Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials

In their article “Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials,” Makhlouf et al¹ summarize a multidisciplinary meeting of stakeholders at which the important topic of archival tissue submission for clinical trial enrollment was discussed. They provide a final summary of “Workshop Recommendations” highlighting several areas in which there is broad consensus among oncologists, pathologists, and researchers. These include the prioritization of tissue submission for clinical trials being second only to clinical care (because of the potential impact of clinical trials on patient management), the existence of pathologists as custodians of archival tissue on behalf of patients, the need for improvements in informed consent, the need for improved communication among stakeholder groups, and the need for transparency in the relevant policies that exist across clinical trial biobanks and pathology departments.

The authors cite a 2011 College of American Pathologists’ survey regarding block submission for clinical trials.² Considering the most challenging situation (when diagnostic findings are limited to a single block), more than 80% of survey respondents indicated they would not release that block to a trial sponsor, with most preferring to send an alternative, such as unstained slides, which would not deplete the remaining diagnostic material at the health care institution.² In their introduction, the authors indicate that while pathologists are attuned to clinical trial demands, they may stop short of sending entire clinical blocks out due to medicolegal concerns that “blocks may be lost, exhausted, or destroyed in the course of their use in research studies, and unavailable if needed for future patient care.” ¹ In fact, the pathologist does have legitimate medicolegal concerns about depleting the remaining diagnostic tissue, but it would be more appropriate to describe the concerns as both medical and legal. The nature of a pathologist’s work results in interactions with patients’ stored tissue at multiple time points and for multiple different reasons. Considering a single surgical pathology case, the pathologist may be called upon to (1) analyze the sample for primary diagnosis, (2) assess biomarker status of the sample, (3) provide material for specialized clinical molecular diagnostic assays, (4) provide material to a referral center at the request of the patient for consultation/second opinion, (5) provide material to a new health care center at the request of the patient who wishes to transfer his or her care, (6) provide material for clinical trial enrollment (often more than once on the same patient sample), (7) provide material to family members wishing to investigate the presence of hereditary cancer predisposition syndromes, and (8) infrequently provide material to the patient’s legal representative in the case of a medical malpractice investigation. The reluctance of pathologists to deplete remaining diagnostic tissue for a single clinical trial request (even in the face of patient consent) may be interpreted as paternalistic and undermining to patient autonomy, but how many informed consent documents for clinical trials contain sufficient language to educate patients about all of the above risks of tissue depletion? Pathologists, as custodians of tissue, may elect beneficence as their dominant ethical principle because of concerns about the incomplete informed consent process. Pathologists almost certainly have a “longer-term” perspective of all the potential future uses of the patient’s tissue. Importantly, pathologists understand the first clinical trial may not be successful for the patient, whereas a patient may not recognize this.³ Pathologists understand that further along in their disease process, patients may wish to enroll on subsequent clinical trials or may become eligible for targeted treatments newly approved by the US Food and Drug Administration that require biomarker testing.

Patients should be fully informed during the consent process that submission of an entire block of tissue (or significant numbers of unstained sections) may completely exhaust their remaining sample. They must be educated about the important options they could be losing (including sending material to a subsequent clinical trial sponsor if the current clinical trial does not work for them, sending material for second opinions or transfer of care, having material available for clinical testing for newly approved therapies). In addition, patients should be fully informed that only a small amount of material is highly relevant to the current clinical trial (integral/integrated biomarkers) and that additional material is being requested to be stored for future, unnamed correlative science. To increase patient autonomy, consent to send (for example) four freshly cut unstained sections for integral/integrated biomarkers could be required for clinical trial participation, but consent to send the entire paraffin block for future correlative science could be presented to the patient as optional.

Another potential solution is for the research group to hold their “correlative science” tissue requests for a later time point when or if they are needed. In other words, the clinical trial sponsor could immediately request the material that will be needed for integral/integrated biomarker analysis, but the biobank could maintain a “virtual collection” of samples that can be requested from pathology departments for future correlative science. At that future time point, the pathology department could provide freshly cut slides from the paraffin block. This approach would support patient welfare; ensure compliance with federal, state, and accrediting body requirements; and ensure optimal material is provided for research.

The authors suggest the creation of a trusted entity agreement between biobanks and pathology departments.¹ This is a thoughtful and creative potential solution. To be effective for pathologists, this solution would require formal recognition by the Centers for Medicare & Medicaid Services, as this is the federal agency responsible for the enforcement of relevant US law and state legislatures when state-specific tissue retention policies apply. To maximize beneficence, trusted entity agreements should be accompanied by a transparent policy stating that the patient’s block would be returned to the institution not only to facilitate ongoing clinical care but also to facilitate integral or integrated biomarker analysis on a subsequent clinical trial even if the subsequent clinical trial is facilitated by a different governmental agency or a private-sector group.

The authors declare, with a suitable number of references, the consensus that glass slides that have undergone long-term storage are inferior to freshly cut slides from paraffin blocks as a source of material for biomarker analysis.¹ However, the authors discount the use of large reembedded tissue cores as suboptimal without any supporting data. The references that support antigenicity loss on stored glass slides were performed using either stored glass slides from individual tumor blocks or from tissue microarray blocks. Tissue microarray blocks are created by pathologists to support translational research by combining 0.6- to 1.5-mm cores of tumor from many separate patient donors into a recipient paraffin block using a grid template. Review of the references suggests the antigenicity loss is correlated with storage of the slide preparations and not correlated with the cored tissue microarray preparations themselves. None of the cited references specifically addresses the use of large cores of tumor tissue that are reembedded into a recipient paraffin block for clinical trial submission. Manually extracting 3-, 4-, or 5-mm cores of tumor tissue from an original large diagnostic block and reembedding them into a new paraffin block is a creative approach taken by some pathology departments that solves many problems. It allows the original diagnostic block to be maintained at the original institution. It provides the clinical trial biobank with a large sample stored in a way that supports long-term banking and downstream use. It solves the problems of more expensive preparation and shipping of glass slides. Regarding scientific utility, such large-diameter cores have low “edge” to “center” ratios, meaning the main portion of the core is at less risk of oxidation or thermal exposure and likely remains stably infused with paraffin during the transfer. Submission of newly created paraffin blocks containing 3-, 4-, or 5-mm cores of tumor tissue is a promising solution. Additional biospecimen-based research is needed to determine whether unforeseen adverse effects exist from this type of preparation.

Pathologists want to support research and recognize their responsibility to provide appropriate material in support of research. This is supported by the College of American Pathologists’ public policy statement on “Informed Consent for the Donation, Use and Disposition of Human Tissue for Non-Diagnostic Purposes,” which states that “the responsibility to maintain diagnostic material also includes providing appropriate material for institutionally approved research.” ⁴ As more and more limited samples are being requested for more and more diagnostic and research purposes, pathologists, legislatures, oncologists, clinical trial sponsors, and translational investigators should continue this important discourse to identify and implement solutions that maximize patient welfare and autonomy while supporting the successful completion of clinical trials and the advancement of general biomedical research.

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