The burden of breast cancer throughout the world is significant and increasing
Research has shown that a cheap pill (anastrozole) halves postmenopausal women’s risk of breast cancer and continues to be effective seven years after women stop taking the drug
Anastrozole has less side-effects and is more effective than comparable treatments
Government watchdogs both in the UK and US recommend anastrozole
But the uptake of the drug in the UK is relatively low
Doctors are not prescribing anastrozole and women are not availing themselves of the drug
The UK’s NHS should employ new behavioural techniques to influence and change doctors’ and patients’ decisions and increase the uptake of anastrozole to reduce the burden of breast cancer
Will behavioural techniques improve breast cancer outcomes?
Being a woman and growing older are two unavoidable risk factors for breast cancer. Indeed, most breast cancers are found in women who are 50 years or older. Despite significant advances in diagnoses and treatments, breast cancer is one of the rapidly increasing cancers among women and a significant cause of cancer-related morbidity and mortality worldwide. Breast cancer alone accounts for 30% of all new cancer diagnoses among females and has become a major 21st century health challenge.
Study shows long term benefits of a cheap breast cancer pill
The UK’s NHS watchdog, the National Institute for Health and Care Excellence (NICE), suggests that hundreds of thousands of healthy older women should take anastrozole to cut their risk of breast cancer and recommends that the drug is offered to postmenopausal women at moderate to high risk of breast cancer unless they have severe osteoporosis. However, evidence suggests that some doctors in the UK are not prescribing anastrozole and some women are not availing themselves of the drug despite its demonstrated clinical benefits and the fact that anastrozole is supported by NICE.
Jack Cuzick, the lead author of The Lancet 2019 paper, who is Professor of Epidemiology and the Director of the Wolfson Institute of Preventive Medicine at Queen Mary University, London, is concerned because although anastrozole is, “An agent that looks really effective with minimal side-effects and is available on the NHS in the UK; its uptake has been quite low with only a tenth of eligible women receiving it”. Cuzick’s concerns are echoed by Delyth Jane Morgan, Chief Executive of the charity Breast Cancer Now, who said: "It is worrying to hear that anastrozole may not be being offered to all that could benefit. We need to understand the extent of this potential issue. It's essential that we raise awareness of this option among doctors and patients".
In this Commentary
Part 1 of this Commentary explores some of the reasons for the relatively low uptake of anastrozole. Part 2 describes new behavioural techniques, which could be cheaply and easily employed by health systems to increase the uptake of anastrozole and dent the burden of breast cancer. Also the Commentary: (i) describes breast cancer, (ii) provides some epidemiological facts of the disease, (iii) estimates the cost to treat breast cancer in the UK, (iv) describes hormone receptor positive breast cancer, (v) explains how anastrozole works and (vi) reports the findings of The Lancet 2019 study.
Cancer is a group of diseases that cause cells in your body to change and spread out of control. Most types of cancer cells eventually form a lump or mass called a tumour and are named after the part of your body where the tumour originates.
Breast cancer is characterized by the presence of cancer cells in the tissue or ducts of your breast. Most breast cancers begin either in the breast tissue made up of glands for milk production, called lobules, or in the ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective and lymphatic tissues. Advanced breast cancer refers to cancer that has spread outside of your breast to lymph nodes and/or distant locations in your body, often invading your vital organs.
Breast cancer is a common malignancy. Although more and more women are surviving the disease, each year in the UK there are over 55,000 new breast cancer cases: which equates to over 1,000 diagnosed each week. In the US, there are some 250,000 new breast cancer cases diagnosed each year: nearly 5,000 a week. Between 1993 and 2016 the incidence of breast cancer in the UK increased by 24%. Over a similar period, breast cancer incidence in the US declined, but an increasing trend of some 1.1% was observed among American Asians.In China, between 2000 to 2013, breast cancer increased at an annual rate of around 3.5%. Breast cancer rates in China are higher in urban areas than in rural areas: the higher the population density, the higher the rate. It is not altogether clear why breast cancer incidence is increasing. Experts suggest that breast cancer is a complicated disease with a variety of causes. Most cases of the disease are not linked to a family history. Around 5% of people diagnosed with breast cancer have inherited a faulty BRCA1 or BRCA2 gene.However, if you have a faulty gene, it does not mean that you will automatically develop breast cancer, but you are at higher risk. Out of every 100 women with a faulty gene, between 40 and 85 will develop breast cancer in their lifetime. Optimal therapy for breast cancer often requires several different treatment modalities including surgery, radiation, chemotherapy and hormone therapy (see below).
Cost of breast cancer treatment in the UK
The cost of treating breast cancer in the UK is significant and rising. Findings of research on the treatment costs of breast cancer published in the August 1999 edition of The Breast estimated that the average cost per case of breast cancer in the UK to be £7,247 (US$9,418). Although the estimate is dated, it provides a guide. With 55,000 new cases of breast cancer diagnosed each year, the annual cost of treating the newly diagnosed alone, would be about £0.4bn (US$0.52bn). According to the UK charity Breast Cancer Now,an estimated 840,000 women living in the UK have been diagnosed with breast cancer and the charity predicts that this figure will increase to 1.2m over the next decade. Thus, ceteris paribus, we can assume that the current annual cost of treating breast cancer in the UK is significantly higher than £0.4bn and this figure is expected to increase substantially by 2030.
Hormones and hormone therapy
Hormones are chemical messengers secreted directly into your bloodstream, which carry them to organs and tissues of your body to exercise their functions. Oestrogen and progesterone are steroid hormones produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women. These hormones play a critical role in regulating reproduction. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.
Similar hormones are produced artificially either for use in oral contraceptives or to treat menopausal and menstrual disorders. Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive (or hormone-dependent) breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors, which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes that can stimulate cell growth.
Anastrozole is a hormone therapy (also called hormonal therapy and endocrine therapy), which slows or stops the growth of hormone-sensitive tumours by either blocking the body’s ability to produce hormones or by interfering with the effects of hormones on breast cancer cells. Anastrozole blocks a process called aromatisation, which changes sex hormones called androgens into oestrogen. This happens mainly in the fatty tissues, muscle and the skin and needs a particular enzyme called aromatase.
Anastrozole belongs to a group of drugs called aromatase inhibitors, which are specifically designed to treat postmenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer. It is most often prescribed as an adjuvant therapy (after surgery) to decrease the risk of your cancer returning but can also be used in the neoadjuvant setting (prior to surgery) to decrease the size of your cancer in the breast. Hormone blocking therapy is also used to treat breast cancer that has recurred or spread. Most hormone blocking therapy drugs such as anastrozole are taken daily in pill form.
Anastrozole also may be given to reduce the risk of breast cancer in women who have not had breast cancer but have an increased risk of developing it because of their family history. Most experts suggest that your breast cancer risk should be higher than average for you to consider taking anastrozole as a preventative strategy. If your cancer is hormone receptor negative, then anastrozole will not be of any benefit, because these cancers do not need oestrogen to grow and usually such cancer cells do not stop growing when treated with hormones that block oestrogen from binding.
Reasons for the relatively low uptake of anastrozole
There are at least three probably reasons for the relatively low uptake of anastrozole. These include: (i) doctors becoming so used to prescribing the gold standard tamoxifen as an adjuvant hormone therapy, (ii) doctors wanting to be convinced about anastrozole’s long term benefits, and (iii) doctors wanting assurance about anastrozole’s minimal side effects.
Tamoxifen is the oldest and most-prescribed aromatase inhibitor and for the past three decades has become the standard of care as the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. The drug reduces the risk of breast cancer returning by 40% to 50% in postmenopausal women and by 30% to 50% in premenopausal women. Notwithstanding, over the past two decades a new generation of aromatase inhibitors have been developed, and anastrozole is one of these. How does anastrozole compare with the gold standard tamoxifen?
