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  • 15 to 20% of breast cancer patients suffer a type of the disease that could benefit from the drug Herceptin
  • Herceptin is very effective and normally administered for 12-months but it is expensive and can cause heart damage
  • New research has found that the treatment period for Herceptin could be reduced from 12-months to 6 without compromising outcomes
  • A 6-month course would reduce the cost of the drug, increase access and potentially reduce the number of patients suffering debilitating side effects
  • The research findings reignited broader concerns about the sustainability of cancer care and the competing interests of patients, producers and providers
  • Herceptin’s patents are expiring and biosimilars are entering the market which is expected to lower costs and increase access
 
After 20 years of the cancer drug Herceptin is less more?

Findings of a phase III clinical study funded by UK government grants and presented at the June 2018 meeting of the American Society of Clinical Oncology (ASCO) suggest that the time a patient needs to spend on Herceptin, (chemical name trastuzumab), a drug widely used to treat an aggressive form of breast cancer, could be halved from 12 to 6 months. This would save insurers, governments, healthcare providers and patients significant sums of money and possibly reduce the incidence of side effects, which can include heart problems.
 
In this Commentary
 
This Commentary: (i) summarizes the findings of the clinical study and some expert reactions to it and (ii) describes the different subtypes of breast cancer and the drug trastuzumab.  The Commentary also broaches a broader concern about the escalating costs of life-saving or life-extending cancer therapies, which show no sign of either slowing or reversing. According to ASCO, in the US, newly approved cancer drugs cost on average US$10,000 per month, with some costing as much as US$30,000 per month. This causes financial hardship for many American patients and their families. In the UK, which has a large devolved public healthcare system, cancer therapies are a postcode lottery because medicines that patients receive depend on whether their local healthcare provider can afford them. In emerging economies, where the prevalence of breast cancer is rising, only a privileged few breast cancer patients have access to trastuzumab. Notwithstanding, patients should gain some comfort from Herceptin’s patents expiring and biosimilar versions of trastuzumab entering the market, which is expected to make the drug cheaper and more accessible.  
 

Breast cancer and HER2

Breast cancer is a heterogenic disease and biomolecular changes in breast cancer involve the expression of genes. The disease is classified according to the 4 subtypes of genes expressed: (i) luminal A, which accounts for 51 to 61% of all breast cancer patients, (ii) luminal B, which accounts for 14 to 16%, (iii) basal-like, which accounts for 11-20% and (iv) the HER2 subtype, which accounts for 15 to 20% of all breast cancer patients and is the focus of this Commentary. Each subtype has different clinical features, different prognoses and different responses to therapies. HER2 protein overexpression is the result of amplification of the HER2 gene and is associated with aggressive tumour growth and consequent high rates of recurrence and mortality in patients. HER2-positive breast cancer is not inherited but is a somatic genetic mutation, which occurs after conception and therefore the new DNA does not enter the eggs or sperm.
 
Trastuzumab the first gene targeted drug
 
Trastuzumab was first approved by the US Food and Drug Administration (FDA) in 1998 and became the first FDA-approved therapeutic antibody targeted to a specific cancer-related molecular marker. The FDA recommended that the drug should be administered for 12 months. Robert Leonard, formerly Professor of Cancer Studies at Imperial College London, UK, and a consultant medical oncologist specialising in breast cancer at the BUPA Cromwell Hospital, the London Clinic and the London Oncology Clinic describes HER2 positive breast cancer and trastuzumab: see video below.  “We like to talk about targeted therapies since we’ve learnt more about the basic biology of cancer, which uses subtle techniques of investigation including biological and immunological profiling of cancers. We now have the ability for new molecules to target specific abnormalities in cancer cells and these can be effective in sublimating standard breast cancer treatments. A good example are Herceptin and Lapatinib, both of which target the HER2 pathway, which is a very important pathway in breast cancer,” says Leonard.
 
Trastuzumab and advanced breast cancer
Trastuzumab’s approval followed 4 randomized clinical studies involving more than 8,000 patients with stages II or III HER2-positive breast cancers. These showed that when trastuzumab was administered for a period of 12 months in combination with or after chemotherapy agents, it potentiated the efficacy of chemo- and immunotherapy; reduced the risk of breast cancer recurrence by approximately 50% and significantly improved survival. In 2000, trastuzumab's use for advanced breast cancer was approved in Europe and has since been approved in a number of countries outside Europe. In 2002 the UK government’s watchdog, the National Institute for Health and Clinical Excellence (NICE), endorsed the use of trastuzumab for advanced HER2 breast cancer.



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Trastuzumab and early stage breast cancer
Shortly afterwards, trastuzumab expanded its use to early stage HER2 breast cancer. Findings of 2 papers in the October 2005 edition of the New England Journal of Medicine (NEJM), suggested that following initial interventions, a 12-month course of trastuzumab in combination with other agents, could also be a lifesaver for those still in the early stages of breast cancer because it reduced the risk of recurrence and death of patients by 46% compared with chemotherapy alone. In this respect trastuzumab has been viewed as a possible “cure” for early stage breast cancer. Based on these findings, trastuzumab’s approval was extended for the treatment of early stage HER2 cancers. Commenting on the 2 studies in the same edition of the NEJM Gabriel Hortoboagyi, a breast cancer specialist from MD Anderson Cancer Center in Huston, USA, said, “the results reported in this issue of the Journal are not evolutionary but revolutionary. . . . . . trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” In September 2013, a time-saving subcutaneous formulation of trastuzumab was approved in Europe, which can be administered in just 2 to 5 minutes, rather than the standard 30 to 90 minutes intravenously.
 
