Jeremie Calais, MD, MSc, reviews PET molecular imaging of prostate cancer, and describes Prostate Specific Membrane Antigen (PSMA).
Back to Symposium Page » it is now my pleasure to introduce Dr Jeremy Calais, assistant professor and director of the clinical research program of the Amundson Translational Diagnostics division of the Department of Molecular and Medical Pharmacology at UCLA. He will be joining and speaking us on the practical aspects of novel imaging approaches and the management of prostate cancer. Please welcome him. Hello, everyone. It is a real honor for me to be invited to this great conference and to have the opportunity to share my experience in prostate cancer imaging, I would like to thank in particular the organizer and script and the Anderson Cancer Center. Mhm Before I start, here are my disclosure. I will pose on that for a few seconds. All right, let's start. Okay. I was asked to give a presentation entitled Practical Aspects of Novel Imaging Approaches in the Management of Prostate Cancer. I considered for the purpose of this presentation novel imaging approaches as pet molecular imaging. I will not talk about MRI here or any other imaging modalities because 30 minutes is short and also because my main expertise area is pet imaging, not MRI. So just to give a quick refresher of what is better imaging. It is the use of positron emitters, such as the main ones for 18, or gallium 68. We did not probe or tracer that has a specific biological molecular target, and we can detect the radiation emitted with the pet scanner device to make images of the special distribution of the biological or molecular target we're looking at. So the title could read now as practical aspects of pet molecular imaging in the management of prostate cancer and I will focus mostly on the most novel and performance pet imaging technique for prostate cancer, which is PS mm pet prostate specific membrane antigens bet imaging, especially that it has just been recently approved in December 2020 by the FDA at U. C. L. A. And UCSF. So finally, the title of the presentation could be now read as practical aspect of chess. Muppet Molecular imaging in the management of prostate cancer. Mhm. So let's have a little bit of background here and see what we're talking about. PSM, a prostate specific membrane antigens. It is a misleading name. It is also known as a full age one for the metabolic people for late model is one or glutamate chaplaincy. 50 days to for the neurology people, this is a sells your face trans membrane glycoprotein enzyme. Its role remains not perfectly defined, but we know it is used in the neural transmission and also in the full eight metabolism. The benign vitamin here is one proposed mechanism by which PSM contribute to tumor growth and progression of cancer. Basically, PSM can hide, realizes police glutamate fillets into folate and glutamate, and both are involved in mutilation reactions. Probably. I mean synthesis and nuclear diet synthesis required for cell replication and proliferated growth at the end, even if it's not sure what matter is that. Here you can see why PSM is a good target for pet imaging of prostate cancer. This is from the human protein atlas, and it shows the arena expression level of the PSM, or four H one protein. It is very highly over expressed by the prostate cancer cells up to 100 or 1000 folds, and this high over expression is observed in about 95% of the prostate cancer cases by immune arrest or chemistry. Here is a summary of multiple articles showing the percentage of time are stained positive for PSM across primary tumor, lymph node, lymph node, metastases, bone and other metastases at the end. Across all, these 95% of the prostate can sustain positive for PSM. A. So PSM is highly over expressed across all prostate cancer lesions. Therefore, representing an excellent prostate cancer targets, especially at the level of expression in the normal audience, is low. I will go back to that. No small peptides innovators that have a binding motive specific for the extra cereal part of PSM A can bind to PSM A with high affinity and get internalized into the cells just after binding. These peptides can be labeled with position radio nuclear amateurs, such as fewer 89,000,000,068 that we can use to make images of the distribution of the PSM expression. The development of these small peptide speed racers with the specific by an emotive to PSM A exploded in the last two decades here is non exhaustive list of some of them. The mostly used worldwide is gallium 68 PSM A 11 because it was not attended, and here are the main F 18 level compounds that are owned by industry companies just to be clear and sure that we are on the same page. All of these are PS Mm pet. They all perform well. The bar is very high. And if there are some differences, there might be very tiny and therefore very difficult to prove clinically. And this would be the subject of another presentation for very technical imaging oriented