Can you explain the difference between—and tell me if you're doing it differently in
trials or in research—one type of tumor that can be expressed that you can take advantage of as one
that's within the tumor, and one is that you might be born with that mutation. So, it's germline
versus somatic. Can you just give us a 101 course on — do you use both of those types of mutations
that someone's born with and the cancer? And when how how quickly can I use it? Because to me,
if you're starting to use these the moment I'm diagnosed with prostate cancer or I come to you
in your office, I want to know if there's a mutation. Tell me if I'm right or wrong.
Yeah okay, let me address you. This — let me tell you what I do,
but not everybody—even in my practice where we have 11 GU medical oncologist people are
doing it differently—but I'll just tell you my rationale. I, at least, always have a
rationale to back up why I do things the way I do it. So, germline mutations,
let's start there. That means you inherited it in every single cell, and usually, you know, if you
think about the genes there's like two alleles, okay, you might have inherited into one but you
need to lose the other before it really becomes functional or dysfunctional let's say. Alright so,
we at our center tend to look early for germline mutations in patients, and the reason is is Colin
Pritchard who's a laboratory medicine physician in our group did some research and published in the
new journal paper that showed that 12 percent of men with metastatic prostate cancer have inherited
a germline mutation in a DNA repair gene that not only has implications for treatment like
with the PARP inhibitors or platinum, but it also has implications for downstream testing,
cascade testing, family counseling because if you inherited it what's to say your mother, father,
daughter, son, siblings don't also have it? And these genes can predispose not just the prostate
cancer but breast, ovarian, and other cancers as well, and our goal is to identify them and maybe
do early cancer screening in patients that are asymptomatic right now but find a cancer early
and save a lot of lives down the road, so it really has two potential benefits. So,
we're doing that early in anybody with metastatic prostate cancer. If you have earlier
stage disease, let's say high-risk localized disease, the risk is probably a little lower,
maybe three to seven percent depending upon what study you look at. I think that's plus/minus. If
you ask a geneticist who does research and whose whole life is this, they'll say we should screen
anybody with a 10 percent risk or greater. It's not always covered by insurance, but I live by the
those numbers. So, metastatic prostate cancer 12% risk, anybody with metastatic prostate cancer gets
screened here. We have a study where if you can't get it covered by insurance you can go online,
it's called the gentleman study run by Heather Chang, and you can go online fill out 40 minutes
of questionnaires and get a free Color Genomics test sent to you, and you can do do the spit test,
cheek swab, send it back. In about a month or so later, you'll get those results, okay.
And this is for the genes you're born with. So,
you're testing what I was born with at the age of two even though i might be 52?
Yep, right.
So this is not testing the tumor and you're saying anyone who has metastatic disease,
you test them one way or another, right?
Correct.
That is awesome. Okay now, what about — germline — so that's called — so anything I was born with,
you're going to test if there's some kind of deficiency there.
Now what about I have metastatic or non-metastatic, I come see you
and it's not just my family's genes, what about my tumors genes?
Somatic. Okay, so somatic means you acquired the mutation over time and the cancer acquired it.
It's a little bit more challenging because some mutations are drivers of the cancer some are just
bystanders, they're just there and they're not really doing anything to drive the cancer. It
is very clear that when you look for these actionable genes and these things like DNA
repair genes or mismatch repair genes where you can give immunotherapy to, that these things seem
to be mutating and occurring later in the disease course. So, the later you look the higher your hit
rate is when you test. So not all of my colleagues agree on this point. Some of them are testing them
as soon as somebody has metastatic disease or metastatic castration-resistant prostate cancer.
I tend to test later because the hit rate is higher, and so that's kind of my rationale for
that. I test the germline up front which is probably half of the mutations there,
and the other half is somatic and I tend to look for that later. We're also developing
better circulating tumor DNA methodologies where you might be able to get a liquid tumor biopsy and
be able to with a higher PSA level— over 20 maybe even over 10—we're having good successat isolating
those tumor DNAs in the bloodstream and being able to do that sequencing and testing there.
So it's moving toward, you know, you might not even need to touch
the tissue you can just get it from a test tube when you draw some blood.
Right and the advantage to that is you can get a real-time assessment because a lot of
times when people are doing testing they're getting tumor tissue that's archival. Might
have happened from a surgery you know 10 years ago or five years ago or something like that.
Now, if the mutations are dynamic, and it's not a static situation, and these
are new mutations occurring over time, you're gonna miss the boat if you test old samples.
Have you seen profound responses
to the ovarian cancer drug? You know, you talked about the PROFOUND—no
pun intended—you talked about the—I didn't even think about that—you talked about this trial
and people respond to Lynparza which is normally for some ovarian cancer patients. There was also
a response in a trial called POLO that was for pancreatic patients. So are you seeing — I want
to believe you're seeing some profound results to these drugs because it's an oral drug, right?
Absolutely, it's not everybody, but you know, I think I have certainly have patients that respond
very well. I will say it tends to be patients that have BRCA2 mutations where I see more
dramatic responses. Some of the other genes, it's a little bit more iffy. So I think the actual gene
matters and the question, really, is there are still some patients that have these gene mutations
that don't respond or that respond very transiently, and so there's some thoughts
that maybe the way we're going about this by testing just for the gene mutations,
maybe that's not good enough. Maybe we need to look at signatures, downstream effects,
that really show us that there's these, you know, LOH signatures or HRD signatures as
they call it—homologous recombination deficiency signatures—that really take a lot of things into
account to show is the cancer cell acting like it's deficient in these DNA repair mechanisms.
That might be the better way to do this. Right now we're still early in this, so we're learning.