Good afternoon. I'm Matt Cooperberg from
the Department of Urology and Epidemiology
and Biostatistics at UCSF.
It's a pleasure to share some results
with you on prostate cancer epidemiology,
screening and diagnosis, which is
a lot to cover in 10 minutes so we will jump right in.
In terms of the epidemiology,
the patterns of disease across the United States.
Prostate cancer, as many of you probably know,
is by far the most common cause of
cancer identified among men in the US.
Nearly a quarter of a million cases anticipated for 2021.
It is the second most common cause
of cancer death among men,
exceeded only by lung cancer.
But the number of deaths every year is far
exceeded by the number of diagnoses.
This already gets us toward
the dilemma which is faced for many years,
which is identifying those cancers which
might be lethal and treating them while
avoiding over diagnosing and over
treating the ones which were described as indolent,
meaning they would never cause
any symptoms or threat to life if we do not find.
Now over the years, we know with changing
screening policies in the United States,
we've seen major shifts in incidents up and down.
At the start of the PSA era in the 1990s,
prostate cancer incidents shut
up as we've found many tumors.
We settled out to a fairly steady state here.
Then as the US Preventative Services Task Force
recommended more and more strongly against screening,
incidence rates plummeted and over the last decade to
levels we had not seen since
the 1980s and now are starting to recover again.
In the meantime, cancer mortality rates,
which for prostate cancer have fallen
nearly 50 percent at
a steeper trajectory than any cancer except lung cancer,
where the trajectory can be explained
by smoking cessation rates.
This drop in mortality
has actually plateaued in recent years.
In part, not entirely,
but in part because of drops in screening.
It's worth pointing out, we will have a whole talk later
on racial disparities by Dr. Roach.
But it's worth pointing out already
that while we have seen
drops in mortality for
both black and white men in the United States,
this gap, this Delta has not narrowed over the years.
Black men face over
a two-fold increased risk
of lethal disease compared to white men.
This has been true over many decades without much change.
It's also true that the greatest disparity in
terms of race is borne by younger men.
This looks at men in their late 40s,
50s heading up to 60s.
For men in their 40s and 50s,
the racial disparity is 3 and 4 fold
for black compared to white men.
This disparity is actually quite different
from what counts locale across the United States.
This plot here looks at the Delta Delta,
the change over time in the racial gaps.
So the white bubbles here are
changes in mortality for white men compared
to changes in mortality for black men comparing
the early 1990s to the late 2000s.
San Francisco is fairly typical in that there is
a similar drop for both white and black men without
any real change in the gap
in the Delta between black and white men over time.
Some cities have seen greater drop
for white men compared to black men.
Others like Oklahoma up here have
actually seen a rise in mortality
for black men and a drop for white men.
This does not necessarily reflect
specific policies in different cities,
but it does emphasize the fact that a lot of
these trends really do need to be looked
at at the local level.
Now what about screening? To summarize
a very complex history in one slide.
Throughout the 1990s and 2000s as PSA hit
the general usage and
primary care, we didn't do a very good job.
We implemented prostate cancer screening poorly.
We tend to overscreen older men,
we underscreen younger men.
We over-treated low-risk prostate cancer
and under-treated high-risk disease.
Now despite all this,
remember that graph I showed a few minutes ago,
prostate cancer mortality rates have fallen
over 50 percent in large part,
not entirely, but in large part because of screening.
But the cost of this was far too much over-treatment of
low-risk disease and many
avoidable long-term side effects.
Now, the screen none
stands by the US task force when in 2012,
they said, "Don't screen anybody
ever," was not the right solution.
Rather we need to figure out a way to screen smarter.
But I would argue that PSA is actually
the best screening biomarker in the history of oncology.
We just need to figure out how to use it better.
At the heart of
the dilemma is the fact
of diagnosing cancer and what that means.
This is a great cartoon from Laura Esserman
who's a breast surgeon here and Ian Thompson,
a urologist in Texas.
Thinking about screening for any cancer,
the idea is we can screen periodically
over a person's life whether that's PSA testing,
mammography, colonoscopy, doesn't really matter.