people. Mhm. And here is what it looks like in a normal patients. I said earlier. PSM is not expressed only in prostate tissue. You can see here the normal by distribution of the PSM perpetrator with uptake in the salivary gland duodenum. You also have a lot of usually a small intestine uptake, the renal proximal tubular cells and the urinary expression in the kidneys and the bladder. Now let's see how it looks and what it can do in the prostate cancer patients. This is the example of a patient with Gleason nine. Prostate cancer referred for initial staging City and bone scan did not show any obvious lesion, and patient was considering definitive local therapy with creative intent. And here is the PS MM pet treaty map on the left side, you can see very easily these black dots here. This corresponds to a prostate cancer lesions. You can see the very high contrast, high temperature to background ratio that makes PS MEP it fairly easy to read in yellow, the primary tumor in blue pelvic lymph node metastases and in red bone metastases. Yeah, and by showing distant metastases, patient was switched to systemic therapy. So a major impact on patient management. Now let's look at another example in another setting. Here is a patient with biochemical recurrence after surgery and salvage radiation therapy at the PSC level of 1.6. Usually patients like this, they get treated with androgen deprivation therapy. Medical illustration. The PS mm pet shows a single left, very rectal infant metastases. Very tiny four millimeters. The city would have never call it positive, and this one was treated with focal radiation therapy only without a D T. And, she said now, at three years remains undetectable. So he objected. My pets spare the patient from medical castration side effects for several years, so this is a good story. It's not always like that, of course, but it shows how ps map. It can impact patient life significantly. Now let me describe a little bit the recent and the approval of Gallery 68 PSM A 11 pets. The approval indications out here it is men with prostate cancer with suspected metastases who are candidates for initial definitive therapy or with suspected recurrence based on elevated PSA. So we're pretty happy about that and the language we were able to agree on. We believe that will be able to cover most of any prostate cancer staging or restating indication. Now I'm going to describe briefly the data that was submitted to the FDA. First, it was a joint in the exhibition from U. C. L. A. And UCSF. We pulled our clinical data sets obtained with identical study protocols. We used to pivotal studies. Let's look first at the biochemical recurrence setting. What the FDA wants to see for diagnostic nuclear medicine probe is the diagnostic efficacy. We need to know what other performances of the new tests and get some metrics. So the primary endpoint for the PCR trial was the positive predictive value. The PPV of gallium 68 PSM 11 pet confirmed by Easter pathology or a composite referenced under which can be P s a decrease after focal radiation therapy without a deity or other imaging modality confirmation. Our hypothesis was a ppd of 70% or more, and for that we needed 110 patients with pathology confirmation, which is very hard to get in the biochemical. Recommend sitting patient usually don't get biopsy after imaging, and the scans were read by three blinded, independent central readers as per FDA standards. And here are the results published in JAMA Oncology two years ago. The study included 635 patients. The median P S A was 2.1. You can see here the detection rates or the positivity rates for patients increasing with the Syrian PS level 38% under five, 57% between 570.5 and one and up to 97% above five. So one of the first thing to consider when reading a P s m s can is the PSC level. You need to adjust your sensitivity level based on the PSA. Yeah. Then, after meeting follow up of nine months, we were able to obtain validation of reference standard of the PS mm pet positive findings in 217 patients with later is to pathology imaging follow up or PS, decrease after focal therapy and positive predictive value was 92% so very specific. So when you see something, it is very likely prostate cancer. So we met the primary endpoint of the trial to the satisfaction of the f d a. Yeah. Now let's look at the primary staging study cohort. The primary endpoint of the trial was the diagnostic performances of gallium 68 sm 11 pet for the detection of regional nodal metastases and one disease compared to Easter pathology, the gravel of the initial staging of prostate cancer here. The hypothesis was a sensitivity of 65% of this market. For this, we needed 61 patients with nodal disease per pathology to have sufficient statistical power and okay re blinded independent central readers as per FDA standards. And here the results. We enrolled 764 patients in total, all these patients and the winds of Sesame Pet scan, and among them, 277 actually underwent surgery