Tamoxifen and anastrozole compared
Findings of two long-term comparative clinical studies undertaken in North America and Europe involving over 1,000 women with oestrogen receptor positive advanced breast cancer, showed that anastrozole is better than tamoxifen for: (i) increasing the time before the cancer returns in those who experience recurrence, (ii) reducing the risk of the cancer spreading to other parts of the body and (iii) reducing the risk of a new cancer developing in the other breast.
Significantly, studies have shown that anastrozole avoids two of tamoxifen's more serious side-effects: an increased risk of developing a blood-clotting disease and an increased risk of developing womb cancer. Anastrozole can make bones weaker and so it is not recommended for women with osteoporosis and also it can cause stiff joints, hot flushes and vaginal dryness, which clinicians need to recognize and manage. But overall, the benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. However, anastrozole is not a therapy for premenopausal women because it blocks the hormone oestrogen and in effect creates a drug-induced menopause.
Increasing the uptake of anastrozole
For healthcare systems to function effectively and efficiently we expect doctors and patients to behave rationally and make effective and efficient decisions. Traditionally, the rational choice model, which is predicated upon the belief that all human beings (including doctors and patients) act rationally in their own self-interest, has been used to influence people to behave in desirable ways. However, evidence suggests that, despite the well-founded theory and sound evidence to support it, the rational choice approach does not appear to work that well in practice.
A newer theory to explain peoples’ choices and behaviours
A newer approach to influencing behaviour, which builds on decades of research by Nobel prize-winning psychologist Daniel Kahneman, and described in a book published in 2008 entitled Nudge, by Nobel Prize winning economist Richard Thaler and Harvard Law School professor Cass Sunstein, suggests that no choice is ever presented in a neutral way and people - including doctors and patients - are susceptible to biases that can lead them to make suboptimal decisions. The authors suggest that many decisions and consequent behaviours are made automatically rather than after a considered rational decision. And this applies to decisions about your health.
Policymakers have been quick to latch onto the possibilities of these new behavioural techniques. Following the publication of Thaler and Sunstein’s book in 2008, President Obama set up a “Nudge Unit” in the White House and the UK Government, under Prime Minister David Cameron, set up the Behavioural Insights Team, popularly known as the Nudge Unit, in 10 Downing Street, and other governments around the world have since followed suit.
Nudges are particular types of interventions, which are used to change peoples’ behaviour and improve outcomes at lower cost than traditional tools across a range of policy areas. Nudge techniques have been used in healthcare to influence behaviour and decision making to improve patient outcomes. For instance, the behavioural analysis of the decision-making that leads to a patient taking one drug instead of another. A research paper published in 2015 by the UK’s Health Foundation entitled “Behavioural insights in healthcare” suggests that health messages are often inconsistent and confusing to patients and framing them using social comparison via descriptive social norms (pointing out what is commonly done) or using injunctive norms (pointing out what is approved of) has been demonstrated to change patients’ behaviour and thereby have the potential to improve patient outcomes.
Behavioural techniques suggest that more attention should be given to the design of health information because the design and the way information is presented can influence and change doctors' and patients’ behaviour. Clinical guidelines, patients’ checklists and decision aids can all be improved in terms of text and language (e.g. the use of “plain English” and behaviourally specific, concrete statements and presentation of risk) and appearance (e.g. colour, visual stimuli, images etc).
HealthPad advocates that health information can have significantly more influence on the choices that doctors and patients make and on their behaviour simply by presenting critical information in a video format. Over the past few decades people have moved away from consuming information in written and audio formats to consuming information predominantly in a visual format.
Shift to consuming information in video format
Consider the following as being indicative of this shift. 82% of Twitter’s 330m average monthly users consume information in video format. The video channel You Tube has over a billion users and more than 500m hours of video are watched on the channel each day. 72 hours of video are uploaded to You Tube every 60 seconds, and more video content is uploaded onto the channel in 30 days than the major US television networks have created in 30 years. To further put things into perspective, in 2017, 56 exabytes (equivalent to 1bn gigabytes) of internet video content was consumed on a monthly basis, and this figure is expected to more than quadruple to 240 exabytes per month by 2022.
Today, almost all industries, with the exception of healthcare, use video formats to communicate and the overwhelming majority of people who have consumed information in video format say it has influenced their choices and changed their behaviour. With video becoming the most significant influence on consumer decisions, it seems reasonable to suggest that more health information needs to be communicated in a video format if it is to influence and change doctors’ and patients’ behaviours in order to improve medical outcomes, increase the quality of care and slow and prevent chronic lifetime diseases.
Prompts cues reminders and audits
Prompts, cues and reminders have been demonstrated to be generally effective “nudges” that can successfully change the behaviour of healthcare providers and consumers, as well as being relatively inexpensive and easy to administer. Audit and feedback “nudges” are also effective. A set of best practices derived from systematic review evidence suggests that various nudge-type interventions (notably information design and presentation) may offer new ways to enhance choices and change behaviour.
The burden of breast cancer is huge and increasing globally. Research has demonstrated that a cheap pill, anastrozole, halves postmenopausal women’s risk of the disease and continues to be effective seven years after women stop taking the drug. We suggest that healthcare systems should consider using new behavioural techniques to influence and change doctors' and patients’ decisions to increase the uptake of anastrozole to help reduce the burden of breast cancer. Evidence suggests that nudge-type interventions, if suitably applied, can influence and change the behaviour of doctors and patients and thereby contribute to the reduction of the burden of breast cancer. However, given the newness of these techniques the quality of evidence available about their impact is relatively thin and patchy. Notwithstanding, this suggests a need for more quality evaluation and synthesised evidence of nudge-type interventions, their behaviour change potential and their impact on reducing the burden of breast cancer and other chronic lifetime diseases.
Dr. Mohit brings,cancer specialist in Gurgaon has over 13 years of experience in oncology across some of the best hospitals in India such as Artemis Hospital (Gurgaon), VPS Rockland Hospitals (Manesar & New Delhi), Gujarat Cancer & Research Institute (Ahmedabad), and G.C.S. Medical College & Hospital (Ahmedabad). He completed his MBBS and MD in Medicine from Sawai Man Singh Medical College (Jaipur) and DM in Medical Oncology from Gujarat Cancer Research Institute (Ahmedabad). He holds a number of achievements, presentations and publications to his credit. His areas of interest include solid malignancies like breast, colon, lung, prostate, etc. and hematological malignancies like leukemias, lymphoma, and myeloma.
Dr. Rakesh Chopra- Best surgical oncologist in Gurgaon, is among the pioneers of medical oncology in India with more than 43 years of extensive experience. he had been a visiting fellow at multiple international universities and was awarded the prestigious fellowship ‘The Varoon Mahajan Foundation’ for study on Bone Marrow Transplant at the Memorial Sloane Kettering Cancer Center. Dr Rakesh has exceptional expertise in solid cancers including breast cancer, cancers in women, and cancer of the lung, prostate & colon. He also specializes in hemato oncology. He also specializes in precision cancer medicine, cancer genetics, palliative cancer treatment, and advanced chemotherapy treatment.
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 NottinghamUniversity’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. .
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.
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 UKcharity, 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”.
Nottingham University’sCEAC 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.
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 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 Biologysuggested 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 increasedand they are now being used as diagnostic and prognostic biomarkers for various cancers.
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.
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 Scienceentitled, “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.
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.
CanRisk is a new online gene-based health-risk evaluation algorithm for detecting breast cancer
It identifies people with different levels of risk of breast cancer, not just those at high risk
As the infotech and biotech revolutions merge expect authority in medicine to be transferred to algorithms
CanRisk has the potential to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnosis before symptoms present
Breast cancer is the most common cancer in women worldwide and is the 5th most common cause of death from cancer in women
Currently mammography screening, which has a sensitivity between 72% and 87%, is the gold standard for preventing and controlling breast cancer
For every death from breast cancer that is prevented by screening, it is estimated there will be three false-positive cases that are detected and treated unnecessarily
Lack of resources do not support breast cancer screening in many regions of the world where the incidence rates of the disease are rapidly increasing
In the near-term expect interest in the CanRisk algorithm to increase
A new comprehensive gene-based breast cancer prediction device
A new online gene-based health-risk evaluation device called CanRisk has the potential to identify women with different levels of risk of breast cancer; not just women who are at high risk. Predicated on a comprehensive algorithm, CanRisk is one of several innovationscurrently in development, which include novel methods for predicting the recurrence of breast cancer, a new class of molecules that aim to halt or destroy breast cancer, and liquid biopsies,which determine the presence and recurrent risk of the disease through the detection of tumour cells in peoples’ blood.
