It was a monumental task: create a molecular testing guideline for lung cancer. Among other tasks, those involved (representing the CAP, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology) reviewed 1,533 abstracts and read, in detail, 521 full-text articles. There was extensive evidence grading; naturally, new literature was published in the interim, which required even more reviews. The payoff was the first international, evidence-based, multidisciplinary guideline for this part of lung cancer care. It contains 37 items addressing 14 subjects, including 15 recommendations (evidence grade A/B).
“It was a lot of work,” says Neal Lindeman, MD, the lead author of the guideline. The document, a model of clarity, stretches over 122 pages and is bolstered by 322 references.
The guideline’s major recommendations are to test for EGFR mutations and ALK fusions to help select patients for therapy with an EGFR or ALK inhibitor, respectively. The testing should be done in all patients with advanced stage (stage IV) lung adenocarcinoma, regardless of sex, ethnicity, smoking history, or other clinical risk factors. Moreover, EGFR and ALK testing should take priority over other molecular predictive tests.
The guideline is aimed, says Dr. Lindeman, with only small understatement, “at the world.” It establishes the standard of care for molecular assessment of lung adenocarcinomas, including which samples to test, when to test them, and how to test them. For pathologists who aren’t doing the testing themselves, it explains how to select cases for send-outs. And for those who perform testing, it offers guidance on the best way to do the tests, how to validate them, and how to communicate the results back to the clinicians, says Dr. Lindeman, who was also one of the co-chairs of the guideline’s expert panel as well as a member of its steering committee.
The guideline has been jointly published in Archives of Pathology & Laboratory Medicine, The Journal of Molecular Diagnostics, and the Journal of Thoracic Oncology. If one were to compose a tweet announcing the thrust of the guideline, however, it could be a simple phrase aimed at pathologists and oncologists: Talk it out.
There is no shortage of answers and evidence in the guideline. But even in the best of circumstances, pathologists and oncologists need to talk about what the answers mean for patients. And in less than optimal circumstances—there’s no shortage of those, either—the need for talk becomes even greater. The guideline, like a constitution, needs to be a living, breathing document, not a relic. “It requires communication,” says Dr. Lindeman, director of the molecular diagnostics laboratory, Brigham & Women’s Hospital, and associate professor of pathology, Harvard Medical School.
The guideline fills a gap in lung cancer care, says Philip Cagle, MD, another author on the study. Without evidence-based recommendations or at least consensus of expert opinion about how to handle specimens, there’s no consistency in care, and pathologists and oncologists may be making less-than-sound choices.
Dr. Lindeman offers a blunt example: His cousin, who has lung cancer, was not offered appropriate molecular testing because she’s a smoker. “There are some centers where laboratories and physicians are using clinical criteria to determine who should be tested,” says Dr. Lindeman. At one time that may have made sense. Not now. Early studies showed that EGFR mutations were more common in women, never-smokers, people of East Asian descent, and younger people. Likewise, ALK gene fusions have been shown to have strong associations with younger patients as well as never-smokers. “In some centers, patients who don’t meet these criteria are not offered testing. But that’s not appropriate.” That epidemiology may be useful for population studies but not for patient management, says Dr. Lindeman.
The guideline reflects that changing reality. It also follows a model set in breast cancer, where biomarker tests have a longer history and more solid consensus. With lung cancer, only recently has it been validated that biomarker testing is needed and predictive of likely response to therapy. “We began working on these guidelines at the time this was first reported in the literature,” says Dr. Cagle, who is medical director of pulmonary pathology, Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston.
Like any guideline, it raises questions as well as provides answers, all while trying to keep pace with the ceaseless flow of scientific and technological advances, as well as with the best intentions of adventurous clinical colleagues.
With that in mind, here are some of the guideline’s key recommendations, with Drs. Cagle and Lindeman offering a sort of highlights reel.
First, says Dr. Lindeman, EGFR mutation testing and ALK rearrangement testing should be done on any patient with adenocarcinoma of the lung. “It’s simple and straightforward,” he says. “Don’t worry about sex, smoking history, the ethnic background.” All those factors influence risk. But patients without those risk factors don’t have zero risk.
Testing for these predictive biomarkers will help identify whether patients are likely to respond to EGFR or ALK tyrosine kinase inhibitors. About 15 percent of patients with lung cancer have an EGFR mutation, and another four percent or so have an ALK translocation. The numbers are distressingly small, but the impact for each patient with a mutation can
In unselected cases of advanced non-small cell lung cancer, two inhibitors (gefitinib and erlotinib) of EGFR were shown to produce response rates of about 10 percent, with a median time-to-progression of two to three months. In contrast, patients with EGFR mutations in their tumors showed response rates of about 70 percent, with mean progression-free survival of about 12 months. In patients with ALK rearrangements, treatment with the ALK inhibitor crizotinib showed an overall response rate of approximately 60 percent, with about 70 percent having a PFS of six months or greater.
“So the pathologist is now very central to the selection of targeted therapy for the patient,” says Dr. Cagle. “This is a change in the role of the pathologist in regards to lung cancer.”
