The degree of neutropenia after chemotherapy is a surrogate marker of patient’s germline genomic characteristics determining the toxicity and tumor response after chemotherapy in neuroblastoma
The degree of neutropenia after chemotherapy is a surrogate marker of patient’s germline genomic characteristics determining the toxicity and tumor response after chemotherapy in neuroblastoma
Abstract
Purpose: We evaluated whether the degree of neutropenia after chemotherapy is associated with the toxicity and prognosis during and after treatment in patients with neuroblastoma. In addition, we performed genome-wide association study (GWAS) to discover genetic polymorphism responsible for variable degree of neutropenia and variable treatment outcome among patients. Methods: With institutional review board approval, we analyzed whether the degree of neutropenia after first cycle of chemotherapy is associated with the toxicity and prognosis during and after treatment in 266 patients with neuroblastoma who received same chemotherapy. In addition, we performed GWAS with 273,626 SNPs to identify a new genetic predisposition responsible for variable degree of neutropenia. Results: The probability of 5-yr PFS was higher in patients who experienced severe neutropenia (nadir ANC20/μL) as compared to those with moderate (nadir ANC 20-100/μL) or mild (nadir ANC>100/μL) neutropenia (89.4% vs 79.6% vs 61.6%, P = 0.002). To the contrary, the probability of 5-yr treatment-related mortality (TRM) free survival was lower in patients with severe neutropenia as compared to those with moderate or mild neutropenia (90.6% vs 94.0% vs 100%, P = 0.023). GWAS identified novel variants associated with ANC level. Among genes that revealed significant associations for ANC level, AA genotype at rs11786984 of CSMD1 gene was associated with higher TRM rate, higher incidence of second malignancy, more significant late effects, lower EFS, but higher OS after first relapse/progression as compared to AG or GG genotype. Conclusion: In the present study, we showed that the degree of neutropenia after first cycle of chemotherapy can be used as a surrogate marker of patient’s germline genomic characteristics predicting the toxicity and prognosis during and after treatment. GWAS with ANC showed that SNP at rs17404086 in CSMD1 is associated with TRM, second malignancy, and EFS. Tailored treatment based on germline characteristics as well as somatic aberration might improve the outcome in patients with neuroblastoma.