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You are here: Home: BCU 6|2002: Supplement
: Daniel F Hayes, MD
DR DANIEL HAYES
DR HAYES: What we’ve
not found are amplifications or activating mutations, the classic
things we think of as oncogenic steps, like we have with HER2 amplification
or go back to the real oncogenes, myc and ras – mutations
that are clearly oncogenic. You can’t transfect cells normal
cells with estrogen receptor, multiple copies, and make them become
cancer, to my knowledge. I don’t believe Suzanne has been
able to do that with this mutated ER. What I do believe, it’s
probably a secondary phenomenon. I think there are other hits in
the cell that produce genomic instability, P-53 mutations, and a
variety of things like that. Then, in the right milieu, that’s
where you begin to get cancer. So, in the right milieu, you’ve
got difference in coactivators, you begin to get changes in the
way they’re expressed because of some upstream change in P-53
or BCL-2 or BCL-X, or whatever. And that begins to result in downstream
effects that, in and of themselves, aren’t oncogenic, but
set the cell up to be more responsive to external stimuli like estrogen.
DR LOVE: Getting back to your basic model of the
endocrine-dependent breast cancer cell, you talked about SERMs,
Faslodex. You would assume that aromatase inhibitors and LHRH agonists,
that’s fairly straightforward. You’re just taking the
ligand away, correct?
DR HAYES: Well, it’s
straightforward except I think we’re going to find the mechanisms
of resistance to these things are going to be complex.
DR LOVE: Do you want to talk about that?
DR HAYES: Well, again,
I think it has to do with the biology of the cell. In theory, for
example, if the aromatase inhibitors are blocking peripheral conversion
of DHEA and testosterone to estradiol, which is what we think they
do, then one shouldn’t get resistance to those, because those
are sematic enzymes out in the fat. So, they’re not prone
to the genetic instability that cancer cells are. But we know that
resistance develops to these things. Is my point clear?
DR LOVE: Yeah. But, I mean, my understanding was
that cells just become sensitive to a lower level of ligand or estrogen.
DR HAYES: So, then
we have to start saying, why is the cancer cell figuring out how
to get around this, because it’s obviously not the target
of the drug that’s getting around it? One explanation actually
is, perhaps the cancer cells themselves are making aromatase. And
they’re making an abnormal aromatase that’s just happy
as a clam turning DHEA and testosterone into estradiol, because
they have mutated or some other reason, because they are prone to
the sematic changes relative to the instability of the malignant
genotype, as opposed to the normal fat cells, which are not. So,
that’s one explanation. And, again, Tony Howell and others
have looked very hard at the aromatase in the cancer cells themselves.
That’s still an ongoing question, but that’s one mechanism
of resistance that’s possible. Again, this is all speculation.
Another is, of course, that the cell ultimately becomes hormone-independent.
So now, no matter what you do, that cell’s being driven. I
tell my patients it’s like taking a car that drives on gasoline
– so, if the estrogen receptor is the gas tank and estrogen
is the gasoline – now you retrofit it with solar panel. So,
it might still have an estrogen receptor, but it’s running
on solar power. And, so maybe the HER2 or insulin-like growth factor,
we don’t know – some other factor starts pushing the
cell and driving the cell, and it becomes hormone independent.
A third is, it’s still hormone-dependent, but there are things
that have happened that make it, for example, hypersensitive to
really small amounts of estrogen. In that case, you would expect
that a drug like fulvestrant might work when those drugs quit working.
In fact it hasn’t been published yet, but Kent Osborne has
been talking about the results of the Faslodex versus Arimidex trials,
especially the U.S. trial, in which responses are longer with fulvestrant
than they are with Arimidex. His explanation for that is precisely
this, that Arimidex may be shutting down estrogen levels by 99 percent,
but that the cell has become super-sensitive to that one percent
of estrogen; whereas, fulvestrant just doesn’t let the estrogen
get there in the first place. So, again, there are a variety of
explanations. I think, probably, there are more that we don’t
know.
I believe, first of all, this is why most oncologists went into
the business, because of this fascinating biology. I think, if you’re
in the field, it’s important to understand this, because I
think it’s going to dictate how we use these drugs in the
next five years. We don’t know what to do yet, but I think
we will.
