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DR DRULLINSKY: This 35-year-old
woman developed a mass during her
third pregnancy, which was ignored
by her obstetrician because it was felt
to be related to pregnancy changes.
Then, after delivery, the mass persisted.
It turned out to be a 3.5-centimeter,
moderately differentiated infiltrating
ductal cancer, with two sentinel
lymph nodes positive for cancer. It was
estrogen receptor-positive, progesterone
receptor-positive, and HER2-positive
by FISH.
We were participating in the CALGB
trial of adjuvant trastuzumab, and she
agreed to enter the study. She was
randomly assigned to no trastuzumab,
and she received AC times four and
weekly paclitaxel for 12 weeks. She
finished her therapy in January 2005,
at which point she was premenopausal,
and the question came up of whether
we should go with tamoxifen or
anastrozole and goserelin.
Since the tumor was 3.5 centimeters,
two lymph nodes were positive and she
had not received trastuzumab, I put her
on anastrozole and goserelin, knowing
that it’s not standard practice in this
country but based on some preliminary
information on aromatase inhibitors in
HER2-positive disease. Then, after the
ASCO meeting, we actually called her
back, and she’s being provided trastuzumab
for a year.
DR LOVE: A number of questions come
up about this case. First, let’s start with
the hormone therapy. Even though, as
you said, it’s certainly not standard, I
can tell you from our Patterns of Care
studies that probably about a third of
the oncologists in the United States
would have done what was done here,
in terms of using an LHRH agonist plus
an aromatase inhibitor in a high-risk
younger woman with a HER2-positive
tumor. Rowan, what are your thoughts
about that, off protocol?
DR CHLEBOWSKI: The data you have
to support it are a couple of Phase II
trials in metastatic disease with less
than 100 patients. So, in a certain
sense, there’s very limited information.
Alternatively, you could give ovarian
suppression plus tamoxifen. That’s what
we’ve been doing. You deviate off these
protocols in various different ways.
In women under 40 with hormone
receptor-positive disease, we’re
routinely doing ovarian suppression
with tamoxifen. We haven’t utilized
the combination of aromatase inhibitors
with ovarian suppression yet. But I can
see how it may not be an unreasonable
extrapolation to do so.
People should also know about a trial in
the abstract book from the San Antonio
Breast Cancer Conference a couple
years ago. It was a randomized trial in
metastatic disease, showing a benefit
for ovarian suppression plus anastrozole
versus ovarian suppression plus tamoxifen
(Milla-Santos 2000). But that was
a withdrawn abstract. It’s gotten into Medscape, and it’s very difficult to pull
it once it’s out on the internet.
DR LOVE: This also gets into the issue
of when to pull the trigger on a therapy
that hasn’t been proven in a Phase III
study. For the last few years prior to the
release of the data from the adjuvant
trastuzumab trials, I was asking research
leaders on our audio series about
patients like these, “Should you use
trastuzumab off study?” They very
strongly said, “No. Put the patient on a
trial. If not, you don’t use trastuzumab.”
Now it’s been proven to reduce the
relapse rate, and it raises the question
of how much evidence is enough when
you are dealing with a patient like this
woman, with a very high risk of relapse.
So, even though you say there are only
100 patients in these Phase II trials,
there are also thousands of postmenopausal
women who have benefited from
the aromatase inhibitors, and other
people would say, “We’re making the
patient postmenopausal, so let’s use the
best hormonal therapy for postmenopausal
women.”
Tom, what are your thoughts about
this — not just specifically of a
premenopausal woman with high-risk
ER-positive disease — but when do
we pull the trigger?
DR BUDD: It is an interesting question.
I think we have no option but to try
to be evidence-based, when we have
evidence. Now, there are all too many
situations in clinical medicine where we
don’t have data. And we have to reason
in other ways — by analogy to similar
situations, by what we know about the
biology of the disease and so on.
In the adjuvant treatment of any
disease, you can’t monitor the disease
to see what’s happening. The only
way to approach this scientifically
is with randomized trials that have
control groups. So in clinical practice
in general, I try to stick to what’s been
proven. We’ve gone through this many
other times with adjuvant chemotherapy
for node-negative breast cancer and
so on.
What was the wrong thing to do 10 or
15 years ago is now the right thing to
do. You’re going to make mistakes if
you don’t go on the basis of evidence.
Where you have evidence, you ought
to follow it. And where you don’t
have evidence, that’s where you can
be more creative.
DR LOVE: With this woman’s disease
being HER2-positive, you have the
question of whether tamoxifen is going
to be a little less effective. What specific
hormone therapy, in general, would you
be utilizing off protocol?
DR BUDD: I don’t want to criticize,
and I understand where you’re
coming from. I think it’s quite possible
— maybe even probable — that an AI
and LHRH agonist will turn out to
be the best treatment for this patient,
and the International Breast Cancer
Study Group has shown these younger
patients with ER-positive disease have a
bad prognosis, so some improvement in
hormonal therapy is needed.
Off protocol, in general, I use tamoxifen
in premenopausal women. Whether
ovarian ablation adds — in terms of
efficacy — to chemotherapy or tamoxifen,
I don’t think we know. We do
know it adds toxicity. That’s what this
ECOG trial (E3193) in node-negative
breast cancer showed (Robert 2003). It’s
quite possible that it will end up adding
efficacy, if we can select the right
patient population, unconfounded by
early menopause from chemotherapy.
