Gaetane C. Michaud, MD
A Pulmonology Perspective on Biomarker Testing in NSCLC
First of all, I’m a pulmonologist. Therefore, when I think of core biopsies, I think of transthoracic versus endobronchial, transbronchial biopsies. As a bronchoscopist, we usually use imaging techniques that actually aid at increasing our diagnostic yield, particularly things like endobronchial ultrasound or when we’re thinking about peripheral lesions, we combine endobronchial ultrasound also with navigational technologies to try and get out to the lesions. Some other techniques that have been used in the past, especially in the time before a lot of these imaging techniques were using a larger bore needle, so using a histology needle versus a cytology needle, using rapid onset cytology. Rapid onset cytology is available in a lot of centers, but not available in all and it also is very center specific whether you have a cytotechnologist or either a pathologist that’s there or a pathology or cytology fellow. In my experience, I’ve had a lot of success, when I have either the pathologist or the cytopathology fellow and they actually help us a lot because actually they say, oh, you have large amounts of tissue and so we try to go back to those same areas because we’re using imaging to help us sort of identify where in the node we’ve actually been or where we are.
Other things that we can do to actually increase the yield are taking dedicated specimens for moleculars. So, generally, the literature would show for small biopsy samples via the airway that three passes of a needle is sufficient for diagnosis, but if you’re going to actually do moleculars, you need a minimum of four. Now, that said, those studies were done several years ago where we weren’t able to do as much with those samples. So, those are the times of just EGFR, ALK and even prior to PD-L1. So now, at this point, we actually put a couple of passes aside and so, what we do in our institution is we do our diagnostic samples and then we actually generally put in reserve, samples and we look in the cup to make sure that we’re having an adequate amount, but at least a couple of passes dedicated for moleculars.
The other thing you can do is, you know, oftentimes we’re asked to either rebiopsy or biopsy a patient that has been biopsied in another facility where they didn’t do either comprehensive molecular analysis or didn’t do it at all. And in those cases, we don’t really need the immunohistochemistry because we already know, we already have the diagnosis of cancer. In those ones, what we do is we signal to our pathologist in our pathology department, that IHC isn’t necessary and that we actually can reserve that tissue for molecular only. And one of the things that we’ve definitely encountered that goes back to a point that I made just a few minutes ago was, using too much of your tissue for immunohistochemistry, when you actually have a high suspicion of specific tumor type or alternatively, a patient that’s been biopsied before, you can really limit your panel or actually avoid the IHC panel altogether and then go onto using those specimens for molecular only. So, that’s certainly one issue that we’ve seen in the past. As far as other things that we actually find can actually cause an issue are, often patients will have had, especially in the biopsy population, will have had things like radiation to that area and what we do know is that the diagnostic yield can sometimes be lower in a previously irradiated node or alternatively in a previously irradiated lesion. We have a higher tendency to actually have onsite cytology present and to make sure that we are sampling the right area of the node or area where we’re getting adequate tissue. The other thing is, is that we actually, like I said, we send specific panels, so we do some of our molecular testing in-house by staining. And so, what we do is we actually have enough tissue for that and then what we do is we actually take dedicated specimens for things that are going to go out like foundation medicine. An adequate specimen for me is, a specimen that actually allows for comprehensive sampling, a comprehensive both diagnostic workup as well as a molecular workup that was going to help guide therapy and that includes what our in-house testing is and anything that we may need to do later on for sent out testing.
So, we actually have reflex testing in our institution. So, first of all, all of our cases are discussed in our multidisciplinary lung cancer tumor board and then in addition, we actually within our clinic, with the medical oncologist, the surgeons and the interventional pulmonologist and the radiation oncologist, we all work together in the same clinic. So, we actually have open dialogues on a daily basis about that. So, we actually have a very open line of communication. When it comes to molecular testing, so we actually hear from the oncologist what they actually want to start with and then what we do is we turn around and when we go to do our procedure because we have reflex testing, the initial EGFR, ALK, BRAF, KRAS and PD-L1 done by staining is done in house, so that is automatic reflex in the appropriate patients. Then, when we need to do additional testing, we actually can write that into the comments section in our pathology request and so, that is actually done, we actually as the pulmonary doctors have the ability to order the testing directly and we actually, because my entire pulmonary group that does the bronchoscopies and does the needle biopsy, we’re all actually part of the thoracic oncology group, so we actually are very much aware and very informed as to what we’re actually looking for and we order the appropriate tests.
