Gastric HER2, hsALK to join monitored PT list

Monitoring comes with additional requirements for the laboratory, Dr. Meserve says, and that’s why the CAP has compiled an extensive FAQ resource to accompany the new monitoring status. The first frequently asked question is one of the most pertinent: How laboratories should conduct validation and verification. “The issue there is that if labs are already running these assays in-house, they may want to consider increasing the validation documentation to meet the standards set forth in CAP Center guidelines,” Dr. Meserve explains. “If the lab is not currently performing these assays, then they will have to be prepared to meet those requirements.” And, she notes, large validation cohorts are a big ask in certain situations when a positive result is an uncommon event.

The addition of requirements associated with monitoring status may affect whether laboratories perform an assay in-house. Dr. Meserve’s primary institution, Maine Medical Center, is the largest medical center in Maine, but Maine is a state with a relatively small population. “We do not run highly sensitive ALK in-house here because we have not historically had the testing volume to justify validating this IHC assay. If now, due to monitoring status, the case requirements for validation were to increase, we likely could not meet that requirement locally.” Other laboratories may decide the new monitored status is reason to start using a reference laboratory for these biomarker tests.

Those factors have helped make “When to retire an assay from a test menu” one of the FAQs. “The fun part of IHC for most laboratory directors is validating new assays,” Dr. Meserve says. “It helps keep your lab current, and if there’s a new marker out that can help us make new diagnoses, we want to experiment with it. We want to learn from it. But if an antibody’s diagnostic utility has decreased over time, and other research suggests it is not as specific as hoped when it first came out, then laboratory administrators may suggest retiring it if we order it only a few times a year or if it’s become less useful—or both. It’s just as important to be sensitive to the bandwidth of your laboratory as it is to be bringing on new tests all the time.”

The FAQ document is an attempt to say something helpful but not laboratory-specific about how laboratories performing IHC could approach technical issues, Dr. Meserve says. The list of questions was compiled from Surveys participants’ more challenging questions.

A large number of the other questions address what to do if the laboratory has an unacceptable response on a proficiency test. “Those questions are perhaps the most important of the FAQs,” Dr. Bellizzi says.

An unacceptable response, says Dr. Meserve, “means they got one tumor core wrong out of—almost always—10 tumor cores. So they’re 90 percent correct. Eighty percent is the passing threshold for most assays, except for the monitored ones, which is higher. There are many reasons why a laboratory may have one unacceptable response. And not all of them are going to require changing the assay.”

“In contrast, if a lab were wrong on four cores out of 10, you definitely need to do something,” starting with an investigation, she says. Any concern about the performance of an assay in the laboratory should trigger at minimum an informal process improvement assessment (PIA) to determine the cause and triage the problem appropriately, the FAQs note.

The FAQ document outlines the “8D” approach to process improvement, similar to the steps included in Lean/Six Sigma process improvement, through which a team can conduct root cause analysis; devise, implement, and validate permanent corrective action; and prevent recurrence. Included in the FAQs are specific steps following a hypothetical “unacceptable” response on proficiency testing for ER, PgR, ALK, BRAF V600E, and KIT when corrective action is needed.

Action may not be needed in every case. But, as a laboratory director, Dr. Meserve says, “My job in the lab, if we do nothing, is to be able to defend a decision to do nothing. I may make a professional judgment that nothing was the appropriate course of action, and I think that’s hard for some people to sit with. They want to do something. In my opinion, the ‘something’ is the investigation and there may not be a necessary corrective action.”

Nevertheless, with the FAQ document, “We’re trying to make the point that if you have even one unacceptable response, you should take a look at the data,” she says. “What sometimes happens is you have one that’s clearly unacceptable but you have three that are in the borderline range and six that are clearly acceptable. And if there is a trend toward being in this unacceptable category, I would argue you need to look into this. This is your bellwether. This is the canary in the coal mine. I think that’s helpful for laboratory directors, and they should investigate that. Otherwise, they might complete the same Survey again and completely fail, because all three of those borderlines will have transferred to the unacceptable category if there’s drift.”

What assays might be next in line to become monitored? In Dr. Meserve’s view, “It would have to be a predictive marker, something used to drive decisions about therapy for patients. So I think it would be HER2 in other organ systems—certain gynecologic malignancies, lung cancer, sometimes colon cancer. Those three organ systems might have their own criteria, different from breast cancer, for determining positivity. Monitoring of that, even though it’s the same analyte in different organ systems, could be very relevant if the assays are being used to decide treatment, and especially when the thresholds for interpreting them as positive or equivocal or negative are different.”

For the time being, laboratories should do a few things to prepare for the new PT requirements, Dr. Meserve says. “Number one is to generally become aware of the new requirements. Number two would be to subscribe to the now-required proficiency tests. The window just opened for subscriptions for next year. So if people want to participate in the first round of highly sensitive ALK lung testing next year, they have to start enrolling now.” Number three would be to pay attention to other guidance documents, in particular the frequently asked questions. “Lab directors like me,” she says, “should be trending rates of positivity in gastric HER2 results as well.”

When the updated guideline “Principles of Analytic Validation of Immunohistochemical Assays” is released next year, “we’ll need to edit the FAQs to reference that document,” Dr. Meserve says. “In some ways the FAQs are kind of an interim product until that happens.”

But the process improvement assessment component of the FAQs is not likely to be addressed in the guideline. So that section of the FAQs will continue to provide important guidance to laboratories in maintaining quality of testing of these biomarkers, she says.

“Laboratories have many other resources to use for quality improvement, and the FAQ document is just another opportunity, an attempt to consolidate the opinions and knowledge base of the committee into an accessible, somewhat informal document.”

That document, and the new requirements for monitoring gastric HER2 and highly sensitive ALK in NSCLC, are each meant, she says, to be a tool in the laboratory director’s quality toolbox.

Anne Paxton is a writer and attorney in Seattle.