Pediatricians are accustomed to caring for patients with rare diseases. But as all physicians know, common diseases can also behave in rare ways, either presenting in unusual forms or responding only to particular treatments. Recent advances in molecular medicine have confirmed this intuition, particularly in cancer, whose varieties can be virtually as unique as we are ourselves.
Oncologists have formed cooperative groups to meet this challenge long ago. But they remain outmatched by cancer itself: its biology is complex, with different tumors growing as a result of hundreds to thousands of aberrations in cancer genomes and cells. And, until recently, they’ve been limited by the process of traditional clinical trials.
We are beginning to understand some of the genetic aberrations, such as loss of the BRCA1 gene, which predisposes women to breast and ovarian cancer early in life. In addition to causing cancer, loss of BRCA1 also makes cancer cells dependent on a functionally related protein PARP, allowing them to be specifically targeted with PARP inhibitors.
As a result, a number of ongoing clinical trials are investigating the safety and efficacy of these smart drugs. It is possible that incorporating PARP inhibitors into established cancer treatment regimens will lead to transformative improvements for patients with specific loss of the BRCA1 pathway.
What is assured, however, is that these traditional clinical trials will take many years to complete. Combining a smart drug with other personally targeted therapies and conventional drugs may take decades. And, smart as the drugs may be, they may not get a fair test: conventional clinical trials of new cancer therapies typically involve patients with advanced forms of disease, which is often different from disease at initial presentation, and may shortchange drugs that would otherwise be effective.
And paradoxically, as cure rates improve as a result of combination of intensive chemotherapy, radiotherapy and surgery, the number of patients eligible for traditional clinical trials decreases, delaying and sometimes making it impossible to test new targeted therapies that may be less toxic and more effective.
Now, a new clinical trial, termed I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) aims to improve and expedite the drug-testing process for patients with breast cancer, bringing us closer to personalized cancer treatment in general.
Instead of testing new drugs in patients with advanced disease individually and sequentially, and waiting for differences in survival, patients with early forms of breast cancer will be monitored for the immediate effects of new drugs on their tumors in real time. The trial will investigate new drugs designed to target specific aberrations of the individual patient’s breast cancer cells, combining drugs based on their efficacy in shrinking or causing molecular response in tumors. In this way, the trial is intended to “learn” over time how to predict responses to each drug, allowing doctors to identify patients with tumors that are likely to respond to specific combinations of drugs.
This innovative approach would dramatically transform our ability to develop new therapies, certainly for patients with cancer, and perhaps for other diseases as well. The need is made more dire by the exploding knowledge about the molecular causes of disease that makes common diseases rare. Physicians need to take heed of the I-SPY 2 TRIAL, as lessons learned from its outcomes are likely to define the future of medicine for doctors and patients alike.