Was the 12 months treatment time a “guess”?
After regulatory approval in 1998 and following some subsequent clinical studies, a 12-month regimen for trastuzumab became the standard of care. Notwithstanding, some oncologists view the 12-month treatment period as a “guess”, and some smaller trials have questioned the duration of treatment.
 
Clinical study and the 2018 ASCO Meeting
 
The study presented at the 2018 ASCO meeting is the largest and most significant study to-date, which suggests that the treatment time for trastuzumab could be halved. The randomized clinical study followed 4,088 women with early-stage breast cancer across 152 sites in the UK for a median of more than 5 years: 2043 received trastuzumab for 6 months and 2045 received the drug for 12 months. The disease-free survival rate at 4 years was 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. In addition, 4% of patients on the shorter treatment dropped out due to cardiac toxicity versus 8% of those treated for a year. Across both groups, cardiac function recovered within a few months following treatment with trastuzumab but patients in the 6-month group recovered more rapidly.

Helena Earl, Professor of Clinical Cancer Medicine at the University of Cambridge, UK and the study’s lead investigator is confident that the study will, “mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer." According to Richard Schilsky, ASCO’s Chief Medical Officer, “There’s no reason to not immediately change practice. The findings are persuasive”.

 
Expert reaction to the study

Although oncologists view the study’s findings as “persuasive”, changing the length of treatment time for trastuzumab might not occur quickly. Generally, clinicians appear hesitant to immediately support a shorter duration of trastuzumab as a new standard of care. Some believe that since so few women have died or relapsed after being treated with trastuzumab, longer follow-up may be required to make sure the findings hold up before guidelines are changed. 

My guess is that people will continue to aim for a year of treatment' because of lingering concerns that longer use is better, as a smaller previous study suggested,” says Harold Burstein, a breast cancer expert at the Dana-Farber Cancer Institute in Boston, USA. However, Burstein is mindful that a shorter treatment regimen might increase access to trastuzumab for patients in emerging economies where the prevalence of breast cancer is increasing but where many women cannot afford a 12-month treatment course of the drug.  Other experts suggest that the study’s findings are significant for women who suffer the toxic effects of trastuzumab.

Jennifer Litton, a breast cancer specialist at MD Anderson Cancer Center points to another issue the ASCO study raises. She suggests the study’s findings show just how important it can be to study drugs that are already on the market. “It's really important that we continue to have public funding for clinical trials, so we can continue to ask all of these questions for our patients. Scaling back treatment whenever possible is important to patients,” says Litton.

Industry response
A spokesperson for Roche Genentech, Herceptin's developers, suggested that the ASCO study should be viewed along with several smaller studies, which conclude that the optimum duration for trastuzumab is 12 months. The goal of the treatment, “is to provide people with the best chance for a cure.” Courtney Aberbach, a spokesperson for Genentech, which was acquired by Roche, in March 2009 for US$$46.8bn, suggested that previous studies had not found that a shorter duration worked as well as the longer one. She said the 12-month course was still the only regimen approved for early-stage disease by the FDA and recommended by several international organizations that issue treatment guidelines.

The HERA Trial
Industry views are influenced by a clinical study sponsored by Roche in the expectation that the 12-month trastuzumab treatment period could be doubled. Referred to as the HERA trial, the study was conducted by France's Institut National du Cancer and reported at the 2012 meeting of the European Society for Medical Oncology (ESMO). HERA was an international multi-centre, phase III randomized study involving 5,102 women with early HER2-positive breast cancer. After finishing primary therapy with surgery, chemotherapy and radiotherapy, they were randomly assigned to trastuzumab therapy every 3 weeks for 1 year, 2 years or observation.
 
In April 2012, when the study’s findings were presented at the ESMO meeting, the overall survival rate of the 24-month treatment cohort versus the 12-month cohort was comparable. The principal conclusion of the study was that 12-month treatment remains the standard of care for HER2 positive early breast cancer patients. Results also suggested that shortening treatment of trastuzumab to 6 months may offer a worse result than a 12-month course of treatment. While the study’s findings meant that Roche missed an opportunity to expand sales of trastuzumab on the back of a longer recommended treatment period, they were also a relief to the company, which had faced the risk of losing significant sales revenues from trastuzumab had a shorter treatment period turned out to be as effective as the current standard of 12-months.
 
Unsustainable of cancer care

Cancer treatment has always been expensive, but the costs of newer molecular targeted therapies, such as trastuzumab, have escalated, which significantly reduces access for a lot of breast cancer patients to efficacious drugs. According to a 2015 study by the US National Bureau of Economic Research, each year between 1995 and 2013 the prices of cancer drugs increased 10%. This finding led some health professionals to suggest that cancer therapies are becoming “unsustainable”. In England, NICE has come under intense criticism from patient groups for rejecting numerous cancer drugs for use on the NHS because they were not judged to be cost effective. The UK’s Cancer Drugs Fund, which was set up in 2011 to plug gaps in NHS funding for cancer drugs, overspent its allocated budget by 35% between 2013 and 2015. The debate of the rising cost of cancer therapies is exacerbated by the revenues generated by cancer drugs for big pharmaceutical companies. For example, in 2017 Roche-Genentech recorded annual sales of US$6.8bn for Herceptin alone, which some analysts suggested was driven partly by the duration of the treatment and partly by strong sales growth of the drug in Brazil and China.

