Is molecular AP testing in sync with guidelines?

“I was surprised. I thought the strict adherence numbers were rather modest,” says coauthor Keith Volmar, MD, a pathologist at Rex Hospital in Raleigh, NC, and a member of the Quality Practices Committee. “I think that’s relatively low.” But as he and his coauthors confirmed, there are several reasons why strict adherence to guidelines may be difficult.

The study was small but important, says coauthor Raouf Nakhleh, MD, professor of pathology at Mayo Clinic in Jacksonville, Fla., and former chair of the Quality Practices Committee. “The study’s origins actually go back to HER2. With discovery of that oncogene, researchers discovered that tumors with amplification [FISH] or overexpression [IHC] respond to Herceptin.”

“Now a lot of tumors are being tested for gene mutations to be targeted by drugs, and we’re able to predict a therapy or prognosis for certain tumors based on the expression of these molecular markers. There are recommendations for what you should be testing, and we want to see if pathologists are meeting this challenge.”

The NCCN recommendations aren’t the only ones that have been developed. “These recommendations are always in evolution,” and the CAP, in cooperation with other organizations, is putting out its own recommendations, Dr. Nakhleh says. Already published is the CAP/IASLC/AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. In development is a CAP/ASCP/AMP guideline on the use of molecular markers in evaluating colorectal cancer.

The retrospective data collection (26 laboratories, 1,508 molecular tests) of this study was for tests on lung and colorectal carcinomas and melanoma. “We chose those three sites because they are three commonly tested sites, with testing relatively well established. The retrospective approach allowed us to acquire data on turnaround time and specimen adequacy, in addition to adherence to guidelines of the NCCN,” Dr. Volmar says.

With only retrospective data, however, the authors thought they might be missing out on test requests that were never carried out. “That’s why we wanted to do the prospective part of the data collection. We not only collected requests for lung, colon, and skin cancer, but also opened it up to other organ sites in order to get an idea of the breadth of testing out there.” The prospective study included 23 participating laboratories reporting on 722 molecular test requests.

The authors decided to exclude certain testing from the study to make the data set more manageable and the results more informative. “Testing on breast cancers, HPV testing on Pap tests, and molecular testing on hematolymphoid lesions would dwarf all the other molecular testing just in terms of volume,” Dr. Volmar says. So those cancer sites were excluded.

In designing the study, the authors also opted to include “loose adherence” as a descriptor, in part because there are NCCN guidelines for only some tests. “For others, there are non-NCCN guidelines from AMP, CAP, and IASLC, and those are practice guidelines,” Dr. Idowu says. “So we have ‘loose’ adherence not because someone is not adhering to a guideline, but because there is leeway in how the guideline is supposed to be used.”

For example, with lung cancer, the NCCN recommendation is to use targeted treatment (and by extension molecular testing [EGFR and EML4-ALK]) for locally advanced or metastatic disease. “Strict adherence to NCCN guidelines would require performing the test only on stage III and IV lung adenocarcinoma. However, the CAP/IASLC/AMP guideline, while acknowledging NCCN guidelines, indicated that it is acceptable to perform the test for early stage carcinoma,” Dr. Idowu says. “This perhaps highlights some leeway in adherence to guidelines.”

“If you look at the NCCN guidelines for lung cancer,” Dr. Volmar says, “some things are spelled out right within the guideline that you might say are a ‘fork in the road’ for the patient’s treatment.” For example, there is wide agreement for when EGFR and ALK tests are indicated, he says.

“On the other hand, there are things that are in the fine print—for example, at the time of this data collection, ROS1 was a ‘consideration’ for patients known to be ALK negative. Requesting that test would be considered ‘loosely in the guidelines’ because most people would say it’s probably legitimate to do, even though it’s not a true fork in the road in the patient’s treatment.”

Because many practices have become common while evolving outside of the guideline, such gray areas came up often as the authors were confronted with the data. “So we had to find some way to deal with that issue,” Dr. Volmar says.

In some cases, there are no guidelines. In other cases, a particular test is not in a guideline but it’s commonplace to perform it and it does make sense to do so. One example: performing a KRAS test on a lung cancer patient. “If you were doing a sequential testing approach, you might do a KRAS first because if it’s mutated, you can stop doing the other testing. That kind of makes sense, even though it’s not in the guide-
line.”

