New guidance on lung cancer testing

Not all parts of the guideline were created equal. In some areas there simply wasn’t enough evidence in the literature to draw a firm conclusion. In those cases, the authors used the expert opinion consensus.

Turnaround times
Determining the desirable, acceptable, and absolute limits for TATs was nearly impossible based on evidence. Says oncologist David Kwiatkowski, MD, PhD, another guideline author, “You can’t find a publication where they did a randomized trial between getting results back in a week and the results back in two months, and then showing an outcome difference.” The two-week (10 working days) recommendation in the guideline was a judgment call, says Dr. Kwiatkowski, professor of medicine, Harvard Medical School, and senior physician, Brigham & Women’s Hospital and Dana-Farber Cancer Institute.

Given a choice, “Every oncologist would like to have molecular results as quickly as the standard diagnosis,” says Dr. Kwiatkowski, who then laughs. “I know that’s not practical—it’s impossible.” What might be possible—it’s happened at his institution, he says—is for pathologists to speed up the most common findings, with the acknowledgement that the more thorough workup will take more time.

At larger institutions with an energetic, in-house molecular diagnostics laboratory, reflex testing may be the norm. At most hospitals, however, the oncologist makes the decision to pursue molecular testing. That adds to turnaround times. So does sending out specimens. Speed is also a function of workload as well as testing methodology.

It’s possible the guideline will spark discussions about reflex testing at institutions where it’s not the norm. At the very least, says Dr. Cagle, pathologists will need to talk with their oncologist colleagues about how to expedite in-house testing protocols.

“That’s actually a complicated relationship,” says Dr. Kwiatkowski. Reflex testing isn’t cheap, “and it isn’t clear that in every case you need to have everything done. And in some cases you may want a little more done.”

That’s why communication is so important, he continues. If a patient is young, for example, or has a poorly differentiated lung cancer, he’ll discuss with his pathologists whether to perform additional tests. Pathologists may be thinking along the same lines, he says. “But communication is always helpful, to make sure things aren’t misinterpreted or overlooked.”

Immunohistochemistry
One of the more intriguing notions, already mentioned, is the suggestion that IHC markers may gain traction in ALK testing.

“ALK immunohistochemistry is very promising,” says Dr. Cagle. Since the ALK translocation detected by FISH analysis leads to higher expression of the ALK protein, ALK IHC should strongly correlate with ALK FISH as an independent predictor of outcome. However, that’s not yet been shown in a clinical trial.

Next-generation sequencing
The guideline is noticeably silent on this topic, but its authors aren’t.

“We got a lot of questions about this throughout, and even in our editorial review,” says Dr. Lindeman. “It’s here, and it will grow.” It’s simply too early to make evidence-based recommendations about its use.

The next or next-after-that guideline will likely address next-gen sequencing in depth, once technical, logistical, and regulatory issues are resolved.

While next-gen sequencing can offer larger panels than current EGFR and ALK tests, that’s of unclear clinical value right now, says Dr. Lindeman. “If you can’t do it in a couple of days, and if you can’t do it for a relatively inexpensive price, then you’re asking a patient who may be dying of lung cancer to wait weeks for 50, 300, 20,000 genes that are not relevant for them. That’s just not right,” he says.

Dr. Kwiatkowski isn’t holding his breath for a next-gen miracle, either, at least not anytime soon. “I’m not expecting faster turnaround,” he says. “I’m not expecting cheaper.” He concedes that results from next-gen sequencing will be more comprehensive. But that leaves pathologists the unenviable task of sorting through the artifacts and other misleading findings that will invariably be delivered along with more meaningful results, he predicts. As for costs: “Research testing costs are always less than the costs of CLIA-certified testing, so they always look more attractive than when you put them into clinical practice,” he says. “I’d be surprised if any of the next-gen results end up coming in for less than a billable charge of $2,000,” he says.

Pathologists and oncologists, understandably, have their own areas of interest, which played out in creating the guideline. The thoracic oncologists were mostly focused on which patients to test, and when. While they certainly care about testing, says Dr. Lindeman, “They were happy to defer the details of how to do the testing to the pathologists.”

