BIomarkers and Bioethics
Biomarkers in Cancer Screening and Early Detection
Sudhir Srivastava (Editor)
August 2017, Wiley-Blackwell
23 Bioethics and Cancer Biomarker Research, 277
Nathan Nobis, William Grizzle, and Stephen Sodeke
Prepared by world leaders on this topic, Biomarkers in Cancer Screening and Early Detection offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer biomarkers, from their discovery and development to their validation, clinical utility, and use in developing personalized cancer treatment.
Offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer biomarkers
Provides immediately actionable information and hopefully also inspiration to move discovery and clinical application forward
Offers vital knowledge to help develop personalized cancer treatment for individual patients with specific cancers
List of Contributors, ix
Preface, xiii
Part I Foundations of Biomarker Research
1 Nuts and Bolts of Biomarker Research, 3
Sharmistha Ghosh and Sudhir Srivastava
2 Cancer Genome Methylation: Biology, Biomarker and Therapeutic Opportunities, 16
Shashwat Sharad, Taduru Sreenath, Shiv Srivastava, and Albert Dobi
3 MicroRNA Biomarkers for Early Detection of Cancer, 27
WendyWang, Matthew R Young, and Sudhir Srivastava
4 Inflammation and Cancer, 37
Pamela L Beatty, Sandra Cascio, and Olivera J Finn
5 Exosomes: A Valuable Biomedical Tool in Biomarker Discovery and Development, 50
Jocelyn Lee, Sharmistha Ghosh, and Sudhir Srivastava
6 Epithelial-to-Mesenchymal Transition (EMT): Clinical Implications, 64
Elisa CWoodhouse and Suresh Mohla
Part II State-of-the-Science in Organ-Specific Biomarker Research
7 Breast Cancer, 77
Benjamin A Katchman, Christos Patriotis, and Karen S Anderson
8 Ovarian Cancer, 93
Christos Patriotis, Archana Simmons, Karen H Lu, Robert C Bast, Jr, and Steven J Skates
9 Esophageal Cancer Biomarkers, 104
Yanxin Luo, Kishore Guda, SanfordD Markowitz, Amitabh Chak, Andrew M Kaz, andWilliam M Grady
10 Predictive Biomarkers for Therapy in Adenocarcinoma of the Upper Digestive Tract, 118
Heath D Skinner, Qiongrong Chen, Elena Elimova, RoopmaWadhwa, Shumei Song, and Jaffer A Ajani
11 Pancreatic Cancer, 130
Sam CWang and Peter J Allen
12 Colon Cancer, 141
Paul DWagner
13 Prognostic and Predictive Biomarkers for Colorectal Cancer, 151
Upender Manne, Balananda-Dhurjati Kumar Putcha, Temesgen Samuel, and Sudhir Srivastava
14 Early Detection of Lung Cancer, 163
Mohamed Hassanein, Melinda C Aldrich, Stephen A Deppen, Karl E Krueger, Eric L Grogan, and Pierre P Massion
15 Commonalities in Lung Cancer and COPD, 185
MalgorzataWojtowicz and Eva Szabo
16 Prostate Cancer, 197
Jacob Kagan, Ian M Thompson, and DanielWChan
Part III Biomarkers, Screening and Precision Health: Implications for Public Health
17 Improving the Clinical Validity of Biomarker Research in Cancer Detection, 209
David F Ransohoff
18 Cancer Overdiagnosis, Ramifications and Research Strategies, 220
Barbara K Dunn and Barnett S Kramer
19 Predictive Markers and Driver Genes From Treatment Trials: Potential Utility For Early Diagnosis, 231
Brian S Sorg, Sarfraz Memon, Kelly Y Kim, Aniruddha Ganguly, Tracy Lively, James Tricoli, Magdalena Thurin, Lokesh Agrawal, Tawnya C McKee, Barbara A Conley, and J Milburn Jessup
20 Statistical Consideration in Predictive and Prognostic Markers, 245
Fei Ye and Yu Shyr
21 Clinical Validation of Molecular Biomarkers in Translational Medicine, 256
Harry B Burke and William E Grizzle
22 Cancer Biomarker Assays: Performance Standards, 267
Anna K Fuzery and Daniel W Chan
24 Colon Cancer Screening, 283
Molly Perencevich, Jennifer Inra, and Sapna Syngal
Bioethics and Cancer Biomarker Research
Nathan Nobis, Morehouse School of Medicine and Morehouse College, nathan.nobis@morehouse.edu
William Grizzle, University of Alabama at Birmingham, Birmingham, AL, wgrizzle@uab.edu
Stephen Sodeke, Tuskegee University National Center for Bioethics in Research and Health Care, sodeke@mytu.tuskegee.edu
Updated version: 10/1/2014 9:22 AM
Abstract: 145 words
This chapter engages some bioethical issues raised by cancer biomarker research. We discuss some of the actual and potential benefits and harms from cancer biomarker research, concerns that individuals are treated with respect in the course of such research, and concerns that such research is fair and just. Our focus on bioethical issues specific to cancer biomarkers will include the validation of biomarkers; confidentiality, specimen identification, and data protection; and the return of research results. We do not discuss any legal or regulatory aspects of cancer biomarker research. This is because law and regulations vary by place and time and, more importantly, laws and regulations are not a reliable guide to what is ethical: laws can permit, and even require, immoral and unjust behaviors and morally permissible and just actions can be illegal. Our discussion focuses only on ethical or moral aspects of biomarker research.
