Jeff Elton:
Welcome to The ConcertAI Podcast. We have a special session this month as we're going into Prostate Cancer Awareness Month because that is all of September. We're going to kick off with some of our urological cancer specialists here at ConcertAI and gain some of their perspectives.
I'm here in Cambridge, Massachusetts Harvard Square in the ConcertAI podcast room, and I'm with Kathryn Penney and Jen Rider. Some of you have heard Jen Rider and some of our past podcasts. It's a real pleasure to have you here again.
Jennifer Rider:
Great to be back. Thanks.
Jeff Elton:
Perhaps you can just give a little bit of background on yourselves and nature of your work, how you actually came to do work in this particular field.
Jennifer Rider:
Sounds good. Yeah, thanks Jeff. I am Jen Rider. I'm a cancer epidemiologist. I trained at the Harvard T.H. Chan School of Public Health, which is where I met Kathryn Penney, who's also here today. I have done most of my own independent research in the area of prostate cancer and really started out there right around 2004, and it's been a great journey and love the opportunity to continue that work here at Concert.
Jeff Elton:
Great. Kathryn?
Kathryn Penney:
Hi, I am Kathryn Penney. I'm also a cancer epidemiologist as well as a genetic and molecular epidemiologist. As Jen mentioned, I did my training at Harvard and my research also was focused on prostate cancer. Has really been a wonderful journey there for me as well. And we can maybe talk a little bit more about that, too.
Jeff Elton:
Great. Well, Kathryn, maybe since I've got you in a flow talking, what really motivated you to go into the field of prostate cancer research?
Kathryn Penney:
Yeah, sure.
Jeff Elton:
Some number of years ago.
Kathryn Penney:
Right out of college I was a biochemistry major and very much interested in genetics, and I was fortunate enough to have my first job be at what is now the Broad Institute here in Cambridge, Mass. And I was a research technician performing genetic early high throughput. At that time what we called high throughput genetic research. And this was really the early days of GWAS or Genome Wide Association Studies that held a lot of promise for prostate cancer.
And really in the 20 years since then, there's been a lot of success in that field. But after that, I think I just got really interested in the bigger questions around prostate cancer. Why is it so common? Why are the outcomes so heterogeneous? And it was something that I just found really interesting and wanted to explore more of the biology and also have an impact on the public health.
Jeff Elton:
Great. Wonderful. And Jen, maybe how did you get into the field?
Jennifer Rider:
Yeah, I mean, it was somewhat similar. I have an undergraduate degree in Zoology. It was a funny University of Wisconsin thing to not offer a biology degree, but at the time there were lots of opportunities in prostate cancer to incorporate biomarker work. And at the time that really novel and interesting to me. We also had a really unique team of epidemiologists and other clinicians and pathologists. It was this very multidisciplinary team that really made all of that work a lot of fun.
Jeff Elton:
We're going to have another podcast where we actually did an interview with a patient, and in that context of that patient who was African-American and treated by a non-white physician who uncovered that he'd had a family history, which was not part of the family's own history of prostate cancers going back and they could identify the grandfather.
I'm curious, Kathryn, just kind of giving some of the GWAS work and the other stuff, it surprised him that there was a familial characteristic. It had never been anything that he was personally counseled on doing that. What's the history of understanding just sort of the genetic basis of prostate cancer?
Kathryn Penney:
Sure. Well, it's been known for a long time that family history is one of the few really known, established non-modifiable risk factors for prostate cancer. But I do think probably in the last 20 years or so that really has been delved into more deeply to understand the genetic mechanisms underneath it. And I'm not going to get the number correct at this point, but from Genome Wide Association Studies say around 200 or something different genetic mutations or variants have been identified that are now true bonafide risk factors for prostate cancer.
And so that is another way of understanding. Not everyone knows their personal family history for a variety of reasons for cancer. And this I think is an upcoming way for individuals to better understand their risk for prostate cancer and other cancers as well.
Jeff Elton:
And I guess I'm particularly saying this because we also had Dr. William Oh, and we spent some time and he at the time was with the foundation, but they had actually curated my word, not theirs, but several hundred periodicals. And it actually changed the guidelines as to when certain people of certain racial and ethnic background actually should actually go through closer kind of screening, which if you think about the whole period of time that those publications were actually out there, we're talking about decades where those had not found their way actually into guidelines and standard of care.
I mean, this is important and as much as I think Kathryn as you're saying, we've kind of understood it, it's not a generally accessible within the current standard of care, unfortunately.
