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4 years, 11 months ago

Finding the Holy Grail: early detection tests for cancer

HealthPad
Directory:
Cancer
Tags:
autoantibody biomarkers
biomarker
cancer reasearch
commentary
liquid biopsy
  • Bioengineers throughout the world are competing to achieve the Holy Grail: an affordable, point-of-care blood test - liquid biopsy - that detects cancer before any symptoms present
  • Success in achieving this will save millions of lives, substantially reduce healthcare costs and make investors, researchers and organisations billions
  • Despite significant advances no one has yet achieved the Holy Grail and there remains a substantial gap between researchers’ aspirations and reality
  • How close are we?

 
 

Finding the Holy Grail: early detection tests for cancer
 

 

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

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

 

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

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

Findings

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

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

 

Liquid biopsies

 
Liquid biopsies require biomarkers, which are substances, structures, or processes in your body that can be analysed in order to explain the pathogenesis of cancer and other disease states, and thereby inform diagnosis, predict onset and suggest appropriate therapies. Notwithstanding, the multiple types of biomarkers have varying degrees of reliability. Initially, the principal focus of research into EDTs was largely focussed on circulating tumour cells (CTC) and DNA. More recently however, additional biomarkers have become an important focus for such research. Antibodies are just one type of molecular biomarker. Because antibodies function by binding specific antigens, attempts to identify antibody biomarkers have involved using antigens to capture antibodies that are overproduced in cancer. Identifying relevant antigens is critical for discovering antibody biomarkers. Array-based approaches employed by Alfattani and her colleagues depend on exposing serum samples from patients to an ordered array of putative antigens, capturing those antibodies that bind antigens on the arrays and measuring their levels. Antibodies that are present at significantly higher levels in the serum of patients with breast cancer, (compared to control serums from healthy patients) are candidate biomarkers. 
 
Because of the unreliability of such biomarkers, new liquid biopsy tests tend to be predicated upon the levels of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and exosomes. These also pose challenges because of the varying physiological levels of the different biomarker fragments in your bloodstream.
cfDNA refers to DNA molecules that circulate in your blood after cell death. The amount of cfDNA varies significantly depending on the location, type and stage of your cancer. Concentrations of cfDNA can range from 1 to 100,000 fragments per ml of blood.
ctDNA refers to DNA that comes from cancerous cells and is present in your bloodstream. As a tumour grows, your cells die and are replaced by new cells. Your dead cells decompose and their contents, including DNA, are released into your bloodstream. So, ctDNA are small fragments of DNA, the quantity of which varies between individuals and the location, type and stage of your cancerous tumour. Detection of single mutations in ctDNA requires a large volume of blood. The principal challenge of research predicated upon ctDNA is their relatively low abundance in your bloodstream. As a consequence, scientists cannot rely solely on ctDNA, and are forced to search for other genetic and epigenetic mutations in your blood.
Exosomes is another class of biomarker. Cancer related exosomes are nano-size membrane vesicles that play important roles in tumour microenvironment. A 2007 paper in Nature Cell Biology suggested that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of a tumour. Since the 2007 Nature paper, research into exosomes has increased and they are now being used as diagnostic and prognostic biomarkers for various cancers. 
 
CancerSEEK
 
An innovative liquid biopsy called CancerSEEK, which has been developed by researchers from the Johns Hopkins Kimmel Cancer Center, in Baltimore, USA, is expected to make early cancer detection a part of routine medical care. Significantly, the test screens for eight common cancers, which account for more than 60% of all cancer deaths in the US. Currently, five of the cancers covered by the test have no screening test. CancerSEEK combines cutting-edge liquid biopsy technology with a machine learning engine, which is expected to improve the test’s accuracy with every person it screens. Findings of a retrospective study of multiple cancer types published in the February 2018 edition of the journal Science suggested that CancerSEEK has a sensitivity between 69% and 98% for ovarian, liver, stomach, pancreatic and oesophageal cancers, a specificity of 99%. Further, the study suggested that the test  has a false-positive rate of less than 1%. In 2019, CancerSEEK received Breakthrough Device designation from the US Food and Drug Administration (FDA) for the detection of genetic mutations and proteins associated with pancreatic and ovarian cancers, and also raised US$110m to launch a start-up company to develop the technology further.
 
