Score Can Predict Risk of Second Cancers in Pediatric Cancer Survivors

A polygenic risk score can predict the risk of second malignant neoplasms (SMNs) in pediatric cancer survivors who were treated with chemotherapy, according to research published in the Journal of Clinical Oncology.  

The 179-variant score, which was previously validated in adults, “has strong potential for improving SMN clinical risk stratification among nonirradiated [pediatric cancer] survivors treated with specific chemotherapies,” according to researchers.

The researchers tested the polygenic risk score in 10,613 pediatric cancer survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort Study. Most survivors (n=9895) had European ancestry, and a minority had African ancestry (n=718).

The most common primary malignancies were leukemia (32.8% of European survivors and 23.7% of African survivors), central nervous system tumors (15.7% and 15.1%, respectively), Hodgkin lymphoma (11.6% and 10.0%), and kidney tumors (8.0% and 11.6%).

SMNs were diagnosed in 1594 pediatric cancer survivors, including 15.2% of European ancestry and 3.9% of African ancestry. The most common SMNs were basal cell carcinoma, breast cancer, and thyroid cancer.

The polygenic risk score was associated with SMN risk in pediatric cancer survivors with European ancestry (hazard ratio [HR], 1.11; 95% CI, 1.05-1.17; P <.01) but not in those with African ancestry (HR, 1.01; 95% CI, 0.66-1.55; P =.95).

Among survivors with European ancestry, the association was greater for those not treated with radiation (HR, 1.28; 95% CI, 1.13-1.45; P <.001) than for those treated with radiation (HR, 1.07; 95% CI, 1.00-1.14; P =.036).

Among survivors of European ancestry who did not receive radiation, the polygenic risk score in the highest quintile was associated with an increased incidence of SMNs. The 30-year incidence of SMNs by treatment type was:

• Platinum chemotherapy — 46% in the highest quintile and 7% in the lowest quintile (HR, 8.58; 95% CI, 1.89-38.98; P <.01)
• Epipodophyllotoxins — 23% and 1% in the highest and lowest quintiles, respectively (HR, 12.20; 95% CI, 2.94-50.68; P <.001)
• Anthracyclines — 20% and 8%, respectively (HR, 2.86; 95% CI, 1.60-5.09; P <.001)
• Alkylating agents — 17% and 6%, respectively (HR, 2.46; 95% CI, 1.41-4.30; P <.01).

In nonirradiated pediatric cancer survivors of African descent, the polygenic risk score was significantly associated with an increased cumulative incidence of SMNs among those treated with epipodophyllotoxins (HR, 2.68; 95% CI, 1.34-5.39; P <.01).  

“A pleiotropic cancer PRS [polygenic risk score] has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies,” the researchers concluded. “A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer susceptibility mutations.”

Disclosures: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Im C, Sherafeldin N, Yuan Y, et al. Polygenic risk and chemotherapy-related subsequent malignancies in childhood cancer survivors: A childhood cancer survivor study and St Jude Lifetime Cohort study report. J Clin Oncol. Published online July 17, 2023. doi:10.1200/JCO.23.00428