Dr Rana McKay (USA), Dr Elena Castro (Spain) and Professor Yao Zhu (China) share their perspectives on patient selection for genetic testing, which genes should be tested and their experiences with tissue and ctDNA testing.
- [Rana] Welcome everyone. It's a pleasure to be here with you, my name is Rana McKay, I am an GU medical oncologist at the University of California in San Diego. And today we're gonna be discussing prostate cancer diagnostics and reviewing guidelines for genetic and genomic testing and metastatic castration resistant prostate cancer. I'm really excited to be here with my colleagues, Dr. Castro and Dr. Zhu. Dr. Castro, would you like to introduce yourself?
- [Elena] Hi Rana, my name is he Elena Castro, I'm a medical oncologist at hospital, in Madrid, and it's a pleasure to be with you both here today.
- [Rana] And Dr. Zhu, would you like to introduce yourself?
- [Zhu] Hi Dr. McKay and Dr. Castro, I'm Yao Zhu from Fudan University, Shanghai China. I'm a urologist focusing on prostate cancer surgery and the research. Thanks for having me.
- [Rana] Wonderful. So today you know the key purpose of our discussion is gonna really focus around the importance of considering molecular testing for all patients with metastatic castration resistant prostate cancer and sort of understand the different practices across the world globally, and just different perspectives across different specialties. Maybe first we can start with the NCCN guidelines, which were just recently updated and do recommend molecular testing for select individuals with prostate cancer. And at a minimum the NCCN guidelines really hones in on testing for BRCA1, two, ATM, PALB2, CHEK2, HOXB13 and then the MSI genes should be included in panel testing. And really the main reason to include these genes in testing, particularly for patients with advanced disease is 'cause these genes can serve as predictive markers for sensitivity to PARP inhibition and potentially can provide these patients with another treatment option, particularly those individuals who have BRCA1, two alterations, either as monotherapy or in combination with an ARSI. Additionally, testing also opens up the door for the pan tumour indication for pembrolizumab based off of MSI high status or tumour mutation burden. So that kind of level sets us for guidelines in the United States, and you know, Dr. Castro would love to hear your thoughts on where ESMO stands with their guidelines and what differs with regards to the NCCN.
- [Elena] Well, the ESMO guidelines regarding germline and genomic testing were published in 2020 and it's only four years ago, but they're perhaps not outdated, but they don't provide as much detail as we would like to have in daily practice. We need to remember that in 2020 it was the first time that we had targeted therapies for prostate cancer and the aim of the guideline was actually to remark the need to start considering testing for our patients. And so it recommended to assess at least HRR genes and mismatch repair, but without entering into the details of which genes and when was the right timing, and also reinforce the need of germline testing for all patients with metastatic prostate cancer, but again, without detailing which should be the gene panel that should be tested. And the guidelines also recognise that there may be some patients with localised disease but with a family history of prostate cancer or other tumour types that should also be offered germline testing. And also recognise that when we perform tumour early sequencing, there is a high probability that certain alterations have a germline origin and this patient should be referred for germline testing. There's another document, another ESMO recommendation on which are the type of alterations that should be referred for germline intestine based on the variant allele frequency, et cetera, et cetera. And with regards to the genes, there's also a third document based on the recommendations for NGS in oncology that for prostate cancer recommend testing at least BRCA1 and BRCA2 and recommends to expand the panel for tumour testing depending on the access in the different countries or in the different region. But these guidelines, the ESMO guidelines are being updated as we speak.
- [Rana] That's wonderful, thank you for that summary. Dr. Zhu, how are practice patterns and guideline recommendations in the Pan-Asia region?
- [Dr. Zhu] Yes, so first, both the AUA and the EAU guidelines were updated last year, and the two guidelines recommend offering germline testing to patients with a family risk of associated cancers. And those patients with metastasis disease, and specifically the EAU guideline also advise the germline testing for those patients with high risk localised prostate cancer. And for MCRPC patients, both urologic guidelines proposed that the DNA damage repair genes, MSI gene and the tumour mutation burdens should be tested and managed with therapy. And I think the EAU guideline also utilise a prognostic panel comprising the TP53 RRB1 and P10 loss to identify aggressive variant prostate cancer and I think it's maybe used in some high volume centre to indicate early prognostic stratification for these cancer patients. And the Pan-Asia adopted ESMO guideline with a quite similar criteria for genetic testing as the ESMO guideline. However, we can see the guideline still lack the comprehensive details on genetic testing and it may suggest a limited application of this kind of resource in the Asia region.
