In Memoriam: Dr. Bernard Fisher

Abstract

Very few individuals have so profoundly influenced the field of surgical oncology as has Dr. Bernard Fisher, who died on October 16, 2019, at the age of 101. Fisher is widely known for his work on the treatment and prevention of primary breast cancer, where he championed breast-conserving surgery, the use adjuvant systemic therapies, and chemoprevention (i.e., the use of anti-estrogens to prevent breast cancer). However, Fisher’s impact extends far beyond the field of surgical oncology. He questioned the value of observational studies in clinical decision-making and emphasized that large randomized trials with unambiguous endpoints (i.e., all-cause mortality) should form the basis for patient management.

Very few individuals have so profoundly influenced the field of surgical oncology as has Dr. Bernard Fisher, who died on October 16, 2019, at the age of 101. Fisher is widely known for his work on the treatment and prevention of primary breast cancer, where he championed breast-conserving surgery, the use adjuvant systemic therapies, and chemoprevention (i.e., the use of anti-estrogens to prevent breast cancer). However, Fisher’s impact extends far beyond the field of surgical oncology. He questioned the value of observational studies in clinical decision-making and emphasized that large randomized trials with unambiguous endpoints (i.e., all-cause mortality) should form the basis for patient management. Fisher taught doctors throughout the world—and in all fields of medicine—to think critically, and he emphasized the importance of evidence-based patient care.

Bernard Fisher was born in Pittsburgh, Pennsylvania, USA, on August 23, 1918. He earned both his bachelor’s and medical degrees from the University of Pittsburgh. After completing his postgraduate training, he joined the surgical faculty of the University of Pittsburgh School of Medicine, where he ultimately spent the majority of his career. He initially began his research career studying liver regeneration in rats. However, he soon shifted his interests to breast cancer, and undertook animal studies to better understand the pathogenesis of breast cancer metastases.

In 1967, Fisher was appointed chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which was a consortium of academic medical centers organized by the United States National Cancer Institute (NCI) to undertake large clinical trials. Fisher directed the NSABP while at the same time maintaining a busy academic clinical practice at the University of Pittsburgh. He remained at the helm of the NSABP for three decades, and it was during this period that he exerted a tremendous influence in altering the standards for the treatment of breast cancer throughout the world. Under his directorship, the NSABP organized large clinical trials assessing permutations in the local therapy of breast cancer, the use of adjuvant systemic therapies, and eventually medicines for the prevention of breast cancer. Many doctors initially questioned the value of clinical trials, believing that anecdotal experiences alone provide sufficient evidence upon which to base patient care. Fisher fought long and hard to alter this perception, which, at the time, was very pervasive in the surgical community. He once remarked, “In God we trust. All others must have data”.

When Fisher was appointed director of the NSABP, the surgical treatment of breast cancer was largely predicated on the Virchow-Halsted hypothesis. This hypothesis dated back to the mid-nineteenth century, and was based on the belief that breast cancer spread first to the axillary lymph nodes and then to distant sites. Thus, most surgeons believed that the axillary lymph nodes served as the nidus for the distant spread of breast cancer. At that time, the standard treatment of primary breast cancer was the Halsted radical mastectomy, whereby the breast, pectoralis muscle, and axillary lymph nodes were removed en bloc. In keeping with the Virchow-Halsted hypothesis, many surgeons argued that if the patient underwent a meticulous axillary node dissection, and was found to be node-negative, then that patient was cured.

Fisher organized one of the initial NSABP trials (i.e., the NSABP-04) to test the tenets of the Virchow-Halsted hypothesis. In the NSABP-04 trial, women with primary breast cancer were randomized to mastectomy and axillary clearance (i.e., the standard treatment for primary breast cancer at the time), versus mastectomy and radiotherapy to the axilla, versus mastectomy alone (with axillary surgery reserved for patients who developed recurrences in the axilla). There was no difference in mortality between the three arms of the trial, suggesting that the axillary lymph nodes were not the sole nidus for the distant spread of cancer. The results of this trial, along with the results of the similar King’s/Cambridge trial in the UK, were interpreted to mean that blood-borne metastasis, rather than lymph node metastasis, was the key factor in the development of distant metastases.

Subsequently, Fisher organized and led the NSABP-06 trial, which assessed permutations in the local therapy of primary breast cancer: lumpectomy versus lumpectomy + radiotherapy to the breast versus the standard mastectomy. In all three arms of this trial, patients received the standard axillary lymph node dissection. Again, there was no difference in mortality between the three arms of the trial. However, lumpectomy alone resulted in significantly higher ipsilateral breast tumor recurrences (IBTR) when compared to lumpectomy + radiotherapy or mastectomy. This trial, along with 5 other trials undertaken in Europe and North America, resulted in the worldwide acceptance of breast-conserving therapy (i.e., lumpectomy + radiotherapy) as the preferred alternative to mastectomy for patients with primary breast cancer.

Through the NSABP, Fisher also undertook trials that served to establish the efficacy of adjuvant systemic therapy in reducing breast cancer mortality. Additionally, clinical trials showed that anti-estrogens (i.e., chemoprevention) were effective in breast cancer prevention.

Since 1990, breast cancer mortality rates in the USA and many other western countries have declined substantially. This is largely due to the widespread use of adjuvant systemic therapy in the treatment of primary breast cancer. Fisher was one of the pioneers that established the efficacy of adjuvant systemic therapies in the treatment of breast cancer, and therefore deserves some of the credit for the precipitous decline in breast cancer mortality.

I had the pleasure of meeting Dr. Fisher briefly on two occasions, and attended many of his lectures at national and international conferences. He had a profound influence in shaping my career, and the careers of many other oncologists from my generation. We are all deeply indebted to Dr. Bernard Fisher for his enormous contributions to the field of breast oncology and evidence-based healthcare. However, more work is needed to further reduce the global burden of breast cancer mortality. Dr. Fisher would remind us that further progress in reducing breast cancer mortality will require development of new, innovative clinical trials, and the accrual of large numbers of patients into those trials.