ETHICS, MORAL, JUSTICE, CANCER, BIOMARKER, RESEARCH, CONFIDENTIALITY, RESULTS, IDENTIFICATION, DATA
The purpose of this chapter is to engage some bioethical issues raised by cancer biomarker research. We will discuss concerns about some of the actual and potential benefits and harms from cancer biomarker research, concerns that individuals are treated with respect in the course of such research, and concerns that such research is fair and just. Our focus on bioethical issues specific to cancer biomarkers will include:
the validation of biomarkers;
confidentiality, specimen identification, and data protection; and:
the return of research results.
This focus necessitates a clear understanding of bioethics in its broadest sense as well as in a contextual sense specific to cancer biomarker research that will claim our attention in this chapter. We shall not discuss any legal or regulatory aspects of cancer biomarker research. This is because law and regulations vary by place and time and, more importantly, laws and regulations are not a reliable guide to what is ethical: laws can permit, and even require, immoral and unjust behaviors and morally permissible and just actions can be illegal. Our discussion will focus then only on ethical or moral aspects of biomarker research.
What is Bioethics?
To begin, we should explain what we mean by bioethics in the broadest sense, and in a contextual sense. Bioethics has been broadly defined as "not ethics of biology, but ethics in the service of the bios—of a life lived humanly, a course of life lived not merely physiologically, but also mentally, socially, culturally, politically, and spiritually. This means that the practice of bioethics must involve undertaking a fundamental inquiry into the full human and moral significance of developments in biomedical and behavioral sciences and technology." (1) This kind of broad orientation enables us to imagine the significant impact of any scientific activity, action or policies, of which cancer biomarker research is one, on human life and the demands of social justice. Contextually or operationally then, we can define bioethics as the ethical or moral evaluation of actions and policies in biomedical research and healthcare. According to an influential approach to bioethics, the "Georgetown Mantra" (2,3), moral or ethical issues exist when an action or policy results or will likely result in:
Harms, i.e., making someone worse off than they were, in some important way;
Benefits, i.e., making someone better off than they were, in some important way;
Disrespectful treatment, that includes behaviors where someone might be seen as being "used" as a mere "thing," is taken advantage of, or is manipulated, i.e., their power of choice and control over their own lives diminished or eliminated; and:
Unfairness or inequality, that is, differences in treatment and consideration that cannot be justified by any relevant reasons and so are unjust.
Reflecting on cases of moral wrongdoing confirms the relevance of these factors. Many wrong actions result in harms to people and the benefits are either limited or nonexistent. Many such actions also involve individuals being "used" as "mere means," i.e., treated in ways that they would not agree to be treated, if their wishes were taken into account, or treated as mere things, without their preferences take into account. Finally, many morally wrong actions involve the person doing the action treating some persons in ways he would not treat other persons, but for irrelevant reasons: e.g., a racist treats members of other races in ways she would not treat people of her own race, but for no good reasons. Racism, of course, harms the victim, lessens the victim's ability to seeking benefits (and other goods), is disrespectful and is unfair and unjust: moral considerations often overlap and an action or policy can be wrong for many reasons.
These moral factors, or their contrary factors, help explain why actions are right and good also. Right and good actions tend to benefit the recipient of the action. They also tend to lessen the harms that someone might have endured. When individuals are treated rightly, they are treated with respect and their autonomy and self-determination is enhanced. Finally, right actions involve all individuals being treated fairly, with equal consideration and respect, which promotes justice for all. Our concern, then, is how these moral factors are relevant to aspects of cancer biomarker research.
Bioethics, Ethics and the Validation of Cancer Biomarkers
A biomarker is a biological or biologically derived indicator of a process, event or condition. For example, a biomarker may indicate the presence of a disease or the likelihood of a disease outcome. (4,5) For a biomarker to be useful, it must accurately and reliably indicate the event, process or condition so the marker must be validated. (4,5) If it isn't validated, benefits are unlikely and harms are likely, and so ethical problems are likely; thus, if molecular markers (biomarkers) are used in medical care without rigorous validation, untoward consequences may ensue. If medical decisions are made based upon biomarkers that do not reliably aid in these decisions, unneeded medical care may result or alternatively, necessary medical care may be withheld. This will harm patients and increase medical costs.
