|
You are here: Home: BCU 6|2002: Supplement: Melody A Cobleigh,
MD
DR MELODY COBLEIGH
DR LOVE: Last time I saw you one of the things
that I remember very clearly that you mentioned to me is how vexing
it was to you why people don’t respond to Herceptin and what
the mechanism might be. Have you any clues to that since we last
talked?
DR COBLEIGH: Well,
no. But let me tell you about the MASH Unit. MASH stands for Molecular
Assessment of Sensitivity to Herceptin. We have established collaboration
with the original Herceptin investigators and we have retrieved
blocks from the people who were treated with Herceptin as a single
agent. The problem with addressing that question is, you can’t
look at people who’ve gotten Herceptin plus chemo because
the molecular alterations that occur you don’t know if they
are from the chemo or from the Herceptin. So we are up to 70 blocks
and, protocol has been IRB approved for this, both clinical and
tissue repository, and hopefully I’ll have an answer for you
in another year.
But the idea is that this MASH Unit will create tissue arrays from
these tumor specimens, and then anybody who has an interesting question
about sensitivity or resistance to Herceptin, will have sections
from those arrays made available for testing whatever novel idea
that that individual wants to test. This is for not just for private
or academic institutions, but even for companies who have an interesting
idea about a diagnostic they would like to investigate.
DR LOVE: So the idea is that you might be able
to empirically just find something that correlates with response,
sort of to further refine down HER2 so to speak?
DR COBLEIGH: Right,
but there’s more known about the pathway now and so, a rational
thing to do would be to look at downstream elements in the pathway
to see if they’re somehow modified, so that doing something
upstream doesn’t even make any sense.
DR LOVE: I guess the other thing would be, it
might be interesting to do the same thing, and I don’t know
if it’s going to be done in the Iressa-Herceptin trial that
you mentioned, but to do it in that kind of trial.
DR COBLEIGH: Right.
And, I think everybody has gotten the message now that if you do
a trial with a novel biologic you better get the blocks. The problem
with the original Herceptin trials is the blocks were not obtained
and so now we need to ask that question in a difficult situation.
Many people are using Herceptin with chemotherapy, that’s
the way it’s FDA approved in terms of front line therapy.
So we need to get these old blocks and we are also accruing patients
to this archive or this repository who are receiving Herceptin as
a single agent who were not on those original trials.
DR LOVE: Any pet theory about what the problem
is or where the point is where there is a problem?
DR COBLEIGH: My guess
is that it’s downstream of the receptor and people have their
pet molecules. AKT is probably a good bet. But it maybe multiple
hits or maybe different hits in different patients.
DR LOVE: You went through your algorithm for the
HER2-positive patient, what about the HER2-negative patient? And
let’s start with ER-negative in the metastatic setting?
DR COBLEIGH: That
is the most depressing patient to meet. You’re waiting for
the markers, you’re hoping you have something to work with,
and everything that’s benign is negative. The only option
is chemotherapy, so I would give that patient chemotherapy.
DR LOVE: What kind?
DR COBLEIGH: Depends
on what kind of chemotherapy she’s had in the past.
DR LOVE: Let’s start with no chemotherapy
in the past.
DR COBLEIGH: Well,
there is an old fashion regimen called M?F, which was described
by the NSABP and was one of the forerunners to their B-13 trial.
You don’t lose your hair; you don’t vomit; you don’t
end up in the hospital with a neutropenic fever; and you don’t
become postmenopausal. It’s given day one, day eight, every
4 weeks. It’s easy, so that’s probably the one that
I would use.
DR LOVE: Interesting. You like to be different,
don’t you?
DR COBLEIGH: You
can give it forever. There are no cumulative neurotoxicities
DR LOVE: Interesting. So do you do that much?
DR COBLEIGH: Yeah
DR LOVE: No kidding. Wow.
DR COBLEIGH: It’s
cheap!
