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AstraZeneca’s strategy to target early cancer

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Cancer

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pharmaceutical companies

R&D

AstraZeneca has turned traditional biopharma R&D on its head and is targeting early stage cancer
This strategy benefits from some of AstraZeneca’s R&D endeavours
But the strategy faces strong headwinds, which include significant technological and market challenges and substantial Competition from at least two unicorns

AstraZeneca’s strategy to target early cancer

Will José Baselga’s gamble pay off?

Baselga is AstraZeneca's new cancer research chief who has turned traditional biopharmaceutical drug development on its head by announcing AstraZeneca’s intention to target early- rather than late-stage cancer. “We need to spend our resources on those places where we can cure more people and that’s in early disease”, says Baselga, who knows that early detection can significantly improve patient survival rates and quality of life, as well as substantially reducing the cost and complexity of cancer treatment. Baselga also must know his strategy is high risk. Will it work?

In this Commentary

In this Commentary we discuss the drivers and headwinds of AstraZeneca’s strategy to increase its R&D focus on early stage cancer. But first we briefly describe cancer, the UK’s situation with regard to the disease and explain why big pharma targets advanced cancers. Also, we provide a brief description of AstraZeneca’s recent history.

What is cancer?

Cancer occurs when a normal cell’s DNA changes and multiplies to form a mass of abnormal cells, which we refer to as a tumour. If not controlled and managed appropriately the tumour can spread and invade other tissues and organs. In the video below Whitfield Growdon, a surgical oncologist at the Massachusetts General Hospital in Boston US, and a Professor at the Harvard University Medical School explains.

The UK’s record of cancer treatment

In the UK cancer survival rates vary between types of the disease, ranging from 98% for testicular cancer to just 1% for pancreatic cancer. Although the UK’s cancer survival rates lag those of other European countries, the nation’s overall cancer survival rate is improving. Several cancers are showing significant increases in five-year survival, including breast (80% to 86%), prostate (82% to 89%), rectum (55% to 63%) and colon (52% to 60%). Many of the most commonly diagnosed cancers in the UK have ten-year survival of 50% or more. With regard to cancer spending, compared with most Western European countries, including France, Denmark, Austria and Ireland, the UK spends less on cancer per person, with Germany spending almost twice as much per head.

Why big pharma targets advanced cancers?

Most cancers are detected late when symptoms have manifested themselves, which renders treatment less effective and more costly. When cancer is caught early, as in some cases of breast and prostate cancer, tumours tend to be removed surgically or killed by chemoradiation therapy (CRT) and this, for many people, provides a “cure”, although in some cases the cancer returns.

Studies in developed economies suggest that treatment costs for early-diagnosed cancer patients are two to four times less expensive than treating those diagnosed with advanced-stage cancer. Notwithstanding, there are physical, psychological, socio-economic and technical challenges to accessing early cancer diagnosis and these conspire to delay cancer detection. Thus, big pharma companies have traditionally aimed their new cancer drugs at patients with advanced forms of the disease. This provides pharma companies access to patients who are willing to try unproven therapies, which significantly helps in their clinical studies. And further, big pharma is advantaged because regulators tend to support medicines that slow tumour growth and prolong life, albeit by a few months.

Imfinzi: the only immunotherapy to demonstrate survival at three years

A good example of this is AstraZeneca’s immunotherapy drug called Imfinzi (durvalumab) used in unresectable stage-III non-small cell lung cancer (NSCLC), which has not spread outside the chest and has responded to initial chemoradiation therapy. Imfinzi works by binding to and blocking a protein called PD-L1, which acts to disguise cancer cells from your immune system. Imfinzi removes the disguise so that your immune system is better able to find and attack your cancer cells.

Findings presented at the June 2019 meeting of the American Society of Clinical Oncology (ASCO), build on a clinical study of Imfinzi reported in the September 2018 edition of The New England Journal of Medicine, and suggest that Imfinzi is the only immunotherapy to demonstrate survival at three years in unresectable stage-III NSCLC. AstraZeneca has begun a phase-3 clinical study of the PD-L1 inhibitor protein in stage II NSCLC patients.

