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You are here: Home: BCU 6|2002: Supplement
: Daniel F Hayes, MD
DR DANIEL HAYES
DR NEIL LOVE: If there is one buzz word that repeatedly
comes up in interviews with breast research leaders, it’s
the concept of targeted and rationally derived systemic therapy.
The capecitabine-docetaxel biochemical synergy is an example of
how this strategy can be translated into improved patient outcomes.
Targeted biologic interventions have been yielding benefits in breast
cancer for more than a century since Sir George Beatson’s
discovery in the 1890’s of objective tumor regression in women
treated with oophorectomy. The biologic mechanisms involved in endocrine
therapy have been the subject of considerable study, beginning with
the discovery of the estrogen receptor, and our knowledge of the
complexity of these systems is rapidly increasing. This year’s
Miami Breast Cancer Conference included a number of presentations
reviewing the current state of the art, and I met with faculty member
Dr Dan Hayes for his take on what this means to clinical practice
today. He began by commenting on the rapid pace of research in this
area.
DR DANIEL HAYES:
One of the things that’s come out at this meeting, but also
in general in the last five years, is how much we thought we knew
about the estrogen receptor by 1990 and how little we actually knew.
The knowledge that we’ve learned about the biology of the
estrogen receptor, how it works, how it interacts with the other
growth factor pathways like EGFR and HER2, how those play out clinically
and how complex that play-out is in the last five years is just
mind-boggling
Every time I think I understand, if you’re HER2-positive,
you might not respond to hormone therapy as well, then another clinical
trial comes out and says nope, that’s not the answer. It’s
completely different. The complexity of this disease really is staggering,
and that’s why it’s so hard to treat.
DR LOVE: That’s funny.
Yesterday, I saw Tony Howell put up this really complex schema and
I’m sitting there thinking about the ones we had in the mid-‘80s
where there was the little estrogen flowing into the cell. But from
the point of view of a clinician in practice, what are the things
that really mean something in terms of the biology of the estrogen
receptor?
DR
HAYES: Well, it depends on precisely
what you want to do. I think, if you’re just giving pills
to people, maybe not much. But most of us went into oncology –
even, I think, most of people in private practice, for whom I have
a lot of respect – because of the fundamental interest in
the biology of the disease. I interview a lot of young people who
want to go into oncology, and rarely do they say, “I want
to go into oncology to make a lot of money,” or “to
make people’s hair fall out.” It’s usually, “Jeez,
as a med student and resident, I noticed that the biology of cancer
is really fascinating, and even though I may not ever want to go
in the lab, that’s why I’m here.”
So, I would say there really are important things to know. One
of the conundrums of endocrine therapy is why multiple endocrine
therapies work sequentially. You would think that, if they all work
the same way, then one ought to work and then it stops. And that
appears to be what happens in prostate cancer. Right? We don’t
have serial treatments in prostate cancer.
But in breast cancer, I think one of the concepts that has gelled
in my mind in the last five years, that honestly maybe I thought
of but never really had in a concrete fashion, is the concept of
hormone dependence rather than hormone sensitivity. We think of
sensitivity and resistance in terms of treatment, but I think now,
more in terms of biology, that a cell starts out hormone dependent
or hormone resistant – or hormone independent is probably
a better word. And that the cell may stay, or the cancer may stay,
hormone-dependent for many, many years, but become resistant to
specific endocrine therapies. That’s because these therapies
work differently.
So, for example, we know you can treat a patient with tamoxifen;
she can be sensitive to tamoxifen and then become resistant to it.
Then we know that patient will respond to another endocrine manipulation,
like an aromatase inhibitor. So, fundamentally, you would think
that cell would be hormone independent if it is resistant to tamoxifen,
but it’s not. It’s still hormone-dependent. So, the
next therapy coming in works again by changing the hormonal milieu
that that cell resides in.
DR LOVE: I think we’ve always gone off the
antibiotic-resistant model in terms of how we view resistance to
systemic agents in cancer. What I think I hear you saying is it’s
not like that.
DR HAYES: I think
that’s the wrong model, especially for endocrine therapy because
our antibiotics all work differently. But in terms of endocrine
therapy, I think we’ve learned so much. We now know about
the complexity of a ligand, and it can be estrogen, tamoxifen, raloxifene,
droloxifene or phytoestrogens that bind to an ER. Then we know that
that changes the confirmation so that it’s prone to phosphorylation,
and the phosphorylation comes via the peptide growth factor signaling
pathways. With phosphorylation, then one gets two ERs together and
they dimerize, and then they go down and bind to the promoter of
estrogen-sensitive genes, and then that calls for a piling on of
coactivators and corepressors. And we know that there’s then
estrogen receptor alpha, which is the one we’ve always thought
of. Now there’s an estrogen receptor beta. We know that the
estrogen receptor actually can bind to a different part of the DNA
that doesn’t have an estrogen response element in it, called
AP-1. We always thought the AP-1 site was where the peptide growth
factors were working with.
We’re beginning to understand now why tamoxifen has this
funny duality, being anti-estrogenic in some cells and estrogen;
we could never understand that before. To me, it’s fascinating,
and, again, I’m a clinician. And this is playing out in the
clinic. It’s starting to explain why five years of tamoxifen
might be preferable to longer. It begins to explain now why serial
hormone therapies might work. It begins to explain the unexplainable
observation of hormone withdrawal response. We’ve known about
this for 50 years, but no one could ever really explain it. Now
we’re beginning to understand why that happens.
