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Fisher’s Respect for Scientific Methods Propelled Landmark Advances

Cheryl Zigrand
Published Online: Friday, January 10, 2014
Dr.Bernard
Fisher

Bernard Fisher, MD

When Bernard Fisher, MD, first became involved in breast cancer research, the only treatment option available to patients was the radical mastectomy, a horribly disfiguring surgery that had been the undisputed standard of care since the late 1800s. In 1894, William Halsted developed the procedure for the radical mastectomy, which involved removing the entire breast, the underlying chest wall muscles, and all of the underarm lymph nodes. At that time, cancer was widely thought to be a local disease that spread in a predictable way, and so it was believed that extensive surgery could theoretically remove all of the cancer cells and cure the patient. Despite a lack of reproducible data to prove this theory or the success of the radical mastectomy, Halsted’s procedure remained the unequivocal treatment for breast cancer for nearly 100 years. The only thing physicians disagreed about was whether or not the surgery was sufficiently radical.

In the 1960s, Fisher and his brother, Edwin Fisher, MD, a worldrenowned breast cancer pathologist, conducted laboratory experiments that questioned the Halstedian view of metastasis. Through these experiments, which were conducted on animals, they discovered that tumor cells spread via the lymph nodes and the bloodstream, indicating that breast cancer is a systemic disease, not a local one as had always been theorized.

Over the next several decades, Fisher conducted laboratory investigations and prospective clinical trials that systematically advanced the understanding of tumor biology, resulting in an improvement in the standard of care for women with breast cancer. Fisher’s research proved that radical mastectomy is no more effective than the less extensive total (simple) mastectomy, which limits the surgical procedure to removal of the breast only.

Fisher’s subsequent investigations showed that lumpectomy followed by breast irradiation is as effective as modified radical mastectomy (total mastectomy plus the removal of the underarm lymph nodes). Then, in the early 1970s, his research revealed that adjuvant chemotherapy administered after surgery can improve the survival of women with early-stage breast cancer. In another study, he demonstrated that the oral hormonal therapy tamoxifen could reduce the risk of breast cancer recurrence and improve survival, and also that tamoxifen could reduce the incidence of breast cancer by nearly 50% when given to healthy women at high risk for developing the disease.

Step by step, Fisher’s research launched the breast cancer community into the modern era of new, promising treatment strategies that improved patient outcomes. The most important aspect to remember, though, is that each of these advancements was supported by laboratory research and clinical evidence.

In Data We Trust

Something that may not be readily understandable to the modern reader is that clinical trials as we know them today have not always been the answer to clinical questions. The first randomized clinical trial, conducted by Austin Bradford Hill on the use of streptomycin for tuberculosis, took place more recently than one might think, in 1948. Before then, anecdotes were the main source of information informing treatment strategies. According to Norman Wolmark, MD, current chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), who was a protégé of Fisher’s for decades, “Clinical trials were not yet in the mainstream, so Bernie was certainly a pioneer.”

Early on in his medical career, Fisher’s interest in research was initiated by his work in the late 1940s with Julius M. Rogoff, MD, who was professor of Endocrine Research at the University of Pittsburgh, Pennsylvania, and then from 1950 to 1952, when he was under the tutelage of Isidor S. Ravdin, MD, chairman of the Department of Surgery and director of the Harrison Department of Surgical Research at the University of Pennsylvania. When the first clinical trial was being conducted, Fisher was studying liver regeneration, hypothermia, transplantation biology, and biology of metastasis in the laboratory setting. He was invited in 1957 to discuss the creation of the organization that would become the NSABP. As a result of his laboratory experience, Fisher was familiar with the scientific method, and he consequently viewed clinical trials with proper controls, statistics, and other elements as the appropriate venue for evaluating alternative hypotheses such as the worth of radical mastectomy, and then the worth of lumpectomy.

According to Daniel A. Osman, MD, who just recently retired from his 30-year tenure as the director of the Miami Breast Cancer Conference—a conference organized in large part due to Fisher’s groundbreaking data— Fisher had a credo, “In God we trust; all others require data,” which was a radically new viewpoint then.

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