The idea is if you get to
the far right of the graph here,
you've died of something else, usually heart disease.
If you get to the top, you're actually died of a cancer.
There are many prostate cancers that we don't
find even with aggressive screening.
These are the so-called autopsy tumors.
If you live long enough,
almost every man will get a couple of
cancer cells in the prostate and these don't matter.
Then there's the ones that we can find.
We can "cure" them
when they're still confined to the prostate,
but have we not found them,
they would have caused no problem.
These are the over-diagnosed tumors
which we need to avoid treating.
Then there is a population of tumors that we can find.
We can treat them before they would
have gone onto lethal disease.
This is where we really think we have seen
the benefits from screening over the years.
Then finally, there are prostate cancers where the PSA
is 0.6 then it's 0.7 then it's 3.
By the time we do a biopsy,
the cancer has already spread.
These are fortunately very rare in prostate cancer,
but this is why we don't screen, for example,
for pancreatic tumors because of the rate of rise.
The tension really is about the rabbits versus
the turtles and the impact on
the turtle population from chasing the rabbit.
Now we do have a number of trials which help
inform what we know about the impact of screening.
Lots of controversies around these.
But to summarize things very
briefly, two European trials,
the ERSPC and the Goteborg trial in Sweden do show
a drop by about 20-40 percent
in prostate cancer mortality
with screening compared to no screening.
There was a US trial called the PLCO,
which you may hear is a counterweight
to the European trials, showing no benefit.
But in fact, it was not informative because
the vast majority of men who were not
supposed to get screening in
the US arm did in fact get at least one PSA test.
So the US trial really did not answer the question.
The problem though as I alluded earlier
is how we have done screening.
If you look at the typical age
that a man gets a PSA test in the US,
it's in his late 60s and early 70s.
This is far too late because the problem is
PSA is prostate-specific antigen,
it's not prostate cancer specific antigen.
As more things happen to the prostate,
as a man gets older and in particular,
the prostate tends to grow.
There tends to be BPH,
benign growth of the prostate.
PSA becomes harder to interpret.
The ideal time to screen is much younger,
but we don't see much screening for
men in their 40s and 50s.
We've also over-treated and under-treated over the years.
These are data from the capture registry
which we've run at UCSF for many years,
showing that over decades from the 1990s
up to the start of the prior decade,
the use of active surveillance for
low-risk prostate cancer was
typically around 10 percent, far too low.
Went up rapidly to 40 percent
just in the most recent years.
But this is still progress in the right direction,
but still not where we need to be.
In the meantime, we've tended to
under-treat high-risk disease.
Historically, up to 50 percent of men with
aggressive prostate cancer got hormonal therapy
alone with no attempt to
cure surgery or radiation therapy.
This is also improving, but we still have work to do.
Can we do it all better? The answer is yes.
In 2021, we do
have relative consensus across
the different guidelines agencies.
I'm not going to go through the details here,
but all the major guidelines
do now argue for shared decision-making
between primary care doctors and
men about the risks and benefits of PSA testing.
There's disagreement in terms of
the optimal ages to screen,
but there's really less and less
the controversy that screening should be offered.
The question though is how we do it.
As I mentioned earlier,
the best time to screen is
a man who's relatively young and does not have
BPH cloud in the waters in terms of interpreting the PSA.
The thing is when we're screening younger men,
we need to forget all about 4.0
as a threshold to define normal.
Some terrific studies with
very long-term follow-up have been able to
demonstrate that if the PSA is less than one by age 60,
which it usually is,
prostate cancer can basically be taken off
your list of worries for the vast majority of men.
Ninety percent of prostate cancer deaths happen
in men who have a PSA greater than two at age 60.
If we turn back the clock to
look at men in their late 40s,
we can actually make predictions out to
25 years were 3/4 of the population,
that's the bottom three lines here,
can basically not worry about prostate cancer.
All the money is in following those in top quartile.
This is defined by a PSA threshold of about
1.4 for men in their 40s, not 4.0.
How do we screen smarter? We're now doing this at UCSF.
We've implemented this in primary care.