Although over the past two decades there have been significant improvements in the detection and treatment of breast cancer, the disease remains the most common cancer in women worldwide, with some 1.7m new cases diagnosed each year, which account for about 25% of all cancers in women and it is the fifth most common cause of death from cancer in women, with over 0.52m deaths each year.
Game changer for breast cancer
Findings of CanRisk were reported in the January 2019 edition of Genetics in Medicine.Findings of a less comprehensive version of the device’s algorithm were published in the July 2016 edition of the same journal.Commenting on the 2019 study, Antonis Antoniou, Professor of Cancer Risk Prediction at the University of Cambridge and lead author of the two studies said: "This is the first time that anyone has combined so many elements into one breast cancer prediction tool. Itcould be a game changer for breast cancer and help doctors to tailor the care they provide depending on their patients' level of risk”.
When fully developed and approved, CanRisk will be well positioned to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnostic test to detect breast cancer early in people with diverse levels of risk. This might be expected to provide an alternative to the current gold standard population-based mammography screening and assist in making a significant dent in the vast and escalating global burden of the disease.
In this Commentary
This Commentary describes the algorithm that drives CanRisk, which benefits from the increasing availability of vast and growing amounts of genomic and other personal data and significant advances in genomic sequencing technologies. The confluence of these two phenomena facilitates and enhances the quality and speed of data analysis and drives the development of new and innovative diagnostic and prognostic cancer technologies. The fact that CanRisk is based on UK data and its algorithm is available to researchers globally, presents a potential opportunity for medical research organizations in emerging regions of the world where the burden of breast cancer is increasing. The Commentary briefly describes the heterogeneous nature of breast cancer and highlights some of its complexities and risk factors. Originally perceived as a Western disease, breast cancer is growing rapidly in Asia and other regions of the world where it tends to be detected late and managed less effectively. Developed economies prevent and manage breast cancer through well-established population-based mammography screening programs. Because of the lack of resources, such screening programs are not widely available in low to middle income countries (LMIC). As the infotech and biotech revolutions merge expect authority in medicine to be transferred to Big Data algorithms such as CanRisk. This not only could provide an alternative to gold standard mammography screening, but also provide a cheap and effective device for use in developing nations where the burden of breast cancer is significant and increasing.
CanRisk: a world first
CanRisk, developed by members of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, UK, takes advantage of discoveries in both cancer genomics and epidemiology and aims to become a popular device used by primary care physicians, in consultation with their patients, to effectively assess patients’ diverse levels of risk of developing breast cancer. The device is predicated on an algorithm called BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm). This is the world’s first polygenic breast cancer risk model and the only one to-date, which is available to the international research community. Also, it is the first breast cancer risk model to incorporate pathology data and population-specific cancer incidences in risk calculations. The algorithm accounts for over 300 genetic risk factors, including BRCA1, [BReast CAncer gene] BRCA2, PALB2, CHEK2, and ATM, which are genes that have been found to impact a person’s chances of developing breast cancer. The device uses a Polygenic Risk Score (PRS) based on 313 single-nucleotide polymorphisms (SNPs), [SNPs, pronounced ‘snips’, are the most common types of genetic variation in people. Each SNP represents a difference in a single DNA building block and is called a nucleotide] which explains 20% of breast cancer polygenic variance. CanRisk also includes a residual polygenic component, which accounts for other genetic/familial effects; known lifestyle/hormonal/reproductive risk factors and mammographic density [Dense breast tissue can make it harder to evaluate mammographic results and may also be associated with an increased risk of breast cancer].
Authority increasingly being transferred to algorithms
Over the past two decades we have increasingly learnt to accept the authority of Big Data algorithms. For example, without question we expect algorithms to give us directions, tell us what movies to watch, who to date, what clothes to wear, where to go on holiday, what flight to take, what hotel to stay in and where to eat. We are comfortable with algorithms assigning us our credit rating, limiting our overdraft and capping our payments. Furthermore, we are beginning to accept the authority of algorithms in medicine. For example, we are gradually replacing the authority of primary care doctors with algorithms that can diagnose common diseases more accurately and more cost effectively.
In December 2018, for the first time in history, the US FDA approved an algorithm to diagnose patients without a doctor’s interpretation. The algorithm, called IDx-DR, detects diabetic retinopathy by analysing images of the back of the eye. Indeed, we are living on the cusp of history when the twin revolutions of information technology and biotechnology are merging and providing the basis for us to transfer authority in medicine to algorithms. In the next two decades, it seems reasonable to assume that it will become common practice to accept the authority of algorithms such as CanRisk, which will inform us that we are suffering from a medical condition long before we present any signs or symptoms.
Increasing supply of data
CanRisk takes advantage of the fact that genetic and other risk factor data are becoming more easily available in clinical practice through electronic health records, biometric sensors that convert biological processes into electronic information, which computers can store and analyse, cost-effective high speed, high capacity genomic sequencing technologies, and efforts such as the 100,000Genomes Project. A UK Government sponsored initiative completed in December 2018, which collected, stored and analysed data from the genomes and medical records of 85,000 NHS England patients affected by cancer or rare disease. Genomics England, which is wholly owned by the UK’s Department of Health, was set up in 2003 to deliver the project. Because CanRisk solely is based on UK population data, its findings are likely to be more applicable to similarly developed Western populations, and less so to populations in other regions of the world. This provides a potential opportunity for international organizations interested in early breast cancer diagnosis.
International sequencing projects
The UK’s genomes project is part of a much larger rapidly growing and dynamic global genomics market comprised of data and gene sequencing technologies. 100,000 genomes have been the goal of several other nations interested in improving their healthcare - and lowering costs - by carrying out precision medicine based on insights from sequencing data. Currently the global genomics market is estimated to be about US$19bn and projected to reach US$41bn by 2025. The market is driven by increasing government funding, the consequent rise in the number of genomics projects, decreasing gene sequencing costs, growing application areas of genomics and the entry and fast growth of commercial players.
China has become the world’s leader in genomic sequencing. In 2010, the Beijing Genomics Institute(BGI) in Shenzhen was understood to be hosting a higher sequencing capacity than that of the entire US. While most government projects aim to sequence 100,000 genomes, China’s sequencing program is set to sequence 1m human genomes, which include subgroups of 50,000 people, each with specific conditions such as cancer or metabolic disease. The data will also include cohorts from different regions of China, which will facilitate “the analysis of different genetic backgrounds of subpopulations”.
Revolution in genome sequencing
The first human genome project began in 1990, took 13 years and about US$1bn to complete. The last two decades have seen a revolution in genome sequencing with dramatic increases in its speed and efficiency coupled with massive reductions in cost. Genomic sequencing has proved its usefulness as a diagnostic and prognostic tool. Today it is possible to get your genome sequenced for around US$1,000 in a few days and delivered by post from firms such as Dante Labsand 24 Geneticsin Europe, and Veritas Geneticsand Sure Genomicsin the US.
