December 11, 2023
December 11, 2023

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Bernie Fisher V: Prevention and the P-1 Study

It is well recognized that women who have breast cancer have an increased risk of developing breast cancer in the contralateral breast. Logically, whatever etiologic factors caused the initial cancer—genetic, reproductive hormonal, environmental—remain operative and continue to cause breast cancer in the remaining breast, perhaps doubling the risk relative to the general population.

Clinician-scientist Bernie Fisher and his colleagues observed that in their studies of tamoxifen as adjuvant therapy, not only did the tamoxifen reduce recurrence of the initial breast cancer but there was a bonus: There was also a reduction in the occurrence of new second primary breast cancers in the tamoxifen group as compared to the placebo group. The investigators then reasoned that perhaps this preventive effect could be extended to women who had not yet had breast cancer in the first place.

Of course, tamoxifen is a powerful drug with a non-trivial profile of side effects. It can cause menopausal symptoms (it is an anti-estrogen) including hot flashes and night sweats, fatigue and deep vein thrombosis, and paradoxically it can have estrogenic effects, such as causing endometrial cancer. Thus, its casual use as a preventive agent in women at average risk for breast cancer would probably not be wise given the risk-benefit ratio.

They therefore decided that its use should be considered for prevention only in women who were at increased risk for breast cancer. This led to the question of how to determine that risk. For the trial ultimately undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP,) the P-1 Trial, it was decided to use a statistical model called the Gail Model.

Mitchell Gail received his MD from Harvard Medical School and a masters in biostatistics from George Washington University before joining the National Cancer Institute, where he ultimately became chief of biostatistics. He used data from a large screening study of 280,000 women to develop a model or algorithm of a woman’s risk of developing breast cancer based on certain data, including age, age at first menstruation, age at first live birth of a child, number of first-degree relatives with breast cancer, number of previous breast biopsies, and the presence of atypical hyperplasia in a biopsy. The answers to these questions would generate a score and the score would correspond to a risk of breast cancer relative to the general population. I provide here a link to one current website where the reader can estimate her risk using the tool.

The P-1 trial, starting in 1992, enrolled 13,388 women who were deemed to be at increased risk of breast cancer either because they were >60 years of age or because they generated a score of 1.66% or greater on the Gail Model, meaning they had a risk of breast cancer of 1.66% in the ensuing five years. They were randomized to five years of daily tamoxifen or placebo. At the end of 69 months, in a study published in the Journal of the National Cancer Institute in 1998, the incidence of breast cancer was 43.4/1000 women in the placebo group versus 22.0/1000 women in the tamoxifen group, for a 47% reduction.

The conclusion was that, despite the side effects of tamoxifen, chemoprevention with tamoxifen was worthwhile for women at elevated risk for breast cancer. Later studies from Fisher and NSABP were conducted with other agents that include raloxifene, an estrogen modulator, as well as aromatase inhibitors that show that these drugs can have similar breast cancer preventive effects. It is unfortunate that, despite the proven efficacy of these drugs for prevention of breast cancer in these high-risk women, the uptake of use of these drugs for this purpose has not been robust. Probably 15% of women fit the criteria. Nonetheless, of those offered these agents, only about 10% agree to take the drugs. Concerns regarding their long-term toxicity are probably the main impediment to greater compliance.

I hope this series of articles has conveyed the incredible impact that Bernie Fisher had across the gamut of breast cancer management. He was an arrogant, difficult person, profoundly unpopular and hated. In 1991, a scandal erupted when he was 75 years old when one researcher at St. Luc’s Hospital in Montreal (one of very many surgeons who participated in NSABP trials) was found to have falsified data. It had been reported to NCI as per protocol but somehow became a cause celebre and, while no one accused Fisher of having in any way participated in data falsification, he was blamed for the errors and the various studies that included data from this hospital were questioned. He was suspended from his chairmanship of NSABP as well as from the University of Pittsburgh as a result. It was particularly egregious and galling that Pitt, which was receiving over $20 million each year because of his research, did not stand by him. He brought a lawsuit for defamation and, after three years, was reinstated to his position at the University as well as at the NSABP along with letters of apology and $3 million in damages. He retired from the chair of NSABP soon after.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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