The explosive knowledge coming out of the age of genetics is having only a quiet impact in the clinic so far. But the effort to develop molecular profiles of individual patients is moving quickly and in as little as 2 years may dramatically alter how physicians treat and diagnose cancer.
Only a handful of examples now exist where genetic information either the expression patterns of various genes or the molecular fingerprints of single genes helps define which tumors will grow fast and which will respond to various treatment options.
"There are very few genetic tests that have reached the level of the clinic," said Bert Vogelstein, M.D., of the Howard Hughes Medical Institute and the Johns Hopkins Medical Institutions in Baltimore, Md. "But there are many on the drawing boards."
The publication of a paper in the October 15 Science gives a glimpse into the genetics of the future. Looking at the gene expression patterns from 38 bone marrow samples of acute leukemia patients, Eric S. Lander, Ph.D., and his colleagues from the Whitehead Institute in Cambridge, Mass., were able to distinguish between patients with acute lymphoblastic leukemia and those with acute myeloid leukemia.
Although overall they examined the expression of 6,817 human genes, only 50 were necessary to predict the leukemia class. They were also able to help sort out an unusual case initially diagnosed as AML, but with atypical morphology. An expression profile suggested that the cells originated from muscle; a subsequent cytogenetic analysis identified the patient's tumor as alveolar rhabdomyosarcoma, a muscle tumor.
Similarly, in the same issue of Science using a "Lymphochip," a microarray with 18,500 genes involved in the development of antibody-producing B cells, researchers were able to define two classes of lymphoma within 50 cases of diffuse large cell lymphoma. One gene expression pattern seems to carry a good chance of survival while the other does not.
The microarray technology, which both these groups used, is a powerful tool for seeing how thousands of genes are expressed in tumors or normal tissues at one time. This ability is enabling other researchers across the country, for example, to analyze genetic changes retrospectively in large clinical trials allowing them to pinpoint genetic differences between cancer patients who respond well to treatment and those who do not.
David Mack, Ph.D, head of genomics research at Eos Biotechnology in South San Francisco, Calif., is using microarray technology to look at a 5-year cohort of colon cancer patients and identify the genetic differences between those people that have been cured by surgery compared to those that have succumbed to metastatic disease.
"Solid tumor patient management is just beginning," said Mack. "It's early days, but we're beginning to see things happen, and we'll see more of it. Maybe 2 years from now, we'll see something in the clinic."
Neuroblastoma
While researchers are busy collecting data on expression patterns of thousands of genes, several clinicians are using the molecular fingerprints of single genes to make diagnosis and/or treatment decisions.
One of the oldest and most widely used genetic tests looks for N-Myc amplification for neuroblastoma in children. In 1984, Garrett M. Brodeur, M.D., chief of oncology at the Children's Hospital at Philadelphia was one of the pioneers in discovering that N-Myc was amplified in a third of the primary tumors from untreated neuroblastoma patients. He eventually showed in a retrospective study involving two large cooperative group trials that the patients with N-Myc amplification did substantially worse.
|
Nowadays, with the aid of an international staging system first agreed on in 1988, clinicians in the U.S., Europe, and Japan use N-Myc amplification, histopathology, and DNA ploidy (for infants) to determine risk and to direct treatment for neuroblastoma. Brodeur and others are looking for new patterns of gene expression or genetic changes that correlate with clinical outcomes.
Gene amplification also guides treatment with Herceptin, a drug approved last year for the treatment of metastatic breast cancer. Dennis Slamon, M.D., and colleagues at the University of California, Los Angeles, used their discovery that 25% to 30% of metastatic breast tumors overexpress a growth factor receptor protein called HER2 to create a monoclonal antibody (Herceptin) that inactivates the excess receptors. Only patients whose tumors have multiple copies of the gene or who overexpress HER2 protein are treated with Herceptin. Of those treated, about half respond.
Inherited Genetics
Instead of testing tumor samples for particular genetic defects to guide treatment, some investigators are testing the inherited genes of the patient. Although it has been known for decades that patient response to medications varies widely, several enzymes that play a role in individual drug sensitivity have now been identified, including drugs for cancer, asthma, and pain (codeine), among others.
