Against the Tide

Bernard Fisher brought the scientific method to breast cancer treatment
Winter 2018
  (Photo from the collection of Bernard Fisher.)
Cancer didn’t particularly interest Bernard Fisher (MD ’43) early in his career. In 1957, the University of Pittsburgh surgeon was contributing to the development of transplantation and vascular surgery. He performed one of the first kidney transplants. Fisher also directed surgical research at Pitt; as an investigator, he was interested in liver regeneration, hypothermia, and transplant rejection.
Then, a mentor from Fisher’s training at the University of Pennsylvania, General I.S. Ravdin, invited Fisher to, or rather insisted that he attend, a National Institutes of Health meeting convening in 1958. Participants would create a group for conducting clinical trials on breast and colon cancers. Ravdin, who chaired the NIH’s Clinical Studies Panel, was a famed surgeon who had operated on President Eisenhower. “You don’t turn down a two-star general,” Fisher told this magazine in 2002. And maybe this was a chance, Fisher thought, to do something about the problem that many cancer treatments at the time didn’t have strong scientific underpinnings. He became a founding member, and later chair (serving from 1967 to 1994), of the National Surgical Adjuvant Breast and Bowel Project (NSABP) that resulted from the meeting.
Based on research conducted in his Pitt laboratory, Fisher formulated hypotheses that were tested in clinical trials conducted with NSABP in the 1960s and ’70s. The findings from those trials led him to challenge the prevailing breast cancer dogma followed since the 19th century, which assumed that patients were best cured through radical mastectomy—the disfiguring removal of all breast and nearby tissues. Fisher’s ideas did not make him popular among other surgeons at the time. “When radical mastectomy was being evaluated, the idea of performing less extensive operations was considered, at some institutions, to be malpractice,” Fisher said. Besides, he was a rare bird—a surgeon doing science. 
“Sometimes, people don’t think of surgeons as the intellectual members of the [oncology] team,” says surgeon Robert Ferris, director of the UPMC Hillman Cancer Center and Pitt associate vice chancellor for cancer research. He says Fisher became a role model for surgeon-scientists.
In 1971, Fisher led the NSABP in a landmark clinical trial in women with primary breast cancer, comparing radical mastectomy with less extensive total mastectomy. In 1976, he initiated a study comparing total mastectomy with less disfiguring lumpectomy, with or without breast irradiation. Neither study showed a survival advantage from the more extensive procedure. Those studies provided a scientific basis for less extensive surgery. Findings from other Fisher-led studies showed that women who also had systemic, adjuvant chemotherapy or hormonal therapy were more likely to survive than those who had surgery alone. 
By 1985, the rate of radical mastectomies had fallen from 98 percent of breast cancer patients to only 2 percent. Yet Fisher’s work shaped more than the landscape of breast cancer care.  
“He basically illuminated the biology of metastatic cancer in general,” says Arthur S. Levine, Pitt’s senior vice chancellor for the health sciences and the John and Gertrude Petersen Dean of the School of Medicine, who is an oncologist. “His critical observation was that, often, when we make the earliest diagnoses of any cancer . . .  it may already have spread microscopic metastases elsewhere in the body. Therefore, it is not sufficient to simply remove the lump.”
If tumors have already metastasized, says Levine, “chemotherapy must be used to kill those metastatic cells—wherever they are in the body—no surgery or radiotherapy will be effective. Fisher’s trials established this fact.
“That is one of the most important contributions to the practice of medicine that anybody has made in our lifetimes.”
Ferris notes that Fisher—who became a Distinguished Service Professor of Surgery at Pitt and has been recognized with many honors, including the Albert Lasker Award for Clinical Medical Research—was an “intellectual driver” of large-scale clinical trials. “That was a conceptual advance—that moving clinical trials forward couldn’t rely on just a single center or two. 
“The cooperative clinical trials . . . can answer bigger, transformational, practice-changing questions like [Fisher] did.” 
In the 1990s, Fisher investigated the potential benefits of tamoxifen, an anti-estrogen drug, to stave off cancer in high-risk breast cancer patients. “Our 1998 report indicating, for the first time, that breast cancer could be prevented with tamoxifen was probably the capstone of my career,” he said. 
“Certainly, in 1958, when I began this journey, the idea of using an agent to try to prevent breast cancer was . . . science fiction.” 
Fisher, still writing, publishing, and questioning, turned 100 years old in August.   
Radical mastectomy treatment was based on the Halstedian hypothesis, an idea long entrenched in the medical mindset. Master surgeon William Halsted first performed a radical mastectomy in 1882. (He’s shown here, second from left, as one of “The Four Doctors”—the famed founders of Johns Hopkins.) The Halstedians proposed that cancer spreads in an orderly way, progressing from one anatomical site to another. Thus, stopping cancer’s progression necessitated extensive surgery. The hypothesis, derived from anecdotes and induction, persisted for 75 years. (Painting: The Four Doctors by John Singer Sargent, Oil on Canvas, 1907. Courtesy of the Alan Mason Chesney Medical Archives of the Johns Hopkins Medical Institutions. Photograph by Aaron Levin.)
Before the NSABP studies, radical mastectomy (illustrated here) was the accepted treatment for breast cancer; it involved removing not only the breast but also the chest wall muscles, the nearby lymph nodes, and sometimes even both breasts. (Wikimedia Commons.)

