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DR TRACY: I saw a 79-year-old
woman, very active skier, who discovered
a right breast mass, which was four
centimeters or greater in diameter.
Her mammogram and ultrasound were
both pathologic. She had a mastectomy,
which revealed a 7.5-centimeter, Grade
II tumor with lymphovascular invasion.
The tumor was ER/PR-positive and
HER2-negative, and three of seven
nodes were positive.
She had some mild hypothyroidism and
absolutely no major comorbidities. She
experienced some mild chronic pain
as the result of a minor motor vehicle
accident that caused a back injury. Her
family was described as very long-lived.
Her physical exam was completely
negative, with a well-healing chest
wall scar. The staging studies included
a bone scan, which was normal except
for mild degenerative changes, and full
CAT scans, because of the size of her
tumor, which were negative.
DR LOVE: So, she’s a 79-year-old
woman who sounds about as healthy as
one can be at 79. Was she a proactive
patient who wanted to do everything
she could with regard to treatment?
DR TRACY: No. She was not.
DR LOVE: So she was concerned about
the side effects of treatment?
DR TRACY: Absolutely.
DR LOVE: Peter, how do you approach
the question of adjuvant chemotherapy
in older patients?
DR RAVDIN: I think when we see
an older patient, we view things a
little differently. That isn’t necessarily
a reflection of us being ageists but
rather that we recognize, and patients
themselves recognize, that they have
less remaining life expectancy and,
overall, a lot more competing problems.
In fact, most people with node-negative
disease, even if they’re fairly young,
end up dying of something other than
breast cancer. Sometimes looking at the
competing mortality — for this patient
it’s in the range of 30 to 40 percent,
even though she is a skier — puts things
in context, and many patients recognize
that and are less enthusiastic about
aggressive therapy.
The other thing to be said is that there
are some uncertainties as to how effective
adjuvant chemotherapy is in older
patients, not because we have any deep
biological rationale for why it shouldn’t
work but because we have less data on
that patient population.
There’s an excellent paper in JAMA by
Dr Hy Muss that points out that older
patients have about as much benefit as
the younger patients, although they do
have more toxicity (Muss 2005). So, for
decisions where it’s difficult for us to
know what to do, engaging the patient
in the decision is reasonable because
often, when they see the numbers and
think about it, it actually helps them
have a clearer view of what they want.
DR LOVE: How much additional
survival benefit would this patient experience by receiving chemotherapy
in addition to an aromatase inhibitor?
DR RAVDIN: The overview suggests
that a chemotherapy regimen like CMF
has little activity in postmenopausal
women with ER-positive breast cancer
(Early Breast Cancer Trialists’ Collaborative
Group 1998), but other trials
suggest adjuvant chemotherapy with
anthracycline-based regimens actually
has a 20 to 30 percent proportional risk
reduction in this population. In terms
of mortality reduction, chemotherapy
— even that kind of chemotherapy —
isn’t quite as good as hormonal therapy,
but for a patient like this, it could mean
approximately a five percent difference
in mortality.
I think that it isn’t out of the question
to treat healthy women in their seventies
and eighties with adjuvant chemotherapy.
I’d like to point out that this
has been studied in other adjuvant
scenarios such as colon cancer, and
you can clearly see people older than
70 benefiting as much from adjuvant
chemotherapy as younger patients.
DR OSBORNE: Peter, one of the
problems with programs like your
Adjuvant! Online model is that you
can’t consider every single nuance of
every single patient, so you have to
generalize a bit. The program doesn’t
consider PR, and I don’t think it takes
into account quantitative ER, maybe
because the data on those factors are
still new, but I think both are becoming
extremely important. Data from the
SWOG-8814 study show that patients
with high ER/PR-positive tumors
receive no benefit from FAC (Albain
2004). Data from the Ludwig Breast
Cancer Study Group similarly show
that patients with highly endocrine-responsive
disease receive little or no
benefit from chemotherapy of any
kind (Colleoni 2000), and there’s no
benefit for dose-dense chemotherapy in
the patients with strongly ER-positive
disease.
In terms of endocrine therapy for this
patient, the only prospective marker
trial was conducted in the 1980s by
Peter and showed that PR negativity
does, at least in metastatic disease,
predict for less response to tamoxifen
(Ravdin 1992).
There are now three modeling studies
of long-term endocrine therapy of
postmenopausal patients. All three
— Jack Cuzick’s, our own with statistician
Sue Hilsenback, and Dana-Farber’s
— have modeled whether it’s better to
give an aromatase inhibitor or tamoxifen
first. We can’t necessarily go by
models, but I think they can tell us that
jumping over to an aromatase inhibitor
may not be, at 10 or 15 years, a better
strategy.
DR LOVE: Aman, what are your
thoughts regarding these modeling
studies, and what do you think is the
best long-term strategy?
DR BUZDAR: I think modeling studies
are good to keep the biostatisticians
busy until we generate the clinical
data, but you have to go with the facts
that are in front of you. The proper
sequence is an interesting question,
but it’s a research question, and until
we have the answers, we have to
use the data we have. We have data
showing that in patients who are newly
diagnosed, it’s better to start with an
aromatase inhibitor rather than waiting
two to three years. We don’t have
data to show it’s better to start with
tamoxifen and then switch. I think the
major shortcoming of all three models
is that they do not take into account
the adverse effects in those first two
to three years, which could be life
changing for the patient.
DR LOVE: Kent, do these models bring
in the toxicity issues with tamoxifen, including deep vein thrombosis, stroke
and endometrial cancer?
