When I think about Dennis Slamon, I get Good Good Good Good Vibrations (courtesy of the Beach Boys). Yes, here is another of our outstanding California scientists.
Slamon actually came to California by a more circuitous route than most. He was born in West Virginia, the descendant of several generations of coal miners, but somehow got the bug to go on to college and onward from there rather than continuing in the mines as did most of his peers. So he went to Washington & Jefferson College in Washington, Pennsylvania, before going on to an MD-PhD program at the University of Chicago. He did his residency in internal medicine there as well, and then went on to the University of California at Los Angeles for his fellowship in medical oncology. He then joined the faculty at UCLA.
We have previously discussed how there are genes referred to as oncogenes, whose expression, or overexpression, stimulates the manifestation of the malignant phenotype. The HER2-neu gene is such an oncogene. The HER2 (human epidermal growth factor receptor 2) oncogene is over-expressed in about 20% to 30% of breast cancers with its protein on the cell surface. Its presence in a patient with breast cancer is associated with accelerated growth of the tumor and a worse prognosis. In 1986, Axel Ullrich, a scientist at Genentech, began working on trying to find an antibody to inhibit this protein. Slamon heard a talk by Ullrich at UCLA around that time and then teamed up with him to try to develop such a drug. Genentech subsequently lost interest in the project, but later gave small amounts of funds to these two scientists so they did ultimately develop an antibody against HER2.
The team, led by Slamon, developed a monoclonal antibody that inhibits the over-expression of the HER2 oncogene protein. For the next 12 years, Slamon took this antibody through the necessary animal studies to demonstrate its efficacy and safety. He then initiated the early human trials to assess its safety and efficacy under those circumstances. The first clinical trial with 15 women began in 1992. Five women were able to participate fully. One of the women who participated, Barbara Bradfield, who was 49 when she entered the trial in 1992 with metastatic breast cancer, is still alive now at 80 and is still cancer-free.
Subsequently, Slamon undertook the randomized trials to prove its value in the treatment of breast cancer in women with metastatic HER2-positive breast cancer. Just by chance (or luck), I happened to be present in the first row when the results of this trial were presented in 1998 as a plenary paper at the annual meeting of the American Society of Clinical Oncology. The randomized trial showed that Herceptin (trastuzumab) improved overall survival in late-stage breast cancer from 20.3 months to 25.1 months—this is a change in outcomes that is mind-boggling in oncology. Based on this study, it was FDA-approved in 1998.
Subsequent studies have also demonstrated the utility of trastuzumab in the adjuvant setting. It has a profound benefit for women with resected localized HER2-positive breast cancer, and it is administered in that setting for a year or more.
Multiple other cancers have also been shown to over-express HER2-neu as well. It is now the standard of care to test gastric cancer for the over-expression of this gene and, if present, to use Herceptin in its treatment just as it is used for breast cancer. Even more recently it has also been shown to be present as well in some cases of patients with colorectal cancer. Again, its use can improve patient outcomes under those circumstances.
It is not often that an investigator is able to take a drug from the basic science lab, through the drug safety testing, and then through the early human clinical trials and finally to the randomized trials. Slamon is one of the rare individuals to accomplish this unique feat. It is like achieving the Triple Crown in baseball. He went on to become the chief of hematology/oncology at UCLA, a position which he currently holds. Truly Good Good Good Good Vibrations!
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. Email: [email protected].
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.
