Kristine M. Conner
University of Pennsylvania Cancer
Last Modified: May 12, 2001
A panel of American and European presenters came together Saturday afternoon in a special joint session to share perspectives on how the sequencing of the Human Genome will likely affect the clinical practice of oncology is practiced in the clinic. All four speakers agreed that this development holds forth great promise for a better understanding of cancer and its treatment, but they also cautioned that it brings a host of new responsibilities with it?perhaps the most important being the education of physicians and patients.
The promise, as already described by NCI Director Richard Klausner in his morning talk, lies in the clinical applications of the information we can gain about the errors in the genome that are associated with cancer. The presenters pointed to its potential usefulness in helping to diagnose different cancers more accurately, given that tumor samples can often look remarkably similar under the microscope. This information also can be used to divide the same general category of cancer into subtypes based on the patterns of errors in genetic sequence that are present.
Echoing Dr. Klausner, Dr. Jeffrey Trent of the National Human Genome Research Institute at the National Institutes of Health spoke about the promise of "sequence-based biology," and how it really offers the promise of what called a new "taxonomy of cancer." He noted that analysis of gene expression will help us refine cancer subtypes and profile tumor sensitivity to different anti-cancer agents in ways that have not been possible before.
"We hope to be able to identify the differences that can predict each patient's response to a medicine," he noted, and phase I and II trials are already under way to identify sets of genes underlying drug efficacy and reasons for treatment failure.
"This won't replace the art of medicine," Trent said, "but it will add to the science."
At the same time, the speakers made clear, this new "taxonomy" of disease will create a new vocabulary that physicians and patients alike have to learn and understand. Ezekiel Emanuel, MD, PhD, of the Warren Grant Magnuson Clinical Center at NIH, noted that most people do not understand what is really meant by the terms "genetics" and "genetic testing." They automatically associate genetics with inheritance and think of genetic testing as testing for an inherited cancer-associated gene?when in reality, testing can also look for genetic changes that occur as a result of environmental exposures or some other unexplained reasons ("somatic cell mutations"). This will be an important distinction to make clearly, he noted, because somatic cell testing does not have all the "worrisome implications" that testing for inherited genetic mutations does.
"The challenge is to educate doctors and patients that this is not what they're thinking of as ?genetics,'" he noted. In other words, somatic cell testing has nothing to do with the inherited or "germline" mutations that are more often talked about in the news and other sources of health information. As such, "there are no special ethical considerations" associated with this type of testing, Emanuel said, such as impact on other family members and possible psychological trauma. It will be used in much the same way as other tests are currently used to "profile" a person's cancer, such as testing for hormone responsiveness.
"The power is that we'll be able to segment people better, give better prognostic information, and make decisions about what drugs to use," Emanuel said, "and we already do this in medical oncology."
Dr. Martin Fey of the Institute of Medical Oncology at the University of Berne, Switzerland, similarly asserted that most cancers are so-called "sporadic" cancers, rather than inherited cancers, and so this is where most of the knowledge about gene sequencing gained through the Human Genome Project will be applied. At the clinical level, new DNA chip technology will allow for observation and analysis of what Dr. Fey called the "multistep accumulation of changes" that produce cancer. Like Dr. Emanuel, he predicted that the result will be better and more accurate diagnosis and improved prediction of treatment outcomes for certain groups.
So people need to be educated to understand that knowledge about the human gene sequence has implications for all types of cancer, not just those associated with a family history. Nonetheless, the latter have received the most attention in the wake of the news about the Human Genome Project, perhaps because of the many difficult issues associated with testing for inherited mutations.
Dr. James Mackay of the University of Cambridge took on this issue by describing a few examples of real women with strong family histories of breast and ovarian cancer who have approached him for genetic testing for the BRCA1 mutation. He ran through a litany of important considerations that arise.
First, he said, there is a fifty percent chance that the woman inherited a normal gene, and this is important knowledge for the patient to have. If she still wants testing, then she must understand that a positive test will not bring certainty that she is going to develop the disease?and the steps she can take to help herself, such as screening or preventive surgery, are often "less than appealing." Furthermore, testing is only possible after the mutation is confirmed by the testing of an affected relative.
And however the results turn out, there will be definite psychological implications. A woman who always thought she was high-risk may in reality turn out not to be, and this can be a huge psychological adjustment. "It may be very difficult to come to terms with learning that you don't have a mutation when you always thought that you were at high risk," Dr. Mackay said. On the other hand, knowing she has the mutation brings uncertainty: will I develop this cancer and when? And what can I do about it?
Dr. Ezekiel Emanuel raised some of the same issues in distinguishing between somatic cell testing and germline mutation testing. The major issues with the latter, he noted, are the "probabilistic information" it provides, along with familial implications such as stress and worry about the possibility of passing the gene on to other family members.
"Genetic tests do not give you a definite yes-no answer," he said, and yet the very real potential consequences associated with a probable yes are not just psychological trauma and family tension, but also possible discrimination and economic consequences such as lack of eligibility for health and life insurance. "When this technology becomes mainstream, how are we going to address those harms?" Emanuel asked.
He also raised the issue of genetic testing of children for cancer-associated genetic mutations. Parents who test positive may want to know whether children are positive. But the important consideration there, Emanuel noted, whether "there are proven prophylactic or therapeutic interventions for the child." In most cases, the answer is no.
Dr. Ezekiel also raised what he sees as two other very important issues to consider in relation to genetic testing for inherited mutations: cost and demand.
Researchers may be able to develop preventive medications that can counter the effects of a genetic mutation associated with cancer, he noted, but this would require a lifetime of taking the medication. "So it's going to raise costs, there's not doubt about it," he said. "And how we handle those costs is going to be a big challenge."
Furthermore, Emanuel questioned whether the demand is really there for genetic testing, noting that people's demand for such tests has been much lower than expected. He suggested that people's desire for "freedom from predestination" may be at work here.
Overall, these American and European presenters made clear that the Human Genome Project has major implications for how oncologists understand, describe, and deal with both sporadic and inherited cancers, but the latter raise the most pressing ethical questions and considerations.