Pharmacogenetics is starting to provide some new insights into the treatment of nicotine dependence, both on how genetic variation influences dependence and in finding potential targets for therapy, Dr. Caryn Lerman said last week during the Joseph W. Cullen Memorial Award lecture at the American Society of Preventive Oncology annual meeting.
Progress in this area is important, Dr. Lerman stressed. About one in four Americans still smoke, and although two drugs have been approved by the FDA for treatment, they are only effective in a fraction of people.
"Clearly there is a need to develop new models of treatment that can be translated to the clinical setting," she said. Pharmacogenetics offers one possible approach to changing how treatments are delivered in practice, including enhancing outcomes by tailoring the approach according to an individual's genetic makeup.
Dr. Lerman, the associate director for Cancer Control and Population Sciences at the Abramson Cancer Center of the University of Pennsylvania, has led two recent clinical trials that investigated how genetic variation influenced response to nicotine-dependence treatment. In a 600-subject, placebo-controlled clinical trial published in 2002, smokers seeking treatment were randomly assigned to bupropion (Zyban®) or placebo, plus group counseling, for eight weeks. The investigators focused on the CYP2B6 gene, which plays a role in bupropion and nicotine metabolism. Overall, patients on bupropion fared better than those on placebo, although those with a decreased-activity variant of CYP2B6 had lower abstinence rates and increased cravings at the end of the treatment phase. This was especially true in females.
When the investigators looked at craving data, they found that cravings after treatment were not as significant in individuals with the CYP2B6 mutation treated with bupropion compared to those with placebo, meaning that the drug may be reducing relapse in these patients by tempering the craving for nicotine.
In a similar trial that compared two different types of nicotine replacement therapy - nicotine nasal spray or nicotine patch - Dr. Lerman and her colleagues focused on the mu opioid receptor gene (OPRM1). Nicotine increases release of beta endorphin, and the less common Asp40 variant of this gene is associated with greater binding of beta endorphin to the mu opioid receptor (and perhaps the more pleasurable effects of nicotine). The data, currently in press, showed that individuals with the OPRM1 Asp40 variant were more likely to benefit from nicotine replacement therapy but that the effect appeared to be more pronounced during the higher dose phase of the treatment regimen. "This suggests a hypothesis that smokers with this variant may be candidates for extended high-dose patch treatment," Dr. Lerman said.
A possible association between alachlor application and the incidence of lymphohematopoietic cancers - particularly leukemia and multiple myeloma - is being investigated as part of the Agricultural Health Study (AHS). Developed in 1993 by NCI's Occupational and Environmental Epidemiology Branch (OEEB) in the Division of Cancer Epidemiology and Genetics (DCEG), AHS is a large-scale prospective cohort study of nearly 60,000 farmers and other professionals who apply pesticides to crops. Thirty thousand of their spouses are also included in the study, which is designed to evaluate the effects of environmental, occupational, genetic, and dietary factors on the health of farmers and their families in Iowa and North Carolina.
Alachlor, introduced in 1969 under the trade name Lasso, is an herbicide used mainly in the production of corn, soybeans, and peanuts. It is one of the most widely used herbicides in the United States, according to U.S. Environmental Protection Agency estimates.
The study's latest findings, published in the February 15 American Journal of Epidemiology, evaluated the exposure-response relationship between alachlor and cancer incidence, controlling for the effects of several potential confounding factors. Approximately 26,510 study participants reported use of alacholor. A total of 1,466 incident malignant neoplasms were diagnosed in study subjects during the 1993-2000 study period (805 in the alachlor-exposed group and 661 in the nonexposed group). The investigators noted that these findings suggest a possible association between alachlor application and the incidence of leukemia and multiple myeloma in this population but that additional follow-up of the cohort will shed further light on the risks for these and other cancers.
"AHS is the capstone of a major area of research for DCEG," said Dr. Aaron Blair, chief of OEEB. "The prospective design, with detailed information on agricultural exposures and rural lifestyle factors and biologic specimens to assess gene-exposure interactions, will allow us to evaluate a number of potentially hazardous chemicals that may affect the health of farm families as well as the general population."
A retrospective review of 501 patients treated with radical prostatectomy who subsequently underwent salvage radiotherapy for recurrent prostate cancer has found that a significant subset of patients typically considered to be at the highest risk of progressive metastatic disease can achieve a durable response. The NCI-funded study may offer some important insights for clinical oncologists who have been reluctant to use radiotherapy in these patients, presuming that their rising prostate-specific antigen (PSA) levels indicate the disease had spread, meaning radiotherapy would likely prove futile.
In the study, published by Dr. Andrew J. Stephenson and colleagues in the March 17 Journal of the American Medical Association, the four-year progression-free probability was 45 percent. In addition, the authors stressed that "subsets of patients with high-grade disease and/or a rapid PSADT [PSA doubling time] who were thought to be incurable could still achieve a durable response to salvage radiotherapy when the treatment was administered early in the course of recurrent disease."
In a related editorial, Dr. Mitchell S. Anscher of Duke University Medical Center noted that the finding that salvage radiotherapy early after recurrence was beneficial in these patients "probably could have been anticipated." Nevertheless, he said, the study's findings "will provide useful guidance both for better selecting patients for salvage radiotherapy and for designing future clinical trials."