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You are here: Home: BCU 6|2002: Supplement: Melody A Cobleigh,
MD
DR MELODY COBLEIGH
DR NEIL LOVE: Another important targeted treatment
strategy in breast cancer involves the HER2 and EGFR systems. The
June 5 issue of the Journal of the National Cancer Institute contains
two important new reports on quality control of HER2 testing based
on data from ongoing Intergroup and NSABP adjuvant trastuzumab trials.
I met with Dr Melody Cobleigh, a key clinical research leader in
trials of Herceptin, to learn of her take on these and other recent
research developments in biologic therapy. However, like most recent
interviews with breast cancer investigators, our discussion began
with the big research news story of the year, the ATAC trial.
DR MELODY COBLEIGH:
I was surprised by the results mainly because the combination was
equivalent to tamoxifen and anastrozole was better. There are theoretical
reasons for that, but at any rate we are faced with these results
of an aromatase inhibitor being better than tamoxifen. They are
very early results and most of the patients were node negative.
So while it looks impressive in terms of the p values, I would be
delighted to see more long-term information, and particularly more
information on toxicity. I would say that the results are provocative.
I certainly don’t plan on switching people who have been on
tamoxifen thus far. For high-risk patients, for example, node-positive
patients I would tilt toward using Arimidex. I’m not sure
about the node-negative patients yet.
DR LOVE: De novo?
DR
COBLEIGH: Right, de novo.
DR LOVE: I guess another question would be, is
it just going to be Arimidex or you are going to look at letrozole
and exemestane in terms of adjuvant therapy?
DR COBLEIGH: That’s
a wonderful question, and right now, I would just consider Arimidex
because that’s the drug that has been proven. There isn’t
any information on these other aromatase inhibitors. On the other
hand, are we going to have to do prospective randomize trials in
the adjuvant setting in every single one of these drugs? But in
terms of the bottom line, if I were going to pick an aromatase inhibitor
to use in the adjuvant setting it would be anastrozole.
DR LOVE: What about the patient, let’s say
a node-positive patient who is ER-positive, who starts out adjuvant
chemotherapy menstruating and finishes chemotherapy amenorrheic
and is proven by endocrinologic profiles to be postmenopausal?
DR COBLEIGH: I think
you have to be very careful there because while chemotherapy can
induce amenorrhea quickly, that is reversible. The World Health
Organization definition for menopause is a year since your last
period. So, for the patient who was premenopausal prechemotherapy
who is now, not menstruating postchemotherapy, I would not put that
patient in an aromatase inhibitor.
DR LOVE: 43-year-old woman who has 5 positive
nodes, strongly ER-positive, finishes chemotherapy and she’s
still menstruating.
DR COBLEIGH: Tamoxifen.
DR LOVE: Do you use ovarian ablation in that situation
at all?
DR COBLEIGH: No.
There is still not a trial that has shown that chemotherapy plus
tamoxifen in an ER-positive premenopausal patient is inferior to
chemotherapy plus ovarian ablation.
The other thing that I think is of practical importance is this
business about using neoadjuvant endocrine therapy. The initial
paper using letrozole produced phenomenal results, and there was
a poster looking at anastrozole in the neoadjuvant setting that
produced the same pathologic complete remission rates as chemotherapy.
That’s amazing to me because you see 3A or 3B breast cancer
and immediately you reach for your chemotherapy prescription pad.
Thank God for the Europeans because they had the courage to give
them hormones and it looks like it’s just as effective as
chemotherapy. It’s obviously a much more benign thing to do.
So, I think I’m going to be trying that.
DR LOVE: Haven’t done it yet?
DR COBLEIGH: No,
I haven’t done it yet. The Ellis paper impressed me, but now
that I’ve seen this in the anastrozole paper, I’m going
to do it particularly in an older ER-positive patient who presents
with advanced disease.
DR LOVE: Maybe this is getting a little bit ahead
of the game, but if we are going to start moving towards using adjuvant
anastrozole maybe we’ll start to get into the same mode of
chemotherapy. We know if they have a 2-centimeter tumor, they are
going to get the chemotherapy anyhow, so why not give it to them
upfront, shrink it down, maybe make it more likely for best conserving
surgery and see what happens in vivo with the tumor? Maybe that’s
where this will all come together and that they know there are going
to get anastrozole post-op anyhow, maybe give it to them pre-op.
DR COBLEIGH: Right.
DR LOVE: I mean not just for locally advanced
breast cancer.
DR COBLEIGH: Well
if it makes sense in locally advanced breast cancer, it would make
sense to give it earlier if you are going to use neoadjuvant therapy.