Some information about AstraZeneca

AstraZeneca is a British-Swedish multinational biopharmaceutical company with a market cap of US$107bn and annual revenues of US$22bn. The company operates in over 100 countries, employs more than 61,000, has its headquarters in Cambridge, UK, and is recovering after patents expired on some of its best-selling drugs and a failed takeover bid in 2014 by Pfizer.

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A paradigm shift in cancer diagnosis

Patents, legacy drugs and new biologics

When pharma companies develop a new drug, they can apply for a patent that stops other companies from making the same thing. A patent lasts for 20 years, after which point other producers can replicate the drug and its selling price plummets. This happened to AstraZeneca’s when the patents expired on two of its best-selling drugs: Crestor (rosuvastatin), and Nexium (esomeprazole). The former is a statin that slows the production of cholesterol by your body, lowers cholesterol and fats in your blood and is used to reduce your chances of heart disease and strokes. The latter is a drug used to treat symptoms of gastroesophageal reflux disease (GERD) and other conditions involving excessive stomach acid. Unlike some of its rivals, these were oral medicines based on small molecules that are easy for generic manufacturers to copy, which made AstraZeneca vulnerable to cut-price competition immediately after the legal protection of the drugs had expired. Notwithstanding, AstraZeneca’s new generation of biologic medicines, which it launched in the first decade of this century, are protected to some degree by the fact that they are difficult to copy as they are manufactured using cells, instead of big chemistry sets used to make conventional drugs.

AstraZeneca’s history with early stage cancer therapies

Baselga’s gamble benefits from the fact that AstraZeneca developed an interest in the detection of early stage cancer before his appointment. Today, AstraZeneca is active in clinical studies with other biopharma companies and leading academic institutions targeting earlier-stage therapies.

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

Epithelial growth factor receptor (EGFR)

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

Technological challenges

Baselga’s gamble is assisted by advances in liquid biopsies, which work by detecting fragments of malignant tumour DNA in the bloodstream to identify oncogenic drivers, which help treatment selection. The challenge of this approach is that tumours shed meniscal amounts of circulating tumour DNA (ctDNA), which significantly raises the difficulty of detecting the genetic signals that oncologists need to identify specific cancers and select treatments. ctDNA should not be confused with circulating free DNA (cfDNA), which is a broader term that describes DNA that is freely circulating in the bloodstream but is not necessarily of tumour origin.

The good news for Baselga is that in recent years looking for ctDNA has become a viable proposition because of improvements in DNA sequencing technologies, (see below) which make it possible to scan fragments and find those few with alterations that may indicate cancer. While other blood-based biomarkers are being investigated, the advantage of ctDNA is that it has a direct link to a tumour and can be very specific at identifying cancer. ctDNA also provides a means to profile and monitor advanced stage cancers to inform treatments.

Notwithstanding, a paper published in the June 2018 edition of the Journal of Clinical Oncology suggests that, “there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer”, and therefore it is still early to adopt cfDNA analysis for routine clinical use.

Next generation genome sequencing

DNA sequencing is the process of determining the sequence of nucleotides in a section of DNA. The first commercialised method was “Sanger Sequencing”, which was developed in 1977 by Frederick Sanger, a British biochemist and double Nobel Laureate for Chemistry. Sanger sequencing was first commercialized by Applied Biosystems, and became the most widely used sequencing method for approximately 40 years. More recently, higher volume Sanger sequencing has been replaced by next-generation sequencing (NGS) methods, which cater for large-scale, automated genome analyses. NGS, also known as high-throughput sequencing, is a general term used to describe a number of different state-of-the-art sequencing technologies such as Illumina’s Solexa sequencing. These allow for sequencing of DNA and RNA significantly more quickly and cheaply than the previously used Sanger sequencing and has revolutionised the study of genomics and molecular biology.

Can AstraZeneca acquire success?

Baselgo’s gamble is not helped by the relative dearth of biotech companies engaged in clinical studies of early stage cancers. This significantly narrows AstraZeneca’s options if it wants to buy-in clinical-phase assets to fit with Baselga’s strategy.

