In an analysis from the Children’s Oncology Group ALTE03N1 Study reported in the Journal of Clinical Oncology, Zhou et al found a fourfold increased risk of subsequent neoplasms (SNs) among childhood cancer survivors with germline pathogenic/likely pathogenic (P/LP) mutations.
Study Details
The study involved whole-exome sequencing of germline DNA from 499 survivors with SNs (cases) and 625 survivors without subsequent neoplasms (matched controls) from the Children’s Oncology Group study. A clinical risk classifier was developed using estimated associations of demographic, clinical, and therapeutic characteristics and P/LP mutations with subsequent neoplasm risk.
Key Findings
Median time from primary cancer diagnosis to first subsequent neoplasm was 14.11 years (interquartile range [IQR] = 8.31–22.92 years). Median age at first subsequent neoplasm was 21.02 years (IQR = 15.51–32.86 years).
P/LP mutation carriers had a significantly increased risk of subsequent neoplasms vs noncarriers (adjusted odds ratio [OR] = 4.26, 95% confidence interval [CI] = 2.36–7.69).
Interactions were observed between P/LP mutation status and receipt of platinum compounds (P = .047) and exposure to radiation therapy (P < .001) and risk for subsequent neoplasms. The ORs for subsequent neoplasms were 10.66 (95% CI = 4.06–27.96) for P/LP mutation carriers vs noncarriers exposed to platinum compounds and 1.99 (95% CI = 1.03–3.84) for carriers vs noncarriers not exposed to platinum compounds. The ORs for subsequent neoplasms were 2.75 (95% CI = 1.44–5.25) for carriers vs noncarriers exposed to radiation and 7.21 (95% CI = 2.56–20.27) for carriers vs noncarriers not exposed to radiation.
The addition of P/LP mutation status to the clinical risk classifier model (including sex, primary cancer type and year of diagnosis, exposure to radiation and platinum compounds, and length of follow-up) significantly improved (P = .014) the area under the receiver operating curve from 0.79 (95% CI = 0.73–0.84) to 0.82 (95% CI = 0.76–0.87).
The clinical risk classifier identified survivors as at low risk (22%) and moderate-to-high risk (78%) of developing subsequent neoplasms. In total, 86.4% of survivors with any P/LP mutations and 100% of survivors with TP53 and RB1 mutations were in the moderate-to-high risk group.
The investigators concluded: “These findings provide a risk-based approach for identifying childhood cancer survivors who could be referred for genetic testing, informing surveillance strategies on the basis of refined risk classification.”
Smita Bhatia, MD, MPH, of the University of Alabama at Birmingham, Birmingham, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Leukemia Lymphoma Society Translational Research Program, National Clinical Trials Network Operations Center, St Baldrick’s Foundation, and others. For full disclosures of all study authors, visit ascopubs.com.
