Gordon B. Mills, MD, PhD
Cancer treatment is moving from a one-size-fits-all approach to personalized medicine, which means matching the right drug with the right tumor characteristics. Although personalized medicine has seen some exciting advancements in identifying tumor targets through genomic sequencing and developing treatments aimed at those targets, other successes, such as trastuzumab for HER2-positive breast cancer and imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumor (GIST), do not tell the whole story. The Holy Grail may be in sight, but it remains elusive.
“While there is incredible excitement about the potential implementation of personalized cancer therapy, it is easy to contend that the excitement is massively overblown by the press,” said Gordon B. Mills, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the European Multidisciplinary Cancer Congress in Stockholm, Sweden.
“The number of successes—and in most cases these are only found in small subpopulations of patients and are transient—are outnumbered by spectacular failures,” he continued. “The cost of targeted therapy has added a tremendous burden to healthcare for a minor improvement in outcomes in small subpopulations. We are far from overcoming the hurdles associated with the implementation of personalized cancer therapy.”
Mills added, “We are coming closer to having scientific underpinnings for personalized medicine, but integrating our discoveries is an art. We have to ask ourselves whether we are overpromising successful treatments for cancer. Is this hype? Is this fundraising? Will there be repercussions if we don’t deliver on our promises?”
For trials of personalized medicine, each patient represents an “n” of 1. The therapy has to work with the specific patient’s genomics. Just identifying mutations does not mean that they are actionable and druggable; even if a tumor has actionable mutations, many responses to targeted therapy are in small subpopulations of patients and are short-lived. Also, regulatory hurdles need to be overcome for approval of targeted therapies.
In lieu of an ability to treat individual patients based on the changes in the genomes, experts are moving toward stratified therapy and treating groups of patients with similarities in their tumors, but Mills acknowledged that this is fraught with challenges. “Breast cancer is leading the way [in tumor stratification],” he said. “Ductal carcinoma used to be considered one disease; now eight subclasses have been identified. Some of these subgroups are orphan diseases and too small for clinical trials.”
Only subpopulations of patients with a particular biomarker show a response to targeted therapy, and the response is typically not durable. “We need to convert these short-lived responses to durable ones,” he said. He gave the example of the targeted agent crizotinib, which achieved a remarkable response in a subpopulation of lung cancer patients with the ALK mutation, “but every patient has recurred.”
We are coming closer to having scientific underpinnings for personalized medicine, but integrating our discoveries is an art. We have to ask ourselves whether we are overpromising successful treatments for cancer. Is this hype? Is this fundraising? Will there be repercussions if we don’t deliver on our promises? ”
–Gordon B. Mills, MD, PhD
Challenges in Personalized Medicine
The success of any cancer therapy is partly determined by the patient’s nongenetic makeup, the tumor characteristics, and the drug’s therapeutic index and toxicity. Tumor heterogeneity represents a challenge because characteristics of the primary tumor often change at relapse and at metastasis, signaling the need for rebiopsy at stages of disease progression. In some cases, the primary tumor itself may be heterogeneous at different sites. Therapy should be sequenced based on the shift in characteristics at disease progression, Mills told the attendees.
With improved ability to characterize tumors in greater depth, multiple mutations are being identified, posing another hurdle to targeted therapy. When a mutational target is identified and targeted treatment is initiated, compensatory pathways may be activated, causing the emergence of resistance.
One focus of research is to distinguish between “passenger” mutations and “driver” mutations. “Not all mutations are targetable,” said Mills.