American Association for Clinical Chemistry
Better health through laboratory medicine
February 2008 Clinical Laboratory News: Diagnostic Profiles

February 2008: Volume 34, Number 2

Study Calls for Better Established CK Reference Intervals

Use of appropriately established creatine kinase (CK) reference intervals may improve use of statins and control of dyslipidemia in patients with relatively high baseline CK, new research suggests (American Heart Journal 2007; 154: 655–661). In what researchers from two hospitals in Amsterdam, the Netherlands say is the first published study of serum CK activity based on a stratified, random sample of the general population that includes subjects of different ancestry, investigators determined reference intervals for serum CK according to guidelines from the Netherlands’ National Committee on Clinical Laboratory Standards and the Nordic Reference Interval. The Surinamese in the Netherlands Study on Ethnicity and Health (SUNSET) Study included 1,444 individuals age 34–60, of white, South Asian, or African descent who gave samples after 3 days of rest. The calculated upper reference limits equal to the 97.5th percentile for nonblack and black women and men were two to five times higher than that recommended by the assay manufacturer. Thirteen percent of white Europeans, 23% of South Asians, and 49% of black subjects had serum CK activities that exceeded these recommendations. Researchers concluded that variation in CK activity is wider that previously suggested in studies on smaller, nonrandom samples and that relatively high values occur frequently in all subgroups studied after rest. Noting that Adult Treatment Panel III guidelines acknowledge that higher CK activities are found in blacks, the team pointed out that the guidelines do not say how high the upper reference limit should be for blacks and suggested upward adjustment of the upper limit of normal for all the subgroups they studied.

 Genetic Variants Affect Response to Breast Cancer Therapy

Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for certain CYP2D6 alleles can identify breast cancer patients who will have little benefit from adjuvant tamoxifen therapy, according to a recent paper (Journal of Clinical Oncology 2007; 25: 5187–5193). German researchers sought to determine the predictive value of 16 variants of the cytochrome 450 enzymes CYP2D6, CYP2C19, CYP2B6, CYP2C9, and CYP3A5 from 206 patients on adjuvant tamoxifen monotherapy and from another 280 patients who didn’t get tamoxifen. Median follow-up time was 71 months. Researchers isolated DNA from archival material and genotyped it by matrix-assisted, laser desorption/ionization, time of flight mass spectrometry, and by copy number quantification. Tamoxifen-treated patients with four CYP2D6 alleles, all associated with impaired formation of antiestrogenic metabolites, had significantly more breast cancer recurrences, shorter relapse-free periods (HR 2.24, 95% CI, 1.16–4.33), and worse event-free survival rates (HR 1.89, 95% CI, 1.10–3.25), compared with carriers of functional alleles. Patients with the CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (HR 0.45, 95% CI, 0.21–0.92) than carriers of *1, *2, and *3 alleles. “Our findings are particularly important in light of the current debate on the effectiveness of tamoxifen for postmenopausal women with hormone receptor positive breast cancer,” the researchers wrote.

 Analysis of CD40L May Help Stratify Risk in AF

Enhanced soluble CD40 ligand (sCD40L) predicts vascular events in patients with nonvalvular atrial fibrillation (AF), according to new research suggesting that enhanced platelet activation may play a role in clinical progression of the disease (Arteriosclerosis, Thrombosis, and Vascular Biology 2007; 27: 2763–2768). To assess whether sCD40L is a predictor of stroke or myocardial infarction (MI) in patients with nonvalvular AF, researchers from Mount Sinai School of Medicine (New York, N.Y.) and two institutions in Rome, Italy measured plasma levels of sCD40L in 231 patients. Seventy-seven percent had permanent or persistent AF, while 23% had paroxysmal AF. Researchers divided the patients into two groups, one with sCD40L levels above the median of 4.78 ng/mL and the second with levels below that figure, and followed both groups for a mean period of 27.8 months. The two groups had similar distribution of cardiovascular risk factors, age, sex, medication, and serum CRP levels. During follow-up, vascular events occurred in 5.1% of 116 patients with lower levels of sCD40L and 25.2% of patients with higher levels of the marker. Patients with sCD40L above the median were 4.63 times more likely to experience a vascular event (95% CI, 1.92–11.20). Noting that their data can’t be extrapolated to a low-risk population, the researchers called for further study of the marker.

Rapid Chlamydia Test Holds Promise

A rapid chlamydia test using patient-collected vaginal swabs would be an effective, quick diagnostic and screening tool, a recent paper suggests (British Medical Journal 2007; 335: 1190–1194). Although nucleic acid amplification tests for chlamydia are generally more sensitive and specific than currently available rapid assays, their turnaround time—one to two weeks—precludes immediate treatment and partner notification. So researchers from five institutions in the U.K. sought to evaluate the performance of a new 30-minute assay, the Chlamydia Rapid Test, devised to aid in diagnosis of chlamydia and serve as a screening tool in settings where staff lack advanced training or laboratory equipment. The investigators studied the test’s performance in 1,349 women ages 16 to 54, comparing its sensitivity, specificity, positive predictive value, and negative predictive value to that of a PCR test. Compared with the PCR assay, the resolved sensitivity, specificity, positive predictive value, and negative predictive value of the 30-minute assay were—with 95% CI—83.5% (91–109), 98.9% (1224–1238), 86.7% (91–105), and 98.6% (1224–1242), respectively. Compared with strand displacement amplification assays, sensitivity and specificity of the Chlamydia Rapid Test were 81.6% (40–49) and 98.3% (578–588). The investigators noted that their paper is the first published performance analysis for a CE-marked rapid test for chlamyida with a claim for vaginal swab specimens.

Breast Cancer Signatures Predict Chemotherapy Response

Gene-expression signatures in breast tumor samples can accurately predict which women with estrogen-receptor negative breast cancer will not respond to two common chemotherapy regimens, according to a recent paper (Lancet Oncology 2007; 8: 1071–1078). Sponsored by the European Organization for Research and Treatment of Cancer (EORTC), a trial by a research team from institutions in six European countries and Duke University compared a fluorocil, epirubicin, and cyclophosphamide (FEC) regimen for six cycles with a taxane regimen that consisted of docetaxel for three cycles followed by epirubicin plus docetaxel (TET) for three cycles. The team tested 125 estrogen receptor tumors, 66 from the FEC group and 59 from the TET group. For the FEC predictor, the team reported, with 95% CI, a sensitivity of 96% (82–99) and specificity of 66% (50–79), a positive predictive value of 68% (52–80), and a negative predictive value of 96%, (81–99). The TET predictor showed a sensitivity of 93% (77–98), specificity of 69% (51–82), positive predictive value of 71% (55–84), and negative predictive value of 92% (74–98). Analysis of tumor size, grade, nodal status, age, and regimen-specific signatures revealed that the gene signatures were the only independent variables predicting pathological complete response. According to researchers, selection of patients with these signatures would increase the proportion of pathological complete responses from about 44% to 70% among patients in the trials. “We have validated the use of a regimen-specific drug sensitivity signature in the context of a multicenter, randomized trial,” the researchers wrote. “The high negative predictive value of both signatures may allow early selection for patients with breast cancer who should be considered for trials with new drugs.” Researchers also noted that they excluded many patients because their samples contained too few tumor cells or insufficient genetic material for analysis, and that the analysis was performed on frozen biopsy samples. In the U.S, most cancer centers preserve samples with formalin and paraffin.