Founds and directs Pitt’s Laboratory of Surgical Research as the first full-time faculty member in the Department of Surgery

Becomes a founding member of the National Surgical Adjuvant Breast and Bowel Project (NSABP). The group starts its first clinical trial, called B-01, to test the ability of the drug thiotepa to reduce early recurrence rates in breast cancer patients. The trial was a proof of principle that encouraged the group to continue this type of research.

A four-year lab study by Fisher and his brother, Edwin Fisher (MD ’47), a Pitt pathologist, demonstrates that cancer cells can lie dormant for years before developing into detectable metastatic disease. 
  Bernard Fisher with his brother, Edwin Fisher. (Photo from the collection of Bernard Fisher.)

Fisher performs the first kidney transplant in Pittsburgh. It is one of his many contributions to the field of transplantation, which will also include the establishment of Pittsburgh’s organ-sharing network and research into skin transplantation. 

The first official publication from clinical trial B-04 reports that radical mastectomy provided no survival advantage for breast cancer patients when compared with simple mastectomy. With this evidence, the public begins to question the necessity of traditional radical cancer surgery.  

Initial results from the B-06 trial are published, reporting that breast cancer patients with tumors of 4 centimeters or smaller do as well with lumpectomy and radiation as they do with total mastectomy. The results support Fisher’s hypothesis of cancer as a systemic disease that can be treated with less extensive surgery.  

Fisher and the NSABP publish the results of the Breast Cancer Prevention Trial. It shows that the anti-estrogen drug tamoxifen can reduce the occurrence of breast cancer by almost half in women at increased risk for the disease. 

Perhaps Fisher’s most important contribution has been the establishment of a scientific approach to the study of breast cancer. In a 2009 video interview shown at that year’s annual Pitt lecture named in his honor, Fisher said, “No clinical therapy should be determined by emotion or conviction—the determinant must be the scientific method.”

In September 1974, First Lady Betty Ford had a radical mastectomy. Americans had shied away from discussing breast cancer in anything but whispers until she shared her diagnosis with the public. While the first lady underwent surgery at the Naval Medical Center, across the street, at the NIH, Bernard Fisher reported findings from studies that would have a profound effect on the treatment of breast cancer for decades. Fisher’s report showed that less extensive surgery was just as effective as radical mastectomy. He also reported findings from the first clinical trial evaluating the value of postoperative chemotherapy, indicating that a single agent (L-PAM) after surgery led to a better outcome. The first lady was prescribed L-PAM as a result of Fisher’s findings. (Photo: Getty)
  A Fisher paper shows that survival outcomes are similar for women receiving radical mastectomy, lumpectomy plus radiation, and lumpectomy alone.
  Fisher, c. 2010. He turned 100 in August. (Photo by Terry Clark.)