In a study reported in The Lancet Oncology, Neupane et al explored the question of whether cancer treatment and genetic predisposition are primary contributors to the risk of subsequent neoplasms (SNs) in long-term survivors of childhood cancers.
Study Details
The study involved data from the St. Jude Lifetime Cohort (SJLIFE; 4,401 participants) and the Childhood Cancer Survivor Study (CCSS; 7,943 participants), two retrospectively constructed cohorts with ongoing recruitment and prospective follow-up. Multivariable models were used to calculate contributions to the risk of first occurrence of SNs for: radiotherapy and chemotherapy exposures; genetic predisposition, comparing the top two tertiles with the lowest tertile of polygenic risk scores, where the tertile is from the external general population corresponding to SN outcome; and lifestyle factors, including physical activity, smoking, alcohol consumption, obesity, and diet. The study was conducted between January and September 2024.
Key Findings
Median attained age of survivors was 33.0 years (interquartile range [IQR] = 24.1–42.1 years) in SJLIFE and 36.0 years (IQR = 29.5–43.6 years) in CCSS. Overall, 50.4% of survivors were women and 88.4% were White. Median follow-up from primary cancer diagnosis was 24.2 years (IQR = 11.7–35.4 years) in SJLIFE and 28.0 years (IQR = 8.9–37.2 years) in CCSS.
Together, cancer treatments and genetic risk contributed to a large proportion of SN cases, with fractions attributable to these factors ranging from 30% (95% confidence interval [CI] = 6%–49%) for sarcoma to 92% (95% CI = 89%–94%) for meningioma.
Higher exposure to radiotherapy was the greatest contributor to risk, notably in older survivors; for example, among SJLIFE survivors aged ≥ 35 years, higher exposure was associated with 44.7% (95% CI = 41.9%–47.5%) of SNs, compared with 40.0% (95% CI = 37.1%–43.3%) of SNs in those aged < 35 years.
Elevated genetic risk based on polygenic risk scores accounted for a large proportion of SNs, ranging from 1% (95% CI = 0%–7%) for meningioma to 52% (95% CI = 39%–62%) for thyroid cancer. These proportions were greater than those associated with chemotherapy, which ranged from 3% (95% CI = 1%–6%) for second malignant neoplasms to 35% (95% CI = 19%–49%) for sarcoma.
The contributions of lifestyle factors to the risk of SNs appeared to be negligible.
The investigators concluded: “Cancer treatments and genetic predisposition are primary contributors to the risk of SNs in childhood cancer survivors, and lifestyle factors seem to have a minimal effect. These results highlight the crucial need to consider both treatment history and genetic factors in developing effective risk assessment and surveillance strategies for this vulnerable population.”
Yadav Sapkota, PhD, of the Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institutes of Health and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit thelancet.com.