- [Rana] That's excellent. Thank you all for giving that overview. You know, I would probably summarise that the NCCN guidelines have been the most recently updated and do actually provide specifications around the exact genes to add a minimum test for and the reason for testing around sensitivity for therapy selection in the advanced setting. And I think as you all stated, the ESMO guidelines are in the midst of being updated now and the surgical guidelines both AUA and the EAU also touch on the significance of testing, though don't necessarily define the exact specific genes to test for. So you know, moving forward, I think we talked about the gene alterations to test for one of the biggest questions is who to test, and when should you do testing? When should you do germline testing? When should you do somatic tumour profiling. And again, maybe we can start with the NCCN guidelines to level set and then discuss sort of the guidelines across the different regions. For somatic tumour profiling, the NCCN recommends this sort of testing for all patients who have metastatic disease, and that includes testing for homologous recombination repair gene alterations and mismatch repair. You know, that one's the easy one. For regards to the germline testing, there is a little bit more granularity around who to actually test for. Certainly those individuals that are regional, meaning lymph node disease, metastatic and actually also localised very high risk or high risk disease just based off of NCCN criteria, those individuals are eligible for testing. And then for individuals that don't fit that category, if they have a family history of first, second, or third degree relatives with select cancers or have a known family history of a pathogenic alteration or of Ashkenazi Jewish ancestry have a personal history of breast cancer, those individuals should also be recommended for testing. And then there's a caveat for consideration for germline testing for those individuals with intermediate risk disease that have intraductal features or if there's individuals that have a personal history of pancreatic, colorectal and other select tumours. So there's a lot more granularity in the NCCN guidelines around the germline testing in the localised setting. But for people with advanced disease, it's pretty clear, basically test everybody for germline and somatic profiling. So Elena, where does ESMO stand on who to test for both germline and somatic alterations?
- [Elena] Right. The current version of the guidelines recommends both germline and somatic testing. Germline testing for all patients with metastatic disease will the somatic testing in 2020 was recommended for patients with metastatic castration resistant disease. So I wonder whether this will change in the next version of the guidelines. For germline testing, should be considered also all basis in which we have perform tumour testing and a mutation or an alteration in cancer predisposition genes associated with prostate cancer, and as mentioned earlier, there is another document, another set of recommendations that indicates which are the type of alterations that should always be considered for germline alterations because the chances of finding germline mutations are higher. And of course even for patients with localised disease, high risk or even intermediate or low risk, if there is a family history of prostate cancer or other tumour types, we should consider offering germline testing to those patients as well. And in this regard, I think Rana that the best guidelines on the wider recommendation is provided by the Philadelphia Consensus that really tell us which are the genes that we should be looking at and when to expand to other genes based on family history. And to be honest, this is what I apply in my practice, the Philadelphia recommendation.
- [Rana] Yeah, thank you so much for touching on those. And Dr. Zhu, how are things viewed both on the urology side and then also just in the Pan-Asia region?
- [Dr. Zhu] Yeah, so the patient selection I think adhered to the purpose of genetic testing, which was two-fold assessing the hereditary risk and guiding the treatment. And I think both the urologic guidelines, they're focusing on guiding the treatment for patients with metastatic disease and using similar criteria as NCCN guideline. And the AUA guideline, there is lack of clear definition of patients refer to the germline testing. So EAU guidelines underscored the specific family history of cancer associated with germline mutation. So I think there is less clear information about which kind of the patients should recommend germline testing, and it may relate to lack of a strong genetic consultation background of the urological guideline.
- [Rana] That's excellent. You know, we chatted a little bit about what the test for, the settings to test in patient selection. You know, a big question that always seems to come up is, all right, what do I use for the test? Do I use tissue? Which tissue do I use? Archival tissue, CTDNA. And so how do you all, you know, practice differs? You know, in the US we attempt to use tissue whenever available, even if it's from a prostate biopsy, a radical prostatectomy. But when that's not readily available in the metastatic setting, we do have access to ctDNA testing, understanding that sometimes tests can reveal false negatives, but that is readily available. How do you all integrate ctDNA testing and what's the preference around tissue testing in your practices?
