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Clinical Focus

Howard I. Scher, MD; Scott T. Tagawa, MD, MS, FACP; Mary-Ellen Taplin, MD

Medical Crossfire®: How Does Recent Evidence on PARP Inhibitors and Combinations Inform Treatment Planning for Prostate Cancer Now and In the Future?

Patients with elevated CTC count at baseline experienced poor complete response rates and worsened PFS and OS. 

Circulating tumor cell count may serve as a prognostic biomarker in mHSPC

“NSD2 is a cancer specific collaborator of the androgen receptor that essentially rewires its activity to support prostate cancer development," says Abhijit Parolia, PhD,

NSD1/2 may serve as potential therapeutic targets in prostate cancer 

Patients who had mutations in the ERCC2, ATM, or RB1 genes were more than 5 times more likely to achieve a pathologic complete response following cisplatin-based chemotherapy.

Gene mutations associated with response to cisplatin-based chemotherapy in MIBC

"The scale of that linkage and the manner with which we were able to do it is really exciting and opens the door for a lot of future discovery," says Michael S. Leapman, MD, MHS. 

Investigators link genomic and clinical data to real-world outcomes in prostate cancer

"We wanted to look at the importance of genetic testing in patients with GU cancer and the impact that it has on their treatment decision-making, and the pathways that we put them on," says Mouneeb Choudry, MD.

Dr. Choudry and Dr. Durant discuss pathogenic germline variants in GU cancers

Dr. Vince on “Assessing the Clinical Utility of Published Prostate Cancer Polygenic Risk Scores in a Large Biobank Data Set.” 

Dr. Vince on evaluation of prostate cancer polygenic risk scores

study “Assessing the Clinical Utility of Published Prostate Cancer Polygenic Risk Scores in a Large Biobank Data Set.” Vince is an assistant professor of urologic oncology at Case Western Reserve University and University Hospitals Urology Institute, as well as the director of Minority Men's Health at University Hospitals Cutler Center for Men in Cleveland, Ohio.

Please describe the background for this study.

Just for general background, polygenic risk scores incorporate what we call SNPs, which are obtained from what we call GWAS, which is a genome-wide association study. By looking at these SNPs, we're trying to look at the hereditability of prostate cancer. There have been a number of GWAS studies that have developed polygenic risk scores for prostate cancer. And what they found is that there is a really strong association for most polygenic risk scores with the incidence of prostate cancer or the risk of developing prostate cancer. However, what we know is that it is much bigger than just whether or not you develop prostate cancer. Because there's a whole debate among a lot of people in terms of, should we be diagnosing people with low-risk prostate cancer, that's pretty indolent? The reason why some of the guidelines changed in the past to recommend against prostate cancer screening was because we were overdiagnosing low-risk disease and overtreating people with low-risk disease. So now, we know there's a move to try to shift from just diagnosing anyone with prostate cancer, to purely being able to focus in on those men with clinically significant disease. That way, they can move on to biopsies and things like that and potential treatment. What we wanted to do with this was to look at 1) Out of the polygenic risk scores that have been published, how do they perform on an external data set with the association for incidence of prostate cancer and then for those top-performing polygenic risk scores, how do they associate with the aggressiveness of prostate cancer; in other words, does an increase in polygenic risk score correlate with increasing disease aggressiveness?

Considering 16 PRSs were evaluated, can you elaborate on the specific criteria used to identify the top-performing ones for further analysis of aggressive prostate cancer?

In terms of the 16 polygenic risk scores that were selected in general, our external data set from the University of Michigan was predominantly men of European ancestry. And so we wanted to use those polygenic risk scores that would develop on men of exclusively European ancestry. That way, it will be a strong correlation. And then the first step was, again, to look at the association with the incidence of prostate cancer for an increasing polygenic risk score. And what we found is that across the board, all 16 scores did relatively well with the association between an elevated polygenic risk score and prostate cancer incidence. However, what we did was those top 3 performing - so when we look at what we call an odds ratio, those risk scores that have the strongest association with prostate cancer incidence, we then took those polygenic risk score constructs and then applied it to evaluating disease aggressiveness. And so that's how we selected those top 3 polygenic risk scores to determine what to evaluate the association between disease aggressiveness with the increasing score.

This transcription was edited for clarity.

Videos

"What we found is that across the board, all 16 scores did relatively well with the association between an elevated polygenic risk score and prostate cancer incidence," says Randy A. Vince Jr, MD, MS.

Dr Choudry and Dr Durant on “Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study.” 

