Pioneer in Breast Cancer Research Leaves 'Lasting Legacy'

Roxanne Nelson, RN, BSN

October 21, 2019

One of the great pioneers in breast cancer research, Bernard Fisher, MD, distinguished service professor at the University of Pittsburgh School of Medicine, died last Wednesday at the age of 101.

Bernard Fisher, MD

His research led to changes in breast cancer surgery, use of adjuvant therapy, and showed — for the first time — that breast cancer could be prevented.

"Fisher revolutionized our theories and reasoning with regard to breast cancer," commented Gary H. Lyman, MD, MPH, from the Fred Hutchinson Cancer Research Center, Seattle, Washington.

"He made contributions that affected the lives of countless women with breast cancer," said Eric Winer, MD, director of the Breast Oncology Center at the Dana-Farber Cancer Institute, Boston, Massachusetts.

Fisher was a "larger than life figure in oncology" and he was "a true visionary," Winer told Medscape Medical News.

"He conducted the seminal study that established the safety of lumpectomy and radiation," he said. Fisher was also the primary investigator who pushed for the use of neoadjuvant therapy for operable breast cancer and who advocated for breast cancer prevention.

"Without his Herculean efforts, we would know far less about breast cancer treatment," Winer added.

Without his Herculean efforts, we would know far less about breast cancer treatment. Eric Winer, MD

Lyman emphasized the revolutionary nature of his thinking. Fisher recognized long before others that breast cancer was "largely a systemic disease relatively early in its development" and that it needed "truly multidisciplinary approaches addressing both its local origins and spread, and its proclivity to spread to other organs of the body," he commented.

That led to the realization that "if we treat only the local disease with surgery but ignore the regional and distant spread using radiation and/or chemotherapy and endocrine therapy, then we are destining most patients to future distant disease recurrence," he explained.

"Therefore, multidisciplinary multimodality therapy was viewed as the great opportunity to improve clinical outcomes for most women with breast cancer, a premise that was repeatedly demonstrated in randomized controlled clinical trials," Lyman told Medscape Medical News.

Command From Ex-general

A native of Pittsburgh, Fisher attended the University of Pittsburgh, receiving his undergraduate degree in 1940 and his MD in 1943. His interests at this time were in liver regeneration, hypothermia, and transplantation biology, and after completing a 2-year fellowship in experimental surgery at the University of Pennsylvania, he returned to Pitt to conduct research. In his laboratory, he experimented with liver regeneration and organ transplantation in rats. To increase his knowledge about transplantation medicine, he took a position in 1955 as a research fellow at the Postgraduate Medical School of London, England, at Hammersmith Hospital.

Not long after he returned home and back to his lab, eager to resume his work on liver regeneration and transplants, Fisher received a phone call that threw him a curve ball.

The call came from Isidor S. Ravdin, MD, who had served as Fisher's mentor at the University of Pennsylvania and was now the recently appointed chairman of the Clinical Studies Panel of the National Cancer Chemotherapy Service Center at the National Institutes of Health (NIH).

In the spring of 1957, Fisher was invited, along with 22 other surgeons, to meet at Stone House on the NIH campus to discuss the creation of the Surgical Adjuvant Chemotherapy Breast Project, the forerunner of the National Surgical Adjuvant Breast and Bowel Project (NSABP).

"I informed him that I was more interested in continuing my laboratory investigations related to liver regeneration than in conducting breast cancer studies," Fisher said in a 2005 interview published in the Journal of the National Cancer Institute. "However, when someone who had been a two-star general and chief of the China-Burma-India Theater of Operations during World War II, and who had operated on President Eisenhower gives a command, you obey," he commented. "I felt compelled to go to Stone House."

The meeting at Stone House was a turning point for Fisher. It was his first exposure to clinical trials, which were a relatively new phenomena at that time (the first randomized clinical trial, on the use of streptomycin for tuberculosis, had been conducted less than 10 years earlier in 1948).

The NIH meeting resulted in the 1958 launch of the first randomized clinical trial to evaluate using systemic therapy on breast cancer patients who had undergone radical mastectomy. The cohort comprised more than 800 women who were randomly assigned to receive either the alkylating agent thiotepa or a placebo, and Fisher agreed to participate in it.

Up until this point, it had been theorized that the reason women died of breast cancer, despite undergoing radical surgery, was because tumor cells became dislodged during the procedure and spread the cancer elsewhere.

The trial showed a significant benefit in recurrence-free survival in premenopausal women who had adjuvant chemotherapy, which demonstrated that the natural course of breast cancer could be altered. However, the treatment did not benefit all patients, and some women experienced adverse events, so many physicians were reluctant to use adjuvant chemotherapy.

Participating in the trial ignited an interest in tumor metastasis.