Returning tobreast cancer. It is important to note that the disease is not one, but a group of conditionsthat manifest themselves with maladies in the same organ. Breasts are comprised of three main parts: lobules, which produce milk; ducts, which carry milk to the nipples; and fibrous and fatty connective tissue, which hold everything together. The type of breast cancer depends on which cells in the breast mutate, but most breast cancers begin in the ducts or lobules. Some mutated cells in the breast may never spread, however, most breast cancers tend to be invasive and may present with a number of different characteristics in terms of hardness and shape, which can provide some indication of their likely progression. Breast cancer can spread outside the breast through blood and lymph vessels. Further, there are significant differences in breast cancer at the genetic level. A study published in the April 2012 edition of Naturecompared the genetic makeup of breast cancer tumour samples with their other characteristics for some 2,000 women, for whom information about the tumour characteristics had been meticulously recorded; and identified at least 10 distinct sub-types of breast cancer, each with its own unique characteristics. Although the study contributed to how breast cancer is diagnosed, classified and treated, in practice certain characteristics of these tumours were already known and tested for: most notably cellular receptors for estrogen, and progesterone, which are the two most significant steroid hormones responsible for various female characteristics. Their presence or absence generally suggests the potential utility of additional medication to accompany surgery, radiotherapy and chemotherapy.
Despite population screening and advanced therapies breast cancer remains a killer disease
Let us briefly consider breast cancer in the world’s most advanced and wealthiest nation: the US. Although there have been significant improvements in the detection and treatment of breast cancer in the US; still about 1 in 8 American women will develop an invasive type of the disease over the course of her lifetime. In 2019, an estimated 268,600 new cases of invasive breast cancer are expected to be diagnosed in the US, along with 62,930 new cases of non-invasive (in situ) breast cancer. Breast cancer death rates for women in the US are higher than those for any other cancer, besides lung cancer. As of January 2019, there were more than 3.1m women with a history of breast cancer in the US. Although breast cancer death rates in the US have been decreasing over the past three decades and women under 50 have experienced larger decreases, still some 41,760 are expected to die in 2019 from the disease. About 2,670 new cases of invasive breast cancer are expected to be diagnosed in men in the US in 2019 where a man’s lifetime risk of breast cancer is about 1 in 883.
Breast cancer challenges in Singapore
There are also breast cancer challenges in wealthy non-Western developed economies such as Singapore. Over the past four decades, the incidence of breast cancer in Singapore has more than doubled: from 25 to 65 per 100,000 women. Breast cancer is not just the most common cancer for Singaporean women, accounting for one in three cancers in women, but it is also the top killer. Data reported in the country’s Cancer Registry showed that 2,105 women died of the disease between 2011 and 2015. Notwithstanding, Singapore has extensive awareness-raising programs; population-wide mammography screening; excellent, multi-disciplinary primary and long-term care and improving palliative care, which have contributed to a significant increase in the survival rates of breast cancer patients. However, a substantial proportion of Singaporean women still appear to have a patchy knowledge of aspects of the disease, which leads to comparatively low participation rates in the nation’s breast cancer screening services, and this contributes to late presentation of the disease when it is more difficult to cure and more challenging to treat.
Breast cancer was once largely confined to developed Western countries and Australasia, but it has now become the most common cancer in Asia. Although Asian data on breast cancer are patchy, an Economist Intelligence Unit report, suggests that, “since the 1990s, increases in the incidence of breast cancer in Asia, as measured by age-standardised rates (ASRs), is four to eight times that of the global average”. Indeed, as younger cohorts of Asian women age and adopt Western diets and lifestyles (particularly fertility patterns, such as later first childbirth and shorter breast feeding), breast cancer incidence rates in Asia look set to converge with the much higher ones in the West.Further, in LMIC breast cancer is increasing at a more rapid rate than in the West and has become a significant healthcare challenge: 50% of breast cancer cases and 58% of deaths from the disease occur in LMIC.
The significance of early detection
The good news is that if caught in its early stages, breast cancer can be treated effectively, with high survival rates. The average 5-year survival rate for women with invasive breast cancer is 90%. The average 10-year survival rate is 83%. If the cancer is located only in the breast, the 5-year survival rate of women with breast cancer is 99%. In all types of the disease early detection is the cornerstone of breast cancer control.
Gold standard breast cancer mammography screening
The current gold standard for preventing and controlling breast cancer is population-based mammography screening. This is a non-invasive process that uses an x-ray of the breast to look for disease in women who do not have symptoms. The method has reasonable sensitivity (72%–87%) that increases with age and allows for the early detection of breast cancer, which helps increase survival, especially in women between 50 and 70. Notwithstanding, mammograms are not pleasant as the breast is squashed between two metal plates and further some women may find mammograms embarrassing.
Success of population-based mammography screening
Following a landmark Swedish study that began in 1977 mammography screening has been adopted in more than 26 developed countries worldwide. Findings of the study, reported in a 1989 edition of the Journal of Epidemiology and Community Health, suggested that mortality from breast cancer dropped 31% after screening of women aged 39 to 74. More recent findings of the UK screening program published in the June 2013 edition of the British Journal of Cancer,suggested mortality rates from breast cancer were reduced by 20% in the screened group compared to the unscreened group across all age groups. A study published in 2018 in Cancer,which tracked 52,438 Swedish women aged 40-69 from 1977 to 2015, suggested that regular mammograms contributed to a 60% decrease in breast cancer death during the first 10-years of diagnosis, and a 47% reduced risk within 20-years. Research has shown that mammography has relatively little benefit for women under 50.
Diverging views about mammography screening
Despite evidence to support the benefits of population-based mammography screening, there are diverging views among healthcare professionals about the impact of several decades of high levels of screening. Some argue that traditional mammography screening stretches finite resources and is not cost-effective because the majority of people who undergo screening do not have cancer and may never go on to develop it. Others suggest that there are significant uncertainties about the magnitude of the harms from mammography screening especially associated with false positives (a test result, which wrongly indicates that breast cancer is present).
Challenges of mammography screening
The sensitivity of mammography is between 72% and 87%, but is higher in women over 50 and in women with fatty rather than dense breasts. Dense breast tissue can make it harder to evaluate results of a mammogram. According to the Marmot review,for every death from breast cancer that is prevented by screening, it is estimated there will be three over-diagnosed or false-positive cases that are detected and treated unnecessarily. The chance of having a false positive result after one mammogram ranges from 7% to 12%, depending on age (younger women are more likely to have false positive results). After 10 yearly mammograms, the chance of having a false positive is about 50-60%. The more mammograms a woman has, the more likely it is she will have a false positive result. This makes it difficult for doctors to weigh and communicate the benefits and risks of mammography screening programs and fuels interest in innovations such as CanRisk.
Mammography screening for breast cancer is not 100% accurate. Further, knowhow, trained healthcare professionals and significant resources are required to effectively implement and manage a well-organized and sustainable breast cancer screening program that targets the right population group and ensures effective coordination and quality of actions across the whole continuum of care. These attributes tend to exist only in developed wealthy countries. CanRisk, and other innovative breast cancer early diagnostic devices under development, offer the potential for cheap, rapid, reliable and exquisitely accurate diagnosis that can be easily used in primary care settings throughout the world. In time, as authority in medicine passes to algorithms, expect these new and innovative devices to replace mammography screening in wealthy countries and quickly become devices of choice in developing economies and significantly dent the vast and rapidly growing global burden of breast cancer.
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Experts have called for the worldwide eradication of cervical cancer, but this is not likely to happen for a long time
Significant progress has been made to eliminate cervical cancer in developed countries
The overwhelming burden of cervical cancer falls disproportionately on women in low- to middle-income countries (LMIC)
LMIC have relatively low levels of awareness of cervical cancer, patchy prevent programs and limited treatment options
Over 80% of cervical cancer cases and deaths occur in LMIC
Cervical cancer is the fourth most common cancer in women worldwide
In 2018 there were an estimated 680,000 new cases and 311,000 deaths from the disease worldwide
Cervical cancer is caused by sexually acquired infection from high-risk strains of the human papilloma virus (HPV)
The majority of women will be infected with HPV at some point in their life
HPV also causes genital warts and cancers of the head and neck and is also linked to cancers of the anus, vulva, vagina, penis and oropharynx
HPV vaccines protect against 70% of cervical cancers and about 90% of genital warts
Regular screening is also recommended to reduce the incidence of cervical cancer
Challenges to eradicate cervical cancer globally
Cervical cancer is a killer disease, which only affects women. It affects women of all ages from schoolgirls to grandmothers, but it is significantly more prevalent between the ages of 30 and 45.