Notwithstanding, there are at least two biotech companies of potential interest to AstraZeneca. One is Klus Pharma, founded in 2014, based in Monmouth Junction, New Jersey, US, and acquired for US$13m in October 2016 by the Sichuan Kelun Parmaceutical Co., a Chinese group based in Chengdu. Another is Dendreon, a biotech company based in Seal Beach, California, US. In 2014 Dendreon filed for chapter 11 bankruptcy. In 2015 its assets were acquired by Valeant Pharmaceuticals. In 2017, the Sanpower Group, a Chinese conglomerate, acquired Dendreon from Valeant for US$820m.

Klus is recruiting patients with stage-I rectal cancer for a phase 1/2 clinical study of its anti-HER2 antibody drug, and is also working to extend its flagship product, Provenge (sipuleucel-T) as an option for patients with low-risk prostate cancer. Provenge is an autologous cellular immunotherapy. It was the first FDA-approved immunotherapy made from a patient’s own immune cells. Since its approval in 2010, nearly 30,000 men with advanced prostate cancer have been prescribed the therapy.

Unicorns threaten AstraZeneca’s strategy for early cancer

Perhaps the biggest threat to Baselga’s gamble is competition from unicorns, which include Grail, and Guardant Health.

Grail
Grail was spun-out of the gene sequencing giant Illumina in 2016 and backed by more than US$1.5bn in funding, including money from Microsoft cofounder Bill Gates and Amazon founder Jeff Bezos. Grail is on a quest to detect multiple types of cancer before symptoms manifest themselves by way of a single, simple and cheap blood test to find fragments of ctDNA. Grail has made significant progress in its quest to develop highly sensitive blood tests for the early detection of many types of cancer, but it still has to engage in further large-scale clinical studies. At the 2018 ASCO conference, the company presented data from its Circulating Cell-free Genome Atlas (CCGA) project, which showed detection rates ranging from 59% to 92% in patients with adenocarcinoma, squamous cell and small cell lung cancers. The rate of false positives - a major concern for the oncology community - was under 2%.

In an effort to improve its technology and its outcomes, Grail has been working with researchers from the Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center and the Dana-Farber Cancer Institute, to develop a new assay. According to results published in the March 2019 edition of the journal Annals of Oncology, this joint venture has successfully come up with a method, which can detect mutations in NSCLC patients’ blood with high sensitivity. In some cases, the technology was useful when tissue biopsies were inadequate for analysis. The new tool uses Illumina’s “ultradeep next-generation sequencing", which involves reading a region of DNA 50,000 times, on average, to detect low-frequency variants. White blood cells were also sequenced to filter out "clonal hematopoiesis", which are noncancerous signals that can come from bone marrow. The sequencing information was then fed to a machine learning algorithm developed by Grail to determine mutation readouts.

Guardant Health
The other unicorn for AstraZeneca to watch is liquid biopsy developer Guardant Health. Founded in 2013, it is now an US$8bn precision oncology company based in Redwood City, California US. In April 2019 Guardant presented data of its oncology platform at the American Association of Cancer Research (AACR) in Atlanta, US. The platform leverages Guardant’scapabilities in technology, clinical development, regulatory and reimbursement to drive commercial adoption, improve patient clinical outcomes and lower healthcare costs. In pursuit of its goal to manage cancer across all stages of the disease, Guardant has launched two next-generation sequencing liquid biopsy-based Guardant360 and GuardantOMNI tests for advanced stage cancer patients, for minimal residual disease/recurrence monitoring and for early detection screening, respectively.

The Guardant360 test is used to track patients’ responses to drugs and select most effective future therapies. It can identify alterations in 73 genes from cfDNA and has been used by more than 6,000 oncologists, over 50 biopharmaceutical companies and all 28 of the National Comprehensive Cancer Network Centers.