Study underscores importance of genetic testing in genitourinary cancers

study “Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study.” Choudry and Durant are urology residents at Mayo Clinic in Phoenix, Arizona.

What is the take-home message for the practicing urologist?

I think the biggest take-home message is just the importance of genetic testing. I think we were really shocked by the incremental findings or the findings that would have been missed by guidelines and the number of changes that would have happened and impacting patients based on surveillance and cancer screenings and the amount of family members that got tested based on these. And so I think that it's important to remember the guidelines and important to consider genetic testing and just important to consider how germline genetic testing will continue to evolve in its role in GU cancers, as it's important and its implications for treatment decisions, surveillance and impactful for patient family members.

I do want to give a special thanks to the Invitae company; they helped us with this trial. And then a special thanks to our mentors, Dr. Tyson, Dr. Samadder, and Dr. Andrews, who really helped us out with this.

"I think the biggest take-home message is just the importance of genetic testing," says Adri Durant, MD. 

Dr. Choudry and Dr. Durant on questions raised by pathogenic research in genitourinary cancers

I think 1 of the biggest questions that comes from this is that we are identifying these PGVs in the prostate, bladder, and renal cancer populations. But having a better understanding of which PGVs are really putting patients at an increased risk vs others, I think would definitely be something that needs more investigation. And then I think more work needs to be put into, how do we broaden the guidelines? A lot of times, I think what we struggle with in the medical field is, we have a lot of different tools and resources that we can use to help patients in terms of their overall care and guiding their treatment. But much of that comes back to, do insurances cover that, or do patients have the ability to afford that? Many times, these insurance companies will reference guidelines. I think more work needs to be put into better guideline statements on who needs this sort of genetic testing. That's not to say that we need to make it broad right away and say, everyone who has any concern for prostate, renal, or bladder cancer should have that. But I think there needs to be a little more work and investigation there to pinpoint who needs this and who doesn't. And then I think the other part of this, which we kind of touched on a little bit, and I think more questions need to go into is, like Dr. Durant talked about with the cascade testing, and family members uptaking this once they learn that the family member has these concerning PGVs, how to get more of these family members information they need to want to go and pursue genetic testing. And then once they have that information, what do they really do? We know that it's important, but I think some more work needs to be done to better have an understanding of who really needs it, and what do we do about it?

 I agree. This is, I think, an impressive study from the amount of patients we were able to enroll from the Mayo Clinic sites, but still larger population studies are needed to validate these findings as far as what is the pathogenic variant rate within universal populations, and universal screening. And then as Dr. Choudry talked about, what is the infrastructure we need to help guide patients with these pathogenic variant results? What does that mean to them? And this, I'm sure, will continue to evolve as precision medicine continues to evolve in GU cancers as well.

"Having a better understanding of which PGVs are really putting patients at an increased risk vs others, I think would definitely be something that needs more investigation," says Mouneeb Choudry, MD.

Doctors discuss “Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study.” 

Many pathogenic germline variants in GU cancers would be missed according to current guidelines

describe the background and notable findings from the 

We wanted to look at the importance of genetic testing in patients with GU cancer and the impact that it has on their treatment decision-making, and the pathways that we put them on. The identification of germline testing, it's affected patients, and it really has important implications in that treatment decisions and their risk of producing future interventions, and cancer screening in general and also the relevance it has in terms of their relatives and the impact it has on their family members. And in recent years, there's been more of a emphasis or concern that's been placed on finding more targeted therapies for individuals with advanced cancers, particularly if you look at patients with prostate cancer, and you look at patients who have metastatic prostate cancer and the use of the PARP inhibitors. And with the FDA recently approving that, there was more of a concern and more of a need, we felt, to better identify the use of universal genetic testing in the GU cancer population. The only other study that really looked at this before was PROCLAIM trial. That was one of the first times where we really looked at comparing universal genetic testing vs just following the guideline-based genetic testing for patients. With all that, and the recent need for a better understanding of the usefulness of genetic testing, that's the reason why we wanted to dive deep into this idea and get some better answers.

What were some of the notable findings? Were any of them surprising to you and your coauthors?