The cervix, also known as the neck of the womb, connects a woman's womb and her vagina.
Lancet study raises hope of eradicating cervical cancer
Research findings published in the June 2019 edition of The Lancetsuggest that HPV vaccination, which has been available to adolescent girls in wealthy developed countries since 2007, has led to a dramatic reduction in the number of HPV infections, precancerous cervical lesions and anogenital warts and provides hope of eradicating cervical cancer. Marc Brisson, Professor in the Department of Social and Preventative Medicine, Laval University, Canada, who led the research - a meta-analysis of over 65 former studies covering 60m people - said: "We will see reductions [in cervical cancer] in women aged 20-30 within the next 10 years, and eradication of the disease [defined as <4 cases per 100,000] might be possible if sufficiently high vaccination coverage can be achieved and maintained". Over the past two decades, the incidence rates of cervical cancer in developed countries have fallen significantly, and between 1955 and 1992, the incidence rate of the disease decreased 70% in the US. These falls are attributed to effective nationwide screening.
Cervical cancer is the fourth most common cancer in women worldwide and second for women between 15 and 44. In 2018 there were an estimated 680,000 new cases and 311,000 deaths from the disease worldwide. The overwhelming majority of cases are caused by two specific strains of the human papilloma virus (HPV). HPV infection and early cervical cancer typically do not present noticeable symptoms, and cervical cancer may take 20 years or longer to develop after an HPV infection. The overwhelming global burden of the disease falls disproportionately on women in low- to middle income countries (LMIC). There is a significant and growing gap in the incidence and mortality rates of cervical cancer between developed nations and LMIC. Despite international efforts, it seems unlikely that this gap will be narrowed in the medium term.
In this Commentary
This Commentary describes the spread of HPV, the vaccines developed to prevent infection from specific high-risk strains of the virus and recommended vaccination regimens. We describe the nature and significance of complementary screening programs and present evidence to suggest that women who fail to get screened are more likely to contract cervical cancer in later life than women who are screened. HPV vaccination programs are more prevalent in developed economies and are associated with a significant reduction in the incidence rates of cervical cancer. This suggests that the battle to eliminate cervical cancer is being won in some wealthy developed nations. Australia is positioned to become the first country in the world to eliminate cervical cancer. Despite substantial global efforts to reduce the incidence rates of cervical cancer, the gap in preventing, diagnosing and treating the disease between wealthy nations and LMIC is significant and growing. We conclude by suggesting that to eradicate cervical cancer, screening and prevention programs must be linked to easily accessible and effective treatment.
The spread of HPV
Over 70% of cervical cancer is caused by two high-risk strains of HPV. Most women will contract HPV at some stage during their life, but this usually clears-up on its own without the need for any treatment. HPV is most commonly spread during vaginal, anal or oral sex. The virus can be passed even when an infected person has no signs or symptoms. If you are sexually active you can get HPV, even if you only have sex with one partner. Notwithstanding, the risk increases with the number of new sexual partners and their sexual histories. You also can develop symptoms years after you have sex with someone who is infected. This makes it hard to know when you first became infected.
The US Food and Drug Administration (FDA) has approved three vaccines, which prevent infection with disease-causing HPV types. These are Gardasil, Gardasil 9 and Cervarix. All three vaccines prevent infection with HPV types 16 and 18 in women who have not already been infected by these types. These are two high-risk HPV’s that cause about 70% of cervical cancers and an even higher percentage of some of the other HPV-caused cancers. Gardasil also prevents infection with HPV types 6 and 11, which cause 90% of genital warts. Gardasil 9 prevents infection with the same four HPV types, plus five additional cancer-causing types.
About 79m Americans are currently infected with HPV, with roughly 14m people becoming newly infected in the US each year. In the UK, HPV is present in one in three people and 90% of individuals will come into contact with some form of the virus in their lifetime. About 80% of sexually active people are infected with HPV at some point in their lives, but most people never know they have the virus. Whitfield Growdon, a surgical oncologist at the Massachusetts General Hospital and professor at the Harvard University Medical School describes the HPV vaccination as, “one of the most meaningful interventions for reducing cervical cancer”; see video below.
Who should get vaccinated?
All girls and boys aged between 11 and 12 should get the HPV vaccination. Every year in the US, over 13,000 males contract cancers caused by HPV. Catch-up HPV vaccines are recommended for girls and women through the age of 26, and for boys and men through the age of 21, if they did not get vaccinated when they were younger. HPV vaccination is also recommended for the following people, if they did not get vaccinated when they were younger: (i) young men who have sex with men through the age of 26, (ii) young adults who are transgender through the age of 26 and (iii) young adults with certain immunocompromising conditions (including HIV) through the age of 26.
Early cervical cancer is asymptomatic
Because early cervical cancer is asymptomatic, it is important for women to have regular Papanicolaou (Pap) smears - also called Pap tests - to detect any precancerous changes in the cervix that might lead to cancer. This is in addition to the HPV vaccination. In England women are invited to have Pap smears every three years between the ages of 25 and 49, when rates of cervical cancer are at their peak, and every five years between 50 and 65. Other international screening guidelines recommend that women aged 21 to 29 have a Pap smear every three years. Women aged 30 to 65 are advised to continue having a Pap test every three years, or every five years if they also combine it with an HPV DNA test. Women over 65 can stop testing if they have had three consecutive normal Pap tests, or two HPV DNA and Pap tests with no abnormal results.
The HPV DNA test determines the most likely cause of cervical cancer by looking for pieces of DNA in cervical cells and is recommended for women over 30 and not for women under 30. This is because women in their 20s tend to be more sexually active and therefore are more likely (than older women) to have an HPV infection that will go away on its own. Results of an HPV DNA test carried out on a woman in her 20s is not as significant as in and older woman and also may be confusing. The HPV DNA test can also be used in women who have slightly abnormal Pap test results to find out if they might need more testing or treatment.
The Pap smear/test
The Pap smear or Pap test is a method of cervical screening used to detect potentially precancerous and cancerous processes in your cervix. During the routine procedure, cells from your cervix are gently scraped away and then examined for abnormal growth. Abnormal findings are often followed-up by more sensitive diagnostic procedures and if warranted, by interventions that aim to prevent progression to cervical cancer. Detecting cervical cancer early with a Pap smear significantly increases the chances of a cure. A Pap smear can also detect changes in your cervical cells, which suggest you might develop cancer in the future. In the two videos below Growdon describes the Pap smear and other tests for diagnosing cervical cancer.
What is a Pap smear test?
Diagnostic tests for cervical cancer
Women failing to have the Pap test are 6-times at greater risk of cervical cancer
There is evidence to suggest that women over 50 who fail to have a regular Pap smear have a much higher risk of developing cervical cancer compared with other women the same age who have a history of regular screening. Research carried out by Cancer Research UKand reported in 2014 investigated the utility of regular cervical cancer screening after 50, and whether 64 was an appropriate age to stop screening and concluded “yes” and “yes”. The study compared the screening history of 1,341 women between 65 and 83 in England and Wales who were diagnosed with cervical cancer over a five-year period, with 2,646 women of the same age without the disease. Findings suggest that women who did not attend screening tests were six times more likely to develop cervical cancer between 65 and 83 compared with women that did.
Australian the first country to eradicate cervical cancer
Australia is well positioned to become the first country in the world to eradicate cervical cancer. This is largely due to national vaccination and screening programs, which could see the disease effectively eliminated as a public health issue within the next two decades. In 2007, Australia launched a national publicly-funded school immunisation program to reduce HPV, which complemented a national cervical cancer screening program that was launched in the 1990s. These have been shown to reduce the incidence of cervical cancer and significantly increase early diagnosis when the disease is curable.