and this was the efficacy cohort, and among them, 75 were PN one per pathology. So we reached the sample size needed and on these 30 were actually positive by the peace method, Consensus Majority rates. So with that sensitivity was 40% specificity was 95% PPV was 75% and NPV was 81%. So we did not meet our primary endpoint. But the FDA was, I think, able to recognize the fact that probably the biggest impact of just my pet was to exclude patients from surgery by showing disease outside of the prostate in more or less 64% of the cohort. And most of these patients were negative by MRI in cities, so 40% is in a way, way better than zero. The FDA, I think, was also able to appreciate that what it means. We still miss two thirds of the patients with micro metastases. This is it's just too small to be detected, and it means that even with PSM pets, we still see only the visible emerging part of the iceberg. In many patients, PS pet is very sensitive and sometimes can pick up very tiny lymph node metastases of about 2 to 3 millimeters as long as there is sufficient PSM a density here is an example of left peri rectal lymph node or left super clavicle, a lymph node of about few millimeters that were highly ps mm pet positive. Now, careful placement pet has the same imitation than any other pet CT technique and cannot go beyond the detection limit of beds. This very famous figure for MDG pet shows that under tends to the several cells without the genetic pet is not able to detect a lesion. And this is why we still see only the visible part of the iceberg on plasma pets as well. It is clearly not only about the size, it is more about the quantity or the density of the PSM protein expression. The target expression level is another essential key factor for PS, maybe detection rate. Of course, the bigger a lesion is, the more likely you will be able to see it as long as there is what there are sufficient PSM expression. But you cannot go beyond this interesting resolution of PET in that study, which shows the detection rate here in the the Y axis and the size of the tremor deposit here in the lymph node in the X axis, well, it has been shown that 90% of the leave notes with a deposit of five millimeters can be detected by PS. Mm pet, whereas only 50% of the lymph nodes with the deposit of two millimeters are detected by PS. Mm pet. So micro metastases induced false negative finance. It is not per se pitiful. It's just that when the scan comes back, negative can enter. The patient has no disease or the disease is too small to be seen, and you cannot make the difference. You just have to know it. And so this explained the 47 40% of sensitivity that we had in our trial. But even with 40% of sensitivity, the FDA was able to recognize the value of peace methods at primary stage. Now let's look at the main pitfalls that everybody needs to know. And of course, there are some false positives pitfalls, like with every imaging modality, they are now pretty well known. I will go over the most common one now, one of which is the ganglia, not merely nick. Nerves have for some reason some PSM expression and can mimic lymph node metastases because they can be located at the exact same place, especially in the pre sacral celiac or super curricular areas. Uptake is usually faint or intimidate. You can see the ReMax ranging from 1.5 to 3. Here. The main thing is to look at the coronal images, chasing for some kind of symmetry or other similar pattern at the other levels. Usually, when a patient has it at one place, uptake can be seen at the other levels. The city helps also a lot by showing typical shape in band in teardrop, one regular in the cervical area. So after a few cases, you get used to it, and you were able to make a difference with metastases. Like with most of any nuclear medicine tracers, any bone trauma which fracture or not, can show some ps mm uptake. City helps a lot by showing sclerosis for metastases or a fracture like here. But the ribs lesion can still sometimes remains very tricky, especially when isolated and new. You have to use all the other info pretest likelihood of having metastases from a history single versus multiple lesion prisons of other metastases. And at the end, when a single focus with faint uptake without clear sclerosis, it is usually not a metastasis in this single center retrospective study looking at 62 PS method Solitary re regions. Before any treatment, they were able to follow up decisions, and only one was found to be malignant. So at the end, you cannot exclude men from potentially creative local treatment based on a suspicion of solitary piece May Petrie metastases, another one that is kind of common again here, like with most of any pet tracer inflammatory lymph nodes can show some uptake, especially in the inguinal areas or the media sternal areas. These regions drain basically all the dusty and inflammatory process, and again, faint and symmetric uptake suggests more an inflammatory or granuloma to Cisco's