Public Release:  Other highlights in the April 29 JNCI

Journal of the National Cancer Institute

Selecting Patients Based on Genotype May Increase Efficacy of Tamoxifen

Breast cancer patients who carry the wild-type gene required for tamoxifen metabolism may have comparable risk of recurrence when taking tamoxifen or an aromatase inhibitor, according to modeling data.

Cytochrome P450 2D6 (CYP2D6) converts tamoxifen into its metabolically active form called endoxifen. The enzymes encoded by different variants of the CYP2D6 gene metabolize tamoxifen at different rates. For example, women who carry two copies of the CYP2D6*4 allele have less endoxifen in their blood than women who carry two copies of the wild-type allele for CYP2D6. The lower serum concentration of endoxifen may make tamoxifen less effective for the women with the CYP2D6 *4 allele. However, two large randomized trials, which did not test women for their CYP2D6 genotype, showed that breast cancer survivors who take aromatase inhibitors reduce their risk of recurrence more than those taking tamoxifen.

To estimate whether women with wild-type CYP2D6 might derive more clinical benefit from tamoxifen than from aromatase inhibitors, Rinaa Punglia, M.D., of the Dana-Farber Cancer Institute in Boston and colleagues created a mathematical model. The researchers used estimates about the risk of recurrence from past randomized trials.

Punglia and colleagues calculated that women with wild-type CYP2D6 who take tamoxifen would have approximately the same reduction in the risk of recurrence as was seen for the whole population of women who took aromatase inhibitors in the clinical trial. Therefore, women with wild-type CYP2D6 genotype may derive as much benefit from tamoxifen as from aromatase inhibitors.

"Our model raises the possibility that tailored therapy based on pharmacogenomics could be considered for such women," the authors write.

In an accompanying editorial, Daniel Hayes, M.D., of the University of Michigan Comprehensive Cancer Center in Ann Arbor and colleagues review what is known about tamoxifen metabolism and CYP2D6 allele types and their impact on the risk of recurrence for breast cancer patients.

The editorialists comment that the conclusions by Punglia and colleagues are important because they have brought the field of pharmacogenomics to the attention of breast cancer physicians. However, the analysis was based on limited data and on modeling assumptions and must be viewed with caution. "We do not recommend routine CYP2D6 genotyping for all patients who are considering tamoxifen, although we recognize that there are already selected circumstances in which such knowledge might be helpful," they write.

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Stem Cell-Like Cancer Cells Resistant to Standard Therapy, Responsive to Targeted Therapy

A comparison of breast cancer biopsies before and after treatment show that a subset of cells, which have stem cell-like properties, are resistant to standard chemotherapy. Tumors treated with lapatinib, which inhibits a pathway important for self-renewal, retained a smaller fraction of these tumorigenic cells after therapy.

Several research groups have identified a subset of cells in breast tumors that have the ability to form colonies in culture and give rise to tumors in mouse models. These cells, which express CD44 protein on their surface but little or no CD24 (CD44+/CD24-/low), are frequently referred to as cancer stem cells and may be resistant to standard chemotherapeutic agents. Lapatinib, which is approved for treatment of HER2-positive breast cancer, inhibits the HER2 pathway. The drug also inhibits the epidermal growth factor receptor pathway, which may be important for stem cell proliferation.

To find out how the CD44+/CD24-/low cells respond to cytotoxic chemotherapy, Jenny Chang, M.D., from the Baylor College of Medicine in Houston and colleagues compared breast cancer biopsy samples taken from patients before and after standard chemotherapy or lapatinib therapy.

After chemotherapy, the fraction of CD44+/CD24-/low cells increased in 31 paired biopsy samples, from a mean of 4.7 percent at baseline to 13.6 percent after 12 weeks of therapy. Biopsy samples taken after chemotherapy were also more efficient at forming mammospheres, an indication of self-renewal, when grown in culture. By contrast, there was a decrease in the proportion of CD44+/CD24-/low cells in biopsies from 21 women treated with lapatinib, from 10 percent to 7.5 percent.