Obviously pathologists have never been an afterthought in lung cancer testing, Dr. Cagle notes, but prior to the advent of targeted therapies, the issue of identifying cell type was not as crucial for the non-small cell lung cancers, he says. In the past, the most important issue was to distinguish small cell lung cancer from NSCLC. Now it’s vital to distinguish adenocarcinoma from squamous cell carcinoma. In the minority of cases where the answer is unclear on histology, pathologists can use IHC to try to make the distinction. That should reduce the number of equivocal cases to five percent or less, Dr. Cagle says.
The guideline clarifies that neither FISH nor cytogenetic testing is useful for EGFR. “Hopefully most people realize that now, but this was a controversial subject for the first five years of EGFR analysis,” says Dr. Lindeman. Mutation testing is the standard analysis for EGFR and often will be done by PCR, Dr. Cagle says. The guideline calls for using methods that work well with 50 percent or more cancer cell content, though it encourages use of more sensitive tests that can detect mutations in specimens with 10 percent cancer cells.
Testing for ALK therapy should be done by cytogenetic techniques, such as FISH. “We’re fully aware,” says Dr. Cagle, “that immunohistochemistry is on the horizon for ALK screening.” But for now, FISH testing is the standard.
And while the FDA requires a positive FISH result for ALK, from an FDA-approved assay, to give FDA-approved therapy, the guideline veers from that dogma. “We’ve stated that if validated properly, immunohistochemistry can be used to screen samples for ALK-positivity before proceeding directly to FISH,” Dr. Lindeman says. This is, after all, an international guideline, one that extends beyond the FDA’s reach. More importantly, says Dr. Lindeman, “We do think it’s an acceptable practice.”
The guideline also addresses when in the course of someone’s disease to do the test. It’s not that this is a controversial issue, but practice varies from one institution to another.
“We are recommending that all patients with advanced disease should be tested at the time of diagnosis,” says Dr. Lindeman. As the guideline notes, patients with advanced disease have short (four to five months) life expectancies absent treatment, so the goal is to do molecular testing as soon as a diagnosis of adenocarcinoma has been made.
Some institutions will also choose to test earlier stage disease (stage I, II, or III); others won’t. There’s no right answer. But the guideline urges pathologists and oncologists to discuss what they want to do at their institution. “Decide on an institutional policy, rather than handling cases one at a time,” says Dr. Lindeman.
The focus on late-stage disease reflects a sobering reality: That’s when the disease is most often diagnosed. That’s also why these patients are the focus of most clinical studies, and that’s why they’re recommended to receive biomarker testing.
Many early stage lung cancer patients will also develop recurrent and eventually fatal disease. “So we think it’s useful to go ahead and test these patients,” says Dr. Cagle. “That’s not based on the literature, because these patients have not previously been studied. The evidence is not there in black and white.” Researchers are looking at early stage patients with a mutation or translocation to see if they, too, will benefit from the targeted therapies. “Until the data are in, I can’t prove it. I suspect, though, that we’re going to find it’s true,” Dr. Cagle says.
Should squamous cell carcinomas be tested? No, says Dr. Lindeman (and the guideline). EGFR mutations are very infrequent in squamous cell carcinoma specimens that are well characterized, fully excised, and lack any adenocarcinoma component. EGFR mutations are not detected in small cell lung cancer, either, apart from rare cases of SCLC with an adenocarcinoma component.
On the other hand, not every specimen can be identified as “pure” squamous cell carcinoma, nor have all the clinical trials in the literature identified patients’ cell types, Dr. Cagle notes. And some studies, including one by Marc Ladanyi, MD, and colleagues at Memorial Sloan-Kettering Cancer Center (Dr. Ladanyi is the guideline’s senior author and a project co-chair), have shown that lung cancers that were initially called squamous cell carcinomas had EGFR mutations; these turned out to be either adenocarcinomas that had initially been misdiagnosed, or cancers that had an adenocarcinoma component. Even with the best efforts, it’s not always possible to classify cell type. In such cases, it may be appropriate to send those cases for molecular testing.
“We do not want to waste resources,” says Dr. Cagle. “But we do not want to exclude patients from getting therapy who might benefit from it.” So if an oncologist and patient want to go ahead with additional testing, “Maybe they should. They might find that in fact there is a mutation present.” This might be especially true in patients meeting certain clinical criteria, such as young age or never- or light smoker. (Though again, such criteria should not be used as the sole basis for deciding whether to test.)
Pathologists who deal with lung cancer diagnoses inevitably encounter problems with adequate tissue samples. The specimen is small; the demands on it are great. “Ordinarily there will not be any larger surgical resection specimen to examine,” says Dr. Cagle.
How can pathologists make sure the specimen is well used? The guideline emphasizes that the first step is simply being aware of the demands being placed on the tissue. “There’s a temptation sometimes to use up the tissue,” says Dr. Cagle, as pathologists determine the primary site or the cell type, or identify other features that are less crucial—but still related—to treatment. “And sometimes oncologists don’t understand which tests they need to order, and with what priority, in terms of biomarker testing.”
Talk it out. In medicine, failing to communicate is as foolish as a duel.
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.
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.”
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.
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.