rather than an Essene Metric focal uptake by malignant process. We also have now to relearn the pattern of prostate cancer spreading. For example, Learn was thought to be a rare sight of prostate cancer metastases or seen only in very advanced patients. But we have now numerous cases of patients with early disease and Easter pathologic proven solitary pulmonary prostate cancer metastases detected by PS mm pet, whereas the nodal was stable on city for years and we're now discovering even new patterns of flying metastasis of prostate cancer, such as in his very rare case, ground glass nodule that turns out to be a prostate cancer metastasis. So pretty rare Small is the same for peri, rectal and left supermarket, particularly notes that we do see a lot with PSM a pet, and we're still learning again and again. We discovered interesting findings in irradiated prostates, for example, in this specific case of reference, 10 years after radiation therapy piece was 2.6 focal uptake seen here with SUV Max of 91 was seen in the right prostate. But biopsy demonstrated no evidence of viable tumor. There was a marked radiation to rapid changes in residual benign lands. There was cancer treatment effects with balloon sales that were observed and cells with marked peace and expression, as seen here by immuno esto chemistry, whereas adjustment benign glands did not demonstrate peace and expression. So in our biochemical recurrence cohorts, we looked at the suspected local relapse after radiation therapy, for which we had the stroke pathology correlation and 23% some uptake was noted in PSM, expressing benign tissue or tumor remnants with successful radiation treatment response by Easter pathology. So this kind of new is this viable? Is this the source of the patients rising P s A. Does it have any prognostic value? I think there is still a huge and no there. But I thought this was an interesting fighting to report. We're still learning. One of the main weakness of Kissimmee pet is the urinary expression of the tracer leading to high your literal and brother activity. This can make the analysis of the prostate force are sometimes difficult. You can see here local recurrence kind of hidden in the bladder urinary activity with the same intensity visualization. So the first full to analyse properly the prostate fossa is to adjust the SUV scale intensity. In this example, you can see that the maximum of the SUV scale is very high 37. It can allowed to better differentiate the background bladder activity from the tribulation. And so reading pet is a dynamic process and you definitely cannot read a scan with a fixed SUV scale, you need to adapt the intensity to the background activity surrounding your target. And similarly, you always have to look at the nine views actual Corona LSA digital city. Only Patani fused, uh, scrawling into into all the images and, for example, in that case, looking under the bladder for some focal for quality. So I have showed the diagnostic performances parameters and show the main pitfalls. So now let's now that we know that how PS method can do or not do, let's compare it to the other imaging modalities for prostate cancer. It is when you look at the literature, it is now pretty clear that pet imaging of the PSM, a target is the most accurate and sensitive imaging modality for prostate cancer staging Compared to conventional imaging city bone scan Compared to Colin Pet and compared to physical of impact for early stage disease, it is now pretty clear that the PSM ever expression is a more sensitive biological target for pet imaging of prostate cancer than the up regulated metabolism. Let's look in more detail about the current standard of care pet imaging for prostate cancer free, seek lovin pet, or actually mean that became FDA approved in 2016, and now it has been implemented in all clinical guidelines. This is, I mean as inimitably pet imaging tracer. It shows where the I mean as metabolism is increased. Yeah. I mean, I see transporters l 81 or 82 and these I mean, I see transporters are up regulated by the prostate cancer cells. Therefore, representing a good target for prostate cancer. Pet images. We conducted a study comparing head to head accident to PSM. We prospectively evaluated the performances of both tests in the same cohort of patients with early recurrence after surgery with the PS below two. So the population that may be still be cured by, uh, with a salvage radiation therapy tree blinded independent central readers for each modality. And here are the results Detection rates on the patient level, with PSM in red, we're twice than with exhuming in blue. And the inter reader agreements was much higher with PSM than with. And I'm going to show you why in nuclear imaging, everything is about lesion to background ratio. Here is an example of a concordant case who had left iliac lymph node metastases positive on both scans. But the maximum s remark was four and the P s M s remarks was 11. So almost three times