Ethical Aspects of Molecular Pathology

Drs. Kyle Conway, MD, JD and Dane Wuori, MD

Overview

Molecular diagnostics plays an increasingly prominent role in pathologic diagnosis. Ethical considerations are at play in each step of designing, implementing, and interpreting molecular testing, as well as translating this testing to clinical decision-making. Patients benefit from improved diagnostic accuracy and improved ability to identify personalized biomarkers that inform their treatment and prognosis. However, these tests carry risks to patients, including the risk of false positives or negatives, the possibility of incidental results, and the retention of genetic data that may be re-evaluated in the future or shared with other parties. These benefits and risks must be appropriately understood in the context of informed consent, a task that is complicated by the fact that the ordering pathologist typically does not interact with the patient. Finally, considerations of justice are driven by the increasing complexity and cost of diagnostic testing, which can result in unequal distribution of care and resources.

Learning Objectives

  • Apply principles of beneficence, non-maleficence, autonomy, and justice to the implementation and interpretation of molecular testing in a pathology laboratory

  • Differentiate the ethical considerations arising in germline molecular testing from those in tumor diagnostics

  • Design approaches for navigating common ethical situations that arise in molecular pathology

Part 1: Pre-activity Lecture

Review the following lecture, “Ethical Aspects of Molecular Pathology,” before proceeding to the case-based activity.

Part 2: Case-based Activity

Please review the following cases and try your best to answer the accompanying discussion questions.

  • A 49-year-old woman with a family history of lung, prostate, and ovarian cancer submits a DNA sample to a company that performs cancer susceptibility testing in addition to ancestry determination. She and her sister did so primarily to learn about their genetic ancestry together. They are asked to sign consent forms allowing the company to share de-identified data with other corporate and academic institutions. The form provides information about the risks and benefits of the testing, but a face-to-face interaction is not part of the discussion.

    Discussion Questions:

    • Do the sisters understand their risk for an inherited gene that causes cancer?

    • What should their informed consent process include?

    • Suppose their genetic testing identifies a gene associated with a predisposition to cancer. What factors should be weighed in considering the relevant benefits and risks to the sisters?

  • A 22 year-old man is diagnosed with a low-grade brain tumor. Extensive molecular testing, including a next generation sequencing (NGS) panel identifies only a mutation in the FGFR1 gene that is determined, based on a review of the literature and genetic databases to be a variant of uncertain significance (VUS). His tumor is considered benign, but classified as “not otherwise specified.” Four years later, his tumor recurs. Molecular testing performed at another institution identifies the same variant in the FGFR1 gene, which is now confirmed based on new studies to be pathogenic. The identification of this FGFR1 alteration is brought to your attention by the patient’s treating oncologist at your multidisciplinary tumor board. Identification allows more precise classification of the tumor; although treatment likely would have remained the same, classification as likely pathogenic renders the patient eligible for a clinical trial of targeted therapy.

    Discussion Questions:

    • What are the relevant appropriate procedures to have in place regarding reporting, storage, and re-review of molecular data?

    • What are the relative benefits and costs associated with re-reviewing previously reported molecular data?

    • Whose clinical responsibility is it to raise the issue of a potential change in the clinical significance of a previous molecular finding?

  • World Health Organization (WHO) criteria identify deletion of the CDKN2A gene as a biomarker that indicates poor prognosis in meningioma, a common form of brain tumor. You estimate that roughly 1-2% of tumors you test will harbor this alteration. The identification of this alteration carries significant prognostic implications, but treatment guidelines are not established. The WHO does not specify an assay for identifying this alteration, and your laboratory has tasked you with choosing the most appropriate procedure for interrogating it. Your options for testing include:

    (1) Immunohistochemistry (IHC) evaluating loss of a secondary protein as a proxy for CDKN2A deletion (low cost, low sensitivity)

    (2) Fluorescence in-situ hybridization (FISH) testing evaluating only for CDKN2A deletion (intermediate sensitivity and cost)

    (3) Chromosomal microarray (CMA) testing, which evaluates genome-wide chromosomal changes, including CDNK2A deletion (highest cost and highest sensitivity).

    Discussion Questions:

    • Which assay to you recommend for testing for CDNK2A/B deletion, and what factors are implicated in this decision?

    • How do considerations of patient autonomy influence this decision, and how do you incorporate these considerations?

    • How should you incorporate input from your colleagues in neuro-oncology, radiation oncology and neurosurgery?

Learner and Facilitator Materials:

Learner Worksheet (Link)

Facilitator Guide (Link)

Part 3: Post-activity Discussion

Case 1

  • Patients such as the sisters in this hypothetical could have a wide spectrum of understanding of their own pre-test probability of a meaningful positive result. They may have some understanding of their risk from the experience of others in their family, or if they themselves have some medical training. But the direct-to-consumer capabilities of this type of testing result in more patients receiving testing without a clear understanding of the risks and benefits to them.

    Given the complexities of this testing, even educated patients or patients with medical training may not fully understand their pre-test probability, the significance of a positive result, or the integrity of the result depending on the laboratory performing it.

