A Short History of Bernard Fisher’s Contributions to Randomized Clinical Trials

2022 ◽  
pp. 174077452110664
Author(s):  
Stewart Anderson

Dr. Bernard Fisher (1918-2019) was an early proponent of evidence-based medicine using the mechanism of prospective, multicenter, randomized clinical trials to test biological and clinical hypotheses. In this article, I trace how his early scientific work in striving to understand the nature of cancer metastasis through animal experiments led to a new, testable, clinical hypothesis: that surgery to remove only the tumor and a small amount of tissue around it was as effective as the more disfiguring operations that were then the standard treatment. Fisher’s work with the National Surgical Adjuvant Breast and Bowel Project (NSABP) using large, randomized clinical trials to demonstrate the veracity of this hypothesis led to a new paradigm in which the emphasis was placed on how systemic therapies used at an early stage of disease could effectively eradicate breast cancer for many patients. This new therapeutic approach led to the successful development of new treatments, many of which are widely used today. Ultimately, the new paradigm led to successfully preventing breast cancer in women who were at high risk for the disease but who had not yet been diagnosed with the disease. Throughout his entire career, Fisher championed the use of large prospective, randomized clinical trials despite criticism from many in the medical community who strongly criticized his use of randomization as a mechanism for testing clinical hypotheses. The approach he and the NSABP employed is still considered to be the highest standard of evidence in conducting clinical studies.

1992 ◽  
Vol 50 (2) ◽  
pp. 125-129 ◽  
Author(s):  
Cyrus A. Kotwall ◽  
Leo J. Mahoney ◽  
Robert E. Myers ◽  
Linda Decoste

2021 ◽  
Author(s):  
Maria Laura Tognoli ◽  
Nikola Vlahov ◽  
Sander Steenbeek ◽  
Anna M. Grawenda ◽  
Michael Eyres ◽  
...  

AbstractCell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here we show that the novel oncogene RASSF1C drives mesenchymal to amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that amoeboid cells display the cancer stem cell markers CD133, ALDH1 and the pluripotent marker Nanog; are accompanied by higher invasive potential in vitro and in vivo; and employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification.


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