By Billy Candra 
Physicians caring for survivors of childhood cancer later in life should be aware that survivors’ genetics, in addition to their lifesaving cancer treatment, contribute significantly to the risk for secondary cancers. This pivotal finding, which quantifies the distinct contributions of various factors to the risk of a second cancer – the primary cause of mortality for long-term survivors – comes from scientists at St. Jude Children’s Research Hospital. The groundbreaking research, published today in The Lancet Oncology, utilized extensive data from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and the Childhood Cancer Survivor Study (CCSS), two of the world’s most comprehensive childhood cancer survivor studies, both headquartered at St. Jude.
The study underscores a crucial shift in understanding the long-term health challenges faced by a growing population of individuals who have overcome childhood cancer. "We found the burden of second cancer in survivors of childhood cancer is largely contributed by pediatric treatment exposures and genetic predisposition," stated corresponding author Yadav Sapkota, PhD, from St. Jude’s Department of Epidemiology and Cancer Control. "We’ve known treatment exposures and genetics were associated with second cancer risk, but this is the first time we’ve been able to attribute the proportion of their contributions to that risk at the population level." This quantification provides an unprecedented level of clarity, moving beyond mere association to establish the relative weight of each factor.
The Evolving Landscape of Childhood Cancer Survival
Over the past five decades, remarkable advancements in medical science have transformed the prognosis for children diagnosed with cancer. What was once often a fatal diagnosis has become increasingly curable, with overall survival rates for childhood cancers now exceeding 80% in many developed countries. This medical triumph, however, has introduced a new set of challenges: the long-term health consequences for survivors. As these children grow into adolescence and adulthood, they face a heightened risk of various "late effects," including cardiovascular disease, endocrine disorders, neurocognitive deficits, and critically, the development of secondary cancers – new, distinct malignancies unrelated to their primary childhood cancer.
Secondary cancers represent a significant concern for this survivor population. Unlike recurrences of the original cancer, these are entirely new diseases, often arising years or even decades after initial treatment. For long-term survivors, secondary cancers have emerged as the leading cause of premature mortality, surpassing the original cancer itself. This reality has driven extensive research efforts to identify risk factors and develop strategies for prevention and early detection. Historically, the focus has predominantly been on the adverse effects of intensive chemotherapy and radiation therapy, which, while life-saving, are known carcinogens. While the link between treatment and secondary cancer has been well-established, the precise interplay with genetic predispositions and other factors remained less clear until now.
Unprecedented Data: The Power of St. Jude LIFE and CCSS
Addressing the complexities of secondary cancer risk required an extraordinary breadth and depth of data. The St. Jude scientists leveraged the unparalleled resources of the St. Jude LIFE and CCSS cohorts. The CCSS, initiated in 1994, is a multi-institutional study that follows over 35,000 survivors of childhood cancer diagnosed between 1970 and 1999 across more than 25 institutions in North America. St. Jude LIFE, launched in 2007, is a detailed, prospective follow-up study of over 5,000 adult survivors treated at St. Jude Children’s Research Hospital. Collectively, these two cohorts represent the largest survivor population studied in North America, offering an invaluable repository of clinical data, treatment histories, and increasingly, genetic information.
"This kind of high-impact discovery is only possible in the CCSS and SJLIFE cohorts, that in combination, have more than 12,000 survivors with genetic sequencing," highlighted co-author Greg Armstrong, MD, MSCE, chair of the St. Jude Department of Epidemiology and Cancer Control. The sheer scale and comprehensiveness of this combined dataset were critical. It included meticulously documented treatment exposures (types and doses of chemotherapy, radiation fields and doses), detailed health outcomes over decades, comprehensive genetic information (both common and rare variants), and lifestyle factors. This holistic view allowed researchers to move beyond examining individual risk factors in isolation and instead, evaluate their relative contributions to secondary cancer occurrence at a population level.
Quantifying the Risk: A Hierarchy of Influence
The study meticulously compared over 10,000 survivors, analyzing a vast array of variables to quantify the proportional contribution of different factors to secondary cancer risk. The findings provided a clear hierarchy of influence:
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Radiation Exposure: The Dominant Factor: Consistent with prior research, radiation therapy emerged as the most significant contributor to secondary cancer risk, accounting for approximately 40% or more of the overall risk. This finding reinforces decades of understanding regarding the long-term carcinogenic effects of radiation. While radiation has been a cornerstone of cancer treatment, particularly for certain solid tumors and brain cancers, its efficacy has always been balanced against its known adverse effects. Modern pediatric oncology has already seen a significant trend towards lowering radiation doses, reducing treatment fields, or entirely removing radiation from treatment protocols as other therapies (like targeted drugs or intensified chemotherapy) have become more effective. This study provides strong, quantifiable support for these ongoing de-escalation strategies, emphasizing the continued importance of minimizing radiation exposure whenever clinically feasible.