Dr. Volmar was more surprised that the study revealed a considerable range of adherence to the guidelines when different institutions were compared. In the top tenth percentile of laboratories in the prospective study, which included all case types, 70.5 percent of cases strictly met the guidelines, while the bottom tenth strictly adhered to guidelines only 20 percent of the time.

But within that range of performance, a key finding of the study was that testing on lung specimens did have the best record of strict guideline adherence. “I think that can be ascribed to better education and better dissemination of information regarding those guidelines. So that can act as an example for other organ sites,” Dr. Volmar says.

Dr. Nakhleh found the modest rate of strict adherence to guidelines in this Q‑Probes study pretty much as he expected. “When you put out a guideline, you would like 100 percent adherence, but it takes a little while to get adoption.”

The CAP/IASLC/AMP lung cancer guideline has been available only since spring 2013, he notes. “And it’s actually not a lot of time that we’ve been talking about these molecular markers. Adoption is going to be slow. It takes awhile for everything to catch up. Even with the guidelines, you get situations where there’s not a clear-cut yes or no, so you’re going to end up with a bit of a gray zone.”

For the female genital and brain and spinal cord tumor sites, the prospective study found no strict adherence. That was because no guidelines have been developed. For cases involving the female genital tract (excluding cervical cancer), for example, “there is one type of test we do routinely and that’s for microsatellite instability,” Dr. Nakhleh says.

“It’s very similar to a test done in the lower gastrointestinal tract, and it’s the same test we do in endometrial cancers. But there aren’t any other established molecular tests that our guidelines say will indicate treatment.” Similarly, in cancer of the brain and spinal cord, “there’s only a relatively rare tumor that has a specific test that can be done, so there’s also a lack of specific guide-
lines.”

Another guideline gap: Lynch syndrome in colorectal carcinoma. Of the Q-Probes findings, Dr. Volmar says: “It appears that the testing is widely variable in terms of what is performed and which patients get testing. We need a guideline of some sort on that.”

It’s just another instance of the importance of awareness, he adds. “We know a small percentage of patients have this syndrome that predisposes them to cancer, not just of the colon but other sites. And more and more often, clinicians want the patients tested. But it’s a considerable cost, and there’s no agreement on who should get the testing done, or for that matter how the testing should be done.”

The NCCN has tried to rein in Lynch syndrome testing, but there is conflicting advice in the field, he says. “There are working groups recommending that the testing be done on everyone. But others say only if the patient is under 50, or there’s the Amsterdam criteria or the Bethesda criteria. So probably part of the problem is there are too many groups involved right now. We need one to become the standard,” Dr. Volmar says.

Fifty-two percent of participating laboratories require pathology department approval of the molecular tests ordered on solid tumors. “I think most pathology departments are reluctant to try to tell clinicians what to do, even with guidelines,” Dr. Volmar says, despite the high cost of such testing. “Pathologists are a little more aggressive with the tests that are outrageously expensive.”

Of those laboratories that do require approval, 92 percent do so for send-out tests, 67 percent for molecular tests on inpatients, and 58 percent for proprietary molecular tests.

Rex Hospital tries to make use of nurse navigators to assemble various patient factors before some molecular tests are performed. “We don’t just ‘carte blanche’ do all the testing that is ordered. Inevitably there will be patients who the oncologist already knows don’t want to be treated, or who may have various other factors such as comorbidities” that rule out more treatment.

Asked who typically manages such orders, 43.5 percent of labs responded “any available pathologist,” and 17.4 percent said it was specifically designated pathologists. Another 17.4 percent said it was non-MD, non-PhD personnel.

One of Dr. Volmar’s particular interests is the Medicare 14-day rule, which states that if a Medicare patient is a hospital inpatient or hospital outpatient, the laboratory has to wait 14 days after discharge to perform this testing for Medicare to pay for it. The Q‑Probes study found that consideration of the 14-day rule for Medicare patients is inconsistent. “Quite a few labs disregard this rule and just do the testing,” he says.
Fifty-five percent of laboratories ignore the rule and perform the test at the time of request, but only 41 percent ignore the rule when send-out testing is involved.