When vast revenues from the sale of drugs are mentioned there is negative reaction directed at giant pharmaceutical companies. In their defence drug producers stress the vast costs of developing new drugs and the tenure of patents, which limit the time drug companies have to recoup R&D costs before copycats are introduced into the market. According to the most recent report from the Tufts Center for the Study of Drug Development, and published in the May 2016 edition of the Journal of Health Economics; the cost of developing a medicine from invention to pharmacy shelves is estimated to be some US$2.7bn. Patents protect drugs for 20 years after the initial invention. This exclusivity is designed to promote a balance between new drug innovation and greater public access to drugs, which result from copycat versions.  Notwithstanding, big pharmaceutical companies stress that it can take 8 to 12 years after invention to accumulate enough data to get a drug past the FDA.
 
Biosimilars

For 20 years now Roche-Genentech has benefited from its 90% market share of the HER2-positive global breast cancer market. Notwithstanding, the main EU patent for Herceptin expired in 2014 and is due to expire in the US in 2019. Already, the market has experienced the entry of biosimilar versions of trastuzumab, which are expected to be cheaper and therefore extend patient access to the drug. Biosimilars are not to be confused with generic drugs. Regulators require biosimilars to be “highly similar” to the “reference product” but not exact copies of the biologic medicine. Biologic medicines are comprised of large complex molecules, which may be composed of living material. Here we provide some examples of the biosimilar versions of trastuzumab, which are coming onto the market.
 
Trastuzumab biosimilars
 
In December 2017, a biosimilar version of trastuzumab was approved by the FDA and is marketed in the US as Ogivri. Approval of Ogivri was based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data, which demonstrated that Ogivri is biosimilar to trastuzumab. In 2018, Merck Sharp and Dohme (MSD) launched Ontruzan, in the UK, which is Europe’s first biosimilar to Herceptin. Clinical studies have shown Ontruzan to be similar to trastuzumab in terms of its structure, biological activity and efficacy, safety and immunogenicity profile. Studies also showed that in early breast cancer, breast pathologic complete response rates were 51.7% with Ontruzant and 42% with Herceptin, while overall response rates were 96.3% and 91.2% respectively. Mylan and Biocon have launched a biosimilar version of trastuzumab called Canmab in India, and Celltrion, has launched Herzuma, another biosimilar version of trastuzumab in South Korea. According to Mark Verrill, head of the Department of Medical Oncology at the Newcastle upon Tyne Hospitals NHS Foundation TrustUK, “The launch of biosimilar trastuzumab provides a high-quality treatment alternative for patients, while offering significant potential savings for health providers and patients.”
 
Takeaways
 
The clinical study presented at the June 2018 meeting of ASCO suggested that the treatment time for trastuzumab could be reduced from 12 months to 6 without compromising outcomes. This would significantly reduce the cost of trastuzumab and thereby make the drug available to more breast cancer patients. Although the study’s findings are “persuasive” there is a reticence among clinicians to reduce the treatment time of trastuzumab. The ASCO study throws light on the challenges to reconcile the competing interests of patients, healthcare providers and drug companies. While pharmaceutical companies spend billions on R&D they are challenged to reconcile the demands of shareholders and society. Public funds for medical research, while important, are limited especially at a time of relatively slow economic growth and fiscal constraint. Given that there does not appear to be any credible suggestion to curtail the vast and escalating cost of cancer care more generally, the current situation, which incentivises giant pharmaceutical companies to invest in R&D with 20-year patents, appears to be a formula that will prevail for some time to come, and patients will have to wait significant lengths of time before they get access to biosimilars.  
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  • International study shows that while British cancer survival has improved over the past 20 years the UK’s cancer survival rates lag behind the European average in 9 out of 10 cancers
  • 10,000 cancer deaths could be prevented each year if the UK hit the European average
  • Analysis shows that some British cancer survival rates trail that of developing nations such as Jordan, Puerto Rico, Algeria and Ecuador
  • Since the inception of the NHS in 1948 policy makers and clinicians have viewed the problem as the NHS being under staffed and underfunded
  • But the answers to the cancer care challenge in the UK are not that straight forward
  • The world has changed and is changing while policy responses to challenges have remained static
 
UK cancer care lags that of other European nations: reasons and solutions
Part 1

 

This Commentary is in 2 parts
Part 1 focusses on cancer care in the UK, but much of its substance is relevant to other advanced nations with aging populations and large and escalating incidence rates and costs of cancer. Before drilling down into cancer care in Britain we briefly describe the etiology of cancer, the epidemiology of the condition as it relates to the UK and other wealthy nations, mention immunotherapy as indicative of evolving and significant new therapies, which give hope to cancer sufferers. We then describe the CONCORD-3 study reported in The Lancet in 2018. This is a highly regarded and significant international study, whose findings are widely recognised as the “gold standard” of comparative cancer care. It reports that although 5-year cancer survival rates (the internationally accepted indicator of cancer care) have improved in Britain over the past 2 decades, the UK is still trailing that of most large European countries. We conclude Part 1 with a brief description of UK initiatives to close its cancer-gap with other European countries.
 