Kathryn Penney:
Yes, that's definitely true. But I do think it is an area that in the next few years I think we're going to see a lot more progress being made. Yeah.
Jeff Elton:
Okay. That's fantastic.
Kathryn Penney:
Yeah.
Jeff Elton:
Now, I'll use that as kind of a leap off point of saying each of you have been quite productive in your own publication, your own research activity, and maybe Jen, I'll start with you. Of the Prostate Cancer Associated Publications that you've done, which ones are you most proud of and maybe give us a little bit of the background on the publication?
Jennifer Rider:
Sure. Deep in the archives at this point, one of my dissertation papers actually was dealt with Gleason grading. This is how we evaluate the aggressiveness of prostate cancer simply by looking under the microscope. I think it's been around since the early '70s, if not before that, but it's still really one of the best biomarkers we have for determining a man's prognosis.
The paper that I worked on was actually showing that the secondary Gleason score, usually you have two numbers and you add them together to come up with the total Gleason score. That secondary number could actually be really important. Just knowing that a patient had a Gleason score seven tumor wasn't sufficient. You actually had to know that that tumor was a three plus four or a four plus three.
And this was appreciated clinically, but there wasn't a lot of good data linking that to long-term outcomes in patients. And of course, you have to follow prostate cancer patients for decades sometimes. I think that paper ended up having an impact on the field. Now we have Gleason grade groups which much more formally distinguish those Gleason seven tumors depending on the primary and secondary grade. That's one of my favorites, I think.
Jeff Elton:
Great. And Kathryn?
Kathryn Penney:
Yeah, I think my answer is a good follow up to what Jen just mentioned. I'm going to cheat a little bit and have two, but they're somewhat similar in concept. The first was in 2011, and the second one was I think in 2017. And these were two studies that looked at gene expression profiling of prostate tumors and instead of focusing specifically on clinical outcomes, which there are a lot of available tests out there that do this, we were specifically interested in identifying a signature for Gleason score.
And we were able to do this, we developed signatures that could differentiate high from low Gleason score, so specifically Gleason score six versus Gleason score eight to 10. And really interestingly, when we were able to apply that signature to men with this intermediate Gleason score of seven, which Jen was just talking about, we saw that it could improve the prediction of outcomes among men with that sort of intermediate group even beyond just knowing whether an individual was this three plus four or four plus three grade.
Jeff Elton:
And so how, practically speaking, how would that be derived with your sort of scoring algorithm approach?
Kathryn Penney:
Yeah, so we worked with these long-term cohort studies at Harvard. And so we had prostate tumors available to us that had been from radical prostatectomies over many, many years. We did the time different types of gene expression technologies and identified a set of genes through different statistical methods that then we were able to pull together into a specific score.
And then really it is just a statistical calculation. If you are able to identify or perform gene expression testing within a patient, you could combine those genes together into a signature statistically and then predict their outcome based on that.
Jeff Elton:
Very interesting. In your work, my limited understanding, but understanding is that these genes were associated with the prostate cancer microenvironment.
Kathryn Penney:
Yeah, so that was the follow on here. A lot of the specific genes themselves ended up being genes that we felt could have stromal origins, so exactly that the prostate cancer microenvironment not the tumor itself. And that really led to a lot of follow-up work that I was doing through my academic career looking specifically at gene expression within the microenvironment and how those genes are associated with both Gleason score as well as prostate cancer mortality.
Jeff Elton:
Out of curiosity, there's work both in radiological imaging approaches looking at micro and also digital pathology approaches. Do you believe that there would be maybe AI based visualization quantification approaches that may be able to kind of replicate and derive some of this?
Kathryn Penney:
Yeah, definitely. And I think one thing we had always wanted to do, and I personally haven't gotten around to I'm sure someone will, is to look exactly at that, the sort of correlation of these clinical characteristics like Gleason score, the gene expression within the microenvironment and the tumor as well as imaging from MRI and other sources, and looking at sort of how those can interplay together. Can you understand more about the prognosis of an individual, the prediction prognosis of their outcome by combining those sources of information?
Jeff Elton:
Well hold that thought. We may have a new clinical partner that has a very deep expertise in urological cancers where that may be able to actually even do something about that concept.
Kathryn Penney:
Wonderful. That would be exciting.
Jeff Elton:
Jen, I want to kind of come back to the nature of talking about the Gleason scores and the two and kind get the composition and the addition of them. And you're working in an area where you're leading a lot of our outcomes research and you've got the privilege of working with some of the leading biopharma innovators in the area of prostate cancer research and therapeutics.
