Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

Abstract

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. METHODS: For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. RESULTS: Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16-64; median cumulative bleomycin dose 270 mg, range 60-360; median pretreatment creatinine clearance 122 ml/min, range 64-202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11-2.51). Patients with BIP had a lower creatinine clearance. CONCLUSIONS: Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.