Looking beyond fact and fiction
Fleck, JF: Anticancerweb 29(08), 2020
It is not easy to draw a line between fact and fiction. Usually, fiction is universal and the real is particular. Although fact is not entirely detached from fiction, it is often discrete and specific. By definition, a Universal Cancer Test would be a fiction, but important steps are being taken to make it a reality. Using strict criteria, the early diagnosis of cancer in a blood sample will migrate from fiction to reality only when the sensibility and specificity of the test reach 100%. In medicine, the sensibility of the test is its ability to correctly identify patients with the disease (true positive rate), while the specificity of the test is its ability to correctly identify patients without the disease (true negative rate). Consequently, a false negative is a loss in test sensibility and a false positive is a loss in test specificity. Any index of sensibility or specificity below 100% can eventually cause harm. A false negative (loss in sensibility) means that the test was not useful to detect the disease, and a false positive (loss in specificity) creates a disease where it does not exist. An ideal condition will probably never be achieved and a universal cancer test will remain fictional. However, medical science is not entirely accurate. It is based on probabilities, which magnifies the blurred line between fiction and reality. However, this is the nature of medical science, always requiring mutual understanding and a strong commitment between doctor and patient.
Currently, cancer screening is based on a progressively outdated organ-oriented approach. Tumor prevalence, test positive predictive value (PPV) and the scheduled follow-up are used to calculate the number of patients who need to be screened (NNS) to detect a single cancer. The most efficient model is found in colorectal cancer. The combined use of fecal immunochemical test (FIT) and colonoscopy results in an NNS of 12, leading to a US Preventive Services Task Force (USPSTF) recommendation as category A (high certainty of substantial net benefit). In addition, only the Pap smear for cervical cancer is also classified as category A in the USPSTF recommendation. Screening for these two malignant tumors has substantially reduced their incidence and mortality. Breast cancer mammography screening for women age 50 – 74, and lung cancer screening with low-dose CT for 30+ pack years current smokers age 55 – 80, including those quitting within 15 years, are considered USPSTF category B (high certainty of moderate net benefit) recommendation. Although this organ-oriented approach encompasses the three most prevalent tumors in the world, it is far from the ideal concept of a Universal Cancer Test.
The lights came on for the first time in July 2015, when JAMA published a preliminary communication of noninvasive prenatal testing (NIPT) and incidental detection of occult maternal malignancy. A NIPT using massively parallel sequencing of cell-free DNA (cfDNA) in maternal plasma, looking for fetal aneuploidy screening in chromosomes 13, 18, 21, X and Y showed a false-positive discordance in 10/3757 patients. A possible biological explanation for the discordance with the normal fetal karyotype was maternal malignancy. Tumor DNA was presumably shed in maternal circulation and depicted by NIPT. A maternal malignant disease was detected in all 10 discordant patients and based on written consent 8/10 patients were further subjected to genome-wide bioinformatic analysis. A translational study has been recently published, detecting abnormal plasma cfDNA in both localized (50%) and metastatic (80%) malignant tumors. A multi-organ cancer screening (Universal Cancer Test) has being pursued. Breaking a paradigm, it should be performed non-invasively in a single medium, like blood, saliva, urine or breath and should be cost-effective. Published in February 2018 on Science, a multi-analyte blood test called Cancer-SEEK described the detection and localization of eight surgically resectable human cancer types. Using machine-based learning to analyze the data, Cancer-SEEKassessed tumor specific mutations in circulating DNA + eight circulating proteins biomarkers. The test’s sensibility ranged from 69% to 98%, depending on the tumor type and the specificity was higher than 99%. Despite these interesting preliminary results, the test cannot yet be applied to general population. Major limitations include a wide sensibility range combined with its gradually decreasing rate in earlier cancer stages, reaching as low as 40% in tumor stage I. This is the most important caveat, since the main benefit of a cancer screening test is normally restricted to early detection. Additional validation using a different dataset should be pursued with prospective randomized trials demonstrating survival benefit. Epidemiological pitfalls like lead-time bias e length-time bias should also be considered. The Australian Center of Personalized Nanomedicine published in Nature Communications the proposed use of Methylscape as a universal cancer biomarker. The attributed name Methylscape derived after epigenetic reprogramming cancer genome, which creates distinct DNA methylation landscape presented in most cancer types. Differences in DNA solvation and DNA-gold affinity between malignant and normal genomes sustained a colorimetric one-step assay, which can be analyzed in less than 10 minutes. Further efforts in will be necessary to translate this knowledge into clinical setting. Cancer heterogeneity and evolutionary changes also restricts a reliable tumor signature. Combining cancer biological knowledge and bioinformatics, a well-designed start up called Grail, located at Menlo Park, California faced the challenge to discover the millions of unique patterns that define cancer. Grail created a universal task-force producing high quality-data and translating it into actionable information for cancer care. A subset analysis from the Circulating Cell-free Genome Atlas (CCGA) study was recently presented at ASCO Breakthrough in Bangkok, October 2019. It was a simultaneous multi-cancer detection and tissue of origin localization using targeted bisulfite sequencing of plasma cell-free DNA. Plasma cfDNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine learning classifier determined cancer status and tissue of origin. Performance was reported at 99% specificity and the sensitivity ranged from 34% for stage I to 92% for stage IV malignant tumors. However, 99% specificity is still not enough. Dealing with 1% false positives is not yet accepted due to the inevitable fear of false diagnosis imposed on the general population. Despite international efforts, a Universal Cancer Test is still wavering between dream and reality.