  • The informed consent process should include a comprehensive discussion about the purpose and scope of the genetic testing, the potential risks and benefits, the possibility of incidental findings, data sharing practices, and the limitations of the test. This process ideally occurs through discussion with a physician ordering a test or a genetic counselor.

    In the setting of clinical medicine, simply providing a form with risks and benefits would typically not be considered adequate to obtain informed consent for such a complex test containing significant implications for the patient.

  • Identifying a gene associated with a predisposition to cancer could benefit the sisters in increasing their knowledge of their health status or by triggering increased screening or prophylactic treatment. This process is challenging to navigate without the guidance of a physician or genetic counselor. For example, it is critical to distinguish between common variants that have slightly increased risks to certain cancer compared with those that cause high-risk cancer predisposition syndromes.

    Without understanding the test parameters and interpretation methodology (e.g. variant calling), patients may not understand the risk of false positives. As a result, there could be potential risks of unnecessary anxiety or, in extreme cases, treatment or surveillance.

    Patients may also not fully understand the data sharing procedures, including the risk of genetic discrimination. In the United States, the Genetic Information Nondiscrimination Act of 2008 protects patients from some component of genetic discrimination, and genetic information cannot affect your eligibility for health insurance, insurance premiums, and other aspects of health insurance, but does not protect life insurance, long-term care, and disability insurance. Legal protections are variable among countries.

Case 2

  • At the time of diagnosis, there is no gold standard for the decision to call a variant as benign, pathogenic, or variants of uncertain significance (VUS). This decision should be made according to institutional and laboratory procedures, analysis of individual variants, and review of literature and databases.

    Systemic re-evaluation of VUSs is not feasible from a logistic or resource-allocation standpoint for most molecular pathology laboratories. It is important that a laboratory have defined procedures for when and under which circumstances previous variants will be re-reviewed.

  • In the setting of germline testing, literature has shown relatively high rates of change in status of a variant upon re-evaluation in the years after initial testing. Patients with suspected germline disease can significantly benefit from upgrading of a VUS to pathogenic (providing a definitive diagnosis) or downgrading (providing reassurance of their disease-free state).

    In molecular pathology, these considerations are less certain. For molecular diagnostics, the time frame is often shorter. It may be less beneficial, for example, to re-review a VUS for a targeted therapy for a disease that has an expected survival of only a few years. As discussed above, designing an appropriate bioinformatics pipeline for systemically re-reviewing non-diagnostic cases may be unfeasible in the setting of most molecular diagnostic laboratories.

  • Most commonly, this review will be initiated by a patient or clinician. For example, a patient may have pathology reviewed at another institution who re-interprets the VUS. A patient may also be re-reviewed at tumor board or an interdepartmental conference after a follow up appointment. This is an appropriate forum and allows full communication of all parties involved in the patient’s care.

    However, it is important to consider that well-informed, educated patients or patients with more strongly advocating treating physicians may be more likely to initiate re-review, raising considerations about justice in this process.

Case 3

  • While there is no specific correct answer to this question, the decision reflects that all test utilization decisions carry ethical considerations. These decisions are amplified in molecular pathology, which may involve complex tests performed at high volumes. The decision involves the relative weight of diagnostic certainty (beneficence) against cost (justice).

    As with many decisions in diagnostic medicine, the most important implications often occur at the margins. It may be very expensive to move from “good enough” certainty to “near certain” in a diagnosis. As hypothetical posed involves a test with a relatively low pretest probability, and a low-cost test with reduced sensitivity could be appropriate in such settings.

    Yet, such a decision will undoubtedly result in some number of missed diagnoses, which carry significant negative implications for those patients. Relative weights in terms of tests needed or dollars spent to detect a positive result can be calculated, but the relative weight of certainty against cost is imprecise.

  • Many current diagnostic pathology classification systems, including those employed in neuropathology and hematopathology, integrated molecular features of tumors into diagnostic classifications. Therefore, in many settings this testing is ordered by pathologists rather than clinicians. As pathologists typically do not have direct communication with patients, a conversation about informed consent is typically not possible. Nonetheless, it is critical that patients understand the risks and benefits of the test being performed.

    In addition to potential additional costs for a patient, it is important that patients understand the significance of this biomarker, what it means for their prognosis, and what it means for their therapy. They should understand risks of false positives and false negatives.

    Tests that evaluate only a single gene are less likely to identify incidental genetic findings, a factor that can also play a role in the decision of which assay to be performed. Patients should be made aware that this testing may be performed prior to surgery. Communication with treating physicians at interdisciplinary conferences, setting of institutional testing guidelines, and larger scale testing guidelines are options for providing treating physicians with the necessary information to appropriately provide informed consent from patients.

  • In addition to ensuring an appropriate venue for informed consent, treating physicians may play a role in test utilization decisions to ensure an appropriate balance of cost and benefit. While pathologists are ultimately responsible for a final diagnosis, it is important to understand how the treating teams may use the diagnostic information provided by this biomarker in counseling patients or altering management.