NEW YORK (Precision Oncology News) – As the practice of precision oncology advances among oncologists, new pressures have also emerged across the medical ecosystem, including in the pathology lab where technicians are seeing dramatic changes to the types and depth of analyses they perform on a routine basis.
The growth in next-generation sequencing and the launch of more basket and umbrella trials in precision oncology is blurring the once-clear demarcations between research and patient care, and in turn putting logistical and ethical pressures on pathologists about the best use of patient samples. Some of these challenges may be eased by technological advancements, but others may require the goals of research and treatment to be better aligned from the outset by involving pathologists in trial planning and better informing patients, said experts in the field.
Authors of a commentary published in JCO Precision Oncology earlier this year described competing pressures to prioritize limited tissue samples in a way that optimizes patients' interests but also supports new research paradigms searching for signals of treatment efficacy in molecularly defined patient subsets.
"As representatives of our hospitals and specialty, we want to be helpful collaborators in providing the diagnostic tissues necessary for the care of oncology patients. And as patient advocates, because of our legal role as custodians of these tissues, many of us harbor serious concerns about the current informed consent processes and standard practices for tissue handling during clinical trials and translational research," Duke University pathologist Shannon McCall and UCLA's Sarah Dry wrote in their editorial.
According to McCall and Dry, the environment of multiplying basket trials and targeted therapies creates "a difficult choice for pathologists," wherein traditional guidelines regarding the stewardship of tissue, limitations of informed consent, and lofty research goals butt up against one another.
One factor at play is a very simple issue: supply and demand. "More biologic information can be extracted from tissues than ever before, but there is less tissue available for testing," the two wrote.
Massimo Loda, chair of the department of pathology and laboratory medicine at Weill Cornell, agreed that this is a fundamental challenge for the field. "There is less and less tissue and more and more requirements," he said in an interview.
Christopher Moskaluk, a professor and practicing pathologist at the University of Virginia Health System, finds it remarkable that the multiple IHC stains, FISH procedures, and molecular tests now becoming standard of care are even possible for the majority of cancer patients. "In a recent survey at our institution, fully 27 percent of cases failed to have enough DNA for next-generation sequencing gene panel analysis," he added over email, with almost all being from needle core biopsies of cell blocks with limited cancer tissue.
According to McCall, there is reason to be optimistic, though. A variety of technological advances are poised to at least help ease things on this front. For one, the steady shift away from single biomarker testing and toward next-generation sequencing has meant that more patients have information on multiple biomarkers at once, reducing the need for additional analyses that might exhaust their analyzable tumor tissue.
"We are already seeing this happen in lots of areas," she said. However, the translation is not perfect. For point mutations "it carries over directly," but for some others — analysis of microsatellite instability, for example — sequencing can't take the place of other tests, at least not quite yet.
That said, the potential of panels to replace the larger landscape of older, single-marker tests "is very promising," McCall said. "We are seeing that you can get MSI reads from sequence data, even from cell-free DNA," she added.
Such liquid biopsy techniques, which allow the measurement of tumor mutations from blood or other body fluid samples, may also soon offer a way that trial sponsors, or clinicians, can re-interrogate a patient's cancer genome without using up scarce tissue or requiring a new biopsy.
Pathologists, themselves, are also innovating to try to address practical and technological bottlenecks. McCall cited new techniques for optimizing the examination of paraffin tissue blocks by keeping them mounted on a microtome while the pathologist reviews slides. In this way, if additional slides are needed, they can be sliced off immediately without the waste of the refacing process.
Labs are also trying to anticipate additional sample requests by separating multiple biopsy cores into individual paraffin blocks, McCall and Dry wrote.
Moskaluk said that he and his colleagues "often get creative" in responding to demands for tissue from precision oncology clinical trials. "We have in the past provided tissue microarray cores or portions of the tissue cut out of the clinical paraffin block and re-embeded in a second paraffin block to submit to the study sponsors," he wrote in his email.
But, according to McCall and others in the field, technology is not the only issue at play. In their commentary piece, McCall and Dry cite systemic and regulatory requirements that they argue also create roadblocks for the precision oncology-minded pathologist.
For one, pathologists are governed by guidelines in clinical practice that can conflict with the eligibility demands of clinical trials. For example, labs certified under the Clinical Laboratory Improvement Amendments and by laboratory-accrediting bodies such as the College of American Pathologists, must store archival paraffin tissues in a retrievable manner for defined time periods, some up to 10 years.