DR OSBORNE: No. They’re not built
into the models, but the mortality from
those events is, so death from them
would be an issue. We have data on
tamoxifen followed by an aromatase
inhibitor and we see a certain benefit
there. We also have data comparing an
aromatase inhibitor to tamoxifen in the
first five years. So we do have clinical
data. What we don’t have is what
happens, side effect- and benefit-wise,
to the patient after being treated for five
years with an aromatase inhibitor and
then off. We have no data for that, not
even modeling data.
DR BUZDAR: We pick the numbers that
we like to believe. The first publication
on the ATAC trial reported a proportional
reduction in hazard rate at year
one, year two and year three. In year
two, the reduction in the risk of events
was about 39 percent. When you look
at the curves, you are looking at the
overall effect, and when you look at
hazard rates, you look at a certain point.
DR GRADISHAR: In terms of how
I would approach this 79-year-old
patient, I would probably utilize the
data that we have on up-front therapy
— the ATAC data set and more modest
follow-up in the BIG 1-98 trial — and
begin the patient on anastrozole or
letrozole (1.1).
DR LOVE: Do you prefer one or the
other — anastrozole or letrozole — or
do you consider them to be equal?
DR GRADISHAR: The long-term data
at this point — the more mature data
— are with anastrozole, looking at
follow-up of patients from the ATAC
data set.
DR LOVE: What about the issue of
chemotherapy in this patient, Bill?
DR GRADISHAR: The obvious caveat
is that the patient has to be engaged in
the discussion. This patient has been
described as the super-athlete 79-year-old
with a clear mindset about what
she wants to do in her life, not only in
sports but probably day to day in terms
of tolerating certain side effects that are
going to inhibit her activities.
So I would feel comfortable discussing
chemotherapy with her, but she sounds
like somebody who’s going to think
about the numbers carefully and realize
that the added contribution of chemotherapy,
despite her relatively poor
prognosis, is still going to be modest,
and she may elect to get endocrine
therapy alone.
DR LOVE: Would you be comfortable
giving this woman chemotherapy?
DR GRADISHAR: I would, based on
how she was described in terms of
performance status.
DR LOVE: What if she were 85
years old?
DR GRADISHAR: I think you have to
look at the competing morbidities and
mortalities as a patient ages. Peter’s
Adjuvant! Online model takes you out
to 10 years, so when we are talking
about the added contribution of chemotherapy
in an 85-year-old patient, we
have to think about her odds of being
alive at 95. Then I think it becomes a
different issue.
DR LOVE: Peter, there was a paper in
the JCO that evaluated the validity
of the Adjuvant! Online program
(Olivotto 2005). I understand that not
only were the numbers related to breast
cancer validated, but your nonbreast
cancer mortality numbers were also
validated.
DR RAVDIN: We had an interest in
validating the model, which is derived largely from US data. The group in
British Columbia has, perhaps, one of
the larger North American databases,
with very complete clinical data, so
they sent us blinded information about
the patients and their tumors. We then
projected outcomes for those patients,
sent the data back and they compared
that to the actual outcomes of those
patients.
Overall, it was a very tight fit. There
were some groups where we were a
little bit off. For instance, in younger
women it appears that perhaps the
classic pathologic variables don’t tell us
everything that’s different about that
population in that they had a somewhat
worse prognosis than we had projected.
DR LOVE: What specifically would
this 79-year-old woman most likely be
treated with in your clinic, Peter?
DR RAVDIN: Hormonal therapy with
an aromatase inhibitor. This is also
a very active woman who’s probably
going to be taking a few falls, and the
one thing worth emphasizing is that
she’d have to be told about the osteoporosis
risk and actually evaluated for that.
DR LOVE: Which aromatase inhibitor?
DR RAVDIN: I’d probably treat her with
anastrozole, although there are substantial
data for letrozole also. However, the
anastrozole data in up-front therapy is
actually more robust, because it’s based
on almost six years of follow-up now, so
that’s encouraging.
DR LOVE: Aman, there is no survival
difference at this point in the ATAC
trial. How do you think the risk-benefit
stacks up without survival differences,
and what are your thoughts about cost?
DR BUZDAR: At this point, none
of these studies show any statistically
significant survival advantage.
However, there is a trend in the same
direction in every study: With aromatase
inhibitors there are fewer breast
cancer deaths, whether they are used up
front, in the middle, or down the line.
Why hasn’t the ATAC trial, which has
the longest follow-up, shown a statistically
significant effect on survival?
Because the patients in that trial are
the most favorable subset of women in
that the majority are node-negative,
and it takes a much longer time to see a
survival effect. Even the NSABP study,
which consisted of patients with node-negative
disease treated with tamoxifen, took more than seven or eight years to
show a survival advantage (Fisher 1989).
I think if the therapy is effective and it
prevents recurrence, eventually it will
manifest a reduction in mortality down
the line.
DR LOVE: Dr Tracy, what happened
with your patient?
DR TRACY: We discussed these issues,
although a little less scientifically, and
she did not want chemotherapy. We
discussed the slight potential benefit and
the side effects of the different categories
of drugs. Her two sons were in
favor of chemotherapy, but she chose no
chemotherapy. She did receive radiation
therapy to her chest wall and her
draining lymphatics and has not had any
sign of local recurrence.
We put her on anastrozole, and she’s
tolerated it beautifully with no musculoskeletal
side effects. She’s been on it
for more than two and a half years and
has no evidence of metastatic disease.
We did do a bone mineral density scan
initially, and she had very mild osteopenia
and worked with her primary
care physician on that. She did not,
however, choose to take a bisphosphonate.
She and her family are very happy
with her decisions.
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