DR LOVE: Yeah, I’m thinking of a woman who
has a 3-centimeter tumor who is not going to be amenable to lumpectomy
because she has a small breast.
DR COBLEIGH: The
problem there is that since we have these survival advantages that
have been shown for doing chemotherapy plus hormonal therapy, I
think you have a little bit more difficulty.
DR LOVE: You mean as adjuvant post-op?
DR COBLEIGH: Right.
DR LOVE: Well there’s no reason you can’t
give anastrozole pre-op and then anastrozole and chemo post-op,
is there?
DR COBLEIGH: No,
but when you’re dealing with a curable situation I think you
would need a trial to pop to that.
DR LOVE: I think actually, the Europeans are thinking
about that kind of a trial.
DR COBLEIGH: That
makes a lot of sense.
DR LOVE: Yeah, I’m thinking so what they’re
talking about is a 2 x 2 design, randomized pre-op and then randomized
post-op.
DR COBLEIGH: This
makes sense.
DR LOVE: So what kind of patient would you be
thinking about in terms of using neoadjuvant aromatase inhibitors?
DR COBLEIGH: I would
say particularly a postmenopausal patient who had 3B breast cancer,
where the knee-jerk reaction is to go to chemotherapy and maybe
that hormonal therapy is more effective. Certainly, from that anastrozole
paper, anastrozole produced the same pathologic complete remission
rate as was presented in the NSABP study of AC followed by Taxotere.
That was astounding.
DR LOVE: You been involved in some of the key trials
of Herceptin. One of the issues that has gotten a lot of attention
is HER2 testing. Where do you see that right now?
DR COBLEIGH: I feel
very strongly that if you’re going to get Herceptin, you ought
to have your tumor FISHed. There’s all of this argument going
on about how it’s more expensive to do the FISH testing than
it is to do the IHC. Well it costs about $50 to do a FISH test and
it costs about $5 to do an IHC test. But it costs an awful lot of
money to get Herceptin. So I think we really need to get it right,
in terms of thinking about treating a patient with Herceptin. I
would even go one step further and say I think we ought to get it
right from the standpoint of adjuvant therapy. Women who have the
HER2 alteration tend to benefit from anthracyclines, and probably
shouldn’t be denied anthracyclines as long as they have a
healthy heart. So, I’m for FISH testing.
DR LOVE: Does that mean if a patient comes to
you who has an IHC of 3, for example, you are going to FISH them
before they get the Herceptin?
DR COBLEIGH: I will
FISH them because they may not have the amplification.
DR LOVE: What about patients with a zero or 1
by IHC?
DR COBLEIGH: I’ll
FISH them too, because 3% of the zeros are amplified and 7% of the
ones are amplified. So, again it’s a matter of getting it
right, and it’s a matter of life and death.
DR LOVE: I’ve heard people say they will
FISH patients that are zero and 1 if they have a clinically aggressive
course, is that what you do?
DR COBLEIGH: I just
FISH them all.
DR LOVE: So every single patient with metastatic
breast cancer gets a FISH in your practice.
DR COBLEIGH: Yes.
DR LOVE: Makes sense to me. I think there’s
been a lot emphasis on false positives and people being treated
unnecessarily. I agree with you and it bothers me because we know
that breast cancer and all cancer patients for that matter are interested
in even minor chances if they can benefit. You’re talking
about spending $50 dollars to find that out.
DR COBLEIGH: Right.
DR LOVE: How do you approach the patient with
metastatic breast cancer who is HER2-positive, and let’s start
first with ER-negative?
DR COBLEIGH: That
patient, if she does not have life threatening disease, I would
treat her with Herceptin as a single agent. If you look at the trial
that was done by Chuck Vogel — the front-line Herceptin trial
— and look at the disease characteristics of that group versus
the group that went into the chemotherapy with or without Herceptin
trial, you see that they are a very, very similar patient population.
And the longevity, the time-to-tumor progression and so on, was
the same in the Herceptin alone versus the Herceptin plus chemotherapy.
Now that’s not a direct comparison, but the model that we
have always used in breast cancer is that, we can’t cure metastatic
breast cancer and so you use the treatment that will be most likely
to put the patient in remission with the fewest side effects. Clearly,
Herceptin as a single agent is a more benign treatment than Herceptin
plus chemotherapy. So that’s my algorithm.
DR LOVE: Of course we don’t have the comparison
and then I hear people saying, “we know that there is a survival
advantage by combining it with chemotherapy, and we don’t
know that for a single agent.”
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