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Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Anis Hamid who is a medical oncologist from Melbourne, Australia doing a research fellowship and is a PCF Young Investigator award winner here at the Dana Farber, as well as Dr. Christopher Sweeney who is a medical oncologist at Dana Farber and Professor of Medicine at Harvard Medical School. Thank you both so much for being here.

Anis Hamid: Pleasure.

Chris  Sweeney: Pleasure.

Alicia Morgans: Thank you. So Anis I wanted to talk to you about a recently published paper. Actually, it may just be coming out in print now in European Urology, thinking about biomarkers and the way that they may affect disease outcomes for patients with prostate cancer. Can you tell us a little bit about that paper?

Anis Hamid: Yeah, sure. So Chris and I have both been interested in studying biomarkers across the spectrum of prostate cancer from the earliest phase of disease when it's first diagnosed and patients treated with local therapy like radiation and surgery, all the way to the other end of the spectrum which is men with advanced castration resistant disease where the evidence of metastatic disease and where the focus of therapy is mostly systemic treatments. So we know that from interesting pre-clinical studies, especially over the last few years, that a lot of the underpinnings of aggressive disease lie in the tumor genome and in particular we see recurrent losses of particular genes both in early and advanced prostate cancer, and these include tumor suppressors. So the classic tumor suppressors that are commonly mutated across cancers, including prostate cancer, include P53, RB1, and P10. We know that even men with early disease have evidence of mutations in these genes and they become more frequently mutated as these tumors metastasize and they become resistant to standard therapies like hormonal treatment.

So those interesting pre-clinical studies have shown that if you lose these tumor suppressors, something happens to the biology of these cancers, such that they are driven towards this resistant sort of phenotype or behavior. This can occur even early in the phase of disease, at the stage of men undergoing radical prostatectomy or radiation. So we leveraged our data set here at Dana Farber where we are lucky enough to have an in-house sequencing platform where patients are enrolled and undergo a multi-gene sequencing assay, and this is all to drive precision medicine and to inform enrollment for clinical trials and identify genes that may be mutated that we can translate for research in clinical practice.

So we had a cohort of patients with localized disease and metastatic disease and castration resistant disease, and we focused primarily on these three tumor suppressors, P53, RB, and P10. We really wanted to document the frequency of which these genes were mutated across the spectrum of prostate cancer.

By doing that the frequency of genes being mutated is somewhat known, but what is less known is how this leads to... how this is associated with outcomes. Our hypothesis really was that it leads to incrementally worse outcomes if men have more tumor suppressing mutations. So the summary of the findings really are that these genes are mutated, even in early disease at a frequency of about 40%, and this increases in the most advanced disease setting to about 90% of CRPC patients.

In the localized setting, having any one of these mutations in these three genes is associated with an increased risk of relapse after curative therapy and the typical time of relapse was between two to three years.

Chris Sweeney: PSA relapse.

Anis Hamid: PSA and this is driven by PSA relapse, correct. So some of these men were salvaged but some maybe not. This seemed to be a consistent effect across the three disease stages. From localized disease, metastatic hormone sensitive disease, and metastatic castration resistant disease, that if you had one tumor suppressor loss that was associated with detrimental outcome compared to no tumor suppressor loss. But if you have two or three of these genes mutated, these are the sub-set of patients that really had the worst outcomes.

This is sort of very interesting data to us because it tells that this is, well clearly a prognostic biomarker and potentially a predictive one. Though we can't directly answer this predictive question in this data set, it does open up the opportunity to explore it in correlative data sets from clinical trials, whether it be in hormone sensitive disease or castration resistant disease, and see if this is potentially a biomarker for men requiring treatment that is perhaps less focused on targeting the androgen receptive pathway and perhaps looking at a non-AR directed therapy like, say chemotherapy.

Alicia Morgans: So in this data set, and you may not have looked at this, but were you able to look at those patients with localized disease, see those patients who may have had these features and relapsed, and look at outcomes after salvage therapy, or with radiation, or look at which men received adjuvant therapy upfront to see if there's any way that you can impact that higher risk of relapse in the long run? I'm just thinking about how do clinicians, and it's probably too early for them to use this information, but how can they think about these patients if they even identify them in a localized setting?

Chris Sweeney: I'll pick up from there and say, a lot of the work we've done in gene profiling and genomic profiling mutations as a field, to stand up to cancer efforts, a magnificent project around the globe, UK and America based, with showing these mutations. How to action them is a very different question.

Alicia Morgans: Yes.

Chris Sweeney: So we've done a lot of landscape work and we should acknowledge the leading work that the people did to help us get to thinking about these biomarkers and tumor suppressor genes. In 2019 I think the leading data set about how to action upon this is the work that the MD Anderson crew did with our colleague Ana Aparicio and Paul Corn that if you have P53, RB, P10 mutations, two or more, you may benefit from adding carboplatin to cabazitaxel. It's great data, it's evolving, but that's the leading data set and we should commend them for that. The work we're doing is actually taking that to the other stages as well. 

Alicia Morgans: Yes.

Chris Sweeney: The other effort I think is the paper by the West Coast Dream Team, where they've looked at peak RB mutations being predictive of not benefiting from enzalutamide, for example. The work Anis did shows that actually if you have an absence of all three of those geno suppressors you actually do really well, long outcome, in castration resistant.