How are we integrating now some of these data elements into our own research solutions?
Jennifer Rider:
Yeah, no, it's a great question. And really for a cancer like prostate cancer, the quality of the insights that you can derive really is dependent on capturing important variables like Gleason score. Oftentimes, that really important information isn't captured in the structured component of the EMR. And so our approach is to gather that information through curation.
We're actually going through patient charts, collecting information on Gleason score with biopsy or at the time of surgery, and then using that information in our analyses. It's especially important when we're doing studies that are comparing therapies head to head so that we know we have comparable groups of patients.
Jeff Elton:
Yeah, that's great. And Kathryn, I know that Jen a couple of moments ago talked about the high degree of longitudinality that we probably have to have just because this is a, you hope, slow progressive disease. I mean there are more radical forms that aren't, but generally speaking over that. And because it can progress to people that may even have other forms of mortality that have a higher likelihood of being their reason for dying than the prostate cancer itself, this concept of over-treatment ...
Kathryn Penney:
Absolutely.
Jeff Elton:
... kind of comes up and it's kind of a constant theme and oftentimes it's part of the conversation with the patient. How is that being treated now and how is that being received and what do we understand about that?
Kathryn Penney:
Sure. I think one of the major issues, as you mentioned, is over-treatment as well as over-diagnosis initially as well. I do think that a lot of progress has been made in this area, particularly thinking about active surveillance for men who have low Gleason grade disease, particularly Gleason score six or grade group one tumors. And I think more work is being done in this area. There's a really active ongoing discussion about whether or not those tumors should even be called cancer. It's a little bit charged, but I do think that that actually is an area where progress has been made in the 20 years or so that we've been working in the field.
Jeff Elton:
Often the routine thing that most people get is a PSA score in a normal physical, and just even over my personal care life, how that's thought of has changed. And oftentimes, something about level or lack of change was always conceived to be, there was a time that any change was perceived to be a change and it reverted to you need to be scores in the range. How is that now being integrated into classifications and diagnosis?
Jennifer Rider:
Yeah, well, I think Kathryn and I have both seen the pendulum completely swing.
Jeff Elton:
Welcome to my personal care life.
Jennifer Rider:
Yes, exactly. I can imagine. I think when we first started in the field, I think many men were getting a PSA test often without real consent. It was like your cholesterol was being checked and so was your PSA, and so an understanding about the potential outcomes and what this could mean weren't being thoroughly discussed all of the time.
And then many times an elevated PSA would lead directly to biopsy, prostate cancer. There have been some really interesting autopsy studies done where essentially if you look hard enough, you will likely find a prostate cancer in a man who's 70 or 80, but that doesn't mean it's going to be clinically significant.
The interpretation of that PSA test is really critical. And I think many of those over diagnoses early on led to a backlash against PSA screening in general. And now we're kind of back to a place somewhere in the middle. But it has been quite an evolution and interesting story.
Jeff Elton:
Is it getting interpreted now more in combination with other factors to sort of give it a different contextualization or how is it being integrated in now?
Jennifer Rider:
My dad actually was fairly recently diagnosed with prostate cancer, and it was interesting to see his journey of diagnosis, which I'm sure was much, much different than it would've been even a decade before. He was not only having a PSA test and that PSA test repeated several times, but also taking advantage of some of the new genomic tests that are available that just provide more information. For him, it was more reassurance that curative therapy wasn't necessary immediately.
Jeff Elton:
It's pretty interesting. You're actually almost painting a view that it's got some semi-chronic quality to it with different inflection points in the disease state that may require different points of intervention, but it's kind of a much more holistic view of ...
Jennifer Rider:
Absolutely, and I think that is one of the main arguments behind not calling Gleason grade group one cancer. Calling it something that is more like pre-cancer because it's very hard to move past that diagnosis of cancer and accept that you could potentially not do anything about it for some period of time.
Jeff Elton:
This field gets complicated because you're sometimes talking about different care settings. Some of this may start in a primary to a medical oncological. There may be a surgical point in kind of the middle, and that's a little unlike some other forms of cancer. And again, maybe it's the semi-chronic and the slow progressive nature that begins doing that.
But how does one actually then develop true research grade data sets that allow you to glean the insights we need to glean, given everything that you've just been describing?
Kathryn Penney:
Yeah, I mean, I do think that is a challenge. My personal research experience was very much focused in the period of time from diagnosis to progression to METS, and then it kind of stopped for partly this reason that it was hard to combine information from different sources to have in the same population.