- [Elena] We tend to use tissue as much as possible unless it fails or we cannot retrieve the diagnostic biopsy or the prostatectomy or if the patient doesn't have any lesion that is amenable for a new biopsy. And then we may use circulating DNA. I have also used it in the context of different trials and different research protocols. And I think perhaps a circulating DNA would be the future for tumour testing in prostate cancer because we have many difficulties with tissue and that meaning if the sample is too old or if we don't have enough tissue or the way the sample has been processed sometimes destroys the DNA and we cannot perform NGS on those samples. But at the same time we need to be aware of the limitations of ctDNA at present. So I think both, is a mixture of both that we use.
- [Rana] Excellent. Dr. Zhu, how is ctDNA testing integrated in Asia?
- [Dr. Zhu] Yeah, so in many of China for patients with newly diagnosed prostate cancer and have metastasis disease, we usually sequence the primary tumour tissue for the DNA alterations for these kind of patients. However, in patients with metastasis CRPC disease, we usually utilise the ctDNA to identify the candidates for tagged therapy. I think in China the lack of reimbursement and the different criteria to define ctDNA alteration contribute to the under utilisation of this kind of testing. And moreover interpreting ctDNA require more expertise and the physicians should initiate ctDNA testing in suitable patients and also be aware of the chip related false positive results and trying to distinguish between the germline and the somatic alteration, and this all some kind of the barrier to adopting of ctDNA in a wide range in my region.
- [Rana] Thank you for that. It sounds like there is variability in access integration reimbursement of ctDNA testing across the different regions. I think across the board, there's pretty excellent consistency in recommendations for tissue profiling and certainly metastasis biopsy can always be recommended. But I think the fact that there's consistency across the guidelines in testing patients for advanced disease and likely a predilection for tissue just because of availability is something that is consistent. You know, I think as we sort of transition, we touched on this a little bit, but in you all's just regular day-to-day practice, who are you recommending testing for? Dr. Castro, do you wanna maybe start? I think the easiest one is basically testing for all patients with metastatic disease. I think that is a no-brainer where there may be some variability is in the localised patients, just exactly who to test for based off of risk of disease or family history or other features.
- [Elena] Yeah, no, no, that is true. This is what we should be doing, but I really dream of a day where we will do as our lung cancer colleagues that they test absolutely every patient based on ctDNA and that helps them decide which could be the most appropriate therapy for their patient, they can from the very beginning decide which is the path they are going to take for that patient. I think we all agree and all the guidelines agree that it is something that should be implemented in our practice, but the implementation and it's still been a bit tricky. And at least in my practice, sometimes we don't have the, or in my region, we have this issue of testing not being reimbursed sometimes and then patients feel, my colleagues sometimes feel that there is a lot of struggle for a small proportion of patients being eligible for therapies or sometimes we may end up using other treatments and don't really pushing testing as much as I should. And I think this will change as soon as we have other targeted therapies available, though, and we are more like the lung cancer field, colleagues, we have more options. And then I think this is what is really going to change the practice and really push the implementation of testing. But this is for targeted therapies, the other thing is germline and I think we need to make sure that we have germline information for all of our patients. This is different, this is not only for therapy, but I think we can really do a lot of good by identify who are those carriers and then enrolling those families in early detection programmes. But to summarise, my experience is that we need to do better and offer testing, both tumour and germline testing to more patients that we currently do.
- [Rana] I think I would agree with you Elena, that that is sort of our target and our mission. You know, hopefully in the future the breadth of targeted therapies that could be offered for any given patient or clinical trials continues to expand as we begin to understand more about these tumours. Dr. Zhu, what do you consider to be kind of the gold standard approach for molecular testing within the urologic community?