DR LOVE: Any situations like this
where you might use an LHRH agonist
plus an aromatase inhibitor off study,
Jenny?
DR CHANG: We’ll try not to and
try to put them on a study. We have
several ongoing studies, including the
SOFT study (8.1) to consider. We like
to practice evidence-based medicine,
and yes, I tend to agree with Dr Budd,
but it’s very difficult. I understand
where you’re coming from, and you’re
probably making the right choice, but
it’s not evidence-based.
DR LOVE: Eric?
DR WINER: I wouldn’t go so far as to
say that it’s the right choice. I think
that it is a choice. I think there are
really four choices. One is tamoxifen.
One is tamoxifen plus ovarian suppression.
The third is ovarian suppression
alone, which you would argue to do
if you thought tamoxifen might have
a stimulatory effect on the tumor, and
you acknowledge that we don’t know
that adding an aromatase inhibitor to
ovarian suppression in a premenopausal
woman improves outcome. The fourth
is doing what you’ve done.
Trials examining these various issues
are ongoing. I don’t think there’s a
right or wrong. I probably would give
her ovarian suppression and tamoxifen
outside of a trial. She might be the
type of person whom I would switch
to an aromatase inhibitor with ovarian
suppression after a couple of years, even
though she was premenopausal at the
time of diagnosis.
I think this is a trap that we all fall into
— and I’m not suggesting that you did
any more than anyone else — to bring
a lot of emotion into the picture when
you’re dealing with a young woman.
I just think we have to make sure that
doesn’t inf luence us to make decisions
that we would later regret.
DR LOVE: Let’s discuss adjuvant trastuzumab.
Would you consider adjuvant
trastuzumab for a small (under a centimeter)
node-negative tumor? Clearly,
that patient would not have fallen into
the eligibility criteria of the studies that
were reported.
DR CHANG: Basically, it depends on
her risk of relapse. If she has a small
tumor with a low risk of relapse, then the addition of trastuzumab probably
adds very little.
DR LOVE: Eric?
DR WINER: I don’t believe the benefits
of trastuzumab will vary according to
nodal status, but the risk of recurrence
will vary according to nodal status
and tumor size. I find it very hard to
imagine treating a woman with a T1a-
N0 cancer with either chemotherapy or
trastuzumab.
Apart from that, I’m generally comfortable
with the use of adjuvant trastuzumab
in the majority of patients, based
on what we know so far, although I
think we have to watch the toxicity
profile closely over time. One group
that I do still have some concerns
about are women with relatively small
— under two to three centimeters
— ER-positive, HER2-positive cancers
because I’m not so clear that I know the
event rate and the benefits of hormonal
therapy, specifically the aromatase
inhibitors, in that group of women.
DR LOVE: How about the issue of
delayed trastuzumab in patients treated
previously?
DR WINER: In terms of the woman
with five positive nodes who is some
time out, we’ve generally taken the
approach that within six months we
would offer treatment. Up to a year
we’d consider it. I have trouble doing
it beyond a year. One can’t be too rigid
here. I think the thing to remember is,
for that woman with five positive nodes
who is now two years out, her risk of
recurrence is actually substantially lower
than it was at the time of diagnosis
because events in HER2-positive
patients occur early on. So there is good
reason to think that the benefit may be
much less for her.
DR LOVE: Tom?
DR BUDD: I’d use adjuvant trastuzumab
in patients with tumors that are
T1c and above and within six months
post-treatment.
DR LOVE: Rowan?
DR CHLEBOWSKI: It would be size-dependent,
and six months is also
my cutoff. The other thing for me is
ejection fraction, especially dealing
with the older individual. In an older
individual, I like to see a higher
ejection fraction to put that into the
risk-benefit calculation.
DR LOVE: We’ve really become sensitized
to the time course of recurrence
because of the aromatase inhibitor data.
I wonder if, as time goes on, postadjuvant
trastuzumab is going to start to fit
into that model, just like we’re looking
now whether to start letrozole at six
years. We’re looking at the risk and risk
reduction. Are we going to fall into the
same type of model?
DR WINER: I think the fundamental
difference here and the reason we saw
such big differences early on is that
events occur early in patients with
HER2-positive disease and ER-negative
breast cancer. We’re really
talking about somewhat different
diseases than the patient who has ER/
PR-positive, HER2-negative breast
cancer. So I think we’re just going to
have to see over time.
The other comment is that there is great
interest in looking at nonanthracycline-
containing regimens. The whole
way we look at this may be different
in a few years because, in fact, for that
patient at low risk, on some level — not
that I would do this at the moment
— I’m more interested in giving her
trastuzumab than doxorubicin. We’ll
have to see how all this plays out.
DR LOVE: In the trastuzumab studies,
about half of those patients were also ER-positive. What about the natural
history of ER-positive, HER2-positive
disease?
DR WINER: We know much less about
that than we would like to. The one
thing we do know from the metastatic
trials, the preoperative trials and now
the adjuvant trials is that the benefits of
trastuzumab seem to be similar in ER-negative
and ER-positive disease. I think
what we’re less clear about is the risk of
recurrence because we’re still not sure
how much hormonal therapy adds in
that situation, particularly if the aromatase
inhibitors turn out to be as effective
in HER2-positive as in HER2-negative
disease. Then those women are starting
from a much lower risk of recurrence
than the patient with ER-negative,
HER2-positive breast cancer.
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