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You are here: Home: BCU 6|2002: Supplement: John Robertson,
MD, FRCS
DR JOHN ROBERTSON
DR NEIL LOVE: Earlier in the program, Dr Hayes,
in reviewing our current understanding of the mechanism of action
of endocrine therapy, mentioned the newest addition to our armamentarium,
the estrogen receptor downregulator, fulvestrant. In a previous
Breast Cancer Update program, Dr Kent Osborne reviewed the initial
results of two major Phase III randomized clinical trials comparing
fulvestrant to anastrozole. The North American trial, first presented
by Dr Osborne at the 2000 San Antonio Breast Cancer Symposium, demonstrated
that while the response rates in the two arms of the study were
equal, the duration of response was greater in women receiving fulvestrant.
A European trial, with a slightly different design revealed equivalent
durations of response. Fulvestrant is now available for clinical
use and to learn more about where we are in clinical research on
this interesting agent, I met with Professor John Robertson, a key
figure in these studies. He began by commenting on a recent analysis
combining the data from the two major trials of fulvestrant versus
anastrozole in an attempt to learn more about duration of response.
DR JOHN ROBERTSON:
One of the issues to look at was duration of control in the patients
who do respond. In any study, that’s always been problematic,
because you are selecting a population of patients who’ve
responded, and you couldn’t identify those pre-randomization.
So a statistical method has been proposed for doing that, whereby
you allocate those who have never responded a time of zero, so that
all non-responders get a duration of response of zero. When you
look at that, in fact what that shows us is that in the patients
who do respond, you see a longer duration of response on Faslodex
than Arimidex. So that’s, I think, a new finding since that
time.
DR LOVE: Now, is that in the combined two trials?
DR ROBERTSON: That’s
combining them.
DR LOVE: Interesting because the separate trials,
it was just the North American trial that you saw an increased duration
of response.
DR ROBERTSON: And
that was by the historical method of measuring duration of response,
which is only taking the responders. That method has always, as
I say, been regarded as slightly less statistically secure, because
of the fact that you’re only taking a subpopulation of patients;
i.e., the responders. This method takes note of all the patients
and allocates the non-responders a time of zero for the response,
zero months.
DR LOVE: So, basically, it looks at the whole
population in one arm versus the other arm in terms of how much
time patients spent in response?
DR ROBERTSON: Yeah.
Absolutely.
DR LOVE: That’s interesting. So when you
combined both studies it was statistically significant?
DR ROBERTSON: Yeah.
It was significant in favor of Faslodex.
DR LOVE: You’re a researcher. I’m
trying to represent the docs out there in practice, figuring out
what this means. What they want to know is, looking at all this
data and having worked with it and lived with it all this time,
do you have the feeling that there’s an overall greater anti-tumor
benefit from Faslodex than Arimidex?
DR ROBERTSON: I would
describe myself as a doctor as well in the sense that I treat patients
all of the time. I would not say that categorically it was better,
because it’s a retrospectively derived analysis and you’ve
got to be statistically rigorous in your interpretation. But I think
what it does do is it emphasizes that there is at least equivalence
of these drugs in the second-line setting, and gives you even more
confidence to use Faslodex if that was your preference.
DR LOVE: How do you think it’s going to
be used?
DR ROBERTSON: I hope
that people are going to embrace it, because it’s a good drug.
It’s got a very good side-effect profile. I think what you
see is that it’s equivalent in side effects with anastrozole,
and anastrozole was better than tamoxifen in the comparisons. So,
it just shows this is a very safe drug in that sense. And from the
data we have in second-line, I would really hope people would embrace
it, but it’s difficult to choose between two very good drugs.
I think that the other questions will be – what should the
sequence be? Is there any information to say that, if you have Faslodex,
will you respond to an aromatase inhibitor? Or, if you have an aromatase
inhibitor first, will you respond to Faslodex? I think that the
data is coming through, that after you have had Faslodex, you still
can see responses to aromatase inhibitors. And vice versa.
DR LOVE: One of the concerns had been that if
you treat with Faslodex and you “deplete” the cells
of estrogen receptor then patients wouldn’t respond to other
hormones.
DR ROBERTSON: Yes.
I’ve heard that said, too, that Faslodex resistance is hormone
insensitivity. That’s not true. There are two things to say.
One is that we have seen responses post-Faslodex. We have seen good
examples of that, even in our own center. We had a lady who’d
been on Faslodex for six years – she was on the very first
Phase II study we ever ran – she went on to get an aromatase
inhibitor, and showed a partial response in her metastases.
