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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5675-5677 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.1485
In Response to "Drug Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort"Department of Biostatistics and Epidemiology, University of Pennsylvania; Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
CVU Discovery Biometrics, Philadelphia, PA
Division of Hematology/Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
Abramson Family Research Institute, University of Pennsylvania, Philadelphia, PA
Department of Biostatistics, University of Massachusetts, Amherst, MA
Department of Biostatistics and Epidemiology, University of Pennsylvania; Abramson Family Research Institute, University of Pennsylvania, Philadelphia, PA To the Editor: Shortly after publication in August 2005 of our article entitled, "Drug Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort", 1 it came to our attention that a coding error occurred, resulting in a change to four data points used in the analyses that was originally presented. Upon discovering this error, we immediately undertook a thorough quality check and full reanalysis of the data. At this time, we wish to present briefly the corrected analysis. The original report involved the assessment of several germline polymorphisms in the cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes and their relationship to outcome in a cohort of patients with node-positive breast cancer, who had been treated with anthracycline/cyclophosphamide-based adjuvant chemotherapy and high-dose cyclophosphamide and thiotepa with stem-cell rescue on a single-institution phase II study for node-positive breast cancer. 1,2 We studied several functional single-nucleotide polymorphisms that seem to affect cyclophosphamide metabolism, including CYP3A4*1B (rs1067910), CYP3A5*3 (6986A>G; rs776746), CYP3A5*6 (14,690 G>A; rs10264272), and both GSTM1 and GSTT1 homozygous deletions. A multiplex pyrosequencing assay was utilized for CYP3A4*1B and CYP3A5*6, a simplex pyrosequencing assay was utilized for CYP3A5*3, and homozygous deletions at GSTM1 and GSTT1 were identified by multiplex polymerase chain reaction, followed by visualization on a 4% metaphor gel as previously reported.3,4 Polymorphisms were examined both individually and in genotype groups defined based on a priori hypotheses regarding combinations of functional polymorphisms that could impact circulating drug levels and disease outcome. To limit the number of hypotheses to be tested, we developed a prespecified algorithm that allowed us to classify patients on the basis of putative genotype-related metabolism of relevant agents rather than testing all possible associations of individual genotype and outcome. Using this algorithm, we classified subjects into three CYP-GST genotype groups in which subjects in different groups were hypothesized to have varying serum concentrations of active cyclophosphamide metabolites based on known functional significance of the genetic variants studied as described in Table 1. 5-8
The cohort consisted of 90 white patients who had both genotype and clinical outcome information. As of May 2002, 36 patients (40%) had a breast cancer recurrence and 52 patients (58%) remained disease free; recurrence status was unknown in two patients. Thirty-five patients (39%) were confirmed as dead, 54 patients (60%) remained alive at the end of follow-up, and the survival status of one patient was unknown (1%). At the time of this analysis, the median disease-free survival (DFS) of the cohort as a whole was 37 months, and the median overall survival (OS) for the group was 44.5 months. The only coding error identified postpublication was in CYP3A5*3, one of the three CYP polymorphisms examined, in whicha reversal in coding between wild-type and homozygous variant genotype occurred. Table 2 presents the corrected allele frequencies for both individual and prespecified genotype groups. The correction of this coding error resulted in the reassignment of analysis group for four patients for the CYP3A5*3 variant. As a result, three patients moved from the low-drug group to the intermediate-drug group, while one patient moved from the intermediate-drug group to the low-drug group. The Kaplan-Meier curves for the high-, intermediate-, and low-drug groups as well as for the combined high-intermediate versus low-drug groups remain very similar to those presented in the published manuscript (data not shown). However, because of both group-assignment changes for individual patients, as well as a shrinking of the low-drug group from five to three patients overall (substantially impacting power in this small study), the reanalysis of the Cox model (Table 3) with the reassembled genotype groups resulted in a loss of significance of the effect of genotype group on DFS. The reported significant association of genotype with OS remained unchanged. The full multivariate models for DFS and OS included indicator variables for the unfavorable and intermediate genotype groups, estrogen receptor status, number of positive lymph nodes, tumor size, and age. In this model, the unfavorable genotype group did not have significantly poorer DFS than either the favorable or intermediate genotype groups. However, the unfavorable genotype group had significantly poorer OS compared with both the favorable genotype group (HR, 4.6; 95% CI, 1.1 to 20.5) and the intermediate genotype group (HR, 5.07; 95% CI, 1.4 to 17.8). Estrogen receptor status was the only other prognostic factor that was independently associated with outcome, for both DFS and OS.
Despite the change of genotype class in four patients, our findings continue to support the hypothesis that drug metabolism enzyme genotypes are associated with OS in patients with node-positive breast cancer receiving cyclophosphamide-based adjuvant chemotherapy. We are currently in the process of validating this result by analyzing a larger cohort of patients enrolled onto Eastern Cooperative Oncology Group 2190. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES
1. DeMichele A, Aplenc R, Botbyl J, et al: Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort. J Clin Oncol 23:5552-5559, 2005 2. Moore HC, Mick R, Solin LJ, et al: Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: Impact on the delivery of local-regional radiation therapy. Ann Oncol 10:929-936, 1999 3. Aplenc R, Glatfelter W, Han P, et al: CYP3A genotypes and treatment response in paediatric acute lymphoblastic leukaemia. Br J Haematol 122:240-244, 2003[CrossRef][Medline] 4. Davies SM, Robison LL, Buckley JD, et al: Glutathione S-transferase polymorphisms in children with myeloid leukemia: A Children's Cancer Group study. Cancer Epidemiol Biomarkers Prev 9:563-566, 2000 5. Amirimani B, Ning B, Deitz AC, et al: Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen 42:299-305, 2003[CrossRef][Medline] 6. Kuehl P, Zhang J, Lin Y, et al: Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383-391, 2001[CrossRef][Medline] 7. Seidegard J, Pero RW: The genetic variation and the expression of human glutathione transferase mu. Klin Wochenschr 66:125-126, 1988 (suppl 11)[Medline] 8. Seidegard J, Vorachek WR, Pero RW, et al: Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci U S A 85:7293-7297, 1988
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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