Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project

Background The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. Methods The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Results Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0–2.6%) compared with 0.38% (95% CI: 0.22–0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4–25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7–273.4) and 127.7 (95%CI: 25.7–373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19–3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08–0.81) were associated with SMN. Conclusion The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care.