I do think here we are able to look at records across the patient journey from the time of diagnosis through the time perhaps in a urological setting to then in an oncology treatment setting as well. We are able to look across the entire patient journey.
Jennifer Rider:
And I think there's still a lot of questions that we would love to know about the differences between how a urologist might treat a hormone-resistant tumor versus if that patient had ended up at a medical oncologist. I don't know that we have all of those answers yet, but as we start being able to combine more sources of data using information from EMR plus claims, which sometimes captures a more complete patient journey across settings, I think we'll be able to figure a lot of those things out.
Jeff Elton:
Well, let me actually, and Jen, let me just have you stay on that a little bit because I think you've been involved in studies that were both US and Sweden in terms of how to look about this. And if you think about how real-world data, which is kind of the research world we kind of live in, but how it's informed things so far, but also how you think it may make broader contributions going forward given our ability to move and integrate data across settings, greater longitudinality link different elements of that particular patient kind of journey together.
Jennifer Rider:
Yeah, I mean, I think there will always be a ton of potential because not all of the really important clinical questions can or will be answered by a clinical trial. And now that we can capture really long-term outcomes, including mortality, we can capture information across settings. I think we'll continue to rely on real-world evidence more and more.
Jeff Elton:
Maybe this is a question for both of you, because normally we think of RCT studies as being kind of a gold standard of sorts, and oftentimes real-world studies follow on the RCT, and that's kind of been a little bit of the history. This is now taking what we saw from a gold standard and powering it up with all the heterogeneity and limitations and things that kind of come in the real world.
But in this field, depending upon where you were in that particular journey, there may not have been RCT studies. How might one or how might the field more broadly begin to bring maybe some of the rigor level of insights with the confidence that we have around RCT, but to the portions of the patient cancer journey where none of those have actually been performed?
Kathryn Penney:
Yeah, I do think one thing to think about is bringing those important characteristics of an RCT to the real world. There are certain ways that you can try to emulate as much as possible RCT within observational type data. And I think those methods are going to be really crucial for being able to do exactly the things that we'll never be able to answer in an RCT. Hopefully, we'll be able to answer them in real world data.
Jennifer Rider:
ConcertAI is actively involved in a number of trial emulation activities. And part of the value there is really understanding what the limitations of real world data are. Right? What are must haves, what are the circumstances in which we could obtain the same result as the RCT. Stay tuned for results from that work.
Jeff Elton:
In certain disease states, particularly those that have long duration of life post-intervention, there's been some trend towards understanding can we do a post-RCT surveillance phase? And so some people have projected a real world data collection, even for maybe some of the consented subjects who participated in the RCT kind of et cetera.
Do you see some rooms for creative research models that continue to augment some of the data given the longitudinality we need to place around this?
Jennifer Rider:
Absolutely. I mean, I think that's a great point, and I think prostate cancer would be a very good model for that work because you really do need very, very long-term outcomes for the majority of men who are diagnosed with the disease. Yes, I think there are absolutely room for hybrid designs that are taking data from an RCT, but also combining real world elements.
Jeff Elton:
Since we're doing this podcast about prostate cancer awareness, what thoughts would you offer about the importance of that awareness and that importance of having a focus on that, be it for the research community or the clinical care communities?
Jennifer Rider:
Yeah, I think for me, it comes back to what you said earlier, Jeff, about being a prostate cancer patient and discovering your own family history. Sometimes serendipitously. I think having more of an open discussion and just comfort level about prostate cancer as a disease will ultimately help patients.
Jeff Elton:
For sure.
Kathryn Penney:
Yeah, and I do think also from that patient perspective, remembering that oftentimes it's just as have a conversation with your doctor, but that's really true here. There are a lot of different options, pre-diagnosis, understanding risk factors through initial treatment options or choosing something like active surveillance.
And then also there are choices to be made if an individual does end up having a metastatic diagnosis as well. I think there are a lot of options out there now for men with prostate cancer, and it's something to really make sure that everyone is really thinking about what's best for that particular patient.
Jeff Elton:
Well, I want to thank both of you kind of on multiple levels. Thank you for the work you did before you came over to the private sector and did work with ConcertAI. And thank you for making sure that we at ConcertAI do a lot of work in this area. We've had a very strong focus on this probably since you arrived, and we even look for the opportunities to try to do more work in the area. Thank you very much for advancing that as well.
Jennifer Rider:
Thank you.
Kathryn Penney:
Thank you.
Jeff Elton:
Well, we'll close off in the ConcertAI podcast here in Cambridge, Massachusetts. Wherever you are, good morning, good afternoon, good night. Thanks so much.