This was a multi-site study involving Mayo Clinic institutions across the country, and over 600 patients with GU cancers were enrolled. This included patients with prostate, kidney and bladder cancer. Universal genetic testing was offered to them regardless of guideline recommendations. And when we looked at the pathogenic variants identified, we found that overall, nearly 15% of patients had pathogenic variants that were represented on the genetic testing, which was pretty notable. And then when we looked at these pathogenic variants, actually, two thirds of those patients went on to have clinically impactful changes, whether that's increased screening or surveillance. And then when we looked at cascade testing, or whether their families went on to have changes in their care based on that, nearly a third of those patients went on to have family tested based on these results. And then another, I think, really probably the most notable finding of this was the incremental findings of the test. And that means that patients who were identified to have pathogenic variants who would not have been identified based on current guidelines. We identified a very high percentage within this population. And so of patients with bladder cancer, 100% of the pathogenic variants would have been missed based on current guidelines. In kidney cancer, 80% of patients almost would have been missed based on current guidelines, and over 50% of the patients with prostate cancer with pathogenic variants would have been missed based on current guidelines. And so I think that was really the shocking thing that we found and the really clinically impactful thing that came out of this study

"Of patients with bladder cancer, 100% of the pathogenic variants would have been missed based on current guidelines," says Adri Durant, MD.

Dr. Joshua Linscott shares findings on the value of utDNA in high-risk NMIBC

Dr. Linscott on utDNA as a biomarker in high-risk NMIBC

 shares key findings from the study, “Tumor fraction and copy number burden from urinary cell-free tumor DNA (utDNA) to predict minimal residual disease prior to repeat-transurethral resection in high-risk non-muscle invasive bladder cancer (HR-NMIBC),” which was presented at the 2024 American Society for Clinical Oncology Annual Meeting in Chicago, Illinois. Linscott is a urologic oncology fellow at Moffitt Cancer Center in Tampa, Florida.

I think there are a couple important finds that came from the study. Maybe the most important is that urinary tumor DNA does seem to be a good tool for detecting residual disease within this patient population. The way we did that is there are multiple things you can look at within that urine, the genomic contents. One would be that there are large structural changes to your DNA that happen, gain of an entire gene, loss of a chromosomal arm. You can detect those with relatively Low Pass Whole Genome Sequencing. As bladder cancer has some of the highest number of copy number alterations, it's a pretty good marker for residual disease. However, not everyone is going to have that. So, we also looked at some of the individual point mutations, single nucleotide variations. And we did this with a personalized assay based on their baseline tumor. These bespoke assays, where you're really looking for key mutations within the patient itself, give you a tumor fraction. What we found is tumor fraction does a very good job of detecting disease when it is positive, but it's not the most sensitive. So therefore, we combined it with that copy number burden score. The 2 together ended up leading to a 90% accuracy overall on detecting whether or not there was disease or whether these patients were disease free.

This transcription has been edited for clarity.

“Maybe the most important [finding] is that urinary tumor DNA does seem to be a good tool for detecting residual disease within this patient population,” says Joshua Linscott, MD, PhD. 

Dr. Linscott on utDNA as a biomarker for MRD in high-risk NMIBC

Dr. Zeyad Schwen discusses findings from a study on transition vs peripheral zone prostate lesions

Dr. Schwen highlights zonal variations in prostate cancer biology

, highlights the background and key findings from the study, “Transcriptomic features of clinically localized prostate cancer arising from distinct prostate zonal regions,” which was presented at the 2024 American Urological Association Annual Meeting in San Antonio, Texas. Schwen is a urologic oncologist at the Cleveland Clinic in Cleveland, Ohio.

This was a very interesting study that stemmed from some of our acknowledgments and recognition of different behaviors of prostate cancers that arise from different zones of the prostate, namely the peripheral zone compared to the transition zone. We have noticed, from a radiographic side, that a lot of times these anterior and transition zone prostate cancers are oftentimes really scary looking on the MRI. This is actually something that has been presented in a number of different abstracts throughout the AUA this year. We wanted to find out is there any difference in potential behavior or transcriptomic features that we looked at using the Decipher score. We actually had the benefit of having all of the raw genes of the 42,000 ones that were sent from the Decipher microarray. We [looked at] people who had a transition zone lesion and compared those to people who had a peripheral zone lesion, seeing if there were any differences in the transcriptomic signature using the Decipher score.

We actually saw that [in] the transition zone lesions, after we matched these lesions to peripheral zone lesions, they tended to have a lower Decipher score. However, they were, interestingly, larger in size. The outcomes suggests that potentially they could have a lower chance of biochemical recurrence following treatment. We looked at also the various differences in the specific genes that were differentially expressed. There were about 220 genes that were differentially expressed, comparing transition zone to the peripheral zone, and certain patterns arose where certain genes were differentially expressed that have well established roles in prostate cancer biology and tumor genesis. This is something that we looked at in certain specific ones; one of them was SOX2, another is FOXF2, and ERG. These are well known ones in the prostate cancer biology. It's really interesting to see how potentially these differentially expressed genes could suggest a different biology based on the zone that they arose from. So perhaps this is a sign of a need for more study to come forward, looking at maybe how do these cancers behave, maybe they could be managed differently, and maybe watched more frequently than we currently are doing.