Part 2, which will be published in 2 weeks, is an analysis of the cancer-gap between Britain and other European countries. We suggest that for decades, healthcare providers, policy makers and leading clinicians have suggested that the UK cancer-care gap is because of the lack of funding and the lack of healthcare professionals. Since the inception of the NHS in 1948 a policy mantra of “more” has taken root among policy makers, providers and clinicians: predominantly, “more money”, “more staff”, and “the government should do more”. We suggest that, over the lifetime of NHS England, a combination of Britain’s economic growth, its historical ties with Commonwealth countries and, since 1973, the reduction of barriers to the flow of labour between European countries, has given UK policy makers a convenient “get-out-of-jail-card” because they could always provide more money and more staff. Over the past 2 decades, this option has become less and less effective because of a combination of the slowdown of world economic growth, the rise of emerging economies such as India, and more recently Brexit.
 
We conclude with some thoughts about why a significant cancer care gap has opened between the UK and other European nations, and briefly describe some UK initiatives to close the gap. We suggest that the world has changed quicker than the thinking of policy makers and quicker than structural changes in the UK’s healthcare system. Improving cancer care in the Britain will require more than inertia projects. It will require more innovation, more long-term planning, more courage from policy makers, more focus on actual patients’ needs rather than what we are simply able to provide. Since 1948, the healthcare baton in the UK has been with an establishment comprised of policy makers, providers and leading clinicians. Over the past 70 years this establishment has become increasingly entrenched in past and narrow policy solutions. It has failed because the world has changed while It has remained static. It is time that the healthcare baton is passed to people with less self-interest at stake, who are less wedded to the past, and understand the new and rapidly evolving global healthcare ecosystem.

 
The UK’s cancer challenge

While British policy makers and health providers appear keen to stress that trends in the 5-year cancer survival rates (the internationally accepted measure for progress against cancer) have improved over the past 20 years, there is an element of “economy with the truth” in what they say. The UK is being left behind by significant advances in cancer survival rates in other nations. Treatment for 3.7m UK cancer patients diagnosed since 2000 is struggling to progress, especially for people diagnosed with brain, stomach and blood cancers. Further, your chances of dying after being diagnosed with prostate, pancreatic and lung cancer in Britain is significantly higher than in any other large European nation. This is according to CONCORD-3, the largest ever international cancer study reported in the January 2018 edition of the The Lancet.
 

The emperor of all maladies
 
Cancer is the uncontrolled proliferation of cells. In his 2010 Pulitzer Prize winning book, ‘The Emperor of All MaladiesSiddhartha Mukherjee, professor of oncology at Columbia University Medical School in New York describes cancer cells as, "bloated and grotesque, with a dilated nucleus and a thin rim of cytoplasm, the sign of a cell whose very soul has been co-opted to divide and to keep dividing with pathological, monomaniacal purpose." Cancer occurs when a cell starts to divide repeatedly, producing abnormal copies of itself, rather than dividing occasionally just to replace worn out cells. If the immune system fails to destroy these cells, they continue to reproduce and invade and destroy surrounding healthy tissue. A number of forces can trigger these cell divisions, such as certain chemicals (carcinogens), chronic inflammation, hormones, lack of exercise, obesity, radiation, smoking, and viruses. ‘The emperor of all maladies’ is not just one disease. There are over 200 different types of cancer, each with its own methods of diagnosis and treatment. Most cancers are named after the organ or type of cell in which they start: for example, cancer that begins in the breast is called breast cancer. Cancer sometimes begins in one part of the body and can spread to other parts of the body through the blood and lymph systems This process is known as metastasis.
 
A practitioners’ views

According to Whitfield Growdon, an oncological surgeon at the Massachusetts General Hospital and Professor of Obstetrics, Gynaecology and Reproductive Biology at the Harvard University Medical School, Cancer is a complicated set of events, which can happen in any cell in your body. Your body is comprised of tiny cells, which have the ability to grow, stop growing and to re-model, which is necessary to do all the functions that are required for living. But every cell in nature has the potential to lose control of its growth. It is this uncontrolled growth of an individual cell, which we call cancer. Cells can grow, they can spread, and if the cell growth is uncontrolled it can invade other tissues, which can lead to you losing the ability to perform vital functions that are required for your life,” see video below:
 
 
Epidemiology

There is scarcely a family in the developed world unaffected by cancer. But, this has not always been the case. Cancer only became a leading cause of death when we began to live long enough to get it. In 1911, the prevalence of cancer was low compared to what it is today. Then life expectancy in the UK was 51.5 and 52.2 years for males and females respectively. Similarly, in the US, at the beginning of the 20th century, life expectancy at birth was 47.3 years. Today, the median life expectancy in the UK is 81.6 and in the US 78.7.  Significantly, the age at diagnosis for prostate cancer today is 67 and 61 for breast cancer. Approximately 12% of the UK population are aged 70 and above and account for 50.2% of the total cancers registered in 2014. 87% of all cancers in the US are diagnosed in people over 50.
Late diagnoses
 
Every 2 minutes in Britain someone is diagnosed with cancer, and almost 50% of these are diagnosed at a late stage. Every year in the UK there are more than 360,000 new cancer cases, which equates to nearly 990 newly diagnosed cancers every day. Taking a closer look at the UK data, we notice that since the early 1990s, incidence rates for all cancers combined have increased by 12%. The increase is larger in females than males. Over the past decade, incidence rates for all cancers combined have increased by 7%, with a larger increase in females: 8% as opposed to 3% in males. Over the next 2 decades, incidence rates for all cancers combined in Britain are projected to rise by 2%. Incidence rates in the UK are lower than in most European nations in males, but higher in females.

