UBC Theses and Dissertations
The development of dose-adjusted pharmacogenetic prediction models in pediatric oncology Siemens, Angela
Anthracyclines and cisplatin are two widely-used chemotherapeutic agents in the treatment of pediatric cancers. However, their use is limited by severe life-threatening and life-altering adverse drug reactions (ADRs). Anthracyclines cause cardiotoxicity in up to 57% of treated patients, and cisplatin causes permanent hearing loss in 60-70% of patients. Thus, efforts must be made to predict those most susceptible to these ADRs in order to mitigate the risk of toxicity before it occurs. Significant interindividual variability in anthracycline-induced cardiotoxicity and cisplatin-induced ototoxicity has prompted the discovery and replication of several pharmacogenetic variants involved in the development of these ADRs. Clinical practice guidelines have been published outlining the roles of SLC28A3, UGT1A6, and RARG in anthracycline-induced cardiotoxicity, and TPMT in cisplatin-induced ototoxicity. While both anthracycline- and cisplatin-induced toxicities are dose-dependent reactions, no studies have explored the dose-gene relationship in the development of these ADRs. This study seeks to understand how anthracycline/cisplatin dose and pharmacogenetics together contribute to the development of anthracycline- and cisplatin-induced toxicities. In so doing, this work aims to construct dose-adjusted pharmacogenetic prediction models for these ADRs. 595 anthracycline-treated children were stratified into low-dose (≤150mg/m²) and high-dose (>250mg/m²) groups based on cumulative anthracycline dose received, and pharmacogenetic effects in the development of cardiotoxicity were compared. Results revealed that UGT1A6 and RARG risk variants significantly increased cardiotoxicity risk at low-doses (OR 7.18; p=0.0045 and OR 2.76, p=0.057, respectively), while the SLC28A3 protective variant significantly reduced risk at high-doses (OR 0.43, p=0.0093). A separate cohort of 371 cisplatin-treated children were stratified according to cisplatin dose intensity and incidence of ototoxicity was compared. Dose intensity was defined as the amount of cisplatin administered per unit time. Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity (p=9e-07). Further stratification by TPMT-genotype revealed that carriers of ≥1 TPMT variant have increased incidence of ototoxicity compared to their wildtype counterparts, regardless of dose intensity (OR 1.41 per allele, p=0.038). These results may help identify patients able to safely tolerate higher doses of chemotherapy based on their pharmacogenetic profile, as well as those at risk of toxicity even at low exposure-levels.
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