Anis Hamid: Correct.

Chris Sweeney: But this is all institutional and pilot based. So how do we take this information to actually inform our colleagues who are treating patients on a day-to-day? So it's going to take a global, international, collaborative effort. We have got a collaboration going with the CHAARTED samples from the US based study. We have the samples in metastatic hormone sensitive, the STAMPEDE where we're getting gene expression profiling, similar to using the same platform that gets us to DECIPHER but also other signatures at the RNA level and the exon level.

We have developed an analysis plan with the STAMPEDE so we will train in CHAARTED and then validate using the STAMPEDE data, with our colleague Gert Attard and all the team, from the STAMPEDE studies focusing on who gets by with hormones alone, ADT alone, and who actually benefits from adding the docetaxel. Also, other patients who have a high burden of disease, more likely to have their two hits in P53, RB, and P10. 

So we can get to a feel to annotation of clinical phenotype and also responsiveness to therapy and doing proper biomarker predictive prognosis and predictive work with cut points. We're actually getting pretty close to this and it's a global international effort, and we should commend our colleagues from GenomeDx who've actually done the gene expression profiling in CLIA fantastic quality data that we've just got... come to us. We're analyzing that now. The exome data we've got the samples being sent for high quality exome work. 

So it's not going to be done in... It's all being done in CLIA certified so we actually can do the work properly. We will then actually also bring in the ENZAMET specimens where we can look at hormone sensitive in the role of enzalutamide and also the specimens from the abiraterone arms of STAMPEDE. Hopefully we can learn from who benefits from what therapy in the hormone sensitive and then take it to the adjuvant setting to the question you asked before we started filming. Can we identify patients who need surgery alone, radiation alone, radiation plus hormones alone, radiation plus hormones with docetaxel, radiation plus hormones plus enzalutamide or apalutamide or abiraterone?

This, I think, will be three to five year effort, but I'm very confident we will get information. Hopefully, it'll be information telling us what we can do. It may be information telling us this isn't going to work. But I'm hopeful that with this global international collaboration of data sharing and sample acquisition and sharing we can get this information. And what was a science fiction will be science fact. 

Alicia Morgans: Absolutely. And that's really where we do need to go. I commend you on this work, really pushing the envelope for us to understand how tumor suppressors may impact outcomes both of very advanced patients of metastatic CRPC and even those patients with localized disease, because those steps in identifying differences in outcomes really I think are something that we can then identify areas where we can intervene. It sounds like we're on track to figure this out. 

Chris Sweeney: Actually, one question we should probably address.

Alicia Morgans: Yes.

Chris Sweeney: Who's funding all of this?

Alicia Morgans: Funding all of what?

Chris Sweeney: All these millions of dollars-

Alicia Morgans: The collaboration. That's a very good question. I always try to shut my eyes and think who's paying? Never mind. But who is covering this? Because when I think about designing these trials often we get pharmaceutical support for drug provision and for some other things, but it's sometimes hard, given their limited budgets and our long wish list, to get funding for everything that we want to do in some of these trials. So who is funding this?

Chris Sweeney: So I'll start with... you to explain how this led to an award for you?

Anis Hamid: Yes. So it takes a dedicated team of physicians, research fellows, principle investigators, bioinformatics team, biostatisticians to make this festoon fuel effort happen. From a tumor suppressor point of view, which is a hypothesis that will apply to say the CHAARTED data set as Chris was saying, STAMPEDE and ENZAMET and so forth. The Prostate Cancer Foundation have been a fantastic supporter of this work. I've been funded for a PCF Young Investigator Award lasting three years to directly address the sequencing of the CHAARTED samples, to not only characterize metastatic hormone sensitive disease but specifically, I answer this question about the prognostic predictive strength of tumor suppressor loss in metastatic hormone sensitive prostate cancer. 

Chris Sweeney: It's all tallied up. So I think preliminary data and pilot data is generated by institutional funds and investments from foundations like The Prostate Cancer Foundation, and their similar efforts, The Prostate Cancer UK in the United Kingdom, and similar in Australia. So foundations and institutional funding. I personally... A plug for the Pan Mass Challenge where we do a bike ride, ride a 192 miles. That's correct, 192 miles over two days. I ride with a team that raises funds that has really seeded this early work.

We are then able to take this preliminary data, that is requisite data, to the national funding bodies like The National Institutes of Health, National Cancer Institute, Department of Defense, NHMRC in Australia, and also in the United Kingdom their funding bodies, Cancer Research UK. The institutional and the foundation funds seed the preliminary data, which gets us the millions of dollars that we actually need. 

Alicia Morgans: It is no small task to look into these things and to think about incorporating these markers and tumor suppressor approaches into both collaborations across different ongoing trials as well as I'm sure potentially into prospective trials, to think about how these can be integrated for patients in the future. I sincerely appreciate you talking to us about your work and explaining where all the dollars came from to get us there.

Anis Hamid: My pleasure and thanks for having me. 

Alicia Morgans: Thank you. 

Chris Sweeney: And as my back team says, "Teamwork makes the dreams work."

Alicia Morgans: That's wonderful. Thank you. 

Chris Sweeney: Thank you, Alicia.