DR LOVE: It is great stuff, and this conversation
reminds me of some of the conversations I’ve had with Craig
Jordan. When we start talking about mechanisms of action, mechanisms
of resistance, and go down these kinds of topics, one of the things
I like asking him is what his thoughts are about the additive hormonal
therapy, such as high-dose DES, progestins, and particularly the
high-dose androgens, which he has made the analogy to of eye of
newt and that he has no clue. Do you have any clue? (Laughter)
DR HAYES: Well, I
was going to start out and say, of course, none of these are my
ideas. They’re all Craig’s and Kent’s and Tony
Howell and John Robertson – and it goes back to the real giants
in the field, long before any of us were even born. But, anyway,
I think we’re beginning to understand this. It’s always
been counter-intuitive that the treatment of choice for breast cancer
prior to the time we had tamoxifen and all these fancy things, and
even chemotherapy, was, of course, pharmacological doses of estrogenic-like
therapies, like DES. This has been forgotten. But I think we can
now begin to go back and say, “Oh, I get it. Now I understand
why pharmacologic doses of estrogen...” And we saw a very
interesting slide yesterday from Tony Howell, showing this sort
of biphasic response of MCF-7 cells to pharmacologic doses of estrogen.
In fact, I think those were Rob Nicholson’s data, as I recall
he said. I hadn’t seen the slide – showing that with
no estrogen, these cells won’t grow, because they’re
hormone-dependent. This is cell culture work, at modest doses of
estrogen, they grow quite nicely. Just what you’d expect.
And at high doses of estrogen, they quit growing again.
DR LOVE: But that’s kind of an empiric observation.
What do you think is happening in that system?
DR HAYES: So, that’s
consistent with the clinical observation. But then he also showed
that if you precondition those cells in different levels of estrogen
to start with – so, now they’ve set their reset button,
and I don’t know what the reset button is.
DR LOVE: Well, that’s what I want to know.
DR HAYES: Yeah. Well,
me, too. And there are people with a lot more money than you and
me who want to know. But, if you precondition those cells, then
you still see this biphasic response, but it’s shifted to
the right or left in regards to the estrogen concentration that’s
in the soup. That may be really critically important. That may actually
begin to explain all this, that is that the cell, for example, may
have different coactivators and different corepressors under one
estrogenic condition, and then you slam it. You change the hormonal
milieu and suddenly that cell says, “Oh, I can’t do
that.” And then, after a while, it starts to reset its coactivators.
Again, this is the eye of newt. I’m making this up, but I
think this is what we’re going to find with people smarter
than you and me, who are going to do all this in the lab.
So, what’s that got to do with the clinician? I think what
we’re going to learn is that a patient, for example, who was
on hormone replacement therapy, might have a very different hormonal
milieu when they’re diagnosed, than a patient who was not.
And we might want to treat them differently. Now, that’s not
ready for prime time in the year 2002, but I think it may be in
the year 2010. I think we’re beginning to understand the molecular
basis of hormone dependence and, therefore, hormone treatment and,
therefore, hormone resistance.
DR LOVE: That’s interesting. I wonder if
people have looked at response to different hormonal therapies based
on whether the woman was diagnosed on HRT.
DR HAYES: Not to
my knowledge, but I’m not the first guy to think of this.
So, I think you’re going to see stuff. But you almost wonder
whether just, boom, stop the estrogen, and that alone is probably
hormone adjuvant therapy, endocrine adjuvant therapy. Nobody’s
every done that. I don’t think they ever will, but, you get
a hormone withdrawal response, essentially.
DR LOVE: You referred to adjuvant aromatase inhibitors
and, of course, now we’re all looking at the ATAC trial data.
DR HAYES: Yeah, I’d
like to talk about that. All of us, I think, are very enthusiastic
over the potential of the aromatase inhibitors. But I think we need
to be very cautious about over-interpretation of the ATAC data as
they stand, and especially about implementing their therapy in the
adjuvant setting. And why be cautious? I’ll take a step back.
Why be enthusiastic? It’s because of preclinical data and
because of the data in the metastatic setting, we believe that the
aromatase inhibitors are at least as effective and probably more
effective than tamoxifen, especially in the long run. And so these
data fit our bias.
The downside is the real concern about potential major complications
with these drugs. The obvious one is osteoporosis. This is not the
only aromatase inhibitor versus tamoxifen trial going on. There
are at least two others that are similar in design, and then there
are two others in which women have got to five years or are randomly
assigned to aromatase inhibitor versus placebo. I think we need
to see those data, as well as more mature ATAC data before we routinely
offer all our patients aromatase inhibitors in the adjuvant setting
in the postmenopausal patient.
I will say, though, that for the occasional patient for whom tamoxifen
appears to be inappropriate – she has a past history of deep
venous thrombosis, she’s an older woman who’s had a
stroke or a TIA, she clearly has an allergic reaction to tamoxifen
with a rash that won’t go away – those are patients
I have already been using aromatase inhibitors in, and I think it’s
appropriate, now.
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