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Drug-Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort

From the Department of Biostatistics and Epidemiology; Division of Hematology/Oncology, Department of Medicine; Abramson Cancer Center; Abramson Family Research Institute; and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine; and Division of Hematology/Oncology, Children's Hospital of Philadelphia, Philadelphia, PA

Address reprint requests to Angela DeMichele, MD, MSCE, 14 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104; e-mail: dma{at}mail.med.upenn.edu

PURPOSE: Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and glutathione S-transferases (GST), may predict treatment-related outcomes.

PATIENTS AND METHODS: We examined CYP3A4*1B, CYP3A5*3, and deletions in GST µ (GSTM1) and (GSTT1), as well as a priori–defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS).

RESULTS: Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio [HR] = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status.

CONCLUSION: Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.

Supported by grant No. K23-CA81009 (A.D.), University of Pennsylvania Cancer Center Pilot Project (A.D.), and National Cancer Institute Core Grant (J.G.).

Presented at the 94th Annual Meeting of the American Association of Cancer Research, Washington, DC, July 11-14, 2003 and the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

Related Correspondence

• In Response to "Drug Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort"
  Angela DeMichele, Phyllis Gimotty, Jeffrey Botbyl, Richard Aplenc, Theresa Colligon, Andrea S. Foulkes, and Timothy R. Rebbeck
  JCO 2007 25: 5675-5677 [Full Text]

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