Multidisciplinary Perspectives: Molecular Testing in NSCLC

W. Thomas Purcell, MD, PhD, MBA

When to Test

Testing for genetic abnormalities is important for patients with non-small cell lung cancer (NSCLC), both to ensure that as many patients as possible are able to benefit from approved therapies such as erlotinib, afatinib, and crizotinib that target specific mutations and rearrangements, and to continue to advance our understanding of even more targets that may be able to lead to treatments in the future. Here, we extend beyond the guideline to examine several issues related to molecular testing from the perspective of several members of the healthcare team, including medical oncology, pathology, and thoracic surgery.Medical Oncologist W. Thomas Purcell, MD, PhD, MBA, assistant professor of Medical Oncology at the University of Colorado School of Medicine, and associate director of Clinical Services at the University of Colorado Cancer Center, explained why patient characteristics are no longer part of the decision to test: “ForEGFR, the highest percentage of positive patients are Asian, female nonsmokers, but even in the smoker, white male, there can be a 2% to 3% chance that there could be anEGFRmutation. We don’t use gender or race or whether they have been a smoker or not to determine whether to do molecular testing. The yield on the testing goes down as the smoking history goes up, but the yield is not 0, and that’s why we give everybody the benefit of the doubt.”

Dr. Kris on Guidelines for Molecular Testing in Lung Cancer

Kris is the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center.

Controversy still exists, however, regarding whether or not to perform molecular testing on patients with squamous disease. “It’s pretty clear that pure squamous cell carcinomas don’t have the pattern of mutations that you see in adenocarcinoma. So if you have a fully resected squamous carcinoma, and all of it looks like squamous carcinoma, then it’s not worth testing forEGFRandALK, because you’re just wasting time. It’s worth testing for other things, such as FGFR1 amplification, so actually, the histopathology is critical in knowing which studies to prioritize in a given case. The problem arises in patients who were diagnosed with small biopsies, in which case, you only see a tiny piece of the tumor. It does occur in some cases that patients will have a mixture of an adenocarcinoma and a squamous carcinoma. It’s been shown that those patients do have some of the same mutations as pure adenocarcinomas, so it may be reasonable to test these forEGFRandALKas well,” said Pathologist Marc Ladanyi, MD, acting chief, Molecular Diagnostics Service, at Memorial Sloan-Kettering Cancer Center in New York City.

In patients for whom adenocarcinoma components cannot be excluded, “biomarker testing could still be warranted, just to give the patient that treatment opportunity,” said Philip T. Cagle, MD, medical director, Pulmonary Pathology, Houston Methodist Hospital, professor of Pathology and Laboratory Medicine, Weill Cornell Medical College of Cornell University, and editor-in-chief ofArchives of Pathology and Laboratory Medicine. In the rare instance in which a patient with squamous disease has mixed histology that includes either anEGFRmutation or anALKrearrangement, that patient may be able to be treated effectively.

Purcell confirmed from his experience that exceptions in squamous disease can exist. “It’s rare, but I’ve had a couple of squamous patients who have tested positive forEGFR. Typically, we wouldn’t see that in squamous,” he said.

“We want to offer the chance of treatment to the maximum number of patients,” Cagle said. “We’re not trying to prevent patients from having that option, or at least from getting the biomarker testing, if there is a chance that it’s going to benefit them.”

Obtaining a Sample

Testing can and probably should go beyond justEGFRandALKwhenever possible in order to gain more information about other targets that may be able to lead to newer therapeutic options. “Usually we’re finding small subsets of patients who have a particular mutation,” Purcell said. “If we were to do 20 more years of research, instead of having 10% of the subsets, maybe we’ll have 40% or 50% of the subsets. It’s that process of research that makes testing these extra genes important. They may be adding onto the specific mutations that patients get.”Once the decision to perform molecular testing is made, the person obtaining the sample can choose the most appropriate location to biopsy. “If it is the first time that a patient is being considered for treatment, the evidence so far would indicate that one could use a sample either from the primary site or from a metastatic site, which might be easier to sample.” Cagle said. He also added that there is no current evidence to suggest that testing multiple sites within a single tumor is necessary in lung cancer.

Although the location to sample is flexible, the size of the sample is important. “Patients who present with advanced disease often are diagnosed with small-needle biopsies, and those biopsies have to be managed very carefully to preserve enough tissue for molecular testing. Otherwise, by the time the decision is made to test forEGFRandALK, there might be insufficient material left from the biopsy,” said Ladanyi. Therefore, careful consideration should be given to the type of biopsy performed.

Communication in the Healthcare Team

“Sometimes with a fine-needle aspirate, or even a core biopsy, it may not always be successful in terms of getting adequate tissue. Surgical biopsy generally provides more than enough tissue for molecular analysis,” said David Tom Cooke, MD, FACS, head of the Section of General Thoracic Surgery, University of California (UC), Davis, Medical Center.It takes a team of healthcare professionals from a wide range of disciplines to determine the appropriate course of testing and treatment for any given patient with lung cancer. Now that targeted therapies are available and investigational ones are being developed, the role of the thoracic surgeon, for one, has changed and expanded. “Our focus, from a thoracic surgical standpoint, is always on patients with early-stage or locally advanced, or nonmetastatic, disease, because surgery can be potentially curative for those patients. In stage 4 disease, surgery is by no means curative; however, it can provide data that helps our medical oncologists to treat these patients in a better palliative manner with targeted therapy,” said Cooke.

“App”lying Knowledge: Spotlight on CollabRx

Your patient was diagnosed with NSCLC, and molecular testing has revealed genetic abnormalities. What next? Salgia has a suggestion: “We’ve developed an app for molecular analysis and how to interpret those results, and how to think about clinical trials:www.collabrx.com. A group of us—I’m the Principal Editor—have worked to find a molecular application. Let’s say someone has anALK+ tumor, then you click on that for metastatic disease, and then there’s an app that pops up to say to consider crizotinib, but if there’s failure to crizotinib or if you want to consider other things, all these clinical trials pop up as well. That really helps other healthcare providers, community oncologists, patients, anyone who’s interested, to say, if one has anALKtranslocation, what should you do?”

That’s right, there’s an app for that.

A similar case is true for pathologists. “It used to be that the pathologist was mainly as involved in making the pathologic diagnosis, and then, after that, was not really engaged in the patient’s management. But now the pathologist has a much closer role in patient management, because these test results are what decides which drugs the patient’s going to be treated with. It has put the pathologists in a much more intimate interaction with the oncologists,” Ladanyi said.