The Rising Incidence of Second Cancers: Patterns of Occurrence and Identification of Risk Factors for Children and Adults

Abstract

As the population of cancer survivors has increased and continues to age, the occurrence of second cancers has risen dramatically—from 9% of all cancer diagnoses in 1975–1979 to 19% in 2005–2009. The Childhood Cancer Survivor Study, a cohort of more than 14,000 childhood cancer survivors with detailed exposure data and long-term follow-up, has substantially contributed to our understanding of the roles of radiotherapy and chemotherapy in second cancer occurrence. In particular, dose-related risks have been demonstrated for second cancers of the breast, thyroid, central nervous system, gastrointestinal tract, and sarcomas following radiation. Cytotoxic chemotherapy—which has long been known to be leukemogenic—also appears to contribute to risk for a range of other second cancer types. Individuals who develop a second cancer are at particularly high risk for developing additional second cancers. A genome-wide association study of survivors of Hodgkin lymphoma who received radiotherapy identified a locus on chromosome 6q21 as being associated with second cancer risk, demonstrating that recent advances in genomics are likely to prove invaluable for elucidating the contribution of genetic susceptibility to second cancer etiology. Among adults, risk of second cancers varies substantially by type of first and second cancer, patient age, and prevalence of second cancer risk factors, including primary cancer treatments, environmental and lifestyle exposures, and genetic susceptibility. Further research is needed to quantify second cancer risks associated with specific etiologic factors and to identify the patients at highest risk of developing a second cancer to target prevention and screening efforts.KEY POINTSThe population of cancer survivors has increased substantially in recent decades as a result of improvements in survival from advances in early detection, treatment, and supportive care.Approximately 19% of cancers diagnosed today occur among individuals with a history of previous malignancy. Thus, understanding the causes of second cancers has both public health and clinical importance.The most commonly diagnosed second cancers among childhood cancer survivors include nonmelanoma skin cancer and cancers of the breast, central nervous system, and thyroid. Primary cancer treatments—including radiotherapy and, to a lesser extent, chemotherapy—are associated with risk for second cancers after primary childhood cancer.Second cancer risks after adult cancer have a more complex multifactorial etiology with an important role for environmental and lifestyle risk factors in addition to primary cancer treatments.Advances in genomics hold promise for identification of individuals who may be genetically susceptible to the development of second cancers.