References:
1. Paul F. Pinsky: Principles of Cancer Screening, Surg Clin North Am 95(5): 953 – 966, 2015
2. Diana W. Bianchi, Darya Chudova, Amy J. Sehnert, et al: Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies, JAMA 314(2): 162-169, 2015
3. Joshua D. Cohen, Lu Li, Yuxuan Wang, Christopher Thoburn, et al: Detection and localization of surgically resectable cancers with a multi-analyte blood test, Science 359 (6378): 926 – 930, 2018
4. Abu Ali Ibn Sina, Laura G. Carrascosa, Ziyu Liang, et al: Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker, Nature Communications 9: 4915- 28, 2018
5. Oxnard G R, Klein E A, Seiden M, et al: Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA), Journal of Global Oncology 5:44, 2019
7. Photo by CDC on Unsplash
The results obtained in recent studies still do not bring great benefits for the entry of a Universal Cancer Test into clinical setting. The sensitivities are low for the early stages of the disease in the methods used by Joshua et al. and by Geoffrey et al., and the specificity obtained by Geoffrey et al. - although high - is still not enough considering the purpose of early detection of cancer. It is important to notice, however, that a lot of progress was achieved in the past five years. Eventually, a Universal Cancer Test should become reality in clinical setting.
Fact and fiction are very close and practically inseparable. In history, many times, man takes fiction and uses his creativity to create new things and improve others, making fiction a fact. So, fiction can be seen as a fuel for advancement, for example, when I was a child we saw films in which cars listened to their owner and responded to commands, today this is possible. But we need to be careful, fiction can sometimes harm some people who think they can do everything because in a few years we will have new drugs and treatments. Seeing the advances in universal testing is incredible, although we know that medicine is not an exact science and universal testing probably cannot achieve 100% specificity and specificity, it can work in combination with other methods to help define which ones people deserve screeening more often. This shows once again the importance of multidisciplinarity.
To develop an efficient or perfect way of detecting early cancer stages and a universal cancer test is a frequent thought and dream all physicians have, but at the time being is mostly based on hope. With all the controversy around screening or not screening, the only answer would be to achieve an index of 100% sensibility and specificity, where you wouldn’t lose any true nor attribute false positive cases. Even though it may look like fiction, many cancer therapies were considered impossible when they first started to be considered. We may still not have the tools needed to develop a 100% method, but, based on recent experiences, we are leaning towards it. Evidence-based medicine relies on experience and, many times, hope and some failure to show the right path.
The idea of one day having a universal test to screen cancer might sound impossible or unobtainable, but that doesn't mean we shouldn't work to get as close to that as possible. Medical science has witnessed dramatic advancements in the last decades, which gives researches and society hope. We know there are a lot of issues regarding cancer screening, in weighing the potential benefits and harms a screening process can have in our patients. Therefore, having a universal test, with little side effects, that could detect the presence of a malignant tumor through a blood exam and help us direct it for specific screening and treatment would be of tremendous, almost unimaginable value. There are still many obstacles, as discussed before, like achieving a satisfying rate of sensibility and specificity, but that should not stop us from trying to develop, perhaps, the best screening method possible.
It is interesting to recognize the limitations of medical practice, mainly to understand that a universal cancer test is something of a fiction. Advances in the diagnosis of types of cancer, such as breast and colorectal cancer, show us that we can go a long way towards early diagnosis and treatment. Advances like machine learning show that science is advancing, but it still has many limitations, so a universal test for cancer is something that is still in fiction.
A universal cancer test with 100% specificity/sensibility sounds very unlikely for many reasons, but mostly because such percentages are usually unattainable, and cancer has a wide variety of origins and locations. As an example, detecting abnormal DNA in the blood in case of early brain cancer will probably be a hard task due to the blood-brain barrier. Nevertheless, the path towards a perfect universal cancer test could present us with useful and realistic tests along the way, maybe changing the course of the disease and even mortality rates.
A test capable of identifying any cancer in its initial stages would be a great find for medical practice, but knowing the need to achieve a sensitivity and a 100% specificity make this test practically unattainable for contemporary medicine, something that would only be possible in fiction films. However, the search for increasingly better tests would benefit many patients, so the search for these tests becomes essential in medical practice.