This is very interesting, because it played into a theme, like I had mentioned, [of] our recognition of how they look differently on imaging – they're larger, scarier looking. I think a lot of the other abstracts showed that they also were less likely to have clinically significant prostate cancer on biopsy. So, I think this certainly was a theme that I recognized coming from different areas of the prostate cancer research that was presented at AUA. It's great to see people coming to similar findings that we have seen and noticed here at the Cleveland Clinic.

"It's really interesting to see how potentially these differentially expressed genes could suggest a different biology based on the zone that they arose from," says Zeyad Schwen, MD. 

Dr. Schwen highlights zonal-based variations in prostate cancer biology

Dr. Laurence Albiges discusses data showing the potential for KIM-1 as a biomarker in RCC

KIM-1 shows potential as a circulating biomarker in renal cell carcinoma

, shares the background and notable findings from the study, “Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection,” which was presented at the 2024 ASCO Annual Meeting in Chicago, Illinois. Albiges is a medical oncologist focused on genitourinary malignancies and head of the department of oncology at Gustave Roussy Institute in Paris, France.

So, there have been different adjuvant studies [that] clearly depict that there may be some patients of the population who will derive benefit from adjuvant immune checkpoint inhibitors, while others may not. So, there is a need of a biomarker. What we are presenting is the first circulating biomarker analysis conducted in adjuvant trials with immune checkpoint inhibitors. It is a 2-step analysis, which looks specifically at circulating protein. The first part was about discovery. We screened over 3000 protein circulating biomarkers to assess the ones that were more likely to be highly expressed at the time of disease recurrence vs baseline post-nephrectomy. One circulating biomarker [stood] out; it's a protein named KIM-1, for kidney injury molecule-1. It is a protein that is a membrane glycoprotein known for a long time because it has already been analyzed to be associated with the diagnosis of clear cell RCC vs benign RCC tumors, for instance. It also has been investigated in the blood in the ASSURE trial (NCT00326898). This was a trial led many years ago, which investigated the role of TKIs, sunitinib or sorafenib, vs placebo. In this dataset many years ago, the authors were able to demonstrate that high KIM-1 level in the blood was associated with worse disease-free survival and worse overall survival. This potential circulating biomarker is of interest because it is stable, can be dosed both in the serum or in the plasma, and it's very stable. So, it is a good candidate for circulating blood biomarker.

That led us to move on to the second part of our analysis. Part 2 was to look with a high sensitive assay on the sequential blood samples that were collected in the INmotion010 [trial at] baseline, cycle for day 1, and either at time of disease recurrence or at time of treatment discontinuation when there was no disease recurrence. What we were able to establish are different things. The first one [is] we confirmed the prognostic value of KIM-1. Overall, in INmotion010, patients with high KIM-1 clearly had a higher risk of recurrence. So, this is a prognostic circulating biomarker. Second information is that KIM-1 seems to also carry some predictive value. Indeed, patients who received atezolizumab had a better disease-free survival than those who received placebo. So, this biomarker could speak to its potential predictive value. Third, on treatment assessment of KIM-1, we clearly depict the fact that patients that have an increase on treatment of KIM-1 has worse disease-free survival. So, it could be a monitoring tool in the adjuvant space. And last, we looked at time of recurrence, and here with this more sensitive assay, we confirmed that patients that had disease recurrence had a higher level of KIM-1–about 2-fold higher level than at baseline–while those who did not relapse didn't have an increase in KIM-1. 

So taken all together, this is the first time we're having a circulating blood biomarker that could be used as a monitoring tool in the adjuvant space with 3 different aspects. The first one is [it can] assess minimal residual disease. The second one is to define potentially a predictive role of immune checkpoint in the adjuvant setting. And the third one, a monitoring tool to follow-up our patients.

“The first one [is] we confirmed the prognostic value of KIM-1. Overall, in INmotion010, patients with high KIM-1 clearly had a higher risk of recurrence,” says Laurence Albiges, MD, PhD.