Case Study: Prostatic Specific Antigen
These concerns can be illustrated with the current use of prostate specific antigen for early detection of prostate cancer. This example demonstrates that validation of biomarkers is an ethical imperative that cannot be ignored. Since extensive resources are used for biomarker research, ethics requires that biomarkers be validated to ensure that these resources are not wasted and that the harms are reduced and likely benefits increased.
Prostatic specific antigen (PSA) is an example of a biomarker that has been used clinically as a biomarker for the early detection of prostate cancer without definitive validation. PSA is an antigen specific for prostatic glandular tissue and not specific for prostate cancer; thus, PSA can be elevated in the setting of several benign diseases/conditions of the prostate, as well as in prostate cancer. Thus, patients who are evaluated for prostate cancer because of mildly elevated levels of PSA are just as likely not to have prostate cancer as to have prostate cancer. Thus, the use of PSA as a screening biomarker for the early detection of prostate cancer can, at best be beneficial to some patients, and at worst can be erroneous and have multiple detrimental consequences to other patients and society. The issue is that it is problematic if the benefits to some patients are cancelled by harm to other patients and thus to society overall.
For example, when an elevated PSA results in an evaluation to exclude prostate cancer, it could involve multiple biopsies of the prostate. Even if all initial biopsies are negative, they may be repeated resulting in unnecessary costs to the patient and to society and also needless anxiety. In addition, many indolent prostate cancers may be identified by biopsy and these indolent prostate cancers may never have caused clinical disease in the patient; yet, because these indolent cancers cannot be reliably separated by current methods from life-threatening cancers, they sometimes are treated by surgical removal of the prostate or by radiation of the prostate – procedures that frequently have serious side effects including incontinence and impotence.
These problems have led to recommendations for discontinuing the routine use of a single PSA test as an early detection biomarker for prostate cancer. (6-9). However, society and patients cannot recover the wasted resources and medical consequences of almost four decades of the use of PSA as well as the current controversy of trying to discontinue the use of a biomarker which has been sold as an important detection method for prostate cancer that saves lives. Based on this example, one could surmise that a rigorous validation is necessary before any clinical use of a biomarker. This involves several studies leading to a prospective study that should demonstrate the cost-effectiveness of the use of such a biomarker in medical care. (5)
Nevertheless, just as there are ethical issues in not validating a biomarker, there are ethical issues in the validation of a biomarker. These include ensuring that the use of the biomarker is adequately evaluated, the selection of populations tested as to its validity and the methods used in testing. The requirements of validating biomarkers have been described in the literature. Even when these requirements have been adhered to, it is important to understand that the same biomarker can have multiple uses and the validation for one use does not mean that a biomarker can be reliably used in another way in other settings. Validation of a biomarker is for one use which may include the following: risk of disease, early detection and diagnosis, prognosis, prediction of therapeutic responses, or evaluation of therapies or of preventive approaches. For example, while PSA is not a cost-effective biomarker for early detection of prostate cancer, it can be used more reliably to detect the recurrence of prostate cancer following prostatectomy or radiation of the prostate and as an aid in the tissue diagnosis of metastatic lesions males from an unknown primary.
Furthermore, each biomarker must be evaluated for determining a specific endpoint (e.g., prognosis) over a defined period of time (e.g., 10 years) and in a specific population. One other critical point to remember is that the cost-effectiveness for the use (e.g., to determine prognosis) of a biomarker may vary with race and ethnicity. Thus, it is important to ensure that the use of a biomarker is validated for use in minority populations. It is unacceptable to assume that a biomarker validated in a predominantly Caucasian American population can be used reliably in an African American population or even that a biomarker validated for use in an African American population would apply equally to the same use in a population from West Africa. Because prostate cancer is more frequent and aggressive in the African American (AA) population, screening of this population with PSA after a certain age may be more justified than screening in the Caucasian American (CA) population. More studies are needed in this area.
An example of how biomarkers may vary among racial/ethnic populations is the effort to treat lung cancers by targeting the signal pathway of the epidermal growth factor receptor (EGFR). The predicted success of this approach was, in part, based on results from the Japanese population; however, when this approach was tested in the population of the USA, it was not as effective as predicted. This is because the overexpression/mutations of EGFR that would be targeted effectively by this approach were primarily associated with the adenocarcinoma subtype of lung cancers which occur in Japanese females who have never smoked but not in general lung cancers that are typical of the population of the USA. (10-12)
Bioethical Conclusions about Validation:
In the validation and use of biomarkers, the main ethical issues involve benefits and costs to the individual and society definitely need to incorporate and evaluate biomarkers in minority populations and the education of populations about the costs, benefits and limitations of using specific biomarkers clinically.