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Chemotherapy’s Variable Impact: The contribution of chemotherapy to subsequent cancer risk was more nuanced, varying significantly depending on the specific type of cancer. It contributed between 8% and 35% of the risk. Certain classes of chemotherapy drugs, such as alkylating agents and topoisomerase inhibitors, are well-known for their mutagenic potential and have been linked to an increased risk of specific secondary leukemias and solid tumors. The study’s findings provide a population-level quantification of this established risk, highlighting that while substantial, its impact can be more heterogeneous than radiation.
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Genetics: A Previously Underestimated Driver: Perhaps the most compelling revelation of the study was the significant and often underappreciated role of genetic predisposition. While the late effects of chemotherapy have been extensively documented, genetics’ contribution to secondary cancer risk in survivors has been less thoroughly explored at a population level. To understand this predisposition, researchers examined hundreds of common genetic variants previously associated with cancer development in the general population, synthesizing them into what is known as a polygenic risk score (PRS). They also investigated certain rare genetic variants. This polygenic risk score approach revealed that, depending on the specific cancer type, genetic predisposition contributed between 5% and 37% of the risk for secondary cancers.
"Polygenic risk scores are developed for all kinds of diseases for personalized medicine, but generally with precision below what is required for clinical utility in the general population," explained co-author Yutaka Yasui, PhD, from the St. Jude Department of Epidemiology and Cancer Control. "Among survivors of childhood cancer and for estimating their risk of certain types of subsequent cancer, however, they may provide useful information in conjunction with therapy exposures." Dr. Sapkota further emphasized the groundbreaking nature of this finding: "Our findings showed that genetics can be equally or more important than chemotherapy in some second cancers, which is counter to conventional wisdom in the field." This statement challenges the traditional clinical focus, suggesting that a survivor’s inherent genetic makeup can be as, or even more, influential than certain aspects of their initial chemotherapy regimen in determining their future risk of a second malignancy.
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Lifestyle Factors: A Long-Term Consideration: Lifestyle factors, such as diet and exercise, appeared to contribute much less significantly to secondary cancer risk in this particular study, accounting for only 1% to 6% of the risk. However, the researchers provided a crucial caveat: the survivors in this study were primarily in their 20s and 30s. This relatively young age may mean that the long-term, cumulative effects of lifestyle choices on cancer development had not yet had sufficient time to become fully apparent. Dr. Sapkota elaborated, "We know healthy lifestyle choices are important for survivors. In this study, we focused only on the risk of second cancers, which may not be strongly impacted by lifestyle at this young age. However, other research has shown the benefits of healthy choices on other late effects, such as protecting cardiac wellbeing, so it is still important for clinicians to encourage — and patients to seek — a healthy lifestyle." This indicates that while not a primary driver of early-onset secondary cancers, healthy living remains vital for overall survivor health and may play a larger role in cancer prevention later in life.
Reshaping Clinical Guidelines and Survivor Care
The implications of these quantified risks for the clinical care of childhood cancer survivors are profound and far-reaching. The study strongly advocates for a more holistic and personalized approach to long-term follow-up. "Historically, we have paid attention to survivors’ treatment exposures when determining second cancer risk," Dr. Sapkota noted. "Our study suggests that we need to better account for genetic predisposition in this population."
This paradigm shift could lead to several significant changes:
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Personalized Surveillance Strategies: Survivors identified with a strong genetic predisposition to certain cancers, in combination with their specific treatment exposures, could receive more regular and intense cancer screenings. For example, a survivor with a high polygenic risk score for breast cancer and a history of chest radiation might warrant earlier and more frequent mammograms or MRI screenings than a survivor with lower genetic risk and no chest radiation. This targeted approach could lead to earlier detection when secondary cancers are more treatable and likely to respond to therapy, potentially saving lives.
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Integration of Genetic Counseling and Testing: The findings highlight the growing importance of integrating genetic counseling and, where appropriate, germline genetic testing into routine follow-up care for childhood cancer survivors. This could help identify individuals at higher inherent risk, allowing for proactive risk management and informed decision-making.
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Enhanced Patient Empowerment: Survivors armed with a clearer understanding of their unique combination of treatment-related, genetic, and lifestyle risk factors can become more effective advocates for their own health. They can engage more meaningfully with their healthcare providers about the necessity of specific screenings, lifestyle modifications, and proactive health management plans.
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Evolution of Clinical Guidelines: Major professional organizations, such as the Children’s Oncology Group (COG) and the American Society of Clinical Oncology (ASCO), which issue long-term follow-up guidelines for childhood cancer survivors, may need to revise their recommendations to explicitly incorporate genetic risk assessment. This could lead to more nuanced and individualized care plans that move beyond a "one-size-fits-all" approach based solely on treatment history.
Future Directions and the Path Ahead
While this study marks a significant leap forward, it also paves the way for further research. Future investigations will likely focus on refining polygenic risk scores to enhance their predictive power for clinical utility, exploring the complex interactions between different risk factors, and longitudinally tracking the impact of lifestyle choices as survivors age. Understanding these intricate relationships could lead to the development of novel preventive strategies