A research paper about the Australian initiative published in the January 2019 edition of The Lancet Public Health concludes that, “the annual incidence of cervical cancer in Australia is likely to decrease to fewer than six new cases per 100 000 women by 2020 (range 2018–22) and to fewer than four cases per 100 000 women by 2028 (2021–35). The annual incidence of cervical cancer could decrease to one new case per 100 000 by 2066 (2054–77) if the existing HPV-based screening program continues in cohorts who are offered the nonavalent vaccine”; [a nonavalent vaccine works by stimulating an immune response against nine different antigens, such as nine different viruses or other microorganisms]. According to Suzanne Garland, Professor and Clinical Director of Microbiology and Infectious Diseases at the Royal Women’s Hospital, Melbourne, Australia, who led the research, “within 40 years the number of new cases of cervical cancer [in Australia] is projected to drop to just a few”.
The two worlds of cervical cancer
Global efforts to reduce the incidence rates of cervical cancer have focused on HPV vaccination and the Pap test. Although experts are optimistic about eliminating cervical cancer in developed nations, which have advanced healthcare systems and extensive HPV vaccination, screening and treatment programs, they are significantly less sanguine about eradicating the disease in LMIC where there are relatively low levels of awareness of cervical cancer, a dearth of preventative strategies, limited expertise and a narrow band of treatment options. This results in the disease being identified late when it is at an advanced stage, which leads to higher rates of morbidity and death. Indeed, 85% of all cases and cervical cancer deaths occur in LMIC, where the death rate is 18 times higher than in wealthy nations.
Cervical cancer a challenge for LMIC
The gap in preventing, diagnosing and treating cervical cancer between wealthy nations and LMIC is described in a paper published in the November 2017 edition of Gynecologic Oncology Reportsand suggests that, “Developing countries continue to bear a disproportionate percentage of the global cervical cancer burden. Investigations into the growing gap in incidence and mortality between developed nations and LMIC have cited persistent financial, infrastructural and educational limitations as key drivers. Pervasive lack of access to both preventative and definitive care has left a substantial portion of cervical cancer patients with minimal options for disease management”.
WHO strategy to eliminate cervical cancer
Recognising this disparity, in 2018, the Director-General of the World Health Organization (WHO) announced a call to action for the eradication of cervical cancer as a public health problem. In January 2019, the Executive Board of the WHO requested the Director General to develop a draft strategy to accelerate cervical cancer elimination, with clear targets for the period 2020 - 2030.
Vaccination and screening must be linked to effective therapies
The expansion of screening programs for cervical cancer in LMIC is only part of the answer to closing the gap with developed nations and eradicating cervical cancer globally. It is imperative that screening is linked to increased access to effective treatment for women with cervical cancer, particularly in its early stages when it is still curable. In LMIC there is often not only reduced access to preventive HPV vaccines and screening, but limited access to treatment and trained personnel. Notwithstanding, there is evidence to suggest that, in LMIC less-invasive and less–resource-intensive treatment options can be effective and are increasingly being made available.
Late presentation of cervical cancer in LMIC
Women from LMIC generally seek treatment for cervical cancer only after the presentation of symptoms when the disease is advanced and challenging to treat. Also, they often lack awareness of the disease and ways to prevent it. Further, in some regions of the world, cultural norms and myths about cervical cancer pose additional barriers to prevention. Despite such obstacles, the disease can be prevented at low cost by healthcare providers employing relatively simple techniques to screen women for precancerous conditions and treat abnormal tissue early. Among the most promising low cost and low-tech screening alternatives to the Pap smear, is visual screening, which only requires either simple vinegar or iodine solutions and the eye of a trained healthcare provider to spot abnormal tissue.
Screening linked to effective therapy
Increasingly, these simply tests are being linked with effective treatment. Increasingly, in LMIC relatively cheap and simple therapies are being used to either destroy or remove abnormal cervical tissue, depending on the severity, location and size of the affected area. Two such procedures include cryotherapy and loop electrosurgical excision procedure (LEEP). The former uses extremely low temperatures to destroy abnormal tissue and requires no electricity. The latter involves using a thin wire to remove lesions in the affected area. While this procedure requires more medical equipment than cryotherapy, it allows tissue to be removed for analysis, reducing the possibility that advanced cancer will go unnoticed. Although many LMIC have had cervical cancer prevention programs and simple treatment strategies in place for some time, some have failed to reduce death rates of the disease.
Radiotherapy and cervical cancer in LMIC
Research findings published in the May 2019 online edition of The Lancet Oncologysuggest that the availability of radiotherapy in LMIC (where gross national income is <US$12,000 a year) would generate millions of productive life years and billions of dollars in economic benefits for the patients' families and communities. The study suggests that implementing a 20-year strategy for radiotherapy to treat cervical cancer in LMIC between 2015 and 2035, in parallel with an HPV vaccination program, would save the lives of some 9.4m women and provide a net benefit to economies of US$151.5bn as a direct result of women living longer and more productive lives.
According to Danielle Rodin, lead author and Radiation Oncologist at the Princess Margaret Cancer Centre, University of Toronto, Canada, "Vaccination is hugely important, but we can't neglect the millions of women who are contracting cervical cancer and dying in pain without access to treatment. These are women who have curable cancers: even advanced cervical cancer can be cured with radiotherapy. The possibility exists to make this treatment universally available". Radiation therapy makes small breaks in the DNA inside cells. This stops cancer cells from growing and dividing and causes them to die. Unlike cisplatin therapy, [an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy], which usually exposes the whole body to cancer-fighting drugs, radiation therapy is usually a local treatment.
According to the 2019 Lancet Oncology study, HPV vaccination would result in a 3.9% reduction in cervical cancer incidence over the 20-year study period; assuming a best-case scenario of vaccinating every 12-year-old girl in the world starting in 2014. By 2072, when the first vaccinated cohort reaches 70, there would be a 22.9% reduction in incidence, still leaving 41.6m in need for therapy over that time period.
“We know that when administered together (chemoradiation) you can give lower doses of both and get a better kill-rate on the tumour. This is now the backbone of cervical cancer therapy”, says Growdon; see video below.
Abu Dhabi’s endeavours to reduce cervical cancer
For some years, experts have discussed religious and cultural barriers to cervical cancer screening and drew attention to the relatively low levels of cervical cancer awareness and screening for women in Middle Eastern Arab countries. Meta-analysis of cervical cancer studies conducted in Arab countries between January 2002 and January 2017 and published in the December 2017 edition of Nursing & Health Sciences,suggest that in Arab speaking countries there tends to be, “low knowledge of and perceptions about cervical screening among Arab women, the majority of whom are Muslim. Factors affecting the uptake of cervical cancer screening practices were the absence of organized, systematic programs, low screening knowledge among women, healthcare professionals' attitudes toward screening, pain and embarrassment, stigma, and sociocultural beliefs”.
The success of HPV vaccination in Abu Dhabi and the UAE
Notwithstanding, there are signs that this is changing. Leading such changes is Abu Dhabi of the United Arab Emirates (UAE). Over a decade ago, a mandatory free HPV vaccination program for school girls was introduced by Abu Dhabi’s Ministry of Health and Prevention and extended in 2013 to include women between 18 and 26. Also, the Ministry recommends that woman aged 25 to 65 years get a Pap smear every three to five years. Since 2018, HPV vaccinations have been provided free and compulsory for all school girls in Dubai and the Northern Emirates following a campaign to raise awareness.
Although the UAE is among the few countries to have relatively low incidence rates of cervical cancer, the disease still ranks as the third most frequent cancer among women in the UAE and the third most frequent cancer among women between 15 and 44. Estimates suggest that every year, 93 women are diagnosed with cervical cancer and 28 die from the disease in the UAE. Although Abu Dhabi is successfully leading the fight against cervical cancer and provides a roadmap for others to follow, the incidence of cervical cancer in the Middle East generally is expected to more than double by 2035 (>33,000 cases) and be responsible for more than 18,000 deaths. In some countries including Morocco and Saudi Arabia, low societal awareness and relatively low levels of screening results in about one in four women with HPV.
