title: Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials.
abstract: Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Kuptsova
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kopecky
authors.forename: John
authors.initials: J
authors.lastname: Godwin
authors.forename: Jeanne
authors.initials: J
authors.lastname: Anderson
authors.forename: Ashraful
authors.initials: A
authors.lastname: Hoque
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Slovak
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D009363:Neoplasm Proteins