We're recommending early baseline testing for
men between the ages of 45 and 75
with aggressive secondary testing for those with
borderline PSAs before going on to biopsy.
PSA should not be interpreted in a vacuum.
We can think about it with factors
like PSA, family history,
digital rectal exams to
predict not only the likelihood of having cancer,
but of having a high-grade cancer that might need
treatment if we went on to biopsy.
We'll hear a lot of
biomarkers throughout this whole meeting,
but in 2021, we have many,
many markers to help with
pretty much every decision along continuum
from whether we should get a PSA
onto what to do by defense disease.
Specifically for the question of men with
elevated PSA is contemplating biopsy.
We've got a lot of tests that we are now using
routinely at the point of care.
These are non-invasive blood in urine tests to help
us decide whether to go forward with a biopsy.
At UCSF, we're using the 4K, the ExoDx,
and SelectMDx, quite heavily
as well as multiparametric MRI.
MRI is being used more and more around
the world to help guide biopsies.
I think it's controversial whether
MRI can actually replace the biopsy.
I would argue in 2021,
it cannot because there's too much variation
from radiologists in terms
of the accuracy of their interpretations.
This is a nice study from Stanford,
which showed that if you had a PIRADS 5 call,
meaning high-risk lesion on MRI,
the likelihood of actually having
an aggressive prostate cancer ranged from
40 percent to 80 percent depending
on which radiologist happened to read your scan.
I would not claim that things are necessarily
better at any other major center.
The argument really is that MRI can augment
but should not replace a systematic biopsy.
I would also make the point that ultrasound is
still an excellent diagnostic modality.
We looked at a large series of our cases here at UCSF.
It turns out that MRI uniquely
identify the highest grade tumor
only 6.5 percent of the time.
We find as many or more with ultrasound,
and actually with a good systematic biopsy,
we do pick up most of the cancers.
To summarize, we really should be thinking
about screening or offering screening
to most healthy men with a good life expectancy
beyond 15 years,
and we really need to think about tailoring intensity of
screening depending on that baseline
PSA and other risk factors.
Emerging markers can really help us
with decision-making about biopsies,
and we here manage low-risk prostate cancer,
almost entirely with active surveillance
as we will be discussing later on in the meeting.
It goes without saying that if we're going to treat,
it must be high-quality treatment,
minimizing side effects, and we need to keep tabs
very closely on the quality of care we deliver.
Thanks for your attention and we will talk
more about the specific treatments in the next sessions.
At this point in time, we can
field just a few quick questions.
Dr. Cooperberg, comment on
the relationship between PSA density, 4K score,
ExosomeDX, and MRI in terms of screening
and thresholds for first-time biopsy recommendations.
Then are there less invasive tools
to use instead of biopsy?
Those are related questions.
All the tools you just mentioned and the ones
that I'll later show in informal talk
are all non-invasive tests that we
use in terms of improving
decision-making about whether a man
needs to go forward with biopsy.
In 2021, the only way to
diagnose a cancer remains biopsy.
Neither MRI nor any other tests can
conclusively say that there is prostate cancer there.
Not only that but only biopsy will tell us
which are the high-grade cancers that need treatment.
For that reason, biopsy is still the final word.
But in terms of making decisions based on PSA,
we're using all these tests more and more to
try to make better and more refined decisions.
PSA density, so PSA related
to the size of the prostate tries to
get at the question of how much of
the PSA we might comfortably write off to BPH.
These other tests, 4K, exosomes, SelectMDx,
we use them quite heavily for men who have gray zone
PSA is trying to decide if
we should go forward with biopsy.
These tests are all calibrated for what we
call a good negative predictive value.
That means is if we run a test and it's negative,
you can be pretty confident.
It's usually around 90-95 percent
confident that there is no high-grade cancer there.
There might be low-grade cells,
but no high-grade prostate cancer.
If the test is positive,
maybe there's a cancer, maybe there's not,
at least a high enough likelihood we should
consider going forward with biopsy,
but the tests are set up so
that a negative test is very reassuring.
The MRI, like I said, helps guide the biopsies,
but it's not as good as
a screening test to rule men out entirely for biopsy.