Other ethical concerns include validation's effects on individual patients. Efforts at validation of biomarkers should not be undertaken without a clear benefit to individuals. One could argue that, in general, it would be a waste of limited research resources to validate a biomarker for the early detection of a sporadic deadly disease for which there is no treatment; however, for a heritable disease such as Huntington's chorea for which there is currently no cure, individuals may want to know if they will develop the disease or if they are carriers of the disease in order to make reproductive decisions. Thus, channeling resources toward validating a biomarker that could help in such decisions would be morally justified.
Finally, the last step in the validation of a biomarker ultimately requires analysis by an independent investigator (e.g., who did not develop the biomarker or initially test it) in an independent, prospective population. This is an effort that requires extensive resources. A waste of such resources negatively affects society. Thus, clear indications that a biomarker is likely to benefit medical care are necessary prior to most validation studies. Similarly, validation of a biomarker could occur, yet its use might benefit only a few individuals at a great cost to society. This is at odds with the utilitarian worldview of "the greatest good for the greatest number of people," and from the moral perspectives that prioritizes individuals who are worst off, i.e., the poorest of the poor, who would benefit most from receiving a greater share of the existing medical knowledge and care.
Hence, in a society in which resources are very limited, the question becomes whether the benefits to a few members of society justify a burden on society which may result in a shift of resources that harms another group of individuals. We must admit that in some cases the moral calculus may not be the morally justified framework if we hold that regardless of status, each person has equal moral worth as the other; striking a balance would require the perspectives of all stakeholders and all things considered. But this is what social justice requires.
Data Protection, Confidentiality and the Return of Research Results
Our remaining ethical discussion will be brief. While it may be scientifically desirable to retain research subjects' personal information and attach that to any biological samples or specimens, e.g., for follow up or further study, this is risky for the research subjects. This is especially the case for cancer biomarkers, insofar as these data might fall into the wrong hands, resulting in harms to the research subjects. For example, it is possible that insurance companies or employers might unfairly discriminate against persons with certain cancer biomarkers: e.g., refuse cover to those deemed likely to develop certain cancer(s). This discrimination could occur whether these biomarkers are validated or not. Thus, any research participation and results must be protected and confidential.
On the other hand, individuals who participate in research might benefit if they learn their (well validated) biomarker status regarding the development of a cancer. If a validated biomarker shows that it is unlikely that an individual will develop a cancer, he/she might wish that an employer and a health or life insurance company knows, to seek better rates or other benefits. Also, some individuals might like to know if a cancer is likely based on a validated biomarker so that the individual could act in ways to reduce specific risks, an action that would not have been taken without the knowledge provided by a biomarker.
These concerns raise the question of whether research results should be returned to individuals who participate in research. (13,14) Doing this, of course, requires that individuals' data be identified and retained which, as explained above, poses risk for research subjects who might be harmed if their results were revealed. Setting aside that problem, however, we must keep in mind that to return research results to individual study participants requires a lot of resources. This may involve retaining contact with research subjects, individual meetings with subjects, explaining research results to them and often at a stage where the long-term significance of the results is unclear, especially if the biomarker is not yet validated, referring subjects to clinicians and genetic counselors, and so forth. Also, research assays are not performed using the same standards as clinical assays; hence, research results may be wrong and may not apply to all subpopulations.
While the desire to return research results to individual research subjects is noble, the practical difficulties and the amount of resources needed to do this makes it unfeasible in most cases. We not merely mean to say that this task would be difficult, but that the complications in doing this would result in such expenses that researchers simply could not afford the costs. That is to say that if it is required that they return research results to individuals in a responsible way, investigators may wonder whether they could afford to do the research in the first place. It is possible to argue that insofar as the research is morally justified, returning research results could typically prevent that research. (14) Thus, it is important to remind research subjects that they personally may not benefit from participating in research; we hope that others will benefit and that research participants might even be among that group, but there is no such guarantee in medical research.
In sum, we have reviewed a number of bioethical issues that are unique to cancer biomarker research. Our discussion is brief, and surely there are many other issues to discuss. We hope, however, that our efforts to frame the issues in terms of asking about the actual or likely benefits, harms, fairness or unfairness, and respectful or disrespectful treatment have been instructive and insightful. To seek justice on these issues, we suggest that the ethics of any aspect of biomarker research be evaluated from what philosopher John Rawls called "the veil of ignorance": if you didn't know who you were, would you be willing for this research to be done? Asking this question, and answering it from any individual's point of view, will help ensure that research be done ethically.
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