- [Dr. Zhu] Yeah. I think one point I want to add to the Dr. Castro's recommendation is that I think the molecular profiling for patients in under representative group is very important to facilitate the precision oncology in prostate cancer field. For example, in China we do not have the PSA screen and nearly half of our patients newly diagnosed, they have prostate cancer at metastasis disease. So if we can genomic profiles, these patients can add to the information about how the precision treatment initialised early in this kind of patients. And regarding the germline mutation, we know that the variant of uncertain significance is quite high in patients with black race or the Asia region. So if we can gather more information in this kind of the underrepresented subgroup, we may improve our understanding in this patients and we can improve the precision oncology in a wider range for these kind of patients. And for the gold standard question, I think the gold standard is adherence to the specific detection measures in the clinic trials for this kind of the approved drugs. But tissue testing can be very challenging or costly. So in our clinical practice, we integrating more ctDNA testing to enhance the development of precision oncology in prostate cancer patients.
- [Rana] Thank you for that. I'm so grateful that you actually brought up the discussion point around access and ensuring that we have testing across diverse populations in all of our regions. They are melting pots of people that are very heterogeneous with different socioeconomic backgrounds, you know, different levels of health literacy, different access to insurance and coverage. I think it's gonna be critically important that as we are integrating standards for testing across the board, that we identify those barriers across the board for underrepresented patients and think of opportunities to bridge those, you know, access to genetic counsellors is very limited. Can we integrate videos that are culturally sensitive in patients native language that can help demystify, you know, genetic testing and germline testing and offer more clarity around that for patients to really, you know, help them understand and help physicians and APPs, mid-level providers so forth, educate patients around the need for testing and how it can actually benefit that individual. And I think too, you know what a urology practice probably operates very differently than a medical oncology practice. And so ensuring that there's actually additional support individuals, whether it be a nurse or a medical assistant of some sort that can help facilitate the testing for patients. Any other thoughts?
- [Elena] No, not really. Just that some provide more detail than others, but I think now there is this clear agreement that this is something that should be implemented in our practice and looking towards the future, I guess this is something that, now it sounds sometimes like something very difficult reading these genomic reports and everything, but I think we will get used to those, and this is something that is the medicine of, I was going to say the medicine of the future, but is the medicine of the present, right? So we need to make sure that all our patients get that information and we treat them according to the characteristics of their tumours.
- [Rana] Wonderful. Well, thank you all, I'd love to thank you know my fellow speakers for their time and just fantastic inputs throughout this podcast episode. I think I can speak for everyone when I say that we all definitely now have a better understanding of what the guidelines say about genetic testing and prostate cancer, including how they can vary and where there is general consensus. I think we'll be looking to implement testing a bit more in our own practices from now on. And as a final remark, thank you to all of you listening to this podcast today. If you've enjoyed listening to our discussions, be sure to tune in next time and listen to Dr. Steven Yip, Alicia Morgans and Dr. Zhu discussing the predictive value of HRR BRCA mutation status and patient outcomes and treatment decision making and linking how what we've learned today in the guidelines with testing has real world value and benefits for our patients. Thank you so much.
Stay tuned for the next episode in the coming weeks, chaired by Dr Steven Yip: ‘Understanding the predictive value of HRR/BRCAm status in mCRPC’
Meet the experts
Dr Rana McKay
Dr Rana McKay is a medical oncologist specialising in genitourinary tumours. Dr McKay serves as an associate professor of medicine and urology at the University of California, USA, associate director of translational sciences, interim associate director of clinical sciences, and co-lead of the genitourinary oncology program, where she conducts research focused on developing novel therapies for people with advanced prostate and kidney cancers.
Disclosures: Consultant/advisory board fees from Ambrx, AstraZeneca, Aveo Oncology, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Johnson & Johnson, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Telix, and Tempus. Institutional research funding from ArteraAI, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Oncternal Therapeutics, and Tempus.
Dr Elena Castro
Dr Elena Castro is a medical oncologist specialising in prostate cancer. She conducts research at the Spanish National Cancer Research Center in Madrid, Spain. Her work primarily involves the molecular characterisation of prostate cancer and development of new treatment strategies.
Disclosures: Financial support from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Lilly, Medscape, Merck, MSD, Novartis, Pfizer, Sandoz, and Telix.
Professor Yao Zhu
Professor Yao Zhu is a consultant urologist specialising in urologic cancers. He is a professor of oncology at Shanghai Medical College, China. His extensive research in urologic cancers, particularly prostate and bladder cancer, has led to significant contributions to the field.
Disclosures: Financial support from AstraZeneca, Bayer, and Janssen.