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Incidence rates of specific cancers in the UK

In 2015, breast, prostate, lung and bowel cancers together account for some 53% of all new cancer cases in the UK. Over the past decade, thyroid and liver cancers have shown the fastest increases in incidence in both males and females.  Incidence rates of melanoma, small intestine, and kidney cancers have also increased markedly in males over the past 10 years. Over the same period, Incidence rates of kidney, melanoma, and head and neck cancers have also increased markedly in females. Despite the rise in incidence rates, in recent years mortality rates from cancer in England and Wales have fallen. Between 1994 and 2013, mortality rates from cancer for males and females fell by 30% and 22% respectively.
 
New therapies: immunotherapy/biologics
 
What gives hope to people living with cancer is partly new and innovative therapies. Over the past few decades immunotherapy, also called biological therapy, is an evolving treatment, which has become a significant part of the management of certain cancers. Immunotherapy is any form of treatment that uses the body's natural abilities that constitute the immune system to fight infection and disease or to protect the body from some of the side effects of treatment. This may be achieved either by stimulating your own immune system to attack cancer cells specifically, or by giving your immune system components to boost your body’s immune system in a general way. Immunotherapy works better for some types of cancer than for others. It is used by itself for some cancers, but for others it seems to work better when used with other types of therapy.

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London, and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZeneca, UK, “Biological therapies are treatments gaining importance globally as we progress with the management of cancer. Understanding the biology of cancer has enabled us to understand the targets that go wrong in those cancers. We have successfully used many treatments that hit directly those cancer targets in order to inhibit or “switch-off” the cancers. These biological therapies either can be useful on their own or more commonly, combined with standard treatments such as chemotherapy, surgery and radiotherapy.” See video below:

 
 
Why is the CONCORD-3 study significant?

CONCORD-3 reported in a 2018 edition of The Lancet is an international scientific collaboration designed to monitor trends in the survival of cancer patients throughout the world, and involves 600 investigators in over 300 institutions in 71 countries. The study compares the overall effectiveness of health systems to provide care for 18 cancer types, which collectively represent 75% of all cancers diagnosed worldwide. The study is specifically designed to: (i) monitor trends in the survival rates of cancer patients world-wide to 2014, (ii) inform national and global policy on cancer control, and (iii) enable a comparative evaluation of the effectiveness of health systems in providing cancer care. The study is the third of its kind and supports the over-arching goal of the 2013 World Cancer Declaration, to achieve “major reductions in premature deaths from cancer, and improvements in quality of life and cancer survival”.
 
CONCORD’s evidence base
 
The evidence base of the CONCORD-3 study is significant and is predicated upon the clinical records of 37.5m patients diagnosed with cancer between 2000 and 2014. Data are provided in over 4,700 data sets by 322 population-based cancer registries from 71 countries and territories; 47 of which provided data with 100% population coverage. The analysis is centralised, based upon tight protocols and standardised quality controls, and employs cutting-edge methods. The 71 participating countries and territories are home to a combined population of 4.9bn (UN figures for 2014). This represents 67% of the world's population (7.3bn). The 322 participating cancer registries contributed data on all cancer patients diagnosed among their combined resident populations of almost 1bn people (989m), which is 20% of the combined population of those countries. CONCORD-3 contributes to the evidence base for global policy on cancer management and control.
 
CONCORD-3 data base drives national and global policies on cancer control

Despite the care taken of the data management processes, no study is perfect, and It is reasonable to assume that a study the size of CONCORD-3 will have weaknesses. Notwithstanding, the study is “best in class” and its results are comparable within the limits of data quality. The international trends in cancer patient survival reported in the study reflect the comparative effectiveness of health systems in managing cancer patients. The findings of CONCORD-3 form part of the evidence that drives national and international policies on cancer control. For example, the International Atomic Energy Agency use the findings in its campaign to highlight global inequalities in cancer survival. The Organisation for Economic Co-operation and Development (OEDC) use the results of CONCORD as indicators of the quality of healthcare in 48 countries in its Health at a Glance publications, and the European Union use the findings in its Country Health Profiles for EU Member States.
 
Overall cancer survival is improving

Overall findings of the CONCORD-3 study suggest that the prospects for cancer patients are improving throughout the world and survival rates are increasing for some lethal cancers. Several cancers show significant increases in 5-year survival, including breast (80% to 86%), prostate (82% to 89%), rectum (55% to 63%) and colon (52% to 60%); reflecting better cancer management. Notwithstanding, there are significant differences in cancer outcomes between nations.
 
UK has worse cancer survival rates compared with other European nations

Despite the fact that increasingly more people are surviving cancer, British adult cancer patients continue to have worse survival rates after 5 years compared to the European average in 9 out of 10 cancers. Research comparing 29 countries shows survival rates in Sweden are almost 33% higher than in the UK. For ovarian cancer, which affects 7,400 British women each year, the UK comes 45th out of 59, with only 36.2% sufferers surviving 5 years. Some countries achieve nearly double this survival rate. When the largest 5 European countries - Germany, France, Britain, Italy and Spain - were compared for the 3 most common cancers, Britain came bottom for 2 of them. Britain’s survival rates were worse than the other 4 European nations for lung and prostate cancer, and second worst for breast cancer. With regard to pancreatic cancer British patients had just a 6.8% chance of survival, compared to 7.7% in Spain, 8.6% in France, 9.2% in Italy and 10.7% in Germany. This puts the UK 47th out of the 56 countries that had full data for this cancer. Studies suggest 10,000 deaths could be prevented each year if the UK were to keep up with the European average. The UK only exceeds the European average in melanoma. See table below.
 
