New research has shown that childhood cancer survivors (CCSs) with certain germline mutations have higher relative rates (RRs) of secondary neoplasms (SNs) later in life.
Mutation carriers had significantly higher rates of breast cancer and sarcoma if they had received radiation to treat their initial cancer.
Among CCSs who did not receive radiation, the mutations were associated with increased rates of any SN, breast cancer, nonmelanoma skin cancer, and 2 or more histologically distinct SNs.
These findings were reported in the Journal of Clinical Oncology.
Researchers sequenced samples from 3006 CCSs who were at least 5 years from their initial cancer diagnosis as well as 341 samples from cancer-free control subjects.
All subjects were participants in the St. Jude Lifetime Cohort Study, a retrospective study with prospective clinical follow-up.
Thirty-five percent of the CCSs had survived leukemia, and 19% had survived lymphoma.
The CCS’s median age at childhood cancer diagnosis was 7.1 years, and the median follow-up was 28 years. The controls had a median age of 36.4 at follow-up.
There were 1120 SNs diagnosed in 439 CCSs (14.6%). Ninety-one CCSs developed 2 or more histologically distinct SNs. The median time to SN diagnosis was 25.6 years
Non-melanoma skin cancer (580 in 159 CCSs), meningiomas (233 in 102 CCSs), thyroid cancer (67 in 67 CCSs), and breast cancer (60 in 53 CCSs) were among the SNs reported.
There were 15 neoplasms recorded in the control group—14 cases of non-melanoma skin cancer and 1 meningioma.
Pathogenic or likely pathogenic (P/LP) mutations in 32 genes were reported in 175 CCSs. The prevalence in CCSs (5.8%) was nearly 10-fold higher than in controls (0.6%).
The most commonly mutated genes in CCSs were RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12), and TP53 (n=10).
In a multivariable analysis adjusted for sex, age at primary cancer diagnosis, and treatment, P/LP mutation carriers had a significantly higher rate of any SN (RR=1.8).
The rate of subsequent breast cancer was significantly increased among females with a P/LP mutation (RR= 9.4), recipients of chest radiation (RR=7.9), and those with higher anthracycline exposure (RR=2.4).
The rate of subsequent sarcoma was significantly increased for mutation carriers (RR=10.9) and CCSs with greater exposure to alkylating agents (RR=3.8).
Among irradiated CCSs, P/LP mutations were associated with significantly increased rates of breast cancer (RR=13.9) and sarcoma (RR=10.6)
Among non-irradiated CCSs, P/LP mutations were associated with significantly increased rates of any SN (RR=4.7), breast cancer (RR=7.7), nonmelanoma skin cancer (RR=11.0), and 2 or more histologically distinct SNs (RR=18.6).
The researchers said the higher risk of SNs in CCSs with P/LP mutations suggests all CCSs should be referred for genetic counseling.