"It is not uncommon for a pathologist to examine a block of tissue and realize that submitting the material desired by one clinical trial will completely exhaust the remaining biopsy sample," McCall and Dry wrote. "If pathologists fulfill this request, they will violate federal regulations, state laws, and accrediting agency requirements. If they refuse to fulfill the request, the patient will not qualify for the study, which will upset the patient and oncologist and will deny the patient a therapy with the potential to extend their survival and/or improve their quality of life."
Moskaluk also attested that for many patients following clinical diagnostic procedures, there simply is insufficient tissue to fulfill study requirements, often requiring r an additional biopsy of the patient. "In some circumstances, the clinical trial request would exhaust the tissue on hand, and in some instances the request to provide a paraffin block for correlative studies would deplete all residual diagnostic tissue, which in our opinion runs against the CAP/CLIA requirements for specimen retention," he wrote in an email.
This catch-22 presents both ethical and practical concerns, which some of the great achievements of precision oncology only magnify, McCall added. As new drugs with new molecular targets are entering the market ever more rapidly, exhausting tissue to try to enroll a patient in a study may mean that the patient is left without material to receive a newly approved biomarker-driven treatment.
"Will there be enough tissue for all these requests?," McCall and Dry asked in their editorial. "When desperate patients are being consented for clinical trials, do they understand the risks of tissue exhaustion, that they may not be eligible to enroll in subsequent trials, or that they may have to undergo another invasive biopsy procedure?"
Among suggestions to try to bring the requirements of pathology and the advancement of genomic medicine into better harmony with one another, McCall and Dry wrote that at the very least, there should be modernization of regulatory requirements to explicitly authorize pathologists to exhaust tissue if required for clinical trial enrollment.
"There is a growing sense that a biomarker test to gain access to a clinical trial is equivalent to standard of care, so if doing such a test exhausts tissue, so be it," she said.
McCall and Dry also raised the possibility of tweaking trial consent procedures to disclose more clearly the potential for tissue exhaustion, as well as better differentiation of what analyses are truly required for enrollment in a molecularly driven trial versus what trial sponsors want for "correlative science."
"Consents can be 50 pages long … so I'm not sure what all we could add that would be understood," McCall said. But, where documents now typically say only that a trial will "ask the lab for leftover tissue and study it," a better version might add something like "this might use all the tissue you have left, so if you need more testing in the future you might have to have another biopsy," she suggested.
There should also be a way, McCall argued, for regulators, trial sponsors, oncologists, and pathologists to come together to make sure tissue is being prioritized appropriately, and that the goals of treatment, research, and of tissue stewardship are better aligned.
Weill Cornell's Loda said that he views this need for better shared decision making in the trial design process, as a central issue for the field.
"When clinical trials are designed, pathologists are never involved," he said. "The institutional review board passes the trials and then [we’re told,] 'Oh, by the way we need all these biomarker [tests] done,' and it can't be done because there isn't enough tissue to send out and to preserve for future testing."
"If you know you need tissue, and [you need it] processed in a certain way, you should have pathologists weigh in early in the design of the trial," he argued.
McCall agreed that bringing pathologists into this process earlier could help. "I was actually just consulted by a pharmaceutical company in the design of a lab manual for one of their trials, and that’s the first time I'd ever been approached to do work like that," she said.
Trial sponsors have their own internal pathologists, "but there could be a disconnect there," McCall said. "They may not be necessarily thinking from the perspective of the pathologist at a healthcare institution."
Beyond tissue stewardship issues, the pathology field is struggling with other growing pains. Depending on the disease area, the growth of precision medicine and how that requires pathology to evolve is happening at faster or slower rates.
In hematopathology, for example, McCall said, the incorporation of molecular testing has happened steadily and comprehensively over more than a decade. That has meant that the practice of pathology for these patients is practically all molecular pathology. "Pathologists became ingrained in molecular workflows," she said. In contrast, for solid tumors, pathologists may have little knowledge of what comes next for patients after they have sent out the samples.
New pathologists in training are coming into the field with much more molecular literacy, she acknowledged, but there definitely may be a shortage for mid-career folks who are willing to learn. Although we are not quite there yet, in the near future, Loda predicted, it's likely that all pathologists are going to need to be certified in molecular methods.
A final issue, McCall said, is that the evolution of genetic testing is beginning to challenge some of the established structures that separate and define the role of the pathologists in the healthcare system.
In certain fields, like neuropathology, for example, molecular information is now a necessary aspect of diagnosis, she said. But these markers are increasingly being profiled as part of broad NGS tests, allowing for a diagnostic readout alongside other markers of therapeutic sensitivity or prognosis, and in the process potentially negating the need for a pathologist's expertise.