Further, Guardant has launched a new liquid biopsy called Lunar. At the April 2019 AACR meeting the company presented data of Lunar’s use as a screen for early-stage colorectal cancer. The assay was used to test plasma samples taken from 105 patients with colorectal cancer and 124 age-matched cancer-free controls. It is the test’s utility as a screen for early-stage disease that should interest AstraZeneca most. Guardant expects to position Lunar as something approaching a true diagnostic: a screening test to identify solid tumours in the healthy population. Wider clinical studies of Lunar are expected to start soon and Guardant believes that Lunar’s market opportunity as a cancer screen is some US$18bn and sees a US$15bn market opportunity in recurrence monitoring.

Also, in April 2019 Guardant acquired Bellwether Bio, a privately held company founded in 2015, for an undisclosed sum. Bellwether is focused on improving oncology patient care through its pioneering research into the epigenomic content of cfDNA. This could aid Guardant in its efforts to develop a cancer screen and further advance its research into cancer detection at earlier stages of the disease.

Guardant is well positioned to develop individual early indications of cancer. Grail, on the other hand, is well positioned to develop a pan-cancer test. Notwithstanding, both companies need to engage in further lengthy, large-scale clinical studies before it will become clear which of these strategies will be more successful. However, both unicorns and other start-ups are potential competitors to AstraZeneca’s endeavours to target early cancer.

Takeaways

AstraZeneca’sproposed bold and risky shift in its R&D strategy is to be welcomed since the early detection and treatment of cancer should significantly enhance the chances of a cure, which would radically improve the quality of life for millions and substantially reduce the vast and escalating costs associated with the disease. AstraZeneca has some advantages since over the past two decade it has significantly enhanced its technology and been developing a platform of therapies for early stage cancer. Notwithstanding, for its strategy to target early stage cancer to be successful the company will have to overcome intense, fast growing, well-resourced competition and substantial technical and markets challenges.

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A paradigm shift in cancer diagnosis

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Cancer

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personalized medicine

tissue biopsy

People and doctors often miss early warning signs of cancer
Nearly 50% of all cancers are diagnosed late when they have already spread
Each year cancer kills 8m people worldwide and cost billions
40% of cancer deaths could be prevented by early detection
Traditional tissue biopsies used to diagnose cancer are invasive, slow, costly and often yield insufficient tissue
New non-invasive tests are being devised to detect cancer early
Such tests are positioned to significantly reduce the vast and growing global burden of cancer
But before these tests enter clinics, they need to overcome a number of challenges

A paradigm shift in cancer diagnosis

How close are we to developing a simple, cheap, rapid and exquisitely sensitive non-invasive test to diagnose cancer in healthy-looking people?

Recently, attention has been drawn to a breathalyser test for cancer diagnosis, which is just starting a significant 2-year clinical study in the UK. In 2018, a “liquid biopsy” was popularly heralded as “the holy grail” of cancer diagnosis, only quickly to be quashed by medical experts who warned that this conclusion was “premature” and “misleading”. Further, image recognition is increasingly being used as a technique to detect cancer. Given the extent and depth of these endeavours it seems reasonable to assume that, within the next decade, gold-standard solid tumour biopsies for detecting cancer will be replaced by non-invasive diagnostic techniques.

In this Commentary

In this Commentary we describe evolving innovative techniques to detect cancer early, which include a breathalyser, a liquid biopsy and an image recognition test. But first we: (i) briefly describe the epidemiology of cancer, (ii) explain the extent, implications and some of the causes of late diagnosis, which is driving the development of these new non-invasive detection techniques, (iii) describe how ‘personalized’ medicine, predicated upon the molecular signatures of cancer tumours, has become routine clinical practice and demand more efficacious techniques to understand the complexities of cancer.

