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Vol 2, Issue 2: Bernard
Fisher, MD
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| Bernard
Fisher, MD |
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Distinguished Service Professor
University of Pittsburgh
Past Chairman and Scientific Director
National Surgical Adjuvant Breast and Bowel Project
(NSABP) |
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Edited comments by Dr Fisher
Preoperative systemic therapy
Most of the early NSABP trials — the so-called “paradigm-shifting” trials — arose
from research in my laboratory. We evaluated what we now call translational
research — transferring laboratory research data into clinical
practice. The concept of preoperative chemotherapy started in my
laboratory in the 1980s.
Animal studies showed that the tumor kinetics are different when
you remove the tumor compared to treating it before surgery with
radiation therapy, tamoxifen or cytotoxic agents. These observations
resulted in the concept of preoperative therapy.
The NSABP-B-18 trial was the first well-designed, randomized
clinical trial that evaluated the importance of the timing of chemotherapy.
Early studies of preoperative chemotherapy suggested that it doesn’t
really matter whether you give therapy before or after surgery
in terms of distant disease-free and overall survival.
However, the use of preoperative therapy may be of value as a
biological tool. The most important issue is whether or not you
can use preoperative therapy as a surrogate for determining who
will benefit from systemic therapy. Essentially, the question is, “Can
we determine, based on how patients respond to therapy in the first
63 days, who will benefit in terms of disease-free and overall
survival?” The next question to be addressed is, “Would
more effective tumor reduction translate into more complete responders,
and, if so, would that therapy be more likely to have a beneficial
effect on distant disease?” If not, then use of some other
systemic therapy should be considered.
| Biologic
tumor markers and neoadjuvant therapy |
| “Clinical and pathological response are, at best, crude
and late indicators of overall outcome. The key potential of
neoadjuvant therapy is to identify and validate biological
markers during therapy that may predict early for long-term
outcome. These may be biomarkers that are predictive of overall
response, predictive of chemoresistance or predictive of response
to particular agents. Breast cancer presents an ideal model
for this research because of the ease of access to tumour tissue
by fine-needle or core biopsy. Several biological markers have
been studied in this setting including proliferation with Ki-67,
apoptosis, proliferating fraction, ER, PgR, c-erbB2, bcl-2
and p53.” |
| SOURCE: Shannon C, Smith I.
Is there still a role for neoadjuvant therapy in breast cancer?
Crit Rev Oncol/Hematol 2003;45:77-90. Abstract |
Mastectomy versus breast-conserving surgery
One of my agendas associated with preoperative chemotherapy was
to eliminate the need for most mastectomies by the year 2000. Mastectomy
should not be used as a primary locoregional therapeutic approach
in most patients. If a patient has a tumor too large to perform
a lumpectomy, then that patient should receive preoperative chemotherapy
before considering mastectomy. Some patients may still require
mastectomy, but currently we are seeing complete clinical disappearance
of tumors in 50 to 60 percent of patients. This improvement in
our approach to breast cancer is another step that we've taken
in going from radical to modified to simple mastectomy, to quadrantectomy
to lumpectomy and finally to preoperative reduction allowing for
lumpectomy.
| A
commentary on the 20-year results evaluating mastectomy versus
breast-conserving surgery |
“What proportion of women with breast cancer should
receive breast-conserving therapy? The answer depends on
the particular population of women, but a reasonable goal
is that every woman should be informed of the availability
of breast-conserving therapy and of the suitability of the
procedure in her particular case. In a study of 231 women
with breast cancer who were seen for a second opinion between
1996 and 1999, Clauson et al reported that 29 percent of
the women had been offered only the option of a mastectomy
during the initial consultation. ...
“ Efforts to expand eligibility for breast-conserving
therapy and to reduce the associated morbidity are well under
way. Preoperative chemotherapy and endocrine therapy have
been shown to be safe and effective ways to shrink tumors
that are too large for a lumpectomy with a good cosmetic
result. Accelerated fractionation schedules and brachytherapy
are being studied as alternatives to six weeks of external-beam
irradiation. However, if we do not apply what we have learned
from the pioneering work of Fisher and Veronesi and their
colleagues to the treatment of the women with breast cancer
we see today, we will have made little or no progress over
the past 20 years in the search for a rational approach to
the local treatment of breast cancer. It is time to declare
the case against breast-conserving therapy closed and focus
our efforts on new strategies for the prevention and cure
of breast cancer.”
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| SOURCE: Morrow M. Rational
local therapy for breast cancer. N Engl J Med 2002;347(16):1270-71. |
Chemoprevention of breast cancer
NSABP-P-1 demonstrated a proof of principle. Tamoxifen prevented
the clinical expression of breast cancers in about 50 percent of
high-risk women. Epidemiologists question whether this is true
prevention or whether we're simply treating early at the level
of phenotypic expression. That’s possible, but I'm certain
that there will be other candidates for prevention, such as the
aromatase inhibitors. These agents have less toxicity, which will
make them ideal candidates for testing in the prevention setting.
As the mechanisms for detecting breast cancer improve, we are
going to detect more lesions that are “preventable.” The
prognosis for these women is so good that we don't see why we should
treat them. However, in the prevention mode we are treating these
women and are very happy to reduce their risk of breast cancer
by 50 percent. We are in a conundrum, “Should we treat them
or not?”
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