The other thing to say about that – and this is why I think
that the question you asked – is Faslodex resistance hormone
insensitivity? It isn’t. I published a paper called “Estrogen
Response: A Stable Phenotype” to show that the estrogen receptor
is stable between primary and metastasis. But we don’t know
if it will work in sequential biopsies. In some of those patients
we have biopsied the cancer at progression. In fact, one of the
ladies who we biopsied them, was this lady who had a response to
Arimidex after Faslodex. And, at the time of her resistance to Faslodex,
her tumor was still expressing some estrogen receptor.
DR LOVE: That’s fascinating.
DR ROBERTSON: That’s
six years later.
DR LOVE: Interesting. I’ve heard it described
as the fact that, basically, by using Faslodex, you’re changing
the phenotype in terms of expression of estrogen receptor, but the
genotype is still there so when you remove the Faslodex, that gets
expressed. Do you go along with that?
DR ROBERTSON: Well,
this was actually at resistance, when the patient was on Faslodex.
She still had some expression. This is six and a half years later
and clearly we need to know a bit more about what happens over that
time period in terms of the expression of estrogen receptor.
DR LOVE: So, does that suggest that maybe part
of the resistance to Faslodex is developing the ability to make
estrogen receptor?
DR ROBERTSON: Well
that may be part of it. If you look at the presurgical studies,
we saw a greater downregulation with Faslodex than with tamoxifen.
But in a number of cancers, we’ve still not wiped out; there’s
still some expression. And so I think that also may be an issue,
which is that there is still receptor there, and what is the mechanism
by which the cancer becomes resistant to Faslodex in that setting?
And we don’t know that yet.
The second reason is that in some of these tumors which have got
low expression, it may be that, in fact, more of the cells are expressing
ER, but it’s below the level of detection of the assay. So
these are really more positive than you think, but it’s simply
that the assays that we have available don’t detect that,
as well.
DR LOVE: You’ve been one of the leaders
in defining the mechanism of action of Faslodex. Can you review
what we know about that, and has anything new developed over the
last year or so in understanding what’s going on?
DR ROBERTSON: No,
I think there’s not been much more. Essentially, with Faslodex
the mechanism is that, first of all it prevents dimerization of
the receptor, and second of all it increases degradation of the
receptor’s dimerized complex, so that you reduce the half-life
of the protein. The mRNA levels are the same, but the protein levels
are less because the half-life is reduced. By that method, what
you find is that you get less of the dimerized complex and, secondly,
when it then goes along to attach to the estrogen response elements
and genes, you don’t get translation because it switches off
both the activator functions, AF-1 and AF-2. And I think that’s
not changed.
The second question, I think, for the future is – what is
the mechanism of resistance to the pure anti-estrogen? We don’t
think it’s an agonistic property. And I mentioned to you a
moment ago that you can see ER expression on treatment, and even
at time of resistance. I think that that’s going to be one
of the major questions to ask in the future. We are addressing some
of those by sequential biopsies in patients to try and take pieces
of the cancer out to look at that both when they’re responding,
but also when they become resistant.
DR LOVE: Faslodex has been looked at primarily
in postmenopausal women. What do we know about it in premenopausal
women?
DR ROBERTSON: There
is one ongoing study. It’s now actually completed, which was,
again, a pre-surgical study that I was the PI for. What it was looking
at was Faslodex or placebo, pre-surgically, in women who were awaiting
primary surgery. So, they had their biopsy for diagnosis and then,
in the two to three weeks before the operation, they were given
either a placebo injection or they were given Faslodex, 250 milligrams,
and then a piece of the cancer was taken out again at the time of
surgery. We’re looking at, obviously, downregulation of ER
and PGR to see first of all whether we are seeing downregulation?
But even perhaps more significant, are we seeing the same degree
of downregulation, as we see in a postmenopausal patient?
The reason, obviously, for the interest is that Faslodex has an
affinity for the estrogen receptor, which is roughly equivalent
to that of estradiol. And premenopausal women have got a logarithmically
higher level of E-2 than postmenopausal women. So the question is
– with such a high level of estradiol, will this reduce the
degree of downregulation of the estrogen receptor? I’m sorry
to say, today, I don't know. I can’t give you the answer to
that. But it should be available, again, hopefully in publications
and in presentations by the end of the year.
DR LOVE: Any thoughts about what you think you
are going to see? There have been some studies done in premenopausal
women, I guess, mainly for safety purposes. Do we know anything
about its anti-tumor effect?
DR ROBERTSON: Not
in premenopausal patients. If you were to make a guess, it’s
one of two things. You’re either going to see the same as
postmenopausal patients or the other issue you may see is slightly
less downregulation. You can make arguments either way. I’d
rather not speculate, but those would be my two most expected results.
DR LOVE: Is there any reason that a higher dose
hasn’t been tried? It’s a fairly non-toxic drug. It
would be an extra injection, but it seems like it might be something
that could have been looked at?
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