Cancer snapshot

Cancer is among the leading causes of death worldwide. In 2012, there were 14.1m new cases and 8.2m cancer-related deaths worldwide. 57% of these new cancer cases occurred in less developed regions of the world, which include Central America, parts of Africa and Asia. 65% of cancer deaths occurred in these regions. The number of new cancer cases per year is expected to rise to 23.6m by 2030. It is estimated that over 40% of cancer cases are preventable. In the UK there are more than 360,000 new cancer cases and over 166,000 cancer deaths every year. Since the early 1990s, incidence rates for all cancers combined in England have increased by 13% each year. Annual NHS costs for cancer services are over £5bn, but the cost to British society - including costs for loss of productivity - is over £18bn. In the US, over 1.7m new cases of cancer were diagnosed in 2018 and some 0.61m people died from the disease. It is estimated that in the US the annual national expenditure on cancer is some US$150bn. Early diagnosis and cancer prevention would significantly reduce cancer morbidity and mortality and achieve large cost savings for healthcare systems.

The challenge of late cancer diagnoses

The significance of developing a simple non-invasive test to diagnose cancer early cannot be over-emphasised. For a number of reasons, almost half of people who get cancer are diagnosed late, which makes treatment less likely to succeed, reduces chances of survival and significantly increases the cost of care. For instance, in the UK about 25% of all cancer cases only are diagnosed following presentation in A&E. The vast majority of these cases are already at a late stage, when treatment options are limited, and survival is poorer. Further, a substantial percentage of people neither avail themselves of cancer screening nor present themselves to primary care physicians with early symptoms. A good example of this is cervical cancer screening in the UK, which is offered every three years to all women aged between 25 and 64. Despite the test only taking a few minutes, each year over 1.3m women choose not to attend, and non-attendance is the biggest risk factor to developing cervical cancer. Each year, some 220,000 women in the UK are diagnosed with cervical abnormalities and over 800 women die from the disease.

Implications of inefficient healthcare systems

Late diagnosis not only occurs for non-compliance. Some cancers are asymptomatic while others have general non-specific symptoms and are often mistaken for lesser ailments. Further, inefficiencies in healthcare systems can lead to late diagnosis and increased cancer morbidity and mortality. For example, in February 2019 the UK’s National Audit Office (NAO) published an “Investigation into the management of health screening”, which concluded that none of the key screening programs in England - for bowel, breast or cervical cancer - met their targets because of management and IT failures. As a consequence, about 3m women across England have not had a cervical cancer test for at least three-and-a-half years. In 2018, more than 150,000 cervical screening samples piled-up in laboratories due to outdated IT systems, staff shortages and changes in testing procedures. Faulty IT systems also are reported to have resulted in 5,000 women not being invited for breast screening, which in England is currently offered once every three years to women aged 50 to 70. According to the NAO report, in 2017 450,000 women missed a final breast cancer screening test because of a system failure, which is believed to have been responsible for some 270 deaths.

Molecular biology challenges to gold standard solid tissue biopsies

In the past decade, ‘personalized’ medicine predicated upon the molecular signatures of cancer tumours has become routine clinical practice. The identification on tumour tissue of predictive biomarkers of response to personalized targeted therapies is now considered optimal patient care. Notwithstanding, such treatment faces a number of biological and technological challenges associated with traditional solid tumour biopsies' access to tumours and the heterogeneity of tumours.

While some cancer tumours are easily accessed, others have limited accessibility because they are either deep in the body or embedded in critical organs. This makes obtaining a comprehensive “picture” of such tumours challenging and may increase clinical complications. Further, tissue samples from different regions of the same tumour may differ and tissue specimens from primary and metastasized tumours can also differ. In addition, studies have shown the dynamic changes of tumour features over time and the emergence of therapy-resistance. Thus, inter- and intra-tumour heterogeneity pose a pivotal challenge to guide clinical decision-making in cancer therapy as traditional biopsies may be unable to capture a complete genomic landscape of a patient’s tumour.

A non-invasive test, such as sampling blood, urine, salvia and breath can provide the same genetic information as a solid tissue biopsy and has certain added advantages, which include: (i) they are a source of fresh tumour-derived material, unhampered by preservatives and (ii) they provide an alternative sample type in routine clinical practice when tumour sampling is unavailable, inappropriate or difficult to obtain.

Breath test to diagnose cancer

Because of the challenges associated with traditional biopsies, clinical attention is turning to non-invasive tests and recently to a breath test, which promises to be able to diagnose cancer early. A study to detect cancer through breath, which was carried out by researchers from Imperial College London and the Karolinska Institutet in Sweden and presented at the 2017 European Cancer Congress (ECC) in Amsterdam, Holland was promising but inconclusive.