FDA approval for a liquid biopsy developed by Roche
 
In June 2016, Roche, a global biopharma, became the first company to receive FDA approval of a liquid biopsy test to detect mutations associated with non-small cell lung cancers (NSCLC). Notwithstanding, the biopsy is not a universal test to detect the presence of NSCLC, but rather a test, which is being used in people with lung cancer to enhance personalised targeted therapies, and to monitor progression of the cancer. Some patients may benefit from the test's accompanying drug erlotinib (Tarceva), which treats NSCLC.
 
In September 2019, Genentech, a member of the Roche Group, announced positive results from the first prospective phase II/III clinical study to use a liquid biopsy and next generation sequencing to select treatment for people with NSCLC, without the need for a tissue biopsy. Next-generation sequencing facilitates the analysis of minute quantities of cfDNA circulating in the blood. In addition, Genentech is using machine learning algorithms on large data sets to characterize the molecular signatures of various cancer types.
 
Guardant and GRAIL
 
Previous HealthPad Commentaries have described research endeavours by Guardant Health  and GRAIL, which are “betting-on” liquid biopsies. Here briefly we update the developments of these two giant biopharma companies.

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AstraZeneca’s strategy to target early cancer
In 2014 Guardant launched a next generation sequencing cfDNA assay called Guardant360 for treatment selection in a number of solid tumour cancers. In December 2018, the company launched an assay referred to as LUNAR to detect a range of early stage and recurrent cancers. LUNAR is based on data that Guardant collected from 80,000 advanced cancer patients using its 360 technology. In October 2019, the company launched ECLIPSE, a 10,000-patient clinical study to evaluate the performance of a second generation LUNAR blood test to detect colorectal cancer (CRC) in average-risk adults. The study is intended to improve CRC screening rates by offering a simpler liquid biopsy that overcomes challenges associated with current testing methods described above.
GRAIL has developed a prototype cfDNA sequencing assay to detect a range of cancers, many of which are not screened today and often present at late stages. Significantly, GRAIL has developed a prospective, observational, longitudinal clinical study called the Circulating Cell-free Genome Atlas (CCGA). The study has 15,000 participants across 142 sites in the US and Canada and has been designed to characterize the landscape of genomic cancer biomarkers of people with and without cancer. The company’s STRIVE study is fully enrolled with approximately 115,000 women and another study called SUMMIT also is fully enrolled with approximately 50,000 men and women aged 50 and older who do not have a cancer diagnosis at the time of enrolment.
 
Despite advancing technologies, FDA approvals, ongoing clinical studies and large and increasing investments in the development of liquid biopsies, (see a paper published in the June 2019 edition of Clinical and Translational Science entitled, “The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics”) there remains a substantial gap between scientific aspirations and reality. Liquid biopsies still do not provide physicians with a reliable, point-of-care means to detect cancer early and become a reliable substitute for the more invasive and more expensive gold standard tissue biopsy.
 
Takeaways
 
Liquid biopsies represent a large and rapidly evolving area of bioengineering. There are hundreds of research papers published in peer reviewed medical journals, which describe findings of the latest research in this area. Oncologists involved in EDT research are familiar with genomics, the molecular properties of cancer tumours and commercially available innovative therapies, which are by-products of EDT research, but many oncologists are not. This difference of knowhow seems to be creating another gap  between certain personalised cancer therapies advocated by research oncologists and standard cancer management provided in many clinics. Closing these gaps is partly contingent upon continued and open EDT research and more effective education.
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5 years, 5 months ago