higher. Here is another example that's a discordant case. PSM effort was positive for left iliac lymph node metastases which was confirmed by his to pathology and actually mean it was negative. You can see the very high background activity of sick Levin here, which makes the read much more difficult. And that is why the Inter Reader Agreement is much higher with PSM A. The over expression of plasma protein is much higher than the up regulation of 82 or 81 and the background activity is much lower with ps Mm pet than with president of it. Just to be fair, I show here one case that we had with low PSM expression. You can see here the primary tumor and high amino acid metabolism activity per pet imaging. So but this is one case over thousands of scans that we have, so that's pretty rare. Just show that for the for the story, Okay, the next question is what to do with the peace method findings. Now, with a more sensitive tool, we need to relearn the disease stage definition and their management algorithm, for example, what to do when when you see anyone, this is a P S m a pet scan. These patients were in zero pre conventional imaging. So there are some patients in whom what we see on the place map it represents actually the whole burden of the disease. And there are others in whom they are in fact, much more non visible micro microscopic disease. In any case, now I think we start to know that PS methods anyone disease does have high prognostic value. I'm gonna show you here in this nice German study of 230 patients. You can clearly see that the outcome after surgery is much better when the PS mm pet was negative than when it showed anyone or someone disease before the surgery. Similarly, in this prospective multi center Australian study of 260 patients, the outcome of patients after salvage radiation therapy is also much better in patients who had a PSM, a pet scan negative or showing local recurrence on the disease confined to the prostate Phosa than in patients with anyone or m one disease. So to go further, we show that ps mm pet can show lesions outside of the radiation fields in close to 20% of the patients. These non covered out of the lesions are represented here in yellow Primary staging, setting, salvage, radiation therapy sitting And you can see here the treaty targets radiation through active fields of volumes. So obviously radiation therapy would have failed in these patients. And so this provided rational to initiate prospective randomized studies power for outcome. We feel the study design is the following one. In the salvage radiation therapy setting, patients were randomized to standard radiation therapy or PS mm pets before salvage. Radiation therapy will follow the patient for five years, and we'll see at the end if there is a difference between the patients who were selected by PS my pet to get radiation therapy and the ones who did not go undergo PS mopeds. Staging selection Similar design in the definitely radiation therapy primary staging setting The study is still open and recruiting at UCL, so police standards patients. It's a 50 50 chance to get a free scan. The radiation therapy is done with you, not at you. Just the scan is done at UCL in 50% of the case and to go further now, I'm going to talk about PS MM pit as a as a biomarker. That's that would be the next step. I think for peace and opportunity you are may be aware of what is PSM Etireno sticks or radio? Nuclear therapy or molecular radiotherapy? Basically, your going to the same target PS. Mm. But instead of choosing gallium 68 of your 18 pet imaging hygienically you use treatment Radio new Kate Agent and Lucchesi Um, 177 can deliver better radiation therapy radiation to the target that expressed PSM A. Here is a nice example of a patient where you see all the disappearance of all the target lesions that you can see here on the baseline scan after four cycles of mutation. P S m A. Uh that is also confirmed with a very, very nice pills, a response up to undetectable level and the PS methods Imaging features have also some prognostic value for the response to any PSM targeted radio nuclear therapy. Hi and marginals do better than low uptake and also do better than active generals uptake, as you can see here. So maybe in the future we can also implement F g as a entry gate combined PSM NFC debate as an entry gate for PSM, a targeted radio nuclear therapy, Because we know that the patient that are f g positive piece in the negative, they don't respond well to this therapy. So I'm sure in the future will have, like, biomarkers to select therapy for patients like that. This will be much less line. I think you slide always tricky. I'm sure to have Forget someone I hope not. So you all the team that led to this great clinical research program. We have a true sell it on the aeronautics and the PSM target. But we also have other targets. And with that, I would like to thanks again the organizers for inviting me. And I look forward to the questions. Thank you very much.