before they could be used in the clinic.
 

Major advance

A wall of fat marks the boundary of every cell in the human body. The MD Anderson test hunts for tiny spheres of fat, called exosomes, which are shed by the cancers. Scientists looked for unique signatures of cancer in these fatty exosomes, and noticed that a protein called proteoglycan glypican-1 was found in much higher levels in people with pancreatic cancer. Further blood tests on 270 people showed it was 100% accurate at distinguishing between cancers, other pancreatic disorders and healthy tissue.

The need for such a test is huge. According to Dr Raghu Kalluri, one of the MD Anderson researchers, the test is, "not too far" from the clinic. "We think the ability to identify and isolate cancer exosomes is a major advance and provides the possibility of immensely benefiting our patients," says Kalluri.
 

Urine test for pancreatic cancer

Scientists from Barts Cancer Institute, Queen Mary College, London, have developed a simple urine test to detect pancreatic cancer. The UK-Spanish study, published in Clinical Cancer Research in 2015, showed that out of 1,500 proteins found in the urine samples of 500 people, three were seen to be at much higher levels in the pancreatic cancer patients. This provided a "protein signature" that could identify the most common form of the disease, and distinguish between this cancer and the inflammatory condition chronic pancreatitis, which can be hard to tell apart. The signature was found to be 90% accurate. More research is now planned, and scientists will focus particularly on people whose genes put them at particular risk of pancreatic cancer.
 

Advantages of urine over blood 

Lead researcher, Dr Tatjana Crnogorac-Jurcevic, said: "We've always been keen to develop a diagnostic test in urine as it has several advantages over using blood. It's an inert and far less complex fluid than blood, and can be repeatedly and non-invasively tested.  We're hopeful that a simple, inexpensive test can be developed, and be in clinical use within the next few years."

"For a cancer with no early stage symptoms, it's a huge challenge to diagnose pancreatic cancer sooner, but if we can, then we can make a big difference to survival rates," says co-author and Director of Barts Cancer Institute, Professor Nick Lemoine.
 

Takeaways

Although there is a significant amount of work still to do before these tests appear in clinics, the levels of accuracy reported by the researchers are striking, and suggest that, in principle, a liquid biopsy has been found for this devastating cancer, which is good news for patients suspected of having the disease.

 
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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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