 
Takeaways

Here we have introduced and described the findings of CONCORD-3, which suggests the UK lags significantly other European nations with regard to cancer survival rates.  This sets the scene for part 2 of this Commentary, which will briefly describe some of the UK’s cancer initiatives to reduce premature death from cancer and enhance the care of people living with the disorder. Much has been achieved and over the past 2 decades, cancer mortality rates in the UK have been significantly reduced. Notwithstanding, more innovative and effective policies, which address the actual needs of patients rather than provide “more money and more staff” will be required if the UK is to reduce the cancer-care gap.
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1 year, 2 months ago
  • 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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Is cancer avoidable?

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

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

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

Cancer


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


         

         
            (click on the image to play the video) 


 

The Science paper: cancer is unavoidable

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


Related Commentaries


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Is patient engagement the new blockbuster drug? 
We should give up trying cure cancer



The Nature paper: cancer is avoidable

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

Preventing cancer 

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

The UK Position

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

Fear of preventative medicine 

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

Takeaway 

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

 
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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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A breakthrough in the treatment of prostate cancer

  • Experts describe new prostate cancer study as the disease’s ‘Rosetta Stone’

  • Prostate cancer kills nearly 11,000 men each year in the UK alone

  • Men with untreatable prostate cancer could benefit from standard drugs

  • Study opens black box of genetics to treat previously untreatable cancer

  • Mediterranean diet lowers mortality risk for men with prostate cancer

A new UK-US cancer study could transform prostate cancer treatment, and give hope to sufferers whose cancers have become resistant to treatment. Experts’ hail the study as “incredibly exciting and ground breaking”. According to Professor Johann de Bono, of the Institute of Cancer Research, London, who led the British team, the study opens up a new era of treatment, in which men will be given drugs tailored to their tumours. 

Cancer is lethal when it metastasises and becomes resistant to drugs. The study, published in the journal Cell in 2015, involved 150 men close to death whose prostate cancers had spread throughout their bodies, and were not responding to available drugs. 
     

Prostate cancer’s ‘Rosetta Stone’

The research has opened up a black box in cancer genetics, and changes the way we think about and treat prostate cancer. Now that doctors have a map of which mutations to look for, they could search for them using a £200 test. 

De Bono, extracted samples of the cancer from metastatic tumors, and analysed their DNA, which showed that 90% of the men carried genetic mutations in their tumors, which matched drugs already on the market. A third of the men studied had tumors suitable for treatment with new drugs called PARP inhibitors.

‘’We're describing this study as prostate cancer's Rosetta Stone because of the ability it gives us to decode the complexity of the disease, and to translate the results into personalised treatment plans for patients. What's hugely encouraging is that many of the key mutations we have identified are ones targeted by existing cancer drugs - meaning that we could be entering a new era of personalised cancer treatment," says de Bono.

According to de Bono, “We are changing how long these men are living. This gives me hope that I can make a difference for men dying of prostate cancer. There is still a lot of work to do. This is not a cure, but it is a huge step forward.” 
 

Prostate cancer

In an earlier Commentary we discussed the dilemmas men face when they have been diagnosed with prostate cancer. Prostate cancer is the most common cancer in men, and each day in the UK alone 110 men are diagnosed with the disease. Cancer begins to grow in the prostate, a gland in the male reproductive system, and develops slowly. Although it can be cured if diagnosed early, there may be no signs that you have it for many years, and symptoms often only become apparent when your prostate is large enough to affect the urethra. Here cancer expert Professor Karol Sikora describes the symptoms of advanced prostate cancer:

         
                (click to play the video) 

Once prostate cancer begins to spread it becomes difficult to treat, and each year nearly 11,000 men die of the disease in the UK. Treatment options include watchful waiting, surgery, radiation, hormone therapy, chemotherapy, biological therapy and bisphosphonate therapy.
 

Mediterranean diet

According to research published in the journal Cancer Prevention Research, a Mediterranean diet rather than a Western diet may improve survivorship for men diagnosed with prostate cancer.

This is welcome news because there is a dearth of evidence to counsel men living with prostate cancer on how they can modify their lifestyle to lower the risk of mortality. The new study from Harvard’s Chan School of Public Health, investigated the diets of 926 men with prostate cancer for an average of 14 years after their diagnosis, and in 2015 published their findings, which suggest that people living with prostate cancer who ate a predominantly Western diet, high in red and processed meat, fatty dairy foods, and refined grains, were two-and-a-half times more likely to die from prostate cancer, and had a 67% increased risk of all-cause mortality, compared with participants who followed a Mediterranean diet, rich in vegetables, fruits, fish, whole grains, and healthy oils. In comparison, men who follow a Mediterranean diet had a 36% lower risk of all-cause mortality.

Lead author Meng Yang suggests treating the findings cautiously, "Given the scarcity of literature on the relationship between post-diagnostic diet and prostate cancer progression, and the small number of disease-specific deaths in the current study.”
 

