New guidance on lung cancer testing

Karen Titus

April 2013—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
be big.

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.