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World’s first blood tests that detect and locate cancer

The study aimed to test whether a “chemical signature”, composed of five substances, which seemed to typify cancer could be the basis for a diagnostic test for the disease. Breath samples were tested of some 335 patients attending leading London hospitals. Of these, 163 had been diagnosed with oesophageal or stomach cancer and 172 presented with upper gastrointestinal symptoms, but without any evidence of cancer after an endoscopy.

Findings suggested that four of the five chemical substances were expressed differently in the breath samples from those diagnosed with cancer, compared to those where no cancer had been found. The breath test was able to correctly indicate cancer in around 80% of patients who had cancer (sensitivity), and able to correctly exclude cancer in around 80% of cases, which did not have cancer, (specificity). Although the findings were promising, researchers concluded that, "The study shows the potential of breath analysis in non-invasive diagnosis of oesophageal cancer. The potential benefits of this technology to patients may be early diagnosis and improved chance of survival. If placed as an endoscopy triage test, the benefits to healthcare systems may include cost-saving through reducing the number of negative endoscopies. However, these findings must be further validated in an un-enriched larger population of patients undergoing diagnostic endoscopy and in false negative patients the value of repeat testing should be established".

Expanded clinical study for breath biopsy

Following these promising conclusions a large two-year clinical trial of a breath test, called the Breath Biopsy, supported by Cancer Research UK was started in January 2019 at Addenbrooke’s Hospital in Cambridge, UK, and aims to detect whether exhaled airborne molecules called volatile organic compounds (VOCs) can be useful in detecting cancer. The study expects to recruit 1,500 participants including healthy people to act as a control group. Scientists hope the study will lead to a simpler, cheaper method of spotting cancers at an early stage when they are more likely to respond to treatment. Study participants will be asked to breathe into a device called the Breath Biopsy, which has been developed by Owlstone Medical, a private company founded in 2003 and based in Cambridge.

Breath biopsy to target two challenging cancers

In the first instance, only patients with oesophageal and stomach cancers will be invited to try the Owlstone breath biopsy. Both of these cancers are aggressive and tend to be diagnosed late because in the early stages they either cause no symptoms - in the case of oesophageal cancer - or symptoms that are vague and easy to mistake for other less serious conditions - in the case of stomach cancer. Currently, oesophageal and stomach cancers are diagnosed using endoscopy, which involves a camera attached to a flexible tube being passed down the throat. The procedure is invasive, it risks complications and is expensive. If the breath test is successful with these two cancers, it will be expanded to include patients with prostate, kidney, bladder, liver and pancreatic cancers.

Oesophageal and stomach cancers

Oesophageal cancer is the 7^th most commonly occurring cancer in men and the 13^th most commonly occurring cancer in women. In 2018, there were over 0.5m new cases diagnosed globally. The 5-year survival rate for patients with oesophageal cancer is less than 20%. Each year, there are around 9,000 new cases diagnosed in the UK and around 7,900 oesophageal cancer deaths. In the US, it is estimated that there were 17,290 new cases of the disease and 15,850 deaths in 2018

Stomach cancer is the 4^th most commonly occurring cancer in men globally and the 7^th most commonly occurring cancer in women. The disease represents the 3^rd cause of cancer death in the world with about 723,000 deaths each year, which accounts for 8.8% of all cancer deaths. In 2018, there were over 1m new cases of stomach cancer worldwide. The five-year survival rate for the disease is about 30% and the 10-year survival rate 15%. According to the American Cancer Society's estimates, over 27,000 patients are expected to be diagnosed with stomach cancer in the US in 2019, of whom some 11,000 are expected to die. In the UK, there are around 7,000 new stomach cancer cases every year and around 4,500 stomach cancer deaths.