As cervical cancer screening and prevention programs have been growing and extending their reach, so increases the need to provide access to effective treatment. Despite growing awareness of the disease and global efforts to increase availability of appropriate resources, cervical cancer remains prevalent particularly in LMIC where effective treatment has not become widespread. In many LMIC, the default option is often to do nothing, which results in certain death. Researchers and policy makers should consider focusing their activities on how to best to reconcile the use of existing resources with the expected impact on the quantity and quality of life. Although gaps in oncological resources and barriers to treatment still exist, the good news is that there is increased political will and international attention to improve access to safe and effective treatment of cervical cancer. Notwithstanding, eradicating the disease globally appears to be more of a theoretical possibility than a medium term reality.
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
AstraZenecais 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.
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.
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 Valeantfor 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.
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.
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 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 Institutetin Sweden and presented at the 2017 European Cancer Congress (ECC) in Amsterdam, Holland was promising but inconclusive.
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 UKwas 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 studyexpects 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 canceris 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 canceris 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.
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.”
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’sLymph 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.
Shanghai based Yitu Technologyand 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.
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.
A novel drug called niraparib which freezes tumours and can prevent ovarian cancer recurringis now available to NHS patients
Ovarian cancer is a silent killer: each year in the UK it affects 7,400 women and kills 4,100
Oncologists have called niraparib, which is taken as a daily pill, a “game changer”
Approval of niraparib is predicated upon a clinical study that enrolled 553 patients with recurrent ovarian cancer
The endpoint of the study was progression free survival
The study reignited discussion about the relative merits of different metrices used to assess the efficacy of cancer therapies
Patient groups and some oncologists suggest health-related quality of life should be given more significance in the measurement of drugs
Niraparib made available on the NHS to halt the spread of ovarian cancer
There is some good news for women in Britain living with ovarian cancer. In June 2018 niraparib, a life extending drug, was recommended by the UK’s National Institute for Health and Care Excellence(NICE) for inclusion in the Cancer Drugs Fund, (CDF) which will make niraparib available on the NHS to women living with ovarian cancer, who already have had two or more courses of chemotherapy. The drug, which was first marketed in the USA in April 2017, is the first PARP inhibitor (described below) taken as a daily pill to be approved in Europe that does not require BRCA mutation or another biomarker testing. (Women with harmful mutations in the BRCA1 or BRCA2 genes have a 10 to 30 times higher risk than normal of ovarian cancer). Niraparib is expected to benefit around 850 UK patients each year at an annual cost of about £58,661 for the 200mg daily dose or £86,786 for the 300mg dose; but is available to the NHS at an undisclosed discount. Some oncologists have heralded niraparib as a “game-changer” because it freezes tumours and can prevent ovarian cancer recurring for 12 to 16 months.
In this Commentary
This Commentary: (i) describes niraparib and how it halts the spread of ovarian cancer, (ii) summaries the findings of the clinical study, which is the basis on which niraparib has been approved, (iii) describes questions raised about the endpoints of clinical studies and the growing debate about a trade-off between progression free survival and health-related quality of life, (iv) briefly describes the epidemiology of ovarian cancer, (v) uses video of a leading oncologists to describe the standard of care for the disease, (vi) explains the reasons why ovarian cancer is frequently diagnosed late with more video contributions from leading clinicians, and (vii) emphasises and repeats the signs and symptoms of ovarian cancer in an attempt to help educate women and encourage them, whatever their age, to seek immediate attention from their primary care doctor if they have any tell-tale signs of the disease.
How niraparib works
Niraparib is one of a class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors and is indicated for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Because of the high recurrence rates associated with ovarian cancer maintenance therapy, measured by progression free survival (PFS) rather than overall survival (OS), has become the appropriate treatment for this disease. Niraparib is a targeted therapy, which uses agents to identify and attack cancer cells while causing minimal damage to normal cells. Such therapies attack cancer cells' nuclei that contain the programs, which differentiates them from normal healthy cells. Each type of targeted therapy works differently, but they all change the way a cancer cell grows, divides, repairs itself, or interacts with other cells.
NOVA clinical study
The approval of niraparib is predicated upon findings of an international Phase 3 clinical study called NOVA, which were published in the December 2016 edition of the New England Journal of Medicine. The study sought to evaluate the efficacy of niraparib versus placebo as a maintenance therapy for patients with platinum-sensitive, recurrent ovarian cancer. The double-blind study enrolled 553 patients with recurrent ovarian cancer, who had achieved either a partial or complete response to their most recent platinum-based chemotherapy. The primary endpoint of the study was progression free survival.
Researchers were keen to discover whether having a BRCA mutation affected how well the therapy worked. Approximately 66% of participants did not have BRCA mutations. Findings demonstrated that women with an inherited BRCA gene mutation saw the time to relapse increase from 5.5 months to 21 months compared with chemotherapy alone. Niraparib was also shown to help women without a BRCA mutation, doubling the length of time before recurrence from 3.9 months to 9.3 months. So, niraparib significantly increased progression free survival in patients with or withoutBRCA mutations as compared to the control group. The results of the study position niraparib as the first PARP-inhibitor to reduce the risk of ovarian cancer progression or death by 73% in patients with BRCA mutations and by 55% in patients without BRCA mutations. Research is ongoing.
More data needed While the NOVA study represents a significant step forward more data is needed before all asymptomatic patients with recurrent platinum-sensitive ovarian cancer can be treated effectively with niraparib and other maintenance PARP inhibitors. The challenge for clinicians is to select the right drug for the right patient at the right time. To decide which patient receives PARP inhibition and at what point in her therapy is challenging and stands to benefit from further research. Until further research is undertaken on niraparib and other PARP inhibitors, patients with advanced ovarian cancer will continue to incur treatment related toxicity without definitive benefits.
Quality of life versus progression free survival
The side effects from approved cancer therapies raise questions about the metrices clinical studies use to measure their endpoints. All drugs have safety risks. The sole reason why a patient would want to take a drug is because it: (i) improves survival, (ii) results in a detectable benefit, (iii) decreases the chances of developing complications or undesirable side effects. Primary endpoints in clinical studies should be something that are important to a patient and can be objectively measured. When clinical studies use surrogate endpoints, similar tests apply. Thus, clinically meaningful endpoints directly measure how a patient feels, functions, or survives and include overall survival (OS), progression-free survival (PFS) and health-related quality of life (QOL).
The NOVA study used progression free survival (PFS) as its primary endpoint. This is an accepted metric for maintenance therapy for advanced ovarian cancer and other metastasized cancers. Employing PFS instead of overall survival as the primary outcome has the advantage that study completion can be quicker with fewer patients required and it is cheaper. While the NOVA study successfully demonstrated that niraparib helps to stop ovarian cancer returning, it failed to show that the drug reduces health-related quality of life for patients.
There is some evidence to suggest that women with ovarian cancer might be willing to accept lower progression free survival for enhanced health-related quality of life. A study published the December 2014 edition of Cancersuggested that women with recurrent ovarian cancer were prepared to trade several months of PFS for reduced debilitating side effects of chemotherapy, which include nausea and vomiting. The most common adverse reactions to niraparib, which affect about 10% of patients, include thrombocytopenia, anaemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain, mucositis/stomatitis, diarrhoea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnoea, cough, rash, and hypertension.