DR LOVE: What about the patient who has had prior
AC recently and relapsed? Don’t tell me you’re going
to use M?F again?
DR COBLEIGH: (Laughter).
I do actually think that M?F is an option in that patient. Ok so
let’s move beyond M?F. Let’s say that that’s the
only thing she’s had, I would probably use a taxane. I think
that weekly Taxol is very easily tolerated, except for the visits.
So that’s the direction in which I would move.
DR LOVE: Patient has prior ACT.
DR COBLEIGH: There
are a number of options, but I think one of the easier ones for
the patient is Xeloda. It is oral. It is a visit to the doctor once
every 3 weeks. I’m extremely impressed by the activity of
Xeloda. We’ve used it a lot because we’ve been participating
in the Xeloda with or without anti-VEGF trial, and I’m impressed
with two things. One the response rate to Xeloda, on its own, but
secondly the fact that they can tolerate very large dosages. Many
people can tolerate the doses that were described in the original
trial of 2500 per meter squared. We had to start with that in this
trial, normally I would have given a lower dose, but anyway it works.
DR LOVE: Off protocol what dose are you usually
using at this point?
DR COBLEIGH: I would
start with them at 2500 per meter squared, but I think the patient
education piece is really important. At the first sign of anything
in the hands or the first sign of diarrhea, we have a call in program.
If you monitor the toxicity carefully many patients can tolerate
the higher doses amazingly well. At the first sign of toxicity you
drop back with a 25% dose reduction, and so on.
DR LOVE: When you take that type of aggressive
patient education approach, how often do you see a problem that
really is bothersome in terms of hand-foot?
DR COBLEIGH: Only
when the patient decides not to listen to you. Some patients have
this idea that “if I hit this really hard, I’ll be cured
or that I can take this.” That’s a really bad strategy.
DR LOVE: Are there patients that you’ll
use Xeloda before a taxane?
DR COBLEIGH: I haven’t
done that yet, it may just be because that’s what I’m
used to doing, but I don’t think there’s anything wrong
with that necessarily. The drug is approved by the FDA for people
who have progressed after an anthracycline and a taxane. But I don’t
frankly think there’s anything wrong with using it any sooner.
DR LOVE: Any gut feeling about what the relative
activity of Xeloda versus the taxanes?
DR COBLEIGH: No.
DR LOVE: What about combination chemotherapy,
do you use that at all?
DR COBLEIGH: Nope.
DR LOVE: Life threatening disease?
DR COBLEIGH: (Pause)
OK (Laughter). If it’s really life threatening.
DR LOVE: What kinds of combinations are you using
in that situation?
DR COBLEIGH: Again
it has to depend upon what the patient has had before, but AT for
someone who’s not had an anthracycline or a taxane recently.
Xeloda-Taxotere is another possibility for someone who’s recently
progressed on an anthracycline. But that’s the rare patient,
and I think it’s really unfortunate that patients with metastatic
breast cancer who are not curable are routinely getting combination
chemotherapy, when single sequential agent treatment is just as
effective in terms of survival. I think that the model for a clinical
trial in terms of comparing regimen A with regimen B, is E-1193
of the ECOG study that looked at adriamycin versus Taxol with a
crossover at progression versus the combination of the two. Here
you have two of the most active drugs in the world for breast cancer
and there was no difference in survival.
DR LOVE: Most people site that study as why not
to use combination therapy, but I’ve heard it cited as a reason
to use it because there’s more responses, maybe better tumor
control, better quality of life.
DR COBLEIGH: Well,
you’d have to prove it in terms of a quality of life instrument.
I can tell you that people who have AT have a lower quality of life
than people who get sequential single-agent therapy do. They have
more side effects. The bottom line is people want to live to see
their grandchild or their child graduate from high school or whatever,
and loading on these combinations of drugs when single sequential
treatment is just as effective, I think is unfortunate.
Page 3 of 3
Back
|