DR LOVE: Can you dissect out some of the major
hormonal therapies in terms of what we understand right now in terms
of mechanism of action using modern biologic understanding of the
ER and, also, what happens when the cells become resistant? You
would say they become resistant?
DR HAYES: Yeah, they
become resistant to specific strategies. One thing I’m actually
fond of saying it’s always interesting to me how little history
we remember. As we see Gleevec come on board, there’s so much
excitement about Gleevec being the first rationally designed drug
that works that’s targeted. That’s baloney. In 1892,
George Beatson removed a growth factor from its receptor by doing
oophorectomies and saw responses in two out of three women with
locally advanced disease. In my opinion, that was the beginning
of true designer-drug molecular medicine, if you will. We’ve
been doing targeted medicine in breast and prostate cancer for 100
years.
It’s just that we didn’t entirely understand what we
were doing. But for the last 30 years, we have with Jensen’s
discovery of the estrogen receptor, and then McGuire’s discovery
of the correlation between estrogen receptor and response, and so
on and so forth. Again, this is just another step forward, in my
opinion. So, I’m a little off your question, but I think the
good news of endocrine therapy for breast and prostate cancer is
we’ve known for 100 years that we can do target-directed therapy.
We just needed to find the targets.
For years and years, people said, “Why are we doing this
basic research? Why are spending all this money on this?”
It’s because ultimately, this has got to pay out. You get
smart guys like Brian Drucker, who is a clinician and a lab guy,
who starts to say, “Jeez, I can put two and two together and
come up with four.” I think Iressa is another example of that.
Looks like it’s going to be an active drug in lung cancer.
There is a whole host of these coming down the pike.
Okay. Having said that, let’s go back to breast cancer a
little bit. We know that the so-called SERMs – tamoxifen,
toremifene, raloxifene, droloxifene, and idoxifene – all bind
to the ER just like estrogen does. They all induce phosphorylation.
They all induce dimerization. They all induce binding to the ERE
in the promoter of the specific genes. But what they then do is
that they call for a different piling on, if you will, of different
coactivators and corepressors that are already in the cell. So,
how a specific cell responds to a specific ligand depends on a number
of things – how much estrogen receptor alpha it has and how
much estrogen receptor beta it has. That balance seems to be important,
as well as what kinds of coactivators and corepressors it has sitting
around. So, the cell is primed to see these things as estrogens
or anti-estrogens. In fact, it’s probably not even a specific
cell. It may be even related to more the genes that are already
turned on one cell versus another.
And so these ligands then have very different effects, even though
they fundamentally do the same thing – induce dimerization,
induce phosphorylation, and induce binding to ERE of the genes.
But then you get different effects, and so not only is it the pre-existing
state of the cell, it’s then the way the ligand – and
Craig Jordan, for example, has shown us a lot of this – it’s
the way the ligand itself fits into the conformational structure
of the dimer. And that allows a different infrastructure for the
same balance of coactivators and repressors to pile on and give
you different downstream effects for the same gene.
So, the question is can we actually design new SERMs that really
do exactly what we want to do; there are anti-estrogens in one place
and estrogens in another, and the way we want them?
DR LOVE: We’ve been hearing Craig talk about
that for a long time. Do you think we’re ever going to get
to a point where we get to that ideal SERM that he’s been
talking about?
DR HAYES: So, this
is speculation, because it’s just too complex for me to fully
understand. But I said 15 years ago that I wouldn’t spend
any more time on endocrine therapy, because I couldn’t believe
you could squeeze anymore effect out of the ER. "We’ve
gotten all we could with tamoxifen" And I was absolutely wrong
there, it appears. I’ve been wrong sufficiently in my life
that I’m willing to have smart people like Craig Jordan prove
me wrong.
The other one then is fulvestrant, Faslodex, coming down the pike.
This is exactly the question you’re asking, which is that,
unlike the SERMs, in which you induce some biological response –
and what the response is depends on the ligand – with fulvestrant
it binds to the ER and completely shuts the system down. It stops
phosphorylation, or prevents it. It keeps the ERs from dimerizing.
It prevents binding to the ERE. It’s truly an anti-estrogen.
It was developed as a rationally designed drug to do just that.
And it looks like it’s going to be, again, a step forward.
At least, it looks like it’s going to be as active as the
aromatase inhibitors, another set of designer drugs, rationally
designed drugs.
Now I think it’s almost an embarrassment of riches. The issue
is how do we use these? When do we use these? In what order? As
they’re beginning to hit the clinic now, I’m getting
phone calls from my colleagues in practice asking, “What order
do I use these in?” Well, I don’t think we know. I think
that’s the challenge for the major cooperative groups and
the companies, is to start doing trials of serial therapy and combination
therapies to see where we’re going. Then, even more –
I know this is a long-winded answer to your question – but
now I think the real challenge is to start to figure out the other
pathways that modulate these. I’m convinced what we’re
going to find – this is right down the alley to your answer
to your question – that different subgroups of patients will
actually respond differently to the different endocrine therapies.
So, just like we used to use ER to pick who gets endocrine therapy,
I believe in the future we’ll start using not only progesterone
receptor and HER1, 2, 3, 4, and actually begin to start measuring
some of the coactivators and corepressors, the amplified in breast
cancer 1, which came out of the NCI with Paul Meltzer and now Kent
Osborne, his group are looking at. Looks like they’re going
to start telling us, “Jeez, this patient should get tamoxifen
or a SERM, this patient should get an aromatase inhibitor, this
patient should get fulvestrant.” We’re always from that,
but I think we’re going to see that happen.
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