Oral Presentation Advances in Neuroblastoma Research Congress 2016

Second malignancies in patients with neuroblastoma: a report from the international neuroblastoma risk group project (#92)

Mark A Applebaum 1 , Zalman Vaksman 2 , Hungate Eric 1 , Tara Henderson 1 , Wendy London 3 , Navin Pinto 4 , Sam Volchenboum 1 , Julie Park 4 , Arelene Naranjo 5 , Andy Pearson 6 , Barbara Hero 7 , Susan Cohn 1 , Sharon Diskin 2
  1. Pediatrics, The University of Chicago, Chicago, IL, USA
  2. Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
  3. Pediatrics, Boston Children's Hospital, Boston, MA, USA
  4. Pediatrics, University of Washington, Seattle, WA, USA
  5. Biostatistics, University of Florida, Gainsville, FL, USA
  6. Pediatrics, Royal Marsden Hospital, Surrey, England
  7. Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany

Background: Radiation and chemotherapy exposure are associated with the development of second malignant neoplasms (SMN) in neuroblastoma survivors. However, whether the incidence of SMN has changed with modern, intensive treatment is unknown. Further, the role genetic factors play in the etiology of SMN remains unclear.

Methods: The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1974-2013 was analyzed. SMN risk was measured by cumulative incidence, standardized incidence ratios (SIR) and absolute excess risk (AER). Poisson regression estimated incidence rate ratios (IRR). Genes previously linked to SMN were evaluated in a candidate association study identifying germline polymorphisms associated with this phenotype.

Results: 9,269 of 16,520 patients in the INRG database had SMN data. 81 (0.87%) patients developed SMN, including leukemia/lymphoma (n=40), sarcomas (n=19), carcinomas (n=10), CNS tumors (n=10), hepatoblastoma (n=1), and nephroblastoma (n=1). The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% CI: 1.2-2.5%) compared to 0.43% (95% CI: 0.19-0.89%) for low-risk patients (p=0.002). Compared to 1990-1997, those treated after 1997 when stem cell transplant became standard practice had an IRR of 1.97 (95% CI: 1.16-3.55; p=0.007). The SMN incidence of the entire cohort was 9-fold higher than expected (SIR=9.2 (95% CI: 7.3-11.4), AER=13.7). High-risk patients had a 20-fold higher incidence of SMN than expected (SIR=20.5 (95% CI: 15.0-27.4), AER=33.3). Intermediate-risk patients showed a 6-fold rise in SMN (SIR=6.2 (95% CI: 3.3-10), AER=8.3) and low-risk patients showed a 3-fold increase (SIR=3.0 (95% CI: 1.2-6.2), AER=3.5). rs861539 in XRCC3 (p=0.004) and rs17036651 in MSH2 (p=0.009) were most associated with developing SMN though neither retained significance after multiple testing corrections.

Conclusions: Exposure to modern, high-risk neuroblastoma therapy increases the SMN risk. Genomic variation in DNA repair genes may influence SMN susceptibility. Further understanding of treatment exposures and genomic variables enhancing SMN risk is critical for optimizing survivorship care.