A universal cancer test would be a remarkable way to detect early stages of cancer in a blood sample with a multi-organ screening approach. However, we know there are several types of cancer, with a large variety of locations and histotypes. Furthermore, this test still would need a specificity of 100% to avoid the risk of false-positive results in the population. Therefore, this multi-organ cancer screening may never be achieve, although the pathway towards this unreachable dream can lead us to the development of new cancer tests with higher specificity and sensibility, and with fewer adverse effects.
One of the "evils" that got stuck inside the pandora's box was the hope that for the Greeks consisted of suffering. When mentioning the possibility of a universal cancer test, the Pandora's Box opens up giving men the hope of a test that could detect the presence of cancer, however as mentioned in the article above for there to be such a test it is necessary that it presents high sensitivity and high specificity, which is not yet possible, thus demonstrating how the Greeks affirmed that hope also consists of suffering.
Following the principle of Plato's Theory of Ideas, everything that exists in the material world today is the product of something that already exists in the plane of ideas. This is where the concept of fiction comes in and can often become reality. Undoubtedly, a universal test for cancer detection would represent a great advance in science. For this, it is necessary to use determination on the mental plane and the constancy and perseverance of scientists on the physical plane, because where there is a will, there is a way.
We know that cancer has many "faces" and it is one of the main causes of death worldwild, so just the idea of having a tool that can help avoid it (with the knowledge of its probability) and help with early detection (detection of early stages is related with better survival rates) is really amazing. But we should always have in mind the principle of non-maleficence when putting those ideas in practice so no harm will be caused.
A 'Universal Cancer Test' seems to be a pipe dream, considering it necessitates 100% specificity and sensitivity, something that modern medicine hasn't quite achieved yet. However, it is true that modern medicine would only be pipe dreams to ancient men. Thus, we face the only path that can make us turn this dream into reality: science. Through it, we may, someday, have this tool available to us. In the meantime, scientific research helps us improve the tools we have and continue to discover others; perhaps not as universal as we wish, but, nonetheless, means to win this battle against cancer.
The scientific community struggles to find a Universal Cancer Test. This test would work if it could accurately detect all cancer cases. In a technical definition, it means to dismiss all false positives and false negatives. However, the question that remains is if a Universal Cancer Test is at all possible. There were several attempts to find it, all of those without a definite result. However, even if a Universal Cancer Test is fiction, something impossible to come true, why should we stop looking for it? We may discover something else while inquiring.
Until this day, the most efficient way to treat and cure cancer is to make premature diagnosis. This is demonstrated in the reduction of incidence and mortality in cervical and colorectal cancer since the development of accurate screening tests. In this sense, an efficient Universal Cancer Test would represent a tremendous outbreak in the worldwide fighting against cancer. Although this might be a fiction idea for now, the pursuit of cost effective, non-invasive and efficient test to detect at least the most lethal and prevalent cancers should continue in order to reduce maximum as possible cancer mortality.
Reading the text and comments here, I found interesting what Giulia said about Plato's Theory of Ideas. I think that it summarizes my general opinion about this topic: I think that the fact that we are in a moment of history that we can even think about developing a universal cancer test is fantastic. Even though there are problems that we need to face by studying the methods of screening that are being developed - by every test that is developed, a new obstacle appears -, researchers are learning a lot from every problem that they need to face during their studies. By learning to solve this problems, to develop a better test, to magnify its specificity and sensibility, we are going to see, maybe in few years, maybe in decades, the idea of creating a universal cancer test turning to a fact. This process, followed by failures and successes, is building step by step our way to a moment where all this will be more possible - where all this will be more fact than fiction.
Science is evolving at a growing pace. We can already see exoskeletons being built to help people with mobility impairments, wireless brain sensors. In the last century, one of the gratest achievments of medicine was created, the cardiac pacemaker. All this enovations required a lot of thinking, time and successions of tries and errors. Now, more than ever, we can comunicate with each other from different parts of the world and think together.
An universal biomarker that could act as a screening tecnhique and provide significant insight into the cancer risk or its presence in a given patient is a long time fantasy shared between physicians and the society. That futuristic biomarker is even more important considering the current screening methods being used for premature diagnosis and their flaws. Thankfully, with all the mutations and genetic differential expression knowledge being brought up, the understanding of the cancer physiopathology and the recognition of a growing number of circulating neoplasic antigens are beginning to create hints about possible candidates. Considering the stigma that cancer still occupies in the popular imaginarium and the ageing of the population, such strategies will bring light to the management of such diseases that trend to grow in incidence year after year.