Chemical signature

According to the lead investigator of the breath biopsy clinical study, Rebecca Fitzgerald, professor of Cancer Prevention at Cambridge University and Consultant in Gastroenterology and General Medicine at Addenbrooke's Hospital, “We urgently need to develop new tools, like this breath test, which could help to detect and diagnose cancer earlier, giving patients the best chance of surviving their disease. Through this clinical trial we hope to find signatures in breath needed to detect cancers earlier. It’s the crucial next step in developing this technology.”

Liquid biopsies

Following the presentation of research findings of liquid biopsy clinical studies at the 2018 annual conference of the American Society of Clinical Oncology (ASCO) there were press reports suggesting that the new test was the “holy grail” of cancer diagnosis. This was quickly quashed by medical experts who described the press claims as “premature” and “misleadingly”.

A “liquid biopsy“ has the potential to detect and classify mutations from minute fragments of circulating tumour in a blood sample and entails assessing circulating tumour cells (CTCs) and cell-free DNA (cfDNA) and its subsets of circulating tumour DNA (ctDNA) and cell-free RNA (cfRNA). Liquid biopsies are considered to provide significantly superior biomarkers than the traditional cancer biomarkers such as the prostate specific antigen (PSA) and cancer antigen 125 (CA125) tests, which have been used for decades to support the diagnosis and management of cancer. With the exception of the PSA test, which is used as a screening test for prostate cancer, none of the traditional cancer tests are recommended for population screening because their sensitivity and specificity are not accurate enough.

Liquid biopsies effective only after diagnosis

While promising, liquid biopsies represent an emerging technology, which has been shown to be effective in personalizing therapy after diagnosis but has yet to demonstrate its clinical utility against the current gold standard tissue biopsies for confirming a cancer diagnosis. There is a relative dearth of evidence on the capabilities of liquid biopsies for detecting cancer early. Expert consensus suggests that liquid biopsies have significant limitations and the tests are not sufficiently developed for widespread use. Liquid biopsies are neither as good nor better than existing screening methods and are not ready for meaningful clinical application because their accuracy, reliability, and reproducibility are still unknown.

US biotech start-up conducting large clinical studies of liquid biopsies

Notwithstanding, the development of liquid biopsies continue at a pace. Not least the R&D being undertaken by GRAIL Inc., a private US biotech company, spun out in 2015 from San Diego-based Illumina, the world’s largest gene sequencing company. GRAIL is currently valued at US$2.5bn and since its inception has raised US$1.5bn. The company has started two large long-term clinical studies aimed at developing a liquid biopsy for early cancer detection.

Early test results suggest that it is not money holding these liquid biopsies back, but basic biology. To evaluate potential blood screens, thousands of patients will have to get tested - and then researchers will have to wait for some of them to actually get cancer, which is the only way to determine not only the predictive power of the tests, but also whether they lead to improved patient outcomes.

Image recognition and medical diagnosis

Image recognition is another technology being used to develop non-invasive cancer diagnostic tests. Examples include Google’s Lymph Node Assistant (LYNA), which claims to be better than doctors at spotting late-stage breast cancer. LYNA can detect secondary cancer cells in medical scans with 99% accuracy. Secondary cancer cells are responsible for spreading cancer and detecting them is time-consuming and challenging for pathologists.

A study published in the August 2018 edition of Nature Mind reports findings on the first phase of a study undertaken by Moorfields Eye Hospital and Google’s DeepMind, which enables computers to analyse high-resolution 3D scans of the back of the eye to detect more than 50 eye conditions.

A study published in the October 2017 edition of the journal Frontiers in Psychology, report findings of research conducted by scientists from Macquarie University in Sydney, Australia, which suggests facial shape analysis can correctly detect markers of physiological health in individuals of different ethnicities.

Shanghai based Yitu Technology and Beijing-based Infervision are among start-ups racing to improve medical imaging analysis by using the same technology that powers facial recognition and autonomous driving. These examples, and others, are indicative of an intensifying competition between the US and China to dominate the life sciences, which is a significant growth industry of the future. In a forthcoming Commentary we shall describe this competition in more detail and explain the comparative advantages of the two nations.