Epithelial ovarian cancer accounts for 90% of all ovarian tumours. It typically presents in post-menopausal women and is a significant challenge for gynaecological oncologists since most patients are diagnosed when the disease is already advanced and therefore have a poor chance of survival.The natural history of the disease is characterized by a high response rate to primary treatment of debulking surgery followed by platinum-taxane chemotherapy, which is quickly followed by early recurrence and a second-line treatment with platinum; then most patients experience further platinum-resistance and die from the disease. Although ovarian cancer is relatively rare - based on 2013-2015 data1.3% of women are expected to contract the disease sometime in their lifetime - it is the 7th most common cancer in women worldwide. In 2012 there were 239,000 new cases of the disease diagnosed globally. In the UK ovarian cancer is the 5th most common cancer in females, the 2nd most common malignant gynaecological disease and the 1st cause of death from gynaecological malignancy. The UK has one of the highest incidence rates of the disease in Europe, affecting some 7,500 women every year, and its survival rates are among the lowest. Every year 4,100 women in Britain lose their lives to the disease, which equates to about 11 women every day. Over the past 2 decades there has been a slowing of the rate of diagnosis of ovarian cancer in the UK, which is partly due to the large number of women having taken the oral contraceptive pill after it was made available on the NHS in December 1961 and is known to have a protective effect. According to the World Ovarian Cancer Coalition,over the next 2 decades the incidence rates of ovarian cancer worldwide is expected to rise by 55% and by 15% in the UK. This is mainly because: (i) post-menopausalwomen are living longer, (ii) populations are increasing, and (iii) there is a significant increase in the rate of urbanization.
The standard of care for ovarian cancer
Although advances in research and technology have contributed additional and sometimes more effective therapy options for women with ovarian cancer such as niraparib and other PARP inhibitors, both the American and European guidelines recommend surgery as the initial approach to ovarian malignancies. After surgery, adjuvant chemotherapy is mandatory in cases of suboptimal debulking, advanced stages, or early stages with a high risk of recurrence. Mike Birrer, Professor of Medicine at Harvard University Medical School, Director of Medical Gynecologic Oncology and also Director of the Gynecologic Oncology Research Program at the Massachusetts General Hospital Cancer Center describes the standard treatment for ovarian cancer. “Ovarian cancer is diagnosed surgically. It’s important that the patient undergoes proper diagnostic and staging procedures. This would include an exploratory laparotomy (a surgical procedure, which involves an incision through the abdominal wall to gain access into the abdominal cavity), which would then evolve onto a staging laparotomy, (to determine the extent and stage of a cancer), which would include a TAH (total abdominal hysterectomy), BSO (bilateral salpingo-oophorectomy, which is when either the uterus plus one ovary and fallopian tube are removed, or the uterus plus both ovaries and fallopian tubes are removed), removal of the ovaries and the uterus. The removal of the omentum (a layer of fatty tissue that covers the abdominal contents like an apron; the procedure to remove it is called an omentectomy, which involves removing the uterus, cervix, fallopian tubes and ovaries), and lymph nodes in the regiterial cavity, scraping of the upper abdomen and then a peritoneal lavage (a procedure to determine if there is free floating fluid, most often blood, in the abdominal cavity). This would give accurate staging for the patient and anything less would be considered less than the standard of care. Once the stage is established and the patient has an advanced stage of the disease, which has spread throughout the abdomen or outside the abdomen, the patient would then undergo further therapy. This would inevitably involve a combination of chemotherapy. The specific regimen would depend, in part, upon the surgical results.” See video below.
Current options for ovarian cancer maintenance therapy
In addition to niraparib, current options for ovarian cancer maintenance therapy include bevacizumab and olaparib. The former is a monoclonal antibody designed to block a protein called vascular endothelial growth factor (VEGF). Some cancer cells make this protein and blocking it may prevent the growth of blood vessels that feed tumours, which can stop the tumour from growing. Notwithstanding, bevacizumab can only be given once and improves progression-free survival by just a few months. Olaparib is a PARP inhibitor, which blocks how PARP proteins work in cancer cells that have a BRCA gene mutation. Without PARP proteins, these cancer cells become too damaged to survive and die. In the first instance, olaparib was only approved in patients with a germline BRCA mutation, which accounts for about 10–15% of ovarian cancer patients. In 2014, when olaparib was approved in Europe and the USA, it was the first cancer treatment targeted against an inherited genetic fault to be licensed. Subsequently, evidence suggested that the drug could also benefit patients whose tumours have defects that are not inherited.
Non-specific signs and symptoms
The unresolved challenge for ovarian cancer is that in its early stage it rarely presents with any symptoms. Compounding this is the further problem that later stages of the disease may present few and nonspecific symptoms, which are commonly associated with benign conditions. Were ovarian cancer detected in its early stage when the disease is confined to the ovary it is more likely to be treated successfully. Ovarian cancer suffers from another challenge because screening for the disease in not an option, as we explain below. Further, often women do not know what symptoms to look out for and primary care doctors misdiagnose the disease especially in younger women. This results in about 80% of ovarian cancer cases being diagnosed late when 60% have already metastasised, which reduces the 5-year survival rate from 90% in the earliest stage to 30%. Signs and symptoms of ovarian cancer include abdominal bloating or swelling, quickly feeling full when eating, weight loss, discomfort in the pelvis area, changes in bowel habits such as constipation, and a frequent need to urinate.
A patient’s view “The 3 primary symptoms of ovarian cancer are bloating, feeling full and pelvic pain. Secondary symptoms include fatigue, bowel and urinary issues. In reality women don’t have all the primary symptoms and they may not have any of the secondary symptoms but may have a combination of the 2. The most prevalent symptom is bloating, especially if it persists. If this occurs women should immediately go to their doctors and ask for a CA-125 blood test. And whatever the outcome of the test they should also insist on a TVUS scan. There is no one easy method of diagnosing ovarian cancer and doctors sometime mistake the symptoms for something less serious like irritable bowel syndrome,” says an ovarian cancer patient. In addition to a pelvic examination, the 2 most frequent diagnostic tests for ovarian cancer are transvaginal ultrasound (TVUS), which puts an ultrasound wand into the vagina to examine the uterus, fallopian tubes and ovaries and the CA-125 blood test, which measures the amount of the protein CA-125 (cancer antigen 125) in your blood.
According to Christina Fotopoulou, Professor of Surgery at Imperial College London and Consultant Gynaecological Oncologist at Queen Charlotte’s Hospital NHS Trust , “Ovarian cancer is a very silent disease. It has a tumour dissemination pattern of very small nodules spread throughout the whole skin of the abdomen. In the beginning these nodules are so small that they go undetected. The nodules are only detected when they get larger and produce water. So, women with ovarian cancer get abdominal distention and water in their tummies, which prompts them to seek advice from their doctors. But then it’s too late because it’s already at a late stage of the disease.” See video below.
The ‘bar’ is too high to screen for ovarian cancer
Hani Gabra, Professor of Medical Oncology at Imperial College London and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZeneca, UK supports Fotopoulou and says, “Ovarian cancer is often diagnosed late because in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers the notion that ovarian cancer goes from stages 1 to 3 is possibly a myth. In reality these cancer cells often commence in the fallopian tube with a very small primary tumour and disseminate directly into the peritoneal cavity. In other words, they go from the earliest stage 1 directly to stage 3, which renders screening a significant challenge. This is compounded by the fact that ovarian cancer is relatively rare in the population. So, to be effective a screening test would have to be extremely sensitive and extremely specific, which it does not have to be for commoner cancers. The combination of these makes screening for ovarian cancer extremely difficult to achieve.”
Ovarian cancer is a devastating disease, which is diagnosed more infrequently and often at a later stage. Patients are typically older, symptoms are non-specific and easily confused with a number of benign conditions. In its earliest and most curable stage, there may not be any physical symptoms, pain or discomfort. Standard treatment is radical and a harrowing experience for women diagnosed with the disease. About 85% of patients experience a recurrence of the disease after their first treatment cycle, which means that they often face repeated bouts of chemotherapy to keep the disease under control. In a significant proportion of cases even after a second round of chemotherapy the cancer can recur. Previously, at this point patients have had limited pharmacological help, but as research advances, this is beginning to change, and some novel and efficacious drugs are entering the market. Niraparib is one of the latest PARP inhibitors, which has demonstrated efficacy in the treatment of advanced ovarian cancer.