Joel Neal, MD, presents a second case of a 67-year-old man with no smoking history who was diagnosed with RET-rearranged mNSCLC, while Michelle Shiller, DO, AP/CP, MGP, touches on molecular testing approaches in patients who are suspected of having a RET alteration.
Joel Neal, MD, PhD: We'll move on to our second case. This is a patient with RET rearranged non-small cell lung cancer, a 67-year-old Asian man with cough, dyspnea, neck pain, and chest discomfort. Past medical history, just of hypertension. Again, a never-smoker. Physical exam decreased breast sounds, ECOG performance status is good. CT scan demonstrates a primary mass in the right lower lobe plus mediastinal lymph nodes and bone metastases bulky causing the cough and dyspnea. Brain MRI is negative. Lab work all shows good organ function. And CT-guided biopsy is done demonstrating stage four lung adenocarcinoma. As we talked about at the beginning, here, we're very patient. And despite the symptoms, the patient is willing to wait. And next generation sequencing demonstrates a RET gene rearrangement. Michelle, do you do RET fish testing for rapid turnaround? What do you think the average turnaround is from the time of diagnosis of the sample to finding a RET rearrangement and what's the sensitivity of finding RET rearrangements with DNA NGS?
S. Michelle Shiller, DO, AP/CP, MGP: The turnaround time of RET fish is going to run about three to four days quicker, at least in our lab. So, we're running 10 to 11 days in most cases for our blood profiling, and the fish will come back a few days earlier than that. You have additional other steps with fish that are different. Obviously, the NGS. Do we perform it? We do. Do we standardly perform it? No, we don't. But we can if we need to, particularly again, if there's a unique rearrangement detected by DNA testing. And then with respect to sensitivity, the fish is going to be very sensitive at detecting a rearranged partner. It's slightly more sensitive than a generic rearranged partner, whereas with the NGS you will know what that rearranged partner is for the RET gene. With respect to DNA versus RNA-based testing; on the average, around one in 10 cases could be missed by DNA-based testing that are relevant alterations tested by RNA. So, then we start thinking about patient populations we expect to see that in. Again, it's going to be non-smokers, often. And so, one thing to mention here is that immunohistochemistry is not a good orthogonal method for rearranged non-small cell lung cancer. Also, important to be clear, very clear, because there's a few therapies in this or a few scenarios in which there's FDA approvals for RET alterations, so in non-small cell lung cancer we are looking for that rearranged event, not for a mutation. Those mutations are more commonly seen in medullary thyroid carcinoma. So, the FDA approvals for a rearrangement event and then those would be the ways that it would be detected. The reason why RNA is better sometimes is just due to post-translational modification events, things that are occurring around splice sites or enlarged intronic regions.