For Dr. Idowu, another study finding stood out. “I find it encouraging that pathologists are involved in block/slide selection for molecular testing 100 percent of the time. Determining the adequacy of tumor sample for testing is critical. Selecting blocks/slides where the tumor is perhaps diluted by benign epithelium or inflammatory cells might lead to a false-negative result.” CAP laboratory accreditation checklist MOL.32395 requires a pathologist to be involved in the process.

For the data reported by labs in the study, the median turnaround time from test request to completion was eight days, which meets the 10-day goal recommended in the CAP/IASLC/AMP lung testing guideline. Most laboratories in the study (78 percent) did not report having a written policy for turnaround time goals for molecular testing on solid tumors.

That finding is to be expected, Dr. Nakhleh notes. “For this type of testing, most of the time it’s not critical to get it done in a week. Usually the person has to recover from surgery before they need to go on to the next stage of therapy, especially if the treatment involves chemotherapy or radiation.”

Pathologists continue to be challenged to accomplish increasingly more with less material. Both the retrospective and prospective data collections found that a minority of the tested specimens were excisions—42 percent in the prospective study and 33 percent in the retrospective study.

This can create problems, Dr. Nakh­leh says. “Typically you would get a fine-needle aspiration specimen on a lung mass. It’s just a very small amount of tissue. So we’re hoping to produce a guideline that addresses the best way to deal with small specimens. But it’s always a tricky proposition to set up a test on tiny tissues.”

There may be a need for more training on what is an adequate specimen, Dr. Idowu says. “These days, with improved molecular technology, a small number of tumor cells may in fact be adequate for testing, as long as the test validation takes this into account.” But he believes it’s important for pathologists to correctly determine when to use microdissection to enrich the percentage of tumor cells, and when to say this sample is inadequate or suboptimal for testing.

The study found that 65 percent of laboratories routinely incorporate molecular testing into a comprehensive anatomic pathology report. “This can be improved, because having all the results in one report not only minimizes the valuable time that might be spent by the treating physician looking for a test result, integrating the results in a report is good practice,” Dr. Idowu says. Sixty-seven percent of the labs routinely add correlative information about the significance of molecular test results.

Fifty-seven percent of participating labs routinely initiate reflex molecular testing on solid tumors, and only 39 percent require a standing order for it. The most common reflex tests performed routinely are MMR-IHC for colon cancers, ALK and EGFR for lung cancers with appropriate histology, and KRAS for colon with appropriate histology.

The Q‑Probes study found, not surprisingly, that larger laboratories are more likely to perform molecular testing in-house. “The problem is the volume,” Dr. Idowu says. “For most small labs, it may be more cost-effective to send the test to a reference laboratory than to run it in-house.”

It costs a substantial amount of money to establish a molecular lab and to get it running, Dr. Nakhleh notes. “There is a big investment and an expectation in the public that these tests will be done when appropriate.” Molecular testing labs are being established in increasing numbers, he adds, but not all laboratories want or can have that luxury.

He was involved in a study that looked at two surveys of laboratories performing HER2 testing, three years apart. “We found over time that some labs actually decided it was more optimal for them to send the test out” than to do the full procedure. “About 25 percent of labs will send slides elsewhere for somebody to do HER2 staining, then get them back and interpret them in-house.”

One other factor should be taken into account in interpreting the results of this study, Dr. Idowu cautions: The study is addressing single-gene testing. “An increasing number of laboratories are using next-generation sequencing, which looks at multiple genes using the same sample, some of which may not be directly addressed in the guidelines. So the definition of strict adherence, loose adherence, and non-adherence to guidelines may need to be redefined if we include next-generation sequencing.”

As a sign of how quickly things are changing in molecular testing, the CAP is already planning to update its 2013 lung cancer guideline. But much work remains to ensure that molecular testing in AP follows the guidelines, Dr. Nakhleh says.

“This particular study shows that anatomic pathologists are trying very hard to meet the guidelines for molecular testing that are known and available,” he says. “I think a lot more clarity is needed in the guidelines. Better guidelines should be developed and modified over time, and that’s what CAP is aiming to do. It’s a long road and we’re just starting on this molecular path.”
[hr]

Anne Paxton is a writer in Seattle.