Some advice that I actually have, our number one, you know, ensure that you know what you’re looking for. So, if you already have a diagnosis, minimize your IHC, like really decrease your panel. Two, really make sure you get dedicated specimens for your molecular testing. I find that you can actually sample different lymph nodes and especially if you’re doing staging at the same time as diagnosis, you know, you may actually have a node that is actually larger, more likely to have tumor within it. You really want to use that to maximize your yield. The other thing I would tell you is that with endobronchial ultrasound, using your image guidance, you can also see areas where you actually have frank necrosis based on the echogenicity of the node. Those are the areas that you want to stay out of because your diagnostic yield and particularly for moleculars, you’re just not going to get a lot of viable cells because you actually have to have a very cellular specimen.
The other thing to know is actually you can use your onsite cytologist to tell you where to go. So, when your biopsying, if they’re telling you oh, you’re getting a great sample there, go back to that area. The other thing you can do is if you don’t have that is actually go through different areas of the lymph node. We often say we want to stay to the periphery of the node and that’s actually because if the node is going to necrose it necrosis from the center, and so your diagnostic yield and particularly for moleculars, is actually much higher on the periphery of the lymph node.
A few considerations that I would have actually looking at this case. So, number one, your primary lesion is on the contralateral side of your pleural effusion. You did get some cancer cells, so you could say that you’re staged, you have stage 4 disease. My recommendation would be to actually go after the pleura because you actually have cancer cells there, so you’re going to have a really high yield. When you do a medical fluoroscopy under moderate sedation, it’s extremely comfortable for patients. It allows us to get in there, take those big strips of pleura where we can actually see under direct visualization that we actually have tumor involvement. So, you’re going to have a really high yield, well over 95% in that case. So, that’s one thing to consider sort of alternative ways of getting tissue. Number two, a transthoracic core is actually associated with at least a 25% risk of pneumothorax and when you’re considering like your option between a transthoracic core biopsy versus an airway biopsy, your airway biopsy is a much safer option. With a lot of these novel technologies, like endobronchial ultrasound and navigation, we can get out to some pretty small lesions and even, we can sample and stage at the same time, the mediastinum. Because actually staging is really important. There are trials that you need to prove staging for, for new agents. It can really influence what you’re doing and you may actually have a larger yield because that lesion on the right side is actually small. And so, you know, you could actually hemorrhage, you could get a pneumothorax, there’s just so many different things to consider. Some of the things that we need to be thinking about is, in this era of evolving knowledge about molecular testing and molecular testing actually driving therapeutics, what we know is these patients often require multiple biopsies over time because the tumor can change and the molecular profile can change and we may have an additional line that we didn’t know about. And also, with this rapid evolution of medications that are targeted towards these lesions, you know, I think that we are actually rebiopsying more frequently. And so, we need to remember that on the other end you actually have a patient and so, if you give them a pneumothorax, if you cause them pain, they’re going to be less apt to want to actually undergo another procedure. So, we want the most information with the fewest number of procedures possible and the greatest patient comfort and safety.
Another recommendation that I would have for pulmonary doctors, interventional pulmonary doctors and even actually for interventional radiologists going to do biopsies, core biopsies, is that I would actually speak to your pathologist. Ask them how they want their specimen prepared. In my sort of almost 20 years of experience, there is no two pathologists that want their specimens prepared exactly the same way and there is a direct correlation between your diagnostic yield, your ability to do molecular testing and the willingness to evaluate your specimens, if you actually are in concordance with what the pathologist asks you to do.
CASE STUDY ON BIOMARKER TESTING IN ADVANCED NSCLC
Patient Case: Biomarker Testing in Advanced NSCLC