The Biology of Prostate Cancer - Kenneth Pienta

Kenneth Pienta joins Charles Ryan at the 26th Annual Prostate Cancer Foundation Scientific Retreat 2019 (PCF 2019) to discuss the biology of prostate cancer, and to share a clinician's perspective of thinking about the biology of this disease. This is a look at the current year and some of the significant findings that have changed the way we look at treating prostate cancer.  The STAMPEDE data showing that treatment of the primary in metastatic disease is significant to the patient's overall survival.  It leads to a series of considerations such as when does systemic disease start? And when should we not treat the primary? Should we always treat the primary? And, the question of qualitative versus quantitative. Is the primary qualitatively different than the metastases, such that even if you have metastatic disease, your primary is still shooting out metastatic, or potentially metastatic cells? Or is it simply a quantity issue? 

Biographies:

Kenneth J. Pienta, MD, The Donald S. Coffey Professor of Urology, Professor of Oncology, and Professor of Pharmacology and Molecular Sciences, The Johns Hopkins Hospital, Baltimore, MD

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation.


Read the Full Video Transcript

Charles Ryan: Hello from PCF 2019 in La Costa, Carlsbad, California. I'm delighted to be joined by Ken Pienta, who is the Donald S. Coffey Professor of Urology. He's a Professor of Oncology, and a Professor of Pharmacology and Molecular Sciences at Johns Hopkins in Baltimore. Ken, always a pleasure to talk to you.

Kenneth Pienta: Glad to be here.

Charles Ryan: Lots to talk about. Lots going on in our field as usual, and this is really the big event of the year where we hear so much great science. As you think about the science over in the current state, what do you think are the highlights that we should know about the biology of prostate cancer, and how clinicians and patients might be thinking about the biology of this disease?

Kenneth Pienta: I think it's been a really interesting year. The publication of the STAMPEDE data suggesting that even with metastatic disease, we should treat the primary. And that appears to help guys live longer. It really shook the field up from the standpoint of how do you view what's happening in the communication between the primary and metastatic disease, and when does that start? When does systemic disease start? And when should we not treat the primary? Should always treat it? And really, we've always wondered in the life history of a prostate cancer, especially when you're diagnosed with a prostate cancer, how long has the man had that? I mean we estimate often 20 or 30 years, but we don't know. As soon as a cancer gets to be the size of a thumbnail, it's probably spitting out some circulating tumor cells that may have the ability to go sit somewhere for a long time. Is that systemic disease? Will they ever wake up? I think there's some really interesting questions that are being asked again.

Charles Ryan: So you bring up the question of qualitative versus quantitative. Is the primary qualitatively different than the metastases, such that even if you have metastatic disease, your primary is still shooting out metastatic, or potentially metastatic cells? Or is it simply a quantity issue? The proponents of the quantity case would say, "Hey, you're only seeing this benefit in oligometastatic, and it's kind of a modest benefit", right?

Kenneth Pienta: Right.

Charles Ryan: And we do have ongoing studies with more high volume disease where we're going to look at both radiation and surgery in that context. But do you think the primary is qualitatively different than the metastases, such that treating it leads to a biological change that is beneficial?

Kenneth Pienta: I do. I think one of the interesting questions is, if prostate cancer is in the prostate, was there for so long, what's controlling it, so to speak, from getting bigger and bigger? And how does that work? So when you get a metastasis to the bone, it seems to grow much faster. We don't know that, but is that a microenvironment ecology control system? I don't know. But I do think multiple, certainly experimental studies have shown that the primary doesn't stop doing bad things just because you have metastatic disease. In fact, there's some evidence that a tumor cell in a metastasis can circulate back to the primary and cause some kind of positive feedback. So this idea of cutting the circuit is, I think, one that should be done. And as you and I know, we probably want to treat that primary anyways just so guys, if they're not cured, don't have to deal with obstruction issues down the line.

Charles Ryan: Right. I think from a clinical perspective, getting the symptoms and the potential problems of the primary out of the way is important. I'm a little skeptical about the biology. I'm very curious about this point about the cells circulating back into the prostate. I don't really know that data. That's really quite interesting.

Kenneth Pienta: Yeah. They've shown that, Joan Massagué from Memorial Sloan Kettering has shown that in breast cancer models. We've seen it in prostate cancer models. We can't, of course, prove it in humans, but it makes biologic sense. It makes evolutionary sense. Yeah.

Charles Ryan: It does, yeah. It's an iterative tumor. Cancer is iterative and fascinating. I have to say, we were talking before about this idea of how many cells it takes to create a metastasis. I think that your work on this was really prescient, as we now have this conversation going on about non-metastatic disease. We're defining a disease by what it's not, so to speak, but we all know that the cancers in there somehow. And what are your thoughts on how a clinician should think about what non-metastatic disease is, and the burden of actual cancer in a patient with non-metastatic disease?

Kenneth Pienta: Yeah, I'm really worried right now that we're under-treating some guys because we are victims of our own imaging. So when we had bone scans, CT scans, MRIs, we said, "Oh, you need a thumbnail of tumor." It's a billion cells. That's what we see clinically. That's metastasis. Now with Axumin scans and PSMA imaging, we can go down to two or three millimeter deposits of tumor. That's still 25 million cells. But now that's going to be the new standard soon for defining metastatic disease. When we get a better imaging agent, or a better camera to see things, well, is it going to be 5 million? 1 million? 1? All metastatic deposits start with one cell. When does it become relevant to the life of a patient? We don't know, but pretty much I think we're all worried that when you have high-risk disease and ... What does high risk mean? Means you have a high risk of recurrence. Well, that means the cancer already got out.

We don't think enough about why aren't guys cured by radiation or radical prostatectomy? They're high risk. They're high risk for recurrence. Well that recurrence was already out there.

Charles Ryan: It's not a recurrence.

Kenneth Pienta: It was already systemic disease. So how do we deal with that? And how do we define that? Is there some kind of biomarker we can find? We know we can't do it with circulating tumor cells. So we and others have looked at can you find circulating tumor cells at the time of prostatectomy? Can you find disseminated tumor cells in the bone marrow? The reality is, is you can once in a while, but not at the rate that guys recur.

Charles Ryan: Well, and also some of that data, don't they suggest that you can find those disseminated cells, or even those circulating cells and you can follow that patient after his radical prostatectomy and he won't recur?

Kenneth Pienta: Correct.

Charles Ryan: In other words, not all cells that escape the prostate are going to develop into metastatic disease.

Kenneth Pienta: Right. They can lay dormant forever. The original Hellman and Weichselbaum hypothesis of oligometastatic disease was actually that those were early cells that got out, grew up, and couldn't do anything else. They were functional dead ends. We forget that, that that's not how we define oligometastatic disease now. We say it's all less than five mets. But when Hellman gave the initial Karnofsky lecture describing it, he said, "We should treat those because they're not going to go anywhere". So there are some of those, we see them.

Charles Ryan: We sort of flipped that biology.

Kenneth Pienta: But we flipped it.

Charles Ryan: We said those are the risks for the cancer to spread. It's interesting. Yeah. Okay. Very good. So as usual, lots of different insights on the biology of the disease and how we can think, and should think, I think a little bit more biologically about this disease that we're treating, as opposed to simply about gray and white pictures on a bone scan, and things like that. So I always learn a lot talking to you for the moments we get at PCF. So enjoy the meeting and great talking to you.

Kenneth Pienta: Thanks a lot.