Age dependence

There is strong epidemiologic evidence that one of the most important factors for determining likelihood of developing a secondary malignancy is the age of the patient at the time of radiotherapy. It appears that the younger the patient is at the time of radiation treatment, the higher the risk is of a future second cancer. The strongest evidence of this age dependence comes from two large studies – the atomic bomb survivors Life Span Study and the Childhood Cancer Survivors Study.1–4,13,14 The Life Span Study group estimated that relative risk decreased by about 17% per decade increase in age at exposure. For the Childhood Cancer Survivors Study group and their most recent analysis of more than 14,000 survivors of pediatric malignancies, there was a cumulative incidence of 7.9% for invasive cancers at 30 years from primary cancer diagnosis, demonstrating the significant secondary malignancy risk for this population.15 Among this cohort, the highest cumulative incidence was for survivors of Hodgkin’s lymphoma, followed by survivors of Ewing’s sarcoma, and then survivors of soft tissue sarcomas. It is notable that the cumulative incidence of secondary malignancies at 30 years of follow-up was higher among those who received radiotherapy (10%) versus those who did not (5%).

Among the cohorts of long-term cancer survivors, perhaps the most well studied group in characterizing secondary malignancy risk are the survivors of Hodgkin’s lymphoma treated with radiation therapy. In their latest update, the Late Effects Study Group followed a cohort of 1,380 children with Hodgkin’s disease and tracked their incidence of second neoplasms. After their primary disease relapse, second cancers were the next most common cause of mortality in these patients. The estimated incidence of any second neoplasm was 7% at 15 years after diagnosis of Hodgkin’s disease in this cohort.13 The most common solid tumor in the Late Effects Study Group cohort was breast cancer, and it was recommended that greater systematic screening be implemented for this higher risk population, as their risk of developing future breast cancers was comparable to that of the BRCA population. The findings of the Late Effects Study Group were corroborated by the findings from the Stanford cohort characterizing their long-term survivors of Hodgkin’s lymphoma.16

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From these key major epidemiologic studies, one notable aspect that has consistently been demonstrated is the sensitivity of subsequent secondary malignancy risk and the age at time of radiation treatment. For example, the risk of patients developing subsequent breast cancers was significantly higher for those patients receiving radiation treatment before the age of 30. This age dependence increased with earlier age with the highest relative risk for those patients treated before the age of 15, suggesting that the highest risk for secondary cancers after radiotherapy may be for those patients receiving their radiation treatment during the teenage or young adult years. For those patients receiving radiation treatment after the age of 30, the risk appeared to be small or not elevated.17

Genetic factors

The rapid advances in molecular genomics have reshaped our ability to understand genetic susceptibility to second cancer risks after radiotherapy. Genome-wide association studies have been used to identify potential genetic markers that can be associated with increased second cancer risks, particularly single-nucleotide polymorphisms or genes associated with the radiation response pathway. This genetic marker approach may better characterize the heterogeneous radiation-associated secondary cancer risks within patient subpopulations in the future.

One of the most prominent investigational groups in this area has been the Women’s Environment, Cancer, and Radiation Epidemiology cohort study.5,18–20 This large study follows over 52,000 female breast cancer survivors to study the interaction between radiation exposure and genetic predisposition toward breast cancer. Among the myriad potential pathways, there has been particular emphasis from Women’s Environment, Cancer, and Radiation Epidemiology on ATM and BRCA1/BRCA2 mutations and its association with radiation-related contralateral breast cancer, likely due to the role of these genes in the radiation response pathway and their association with genomic instability and perhaps with increased radiation-associated second cancer risk.19 Among the key findings from this cohort study is that there was no clear evidence of increased contralateral breast cancer risk for patients treated with breast radiotherapy among carriers of BRCA1/BRCA2 deletion mutations.20 However, patients who carried rare ATM mutations appeared to be at an increased risk of contralateral breast cancer after radiation.5

With the emergence of numerous genome-wide association studies and other genome-wide study methodologies, there is a potential cascade of future genetic markers or pathways that will be discovered to be associated with increased second cancer risks for particular genetic populations. In addition to the ATM and BRCA pathways, other potential markers of secondary cancer risks include p53, CHEK2, PALB2, and PTEN.21 One particular pathway of interest that has been proposed is the PRDM1 gene, which has been implicated in radiation-associated secondary malignancies after Hodgkin’s lymphoma,6  perhaps by serving as a radiation-responsive tumor suppressor. Two genetic variants at chromosome 6q21 have been proposed as risk loci for secondary malignancy predisposition. Current studies are undergoing in characterizing the PRDM1 and other pathways, reflecting the way that the field will likely evolve. Future studies will emphasize understanding at a molecular level of the complex interactions between genetic predisposing factors and the processes underlying radiation-associated carcinogenesis.