Dietary supplements and vitamins

Researchers continue to look for foods (or substances in them) that can help lower prostate cancer risk. Scientists have found some substances in tomatoes (lycopenes) and soybeans (isoflavones) that might help prevent prostate cancer. Studies are now looking at the possible effects of these compounds more closely. Scientists are also trying to develop related compounds that are even more potent, and might be used as dietary supplements. 
 

Takeaways

Some studies suggest that certain vitamin and mineral supplements (such as vitamin E and selenium) might lower prostate cancer risk. But a large study of this issue, called the Selenium and Vitamin E Cancer Prevention Trial (SELECT), found that neither vitamin E nor selenium supplements lowered prostate cancer risk after daily use for about five years. In fact, men taking the vitamin E supplements were later found to have a slightly higher risk of prostate cancer.

De Bono’s breakthrough in cancer genetics means that many men whose prostate cancer was thought untreatable could be given drugs that are already on hospital shelves. Some patients have already benefited, and are alive more than a year on, despite only having been given weeks to live.

 
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Is immunotherapy a breakthrough in cancer treatment? 

  • Immunotherapy drugs heralded as game changing cancer treatment

  • MD Anderson Professor Allison stripped cancer’s ability to evade attack

  • Nivolumab focuses on the environment around a cancer

  • Immunotherapy drugs are too expensive as sustainable treatments

  • The future is personalized medicine says cancer expert Karol Sikora

A new drug class that neither directly treats nor kills cancer is heralded as a game changer in cancer treatment. 
 

New hope for late stage cancer patients

In March 2015, the American Food and Drug Administration (FDA) awarded an expanded approval for Opdivo (nivolumab), to treat non-small-cell lung cancer, which is the most common type of lung cancer, and means lung cancer patients who have failed other therapies and have no other treatment options, have another shot at containing their tumors. In June 2015, the European Commission approved the same Bristol-Myers Squibb drug in a fast track assessment for previously treated advanced melanoma patients.

Accelerated assessment was given in Europe because Opdivo (nivolumab) qualified as a “Medicinal product of major interest from the point of view of public health, and in particular from the viewpoint of therapeutic innovation.” 

FDA and EU approvals of the drug Opdivo, opens the door for other, next-generation immunotherapies to treat advanced cancers. These are heralded as a new class of game changing drugs. But are they? 
 

The genesis

Because cancer is a result of your body’s own cells growing abnormally, your immune system is held back from recognising cancer as foreign and potentially harmful. This is important because without such checks your immune system would kill you.  

Professor James Allison, director of MD Anderson’s immunotherapy platform, which cultivates, supports and tests new developments of immunology-based drugs and combinations, is credited with ground-breaking research that stripped away cancer’s ability to evade attack by the immune system. Allison’s discoveries led to nivolumab to improve the survival rate of patients with metastatic melanoma, and his insights into the basic biology of immune system T cells is broadly applicable to a variety of cancers. 
 

How it works

These new drugs release the body’s own weapons: killer white blood cells called T cells, and have been likened to taking the brakes off the immune system so that it is able to recognise tumors it wasn't previously recognising, and react to destroy them.

Unlike traditional cancer therapies such as surgery, chemotherapy, radiation or the anti-cancer drugs, immunotherapy does not target the tumor itself. Instead, it focuses on the environment around the cancer, and releases a check on the immune system’s appetite for anything that it does not recognize, so the body’s own defences can recognize tumor cells as targets. Allison says, “This drug doesn’t treat cancer; it doesn’t kill cancer cells so you can’t inject it and expect cancer to melt away immediately because it won’t.” 

However, when nivolumab is combined with tumor-targeted treatments, it lowers the risk of recurrent cancers. It does this by training the body’s T cells to recognize specific features of tumors, just as they do for viruses and bacteria. Thus, the immune system itself is programmed to destroy any returning or remaining cancer.
 

Too costly

Although immunotherapies are generating excitement among cancer clinicians and researchers, clinical studies on melanoma patients show relatively modest prolongations of life, compared with historical norms, at significant costs. For example, the cost of Opdivo (nivolumab) for one patient is about £100,000 per year.

Speaking at the 2015 American Society of Clinical Oncology (ASCO) conference in Chicago, Dr Leonard Saltz from Memorial Sloan Kettering Cancer Center, New York City, suggested that new immunotherapies would cost more than US$1 million per patient per year at the higher dose currently being studied in many different cancer types, and warned, "This is unsustainable.... We must acknowledge that there must be some upper limit to how much we can, as a society, afford to pay to treat each patient with cancer . . As someone who worries about making cancer care available to everyone and minimizing disparities, I have a major problem with this: these drugs cost too much."
      

Takeaway

According to cancer expert Professor Karol Sikora the future of cancer treatment is personalized medicine rather than new immunotherapy products. Personalized cancer care takes into account the individual’s disease, and their personal circumstances. According to Sikora, “The extent to which treatment can be tailored to an individual has been limited by crude descriptions of their disease, and generic treatment options. Advances in genomics and drug responsiveness are leading to more detailed descriptions of a patient’s cancer and better-targeted treatments, which offer significant advantages over blunderbuss chemotherapies. Personalised medicine is the real future for all our patients. Forget the drug hype; this is where the real hope lies”

Here Mike Birrer, Professor of Medicine at the Harvard University Medical School, and Director of the Cancer Center at Massachusetts General Hospital describes personalised medicine:  

         
                (click on the image to play the video)

 

 
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We should give up trying cure cancer

  • Leading cancer scientist says we should abandon looking for a cancer cure
  • Another leading cancer scientist discovers key to killing all cancers
  • Cancer is an inevitable consequence of our multicellular make-up
  • Each person's cancer is unique
  • One in three people will develop cancer in their lifetime
  • Every day 1,500 Americans, and more non-Americans, die of cancer
  

Most cancers cannot be cured and scientists should devote their efforts to preventing and managing the disease instead of trying to find a cure. That’s the view of Melvyn Greaves Professor of Cell Biology at the Institute of Cancer Research, UK.
 