We have already seen the impact that eficient screening methods have on the early detection and intervention on specific types of cancer, reducing cancer-related mortality. The first one to be implemented was the Papanicolau test for HPV, an infection strongly related to cervical cancer, and this method, in conjuction with new ways to treat cancer was able to reduce drastically mortality, mostly in underdeveloped countries. Today, more than half a century later, we can grasp the idea of an universal cancer screening test, which could do to all types of tumors what the papanicolau test did to one specific type.
The idea of an universal cancer test with high sensibility coming closer to reality makes me think that the "cure" for cancer may not be in an all-encompassing anti cancer drug, but in having a reliable universal screening method that can detect cancers in its early stages, thus preventing malignancy.
A universal cancer test would be a huge step towards early detection of tumors for which we don’t currently have screening options. The wide range of cancer types and subtypes and it’s highly mutable nature are factors that make such a test a really hard thing to achieve. The more we study cancer, the more we see how particular every tumor is in terms of clinical behavior, biomarkers and even treatment response. Although a universal cancer test may sound unachievable, many exams we use in current practice sounded unrealistic just a few years ago, such as MRIs and complete genome mapping. Thus, we should keep pursuing to improve blood analyses and other kinds of possible screening tests so that we can gradually get better sensibility and specificity and, maybe, one day, achieve this end-goal, which would probably be the one of the biggest breakthroughs in medical history.
The fiction moves the world. When we would imagen do a surgery in a pacient by a robot? All the advances we have today have come from the imagination and the hope of making them real. A test with this sensibility and this specificity, even far away of our reality, could guide us to a path with more diagnoses resources, since the mecanism that we have currently, one day, was seen as something unreachable. Therefore, we must keep trying, finding new paths and increasing the range of knowledge we have about cancer today. Worth the attempt when the result can make a change.
It is important to keep in mind the notion that medical practice has its limitations in order to understand that a universal cancer test is, in some ways, a fiction. However, advances in the diagnosis of different types of cancer demonstrate that we have come a long way and can go even further in regard of early diagnosis and treatment.
Tumor markers are not usually 100% sensitive and specific for cancer, and may be altered by other conditions, therefore a screening blood test for all types of cancer would easily generate false positives or negatives with technology available. However, tumor markers are important to verify staging, responses to treatment and relapses. Although really specific cancer markers aren’t currently available, for screening test which constitute an important gap in clinical knowledge therefore researches on that area and search for possible new markers should be encouraged.
A universal cancer test sounds like a dream. When we think about cancer, sometimes we forget that it is not a single disease, therefore developing a test that can detect early stages of multiple types of cancer is a huge challenge. The paradigm of sensitivity/specificity duality brings even more complications to this dream, even more with the current discussions about whether or not to perform screening tests, precisely because of the risk of false negatives; as well as the tests for the detection of genetic mutations, that still have very particular indications. However, what moves humanity, if not dreams? Certainly, technology still has a lot to evolve and perhaps, in the near future, the universal cancer test doesn't sound like a dream.
Cancer diagnosis is still, justifiably, stigmatized. This, however, narrows the acceptable limits of both false positives and false negatives for universal test development. Although a test with high sensitivity and specificity avoids unnecessary patient distress, these demands - rightly made - ultimately delay the use of universal screening.
Cancer is a well-known disease in the general and medical population, but we still haven't mastered all its mechanisms. Dreaming of tests that help make an earlier detection is ignoring that we still have to learn and understand this pathogenesis. I emphasize that we cannot get too excited about the universe of fiction, we must take steps back to better understand the spread (metastasis) of cancer, for example.
It would be really great to be able to detect cancer at an early stage and be able to offer the patient adequate treatment early. However, the lack of a method that has 100% sensitivity and effectiveness, as would be ideal, makes us reflect on the pros and cons of screening. The damage a false positive can cause is often underestimated. Therefore, it is necessary to continue to seek more sensitive and specific methods for early detection of cancer.
We have been waiting for a long time to get a test with high sensitivity for detecting cancer. Although this reality is still a long way off, the attempts will certainly guide us to a path of more discoveries and diagnostic resources, Since we will be doing a triage much more effectively.
Despite a Universal Cancer Test is still a mixture of reality and aspiration. Challenges such as cancer heterogeneity, evolutionary changes, and the need for higher specificity continue to hinder its development. Ongoing research, validation, and clinicals trials are necessary to bridge the gap between the dream and reality of a Universal Cancer Test.
Oncology updates itself on a daily basis, with intensive efforts in research, and the pursuit of a universal test is an example of this. A test with sensitivity and specificity of 100%, as mentioned in the text, borders on fiction; however, we have made significant progress in that direction. Furthermore, even though achieving that 100% goal may be unlikely, with research aiming for it, we can achieve many other cancer detection targets, reducing mortality rates for various types of cancer, just like what has been done with cervical and colorectal cancer since the development of accurate screening tests.
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