Polymorphisms of drug metabolizing enzymes and markers of genotoxicity to identify patients with Hodgkin's lymphoma at risk of treatment‐related complications

Abstract

Survivors of childhood Hodgkin's lymphoma (HL) have an increased risk of developing treatment-related complications, especially second malignant neoplasms, as a result of treatment regimens incorporating chemotherapy and radiation therapy. Second cancers include leukemias that generally occur in the first two decades after therapy, and adult-type solid tumors that generally exhibit continued increasing incidence throughout subsequent follow-up. Identified clinical risk factors for second cancers include age at the time of treatment and intensity and type of therapy, with particularly strong associations between the use of radiotherapy and subsequent breast cancer, and alkylator chemotherapy dose-intensity and risk of secondary leukemia. However, second cancers affect a minority of patients, and there is probably great variability in individual susceptibility for this complication. Common genetic polymorphisms in drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug- or radiation-induced genetic damage may lead to increased risk of a second cancer. Studies of the potential role of polymorphisms in the genes encoding the glutathione S-transferases, cytochrome P450 3A4, NAD(P)H:quinone oxidoreductase and myeloperoxidase in the etiology of treatment-related complications are reviewed. Biological markers of drug- and radiation-induced genetic damage may also identify patients at higher risk of immediate and delayed side effects of therapy. The Children's Oncology Group (COG) is examining the roles of polymorphisms in drug metabolizing enzymes and biological markers of genotoxicity in predicting the treatment-related outcomes of patients with HL. These investigations may ultimately allow the use of pharmacogenetically guided therapy to improve the outcome of HL therapy and reduce the risk of therapy-related complications, especially secondary malignancies.