"Results of this study are encouraging and suggest that inhibition of key regulatory pathways responsible for self-renewal could augment the effects of conventional therapy and improve clinical outcome," the authors write.

Contact: Jenny Chang, jcchang@bcm.tmc.edu, (713) 798-1034


Pesticide Metabolites Associated with Increased Risk of Testicular Cancers

Men exposed to organochlorine pesticide metabolites, such as DDE, had an increased risk of testicular germ cell tumors.

Previous research suggested that persistent exposure to organochlorine pesticides may increase the risk for some types of testicular cancer, but that observation had not been replicated in an independent data set.

In the current case-control study, Katherine McGlynn, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues measured the amount of pesticides or their metabolic breakdown products in blood samples from men who were later diagnosed with testicular germ cell tumors and in blood samples from healthy controls. The men were all part of the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants study. The 915 control subjects and 739 case subjects had donated blood samples an average of 14.2 years prior to the current analysis.

When the researchers divided the participants into quartiles based on the concentration of a particular pesticide in their blood, the team saw a trend for an increased risk of testicular cancer in men with higher concentrations. The trend reached statistical significance for some of the pesticides and metabolites tested. For example, men in the highest quartile for DDE (p,p'-dichlorodiphenyldichloroethylene)--which is a persistent metabolite of DDT (p,p'-dichlorodiphenyltrichloroethane)--were 1.7 times more likely to develop testicular germ cell tumors than those with the lowest concentration.

"If the relative risks calculated in this study are accurate, the population-attributable risk of DDE (i.e., the propor¬tion of disease in the study population that is attributable to DDE exposure) would be approximately 15 percent for all [testicular germ cell tumors]," the authors write.

Contact: National Cancer Institute press office, ncipressofficers@mail.nih.gov, (301) 496-6641


Targeted Combination Therapy Triggers Cell Death in Mouse Models of Metastatic Cancer

A combination of two targeted drugs--one that blocks protein breakdown and one that activates the programmed cell death pathway--reduces the number of tumor metastases in mouse models of kidney and breast cancer. The combination also prolonged overall survival in mice with kidney cancer.

Bortezomib blocks the activity of the proteasome, an enzyme complex which degrades misfolded or unwanted proteins. Bortezomib has been approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma, but its activity against solid tumors is still being tested.

The immune system in both humans and mice may use the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) pathway to eliminate precancerous cells by inducing programmed cell death, or apoptosis. Antibodies that bind to the TRAIL receptor can activate the cell death pathway, as does the TRAIL ligand. The research group led by Thomas Sayers, Ph.D., of SAIC-Fredrick Inc., at the National Cancer Institute in Frederick, Md., had previously shown that bortezomib sensitizes some tumors to TRAIL-mediated cell death.

In the current study, the researchers tested whether the combination of bortezomib and an antibody that binds and stimulates the TRAIL receptor-2, called MD5-1, was more effective at killing cancer cells grown in culture than either drug alone. They also tested the combination's ability to improve the outcome of mice that had been injected intravenously with kidney and breast cancer cell lines.

Treating cancer cells with the combination of bortezomib and MD5-1 increased cell death in kidney cancer cells from 34 percent to 95 percent, compared with MD5-1 alone, and from 20 percent to 85 percent in the breast cancer cells. Mice treated with the combination showed a highly significant reduction in metastases as compared with either drug alone. Overall survival was extended in kidney cancer-bearing mice treated with the combination, with 73 percent of the mice alive at 180 days, compared with a median survival of 42 days in the mice treated with the single-agent MD5-1.

"This regimen showed no evidence of host toxicity," the authors write. "These results thus provide a rationale for the administration of bortezomib in vivo to sensitize tumor cells to the apoptotic effects of TRAIL receptor agonist antibodies or TRAIL ligand to promote solid tumor regression."

Contact: Frank Blanchard, fblanchard@ncifcrf.gov, (301) 846-1893

Also in the April 29 JNCI:

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