Game changing cure for all cancers

Greaves’ suggestion comes at a time when Professor Philip Ashton-Rickardt, from Imperial College London discovered a previously unknown protean, which boosts the body’s ability to fight off any cancer or virus. “This is a completely unknown protein. Nobody had ever seen it before or was even aware that it existed. It looks and acts like no other protein . . . . It could be a game-changer for treating a number of different cancers and viruses,” says Ashton-Rickardt.
 

Unanswered questions about cancer

Cancer is an uncontrolled cell proliferation, propelled by mutant genes that invade our tissues and hijack essential body functions.  Some regard this process as a ‘disease of the genome’. Around one in three of us will, at some time in our lives, be diagnosed with cancer; every day 1,500 Americans and vastly more non-Americans die of the disease. Missing from the narrative about cancer has been a coherent framework that makes sense of all its complexities and uncertainties: why are we so vulnerable to cancer, why is there so much diversity between different cancers, and even within single cancer types?  And why does treatment so often fail or only temporarily succeed?

Mike Birrer, Professor of Medicine, Harvard University Medical School and Director of Medical Oncology, Massachusetts General Hospital describes the Cancer Genome Atlas, a landmark cancer research program, which begins to address some of these questions: 


        

        (click on the image to play the video)

                               

Previously undiscovered protein

The protein discovered by Ashton-Rickardt, named lymphocyte expansion molecule, or LEM, promotes the spread of cancer killing T cells by generating large amounts of energy. Normally when the immune system detects cancer it goes into overdrive trying to fight the disease, flooding the body with T cells. But it quickly runs out of steam.

The new protein discovered by Ashton-Rickardt causes a massive energy boost, which generates T cells in such great numbers that the cancer cannot fight them off. It also causes a boost of immune memory cells, which are able to recognise tumors and viruses they have encountered previously so there is less chance that they will return. Ashton-Rickardt, whose studies to-date have been in mice, is hoping to produce a gene therapy whereby T cells of cancer patients could be enhanced with the protein, and then injected back into the body. In three years he expects to begin human studies. If successful, Ashton-Rickardt’s discovery could end the need for chemotherapies, as the body itself would fight the disease, rather than toxic drugs.

Alex Walther, consultant medical oncologist and Director of Research in Oncology at University Hospitals, Bristol describes the challenges of clinical trails in personalised molecular medicine: 

        
                                                 
         (click on the image to play the video) 


Need for smarter cancer strategies

Although sceptical about a cancer cure, Greaves has spent years unravelling the causes of childhood leukaemia by examining the genetic influences and biological pathways that lead to the disease. In 2008, breakthrough research led by Greaves and Professor Tariq Enver, achieved a world-first by confirming the existence of stem cells responsible for childhood acute lymphoblastic leukaemia.

Greaves insists that, “We need to get smarter. Very intelligent people who aren't scientifically minded think there must be a cause, there must be a cure, and it’s just not right. It’s fundamentally wrong . . . Talking about a cure for cancer in terms of elimination is just not realistic. . . . There are a few cancers that are curable, but most are probably not, including the common carcinomas in adults . . . . We should therefore not try to eliminate the cancer, we should try to hold it in check,” says Greaves. 
 

Experts disagree

Leading cancer expert Professor Karol Sikora, is confident cancer cures could still be found, and finds Greaves’ pessimism, “Strange, given that Professor Greaves has done so much to help find a cure for leukaemia. I absolutely think we will find new cures in the future, and the closer we get to understanding the mechanism of the disease, the quicker this will happen.

Professor Peter Johnson, chief clinician at Cancer Research UK agrees with Sikora, “We already have cures for many types of cancer. For example, millions of people who have had breast cancer, prostate cancer or bowel cancer are alive years after their surgery to remove the tumour, if it was caught early enough.” 
 

Molecular Darwinism 

Cancer researchers throughout the world are attempting to find cures for individual cancers using increasingly advanced methods. These include ramping up the body's own immune system to fight the disease; personalized treatments based on the DNA of the tumors, and gene therapies. But Greaves believes no therapy will work in the long term because tumors continue to evolve like all life forms. "Isn't it odd that when you read reports about new cancer therapies they work dramatically, but three months later, cancer is back with a bang. It's almost always the story" says Greaves. 

In his book, Cancer: The Evolutionary Legacy, Greaves describes the Darwinian process by which cancer cells mutate, and diversify by natural selection within our tissue ecosystems. According to Greaves cancer is an inevitable consequence of our make-up as a multicellular reproductive animal. Since multicellular organisms have been around for 700 million years there has been a long time for cancer to evolve; and, without DNA mutation, we ourselves would not have evolved, and adapted into what we are. According to Greaves, "Cancer becomes a statistical inevitability of nature; a matter of chance and necessity." 
 

Takeaways

Evolutionary principles derived from ecology, and the study of human evolution can change the way we think about the big question in cancer research. Will this provide new avenues for more effective cancer control or a cure? 

 
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