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Bernard Fisher, MD

Distinguished Service Professor
University of Pittsburgh
Past Chairman and Scientific Director
National Surgical Adjuvant Breast and Bowel Project (NSABP)

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.”

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.”

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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J Michael Dixon, MD, FRCS
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Edith Perez, MD
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Bernard Fisher, MD
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Michael F Gnant, MD
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