By 1959, Fisher’s research focus had completely switched and he began working together with his brother, Edwin Fisher, MD, a pathologist who had joined the faculty of the University of Pittsburgh in 1958 and who also went on to have a renowned career in cancer research.

They began laboratory investigation of the biology of tumor metastases, and this work would eventually lead him to challenge the status quo of the day.

Mastectomy vs Lumpectomy

The "modern" era of breast cancer therapy actually began in the late 19th century when American surgeon William Stewart Halsted introduced the "radical mastectomy."

Halsted had postulated the anatomic hypothesis of breast cancer metastasis, suggesting that cancer cells from the breast always passed through the lymph nodes before spreading to other regions of the body. Thus, to prevent metastasis, he introduced surgery that involved removal of the entire breast, underlying chest muscle, and axillary lymph nodes.

While this surgery frequently resulted in severe disfigurement of the patient, weakened arm function, and disabling lymphedema, it nevertheless achieved unprecedented local and regional recurrence rates. This procedure, or a modified form of it, steadfastly remained the standard of care and continued to be widely used into the 1970s — nearly a century after it was first introduced.

However, Fisher developed a new hypothesis based on his extensive research of tumor metastases. He theorized that breast cancer was a systemic disease that allowed tumor cells to circulate throughout the body. Extensive locoregional therapy, like the radical mastectomy, would not improve survival in many patients or halt distant metastasis. "As a consequence, less radical surgery was likely to result in similar outcomes to those obtained following radical mastectomy," he said in the JNCI interview.

This alternative hypothesis became the basis for a new generation of NSABP clinical trials. Fisher was appointed chairman of the NSABP in 1967, and beginning in 1971, the NSABP enrolled more than 1600 women in a clinical trial that was designed to compare the effectiveness of radical mastectomy with that of less extensive procedures.

"The 1971 NSABP study he launched randomized women to undergo radical mastectomies vs total mastectomy and showed that more was not better," said Susan Love, MD, chief visionary officer at the Dr Susan Love Foundation for Breast Cancer Research, Encino, California. "He then compared lumpectomy and radiation to total mastectomy and again showed no difference in outcome, demonstrating again that more was not better and highlighting the necessity for systemic therapies."

Love commented that Fisher was an inspiration for her to become a surgeon and then a breast surgeon. "He was a scientist who believed that you should do clinical trials on surgical procedures just as you did for chemotherapy and hormone therapy," she told Medscape Medical News.

"I became a breast surgeon because we had data underpinning what we did and that was thanks to Bernie Fisher. He inspired me and many others to become surgeon scientists and to continue to question the status quo."

However, that was later. At the time when these studies were being conducted, it was an uphill battle getting patients to enroll and clinicians to accept the results. Fisher recalled that the idea of using a less aggressive, breast-conserving surgical treatment was initially met with resistance. "For 50 years surgeons had been trained to do radical surgery," he said. "They felt that performing the lumpectomy was totally inappropriate so at that particular time, my peers were my antagonists."

My peers were my antagonists. Bernie Fisher, MD

It was difficult enough getting doctors to put patients into the trials, but it was even more difficult to persuade women to participate in a study where some would undergo mastectomy while others would have their breasts preserved, he recalled.

For his work in changing the paradigm of breast cancer treatment and creating a new model for its management, Fisher received the 1985 Albert Lasker Clinical Medical Research Award.

Preventing Breast Cancer

Fisher's other most notable contribution to breast cancer treatment was in the realm of prevention. His studies showed that the addition of systemic, adjuvant chemotherapy and/or hormonal therapy (tamoxifen) provided a survival advantage over surgery alone.

In 1991, Fisher and his NSABP colleagues began the first breast cancer prevention trial, which evaluated the efficacy of tamoxifen in preventing breast cancer in women deemed to be at high risk of developing the disease. The findings showed that tamoxifen could reduce the incidence of invasive and noninvasive breast cancer by almost half in this population.

These results (in 1998), showing "for the first time, that breast cancer could be prevented with tamoxifen was probably the capstone of my career," Fisher commented last year in an interview with Pitt Med magazine.

"Certainly, in 1958, when I began this journey, the idea of using an agent to try to prevent breast cancer was . . . science fiction," he added.

Lasting Legacy

Fisher believed that his greatest contribution was conducting laboratory investigations that have altered the understanding and treatment of breast cancer.

Lyman also pointed to his ability to forge strong and enduring multidisciplinary relationships for the purposes of developing, implementing, and completing large randomized controlled trials. Fisher was able to get these "very different disciplines and investigators, often with a prior mindsets and big egos, to work together, develop, and run some of the most innovative, definitive, and practice-changing clinical trials," he said.

The results from these trials "continue to impact on our understanding of breast cancer and lead to improved clinical outcomes and quality of life," Lyman added.

"His legacy is enormous and will long endure as we build on these formative efforts with ever more novel therapies and approaches to improve the lives of patients we care for," Lyman said.

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