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are here: Home: BCU 4|2003: Bernard
Fisher, MD
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 systemic
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 initiate 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 diseasefree 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.”
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| 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 trial results of 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.
No Abstract Available |
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
women at high risk. 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 agents 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?”
Future outlook for breast cancer research
Undoubtedly, molecular genetics will contribute to the treatment
of breast cancer, but I don’t yet know how it will play out.
Somebody, somewhere must seize this information and put it into
a testable hypothesis. The better the hypothesis, the more likely
it will yield positive results. One of the big challenges for the
future is how to test these hypotheses. Whether or not our present
day clinical trial mechanism will be adequate is open to speculation.
Our best chance to make a major impact on breast cancer is to allow
people the freedom to become involved in research. We need totally
dedicated, committed individuals who are zealots about the research
agenda that they want to push forward. I don’t believe this
kind of change will take place through consensus meetings and expert
panels.
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