AstraZeneca’s strategy to target early cancer

HealthPad
Directory:
Cancer
Tags:
big pharma
cancer diagnosis
cancer reasearch
commentary
early stage cancer
immunotherapy drugs
liquid biopsy
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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5 years, 9 months ago

A paradigm shift in cancer diagnosis

HealthPad
Directory:
Cancer
Tags:
breath biopsy
cancer diagnosis
cancer research
chemical signature
commentary
image recognition
liquid biopsy
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 7th most commonly occurring cancer in men and the 13th 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 4th most commonly occurring cancer in men globally and the 7th most commonly occurring cancer in women. The disease represents the 3rd 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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7 years, 7 months ago

World’s first blood tests that detect and locate cancer

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

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

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

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

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

Currently, oncologists look to pathologists for assistance in tumor diagnosis. Indeed, oncologists cannot proceed with therapy without a tissue diagnosis, nor are they able to discuss prognosis with the patient. After detecting a tumor through a physical examination or imaging, doctors use traditional tissue biopsies to gather information on the attributes of a patient’s cancer.
 
These pinpoint a cancer’s mutations and malignancy, but solid tissue biopsies are not always straightforward. While some cancers are easily accessed, others are hidden deep inside the body or buried in critical organs. Beyond the physical challenge, sampling from such tumors can be dangerous to patients, and once achieved, they do not always inform on current tumor dynamics. Further, traditional solid tissue biopsies are costly and time consuming to perform; they can yield insufficient tissue to obtain a good understanding of the tumor, and they can be hampered by a patient’s comorbidities, and lack of compliance.
 
Two significant studies
 
Although solid tumor tissue is still the gold standard source for clinical molecular analyses, cancer-derived material circulating in the bloodstream has become an appealing alternative showing potential to overcome some of the challenges of solid tissue biopsies.

Findings of two significant studies of liquid biopsies published in 2017 promise a more effective and patient-friendly method for diagnosing cancer: one in the journal Genome Biology, and the other in the journal Nature Genetics. Both studies are on the cusp of developing the world’s first simple blood test, which can both detect early stage cancer, and identify where in the body the cancer is located.
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The Genome Biology study
 
​The study, reported in Genome Biology, describes findings of a blood test, referred to as the CancerLocator, which has been developed by Jasmine Zhou, Professor of Biological and Computer Sciences and her team at the University of California, Los Angeles (UCLA). The  Locator detected early stage cancer in 80% of breast, lung and liver cases.
 
Zhou and her colleagues devised a computer program that uses genetic data to detect circulating tumor DNA (ctDNA) in blood samples. Once identified, the ctDNA is compared to a database of genetic information from hundreds of people to identify where the tumor is located.  Zhou’s team discovered that tumors, which arise in different parts of the body, have different signatures, which a computer can spot. “The technology is in its infancy and requires further validation, but the potential benefits to patients are huge  . . . . . Non-invasive diagnosis of cancer is important, as it allows the early detection of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease,” says Zhou.
 
The Nature Genetics study

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

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

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

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

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

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

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

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

Despite findings of the two 2017 studies reported in the journals Genome Biology and Nature genetics, FDA approval of Roche’s liquid biopsy, massive increase in investment, and significant commercial biotech activity, there is a gap between reality and aspirations for liquid biopsies. To provide doctors with a reliable, point-of-care means to detect cancer early, liquid biopsies will have to overcome several significant challenges. The major one is assay sensitivity and specificity for analysis of ctDNA and cfDNA. To compete with the gold standard solid tissue biopsy, and to ensure that patients receive early diagnosis and appropriate treatment, a successful liquid biopsy assay will have to demonstrate a high positive predictive value. Concomitantly, good sensitivity and excellent specificity will be required to yield acceptable rates of false positives and false negatives. Notwithstanding, the race among bioengineers to develop a non-invasive “real-time” liquid biopsy to detect cancer early is gaining momentum.
 
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8 years, 10 months ago

Liquid biopsies to detect pancreatic cancer are near

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pancreatic cancer
 
  • 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. 


            
                

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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