The thoracic oncologists, he continues, were more engaged with the hard-to-answer questions that affected how they’d talk to their patients. Should testing be done only in patients with stage IV lung cancer, or at earlier stages as well? If testing isn’t done earlier, should material be set aside for future testing? Should patients be re-biopsied, or should old samples be used for testing?

“There’s no clear answer for a lot of these questions, unfortunately,” says Dr. Lindeman.

Pathologists should bring a Depression-era sensibility to their work: Do the best you can with the material you have. “But we shouldn’t try to be too heroic,” Dr. Lindeman says. If the sample is suboptimal, tell the oncologist. “Because I’ve seen analyses done on suboptimal samples, and the results can get miscommunicated.” The radiologists and surgeons doing the biopsies also need to know what material pathologists need to do the tests correctly, and to understand that sometimes samples can’t be tested—they may be too heterogeneous—even if they seem physically large enough.

“Just having those conversations will go a long way,” says Dr. Lindeman, who speaks from experience. EGFR mutations were discovered at his institution, he says, “So we’ve been doing them as long as anyone.” When cases can’t be tested, he and his fellow pathologists will show the material to their clinical counterparts. Over the years, he says, the relationship has evolved into a good one. “Having worked with us, they know we’re not cavalier.”

Those discussions will become even more valuable as next-generation sequencing unleashes a torrent of information. How should pathologists present their findings, and how should oncologists act on them? “It’s one thing for a person like me, who’s had an interest in genetics all his life, to be comfortable thinking about these things,” says Dr. Kwiatkowski. “Not all oncologists have that background and experience. They’ve got to work at this.”

Molecular results in general can be vexing. The guideline outlines the best way to report EGFR and ALK results, but that doesn’t mean pathologists can cruise along on autopilot.

Dr. Lindeman notes that within molecular diagnostics and cytogenetics, there’s a movement afoot to standardize nomenclature and use official language. He understands the need, but demurs. “I have to tell you, I acknowledge its value, but I’m not a big proponent of this,” he says, “because the official language is cryptic to most people.” With cytogenetics reports in particular, he says, “It’s almost like another language.”

Whoever writes these reports, Dr. Lindeman continues—whether it’s the molecular lab itself or a central surgical pathologist who receives the information and relays it to clinicians—must convert the molecular and cytogenetic language into the vernacular. Oncologists need to know what the results mean and what to do next.

Moreover, he says, pathologists need to pay close attention to incidental findings that sometimes get passed along in the report, which need to be clearly distinguished from the findings that have implications for patient management. With ALK FISH, for example, polysomy is a common finding. “If those are given equal footing on a report, without a clear explanation of what they each mean, then that can be quite misleading. I’ve seen it happen,” Dr. Lindeman says. “I’ve seen surgeons and oncologists think that ALK polysomy is something that needs to be treated. It doesn’t. It doesn’t respond to therapy; it’s an incidental finding.”

Clarity can also go AWOL with EGFR mutations. Most are associated with response to therapy, but some are associated with resistance to therapy. “So it’s important, when communicating that an EGFR mutation is present, to characterize which bin it falls into,” says Dr. Lindeman. “You wouldn’t want to tell an oncologist to treat a patient with a targeted inhibitor if they have a resistance mutation.”

Given the amount of work that went into the guideline, it seems almost indelicate to ask about how, and when, it will be revised.

“I’m so happy the first version is done!” says Dr. Lindeman. He laughs with relief, then quickly resumes a more business-like tone. Yes, it will be updated. New markers come out all the time, and there are already topics—he points to ROS1 genomic alterations as one example—that arguably should have been included in this initial document. At first the document’s creators discussed revising it every four years—far too slow, Dr. Lindeman now acknowledges. A more useful target would be every 12 to 18 months, although they’re understandably mostly focused now on disseminating this guideline.

In the interim, there’s plenty to do and more to discuss. This is a framework, not an endpoint. Pathologists and oncologists need to decide, together, what the guideline means at their institutions. Unlike a constitution, they can’t rely on original intent.

Karen Titus is CAP TODAY contributing editor and co-managing editor.