Takeaway

It seems reasonable to suggest that over the next decade the gold standard solid tissue biopsy for diagnosing cancer will be replaced with cheap, rapid, non-invasive diagnostic tests, which are able to detect cancer early and thereby make a significant dent in the vast and escalating global burden of the disease.

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New developments in the management of prostate cancer

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Cancer

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prostate specific antigen (PSA

PSA test

vascular-targeted photodynamic therapy

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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8 years, 6 months ago

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Bionsensing technology and cancer detection

Thomas Chen

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10 years, 10 months ago

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Cancer survival and patient-centered healthcare

HealthPad

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Since the early 1970s, there's been significant progress in the survival rates of some cancers, in particular testicular, skin, breast, and prostate cancers where the 10-year survival rates in the UK have increased, on average from 46% to 86%.

However, the UK still lags comparable European countries in cancer survival, and for some cancers, particularly lung, esophagus, pancreas and brain, the 10-year survival rates are only about 10% or less.

Late diagnosis
In Britain 50% of cancer patients are diagnosed late. This is the result of GPs misdiagnosing, and patient's reluctance to visit their doctors.

In his book, Malignant, Stanford University professor S Lochlann Jain suggests cancer diagnosis is missed in young adults because, "doctors often work under the misguided assumption that cancer is a disease of older people." For example, 80% of lung cancers are diagnosed at advanced stages.

Cancer survival rates are expected to improve as technology, and self-education develop. This is expected to reduce the role of primary care doctors, increase patient-centered healthcare, and reduce late diagnosis.

British stiff-upper-lip
In emerging countries, cancer patients present late because of a lack of education and money. In the UK, where medicine is free at the point of care, the British stiff-upper-lip is often the cause of late diagnosis.

A 2013 comparative study published in the British Journal of Cancer found that there was little difference in the awareness of cancer symptoms among patients, yet the British were less likely to act on them. It concluded that the traditional British 'stiff-upper-lip' means cancer patients are dying unnecessarily because they don't want to waste their GP's time with their symptoms or are too embarrassed to seek help.

Genomic medicine
A number of studies suggest that doctor-patient relationships are sub-optimal and based on asymmetry of information.

Such relationships will change when patients have access to information on their own DNA. Genomic medicine is a game-changer because of its potential to personalize patient care.

It only takes a few hours to sequence a person's genome, and costs are low and falling. A recent survey suggests that 81% of all US patients would like to have their genome sequenced. Eventually, this will mean that most people will have their genome sequenced so they can be properly cared for if they get sick.

Already some scientists and clinicians have started taking advantage of genomic sequencing, to tailor their approaches to individual differences. In this personalized, patient-centred healthcare environment, primary care doctors are less important, and patients more important. As this transformation occurs, early cancer diagnosis and survival rates are expected to rise.

Technology driven patient-centered health
Increasingly, patients are employing the expanding array of mHealth apps to diagnose and treat their own ailments and this will increase as the technology develops and prices fall.

For example, patients have started using mHealth apps to measure activity, and changes in their vital signs and bodily functions. Current devices clipped to a finger can measure heart rates, and blood oxygen levels and these data can be transmitted to smartphones. Increasingly consumers will use these tools rather than visit primary care clinics.

Takeaways
Technological developments, self-education, and consumers' increased access to their health records, will help to correct the imbalance in information that now exists between doctors and patients.

As this happens, cancers will be diagnosed earlier, primary care centres will disappear, hospitals will exist only for intensive care, and sick patients with long-term chronic illnesses will be monitored and managed remotely from home.

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11 years, 8 months ago

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What is a bone marrow biopsy?

Robert Leonard

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11 years, 10 months ago

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The use of chemotherapy before surgery in ovarian cancer patients

Hani Gabra

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Using laproscopic confocal microscopy as a diagnostic tool in cancer

Cesar Castro

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11 years, 9 months ago

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What is a normal CA125?

Mike Birrer

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13 years, 6 months ago

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What does malignant mean?

Hani Gabra

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Malignant is a clinical word used to describe a cancerous tumour that has the tendency to worsen and spread by invading adjacent tissue and tissue further away from the initial disease site.

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