Mary V. Relling, Pharm.D., with her colleague, William E. Evans, Pharm.D., at St. Jude Children's Research Hospital in Memphis, Tenn., also publishing in the Oct. 15 issue of Science, did a comprehensive review of the polymorphisms in drug-metabolizing enzymes that have profound effects on the toxicity and efficacy of many medications. (Polymorphisms are small genetic differences in genes that exist stably in the population, one or more of which alters the activity of the gene-encoded protein.)
|
"TPMT typing for kids with ALL is done here and at the Mayo. It's the closest thing to routine testing that I know of. We're such a small group of people dealing with childhood ALL, that we're pretty tuned into it," said Relling.
Although a mutation in both gene copies of TPMT is prevalent in about one in 300 individuals, the probability of people carrying a polymorphism in one gene copy is much more common, one in 10. Relling and her colleagues found that single-mutation carriers also have an altered tolerance to thiopurines, requiring lower than normal dosages. These results appear in this issue of the Journal (p. 2001).
"Because this polymorphism affects such a large proportion of the population, we think patients should be phenotyped before they receive chronic therapy with thiopurines or at least early on in treatment," said Relling.
Genetic alterations in another metabolizing enzyme, DPD (dehydropyrimidine dehydrogenase), can have a profound effect on patients treated with 5-FU, a cancer drug that has been used for more than 40 years for the treatment of various cancers. Both severe neurotoxicity and even death can result in patients with specific alterations in DPD. 5-FU remains the standard first-line treatment for colorectal cancer, even though the response rate as a single agent is usually less than 20%.
Kathleen Danenberg, Ph.D., and her colleagues at the USC/Norris Cancer Center at the University of Southern California School of Medicine in Los Angeles, Calif., found that by measuring DPD levels as well as those of another enzyme, thymidylate synthase (TS), in tumor biopsy specimens, they can predict which advanced colorectal cancer patients will not respond to 5-FU. If enzyme levels were above a certain threshold, patients did not respond. The results will appear soon in Clinical Cancer Research.
The researchers are using these findings in a collaboration with Len Saltz, Ph.D., at Memorial Sloan-Kettering Cancer Center, New York, to decide whether colon cancer patients will be treated with 5-FU or CPT-11, an inhibitor of topoisomerase I. Those with low TS enzyme levels will receive 5-FU and those with high levels will receive CPT-11. The scientists will also try to correlate other genetic information with responsiveness to CPT-11, such as the levels of topoisomerase I, mutations in p53, and bcl-2/bax ratios. They are also looking to see if the levels of three enzymes, TS, DPD, and TP (thymidine phosphorylase), will allow them to make better predictions of a patient's responsiveness to 5-FU. The trial began one and a half years ago.
"This is one of the first times that a patient's therapy is planned on the a basis of a prior genetic analysis," said Danenberg. "In theory, this should increase the overall response rate appreciably without any new drugs or procedures. We do not yet have any definitive clinical results to report."
Danenberg said she knows of no one else who is looking routinely at metabolizing enzymes, and with so many requests from patients for testing biopsied samples, her institution plans to offer it as a service soon.
Even though genetic changes in metabolizing enzymes may have dramatic effects, Relling thinks assessing these enzymes is not going to be that simple. She pointed out that the effect of medications are typically determined by the interplay of several genes encoding proteins involved in multiple pathways.
Although drug companies were not initally interested in pursuing the development of drugs that are affected by polymorphisms, Relling sees that changing. "Now everyone is coming to the realization that almost all genes are polymorphic in the population," she said.
Relling believes that there won't be such a thing as "one drug fits all" because each drug will probably be affected by several enzymes. That means that drugs will be developed to fit some parts of the population and not others.
"But the world is changing fast," she continued. "Every major pharmaceutical company now has a huge research group devoted to SNPs [small nucleotide polymorphisms] and pharmacogenomics. Ever since we published our review in Science, a lot of people are contacting us about new tools for genotyping. Things are moving very fast."
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |