By: Patricia Keegan, M.D.
I have been with FDA for more than 20 years and an oncologist for 30 years. During this time, I have witnessed an evolving change in our understanding of cancer. We once viewed cancer as a single disease, such as breast or lung cancer. Today we understand that most cancers that arise in a single organ or area of the body are often a genetically diverse group of cancers that have different patterns of spread, different rates of growth, and different responsiveness to treatment.
To understand the progress we’ve made today in breast cancer, one has to look back at how changes in treatment expectations among oncologists, emerging scientific discoveries, and greater influence and advocacy from patients all fundamentally changed the nature of cancer drug reviews at FDA.
The late 1980s and early 1990s represented a dramatic shift in how oncologists began thinking about what treatments could achieve. Before this time, the effectiveness of a treatment was often measured by its ability to shrink a tumor, rather than its ability to extend a patient’s life or prevent the cancer from spreading, which is a common expectation of treatment today. In addition, effective drug treatment was often limited to extremely toxic chemotherapies that generally killed healthy cells and cancer cells indiscriminately, further compromising the quality of life for patients with cancer.
During this time, independent cancer experts tapped by FDA recommended that the oncology community expect more from cancer treatments. They advised FDA to approve a greater number of effective drugs, including approvals based on a single study of efficacy—with the understanding that, in some cases, the risks of the new treatments may not be fully known at approval because fewer total patients had been studied. This new way of thinking about cancer care has had a profound effect on FDA’s approach to guiding the clinical development of new cancer treatments.
Arguably, no type of cancer treatment has benefited from this shift in thinking more than breast cancer. Before 1990, there were few effective drugs for patients who developed metastatic disease, in which the cancer has spread to other parts of the body. However, the last decade of the 20th century saw the approval of several new drugs and drug classes. One new drug in particular, Herceptin (trastuzumab), would change the landscape of breast cancer treatment and transform the outcome of a particularly deadly type of the disease for some patients.
Herceptin was approved in 1998 for a specific type of breast cancer known as HER2-positive metastatic breast cancer. It was just the second cancer drug approval for a new category of drugs called monoclonal antibodies and helped usher in the era of personalized medicine in cancer treatment in which a patient’s tumor cells are assessed to determine if a particular drug could be an effective treatment. Herceptin’s complex molecules are manufactured through biotechnology and work by binding to the surface of cancer cells, where they prevent substances in the blood from stimulating tumors to grow and make it easier for the patient’s immune system to attack and kill the cancer cell. While monoclonal antibodies, their production methods, and the identification of patients who might obtain the best results are much better understood today, there was very little experience to draw from in the mid-1990s.
Herceptin forced my fellow reviewers and me to adapt quickly to a number of unexpected findings during the clinical investigations and review of the study results, including the limitations of animal studies in predicting risks for patients. We had operated under the assumption that Herceptin would have side effects that were more like hormone therapies not considered to be toxic. In reality, we learned that Herceptin had unique side effects (i.e., damage to heart muscle) that patients had to be informed of during their participation in these clinical studies.
It was during this time we learned, and better understood, how the amount of HER2 protein on the surface of cancer cells could predict which patients would or would not likely benefit from treatment. We also became aware of the necessity of approving a reliable companion diagnostic test to identify patients most likely to benefit from the treatment, concurrent with approving the drug.
After more than a decade of experience with the use of diagnostic tools to direct patient management, physicians can give these targeted drugs to patients whom they know have the genetic makeup that will enable the drug to be effective.
Cancer advocacy has advanced tremendously as well during the last two decades of the 20th century. I distinctly remember that FDA had to balance the excitement prompted by therapies then under development with the reality that some women living with breast cancer wouldn’t survive long enough to benefit from them, and the need to encourage pharmaceutical companies to provide patients with access to investigational drugs during the drug review process. It was during this time that, through the efforts of FDA’s Office of Special Health Issues and especially the efforts of Patricia Delaney from that office, my colleagues and I became well-acquainted with a highly-organized and well-educated group of advocates, both men and women, who fought tirelessly to get patients access to drugs that are still being studied. They left an indelible impression on each of us.
Today, progress continues. Pharmaceutical companies, the medical oncology community, and FDA have worked together on development of new drug classes, better drug screening, and innovative research to rapidly identify potentially effective new treatments. These efforts have helped save the lives of many women world-wide. While we still have far to go, the pace of change has been rapid and the future of breast cancer drug development looks much brighter!
Patricia Keegan, M.D., is the director of the Division of Oncology Products 2 in the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research