Standardizing Molecular Testing for NSCLC: Q&A With Dr. Gregory J. Riely and Dr. Marc Ladanyi

Gregory J. Riely, MD, PhD

Three leading health organizations—the College of American Pathologists, the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology—have jointly issued a guideline establishing clear standards regarding tests for two common genetic abnormalities linked to lung adenocarcinoma, the most common type of lung cancer.¹

Targeted Oncologyspoke with a medical oncologist, Gregory J. Riely, MD, PhD, assistant attending physician at Memorial Sloan-Kettering Cancer Center and assistant professor of Medicine at Weill Cornell Medical College, and a pathologist, Marc Ladanyi, MD, acting chief, Molecular Diagnostics Service, at Memorial Sloan-Kettering Cancer Center, who was one of three co-chairs of the international expert panel that developed the guideline.

Targeted Oncology: Briefly, what do the new guidelines say about molecular testing for non-small cell lung cancer (NSCLC)?

Dr. Riely:The guidelines are a distillation of what many oncologists have been thinking over the past few years, and they really put into practice the data we’ve seen regarding the two most common molecularly targeted therapies in lung cancer. These are the first pathology guidelines to emphasize the importance of a set of bare minimum molecular testing that should be done for patients with lung cancer, and, as such, it’s a key step forward. Treating patients with lung cancer requires multidisciplinary care. We have patients who have biopsies performed by pulmonologists or thoracic surgeons or interventional radiologists and the tissue is sent to a pathologist. If the patient has metastatic lung cancer, then treatment decisions are made by a third person, a medical oncologist. Getting all these people together and having everyone get the data that they need to treat the patient is critical. Moreover, biopsies are an invasive procedure, and you want to be able to get what you need from a biopsy. You want to learn what you need to know from that biopsy and have it all done right the first time, rather than have a patient go through a process with a biopsy, pathology analysis, and then ultimately see a medical oncologist only to find out that they didn’t have the right testing done. In this situation, they have to go back to the beginning for another biopsy.

Is molecular testing more important for some patients than others?

Dr. Riely:Within non-small cell lung cancer, molecular testing is most important for lung adenocarcinoma. There’s less data to support the use of molecular testing in squamous cell and other histologies of lung cancer. For lung adenocarcinoma, it’s of critical importance. In the beginning of the field, there was some focus on clinical characteristics that might guide us toward doing molecular testing. These included things like the patient’s gender, whether the patient had smoked cigarettes, what their ethnicity was. We found that those were inadequate predictors of the presence of driver oncogenes, and, as such, we don’t believe those factors have a role in determining which patients should have molecular testing.

What can be done for patients as they wait for test results?

Dr. Riely:In a patient with rapidly progressive symptoms, the standard is to recommend initial chemotherapy and then obtain molecular testing results when they’re available, and you can change your treatment approach as a consequence of that.

Do you agree with the current testing guidelines?

Dr. Riely:The guidelines set a bare minimum for what needs to happen for patients with lung adenocarcinoma. They recommend EGFR molecular testing, they recommend ALK molecular testing, but they stay silent on a whole host of other driver oncogenes, and, as a consequence, I think this serves as a starting point for hopefully additional guidelines or additional modifications of the guidelines, which will incorporate newer molecular tests that we are discovering as valuable. For instance, data have been presented on a couple of occasions describingROS1gene rearrangements and their association with response to crizotinib. There’s no FDA approval yet for this broad-based thing, but I think most oncologists believe that treatment of a patient withROS1rearrangement with crizotinib is the most appropriate thing, and, as such, hopefully this will be included in future guidelines. Similarly,BRAFmutations in lung cancer have shown to be responsive to dabrafenib treatment, and that would be another reasonable thing to add.

What else do you think community oncologists need to know about these guidelines and how they affect treatment?

Dr. Riely:This is one more guideline that establishesEGFRmutation testing andALKgene rearrangement testing as the standard of care for lung adenocarcinoma. From the time of suspicion of lung cancer through to initial treatment, it’s critical that doctors who treat lung cancer think about molecular testing and try to have this performed early and comprehensively for all of their patients with lung adenocarcinoma.

What are the most important points of the guidelines?

Dr. Ladanyi:Patients with lung adenocarcinoma should have their tumors tested forEGFRmutations andALKrearrangements, regardless of smoking history. One of the things we were still hearing quite a bit was that oncologists were not requesting EGFR testing in patients who were smokers, but the data do not support excluding smokers from testing. The guidelines also do serve as kind of a state-of-the-art overview of what’s known aboutEGFRmutations: which ones are the most important to test for, their clinical implications, and so on.

How soon do you think the guideline will need to be updated?

Dr. Ladanyi:It’s really the scope of the guideline that I think will need updating very soon, because there are additional targets in lung cancer that we are already testing for quite routinely. For instance,ERBB2/HER2alterations in lung cancer,BRAFalterations in lung cancer,RETandROSfusions—all of these are being routinely tested in many centers already—so there will be a need for guidelines to cover that testing as well in the very near future.

What perspective did each of the organizations involved in the creation of the guideline bring to the task?

Dr. Ladanyi:The College of American Pathologists, of course, represents a very wide community of pathologists from both academic and nonacademic centers, and it also provides nationwide proficiency testing, so it has a very key role in maintaining standards in pathology and molecular testing. The Association for Molecular Pathology is focused very much on molecular testing and brought the perspective of molecular diagnostic lab directors, and so on. And then, of course, the IASLC is a multidisciplinary organization that represents all specialties that are involved in lung cancer treatment: lung cancer pathologists, radiologists, oncologists, and surgeons. The expert input of oncologists from IASLC was critical in reviewing and evaluating the clinical trial data that supported some of the recommendations, and they also provided input on what is practical or acceptable from the clinician’s point of view regarding how long they can wait for test results, and so on.

Does the guideline address communication between pathologists and oncologists?

Dr. Ladanyi:We stress the need to coordinate testing policies between pathologists and oncologists. We make that point for some items in the guideline that are more suggestions rather than firm recommendations, such as the testing of patients with resectable lung cancer at the time of diagnosis instead of waiting for disease recurrence. At some institutions, the pathologists and oncologists have decided that that’s worth doing, whereas other institutions may decide that they don’t want to test any patients who might not absolutely need that information because they have a completely resected lung cancer. So there are discussions that have to take place, and hopefully a consensus emerges between the different people involved in the care of patients with lung cancer.

References

1. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.Arch Pathol Lab Med. 2013;137(6):828-860.