Circulating KIM-1 shows value as a biomarker in renal cell carcinoma

Dr. Chinmay Jani highlights the expanding role of ctDNA in urologic cancers

Dr. Jani on the evolving role of ctDNA in genitourinary cancers

, highlights the evolving role of ctDNA in genitourinary (GU) cancers. Jani is a hematology-oncology fellow at the Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

ctDNA has started having a major role in multiple different arenas for GU cancers, including prostate cancer and kidney cancer–RCC to be precise. ctDNA now can be used first of all for diagnostics. It [gives] us a lot of data about different mutations, alterations, and especially the targetable alterations that can be targeted with the treatment. Starting from the role from diagnostics to then utilizing ctDNA for progression of the disease, monitoring of the disease, checking how the outcomes are doing, whether the treatment is working or not [is] the second thing. Then, the third thing, most important one, is the prognosis. We are trying to evaluate the ctDNA role in prognostication as well–whether if we identify particular mutations and alterations, do they play a role in helping us evaluate and understanding whether a patient’s prognosis is great or poor. So, ctDNA has a big role. There's constant data evolving, whether it is more concordant, but I would also say lots of studies are showing that it's complementary along with the tissue diagnosis, because some cancers would have more detectable mutations when we look into liquid biopsy. So, I think the future will tell us more on how liquid biopsy can be complementary along with concordant for GU cancers.

“We are trying to evaluate the ctDNA role in prognostication as well,” says Chinmay Jani, MD. 

Dr. Washington on “Variations in Genomic expression profiles by age, race, gleason grade group, and geography among men with prostate cancer"

Investigators examine nationwide variations in genomic expression profiles in prostate cancer

 the 2024 American Urological Association Annual Meeting abstract “Variations in Genomic expression profiles by age, race, gleason grade group, and geography among men with prostate cancer.” Washington is an assistant professor of urology and holds the Goldberg-Benioff Endowed Professorship in Cancer Biology at the University of California, San Francisco.

Please provide an overview of this abstract and its notable data.

At UCSF, we do a lot of genomic testing. It helps us understand where men will lie on the risk spectrum. And it helps inform what we may do or how we may counsel patients, knowing that this is 1 more data point, but not a crystal ball that helps us understand where that person may need further work-up, further counseling, or help us understand what expectations we may need to set when we discuss treatment. So for this, we wanted to look at, well, we've been doing genomic expression profile Decipher testing at UCSF; what does that look like nationally? We've seen datasets and publications from other institutions and smaller groups. Now, we have access to over 165,000 men with Decipher testing, including biopsy specimens and radical prostatectomy or surgical specimens. And we looked to see, what are we seeing at a national level, and then how may that be changing depending on where people live, which state they're in? Thankfully, within this cohort, there was almost 10% of Black men who had data within this data set. We noticed pretty broad variation across states, even when we look at how many tests are being done. So we looked at both utilization by state and weighted scores based on the number of tests being done in each state, and noticed pretty interesting variations. We saw that Black men within this cohort had lower Decipher scores across all ages and Gleason scores different than what had been reported in other data sets, which was interesting. We're diving into that more to understand context, because now we really have geography, race, Gleason scores, but we don't understand where these people live, what is happening in these places to help us flesh out why we may be observing this. And then the grid data helped us flesh out expression profiles a little bit more. And this was more consistent with what we had seen in the literature, giving us a little bit of validation of our findings. But it's an interesting hypothesis-generating data set that we're now looking to explore further and layer on more clinical context to understand.

"We saw that Black men within this cohort had lower Decipher scores across all ages and Gleason scores different than what had been reported in other data sets, which was interesting," says Samuel L. Washington III, MD, MAS.

Dr Salari on “Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.” 

Integration of family history, germline genetics is important in defining prognosis of prostate cancer

 describes the implications for screening and decision making in prostate cancer from the recent 

study “Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.” Salari is a urologic oncologist at the Massachusetts General Hospital and Harvard Medical School.

What implications do these findings have for screening and decision making in prostate cancer?

I think the greatest implication the study has is that it tells us that family history and germline genetics independently provide complementary information that's important for risk stratification of localized prostate cancer. Further validation of these findings is definitely warranted, including how rare pathogenic mutations like BRCA1 or BRCA2 mutations, which were not assessed in the study, interact with these more common risk SNPs and family history. I'd also like to acknowledge that the study's cohort was a predominantly White population of European ancestry, and that limits the generalizability to other studies such as Black or African ancestry populations who we know carry a greater than two fold risk of dying of prostate cancer. That just underscores how critically important it is to include diverse populations in future studies.

I would say the take-home message is that integration of family history and germline genetic testing is an important component of defining the prognosis of patients with newly diagnosed localized prostate cancer. And in this era of precision oncology, individualizing our treatment approach should take this type of information into account.

"I think the greatest implication the study has is that it tells us that family history and germline genetics independently provide complementary information that's important for risk stratification of localized prostate cancer," says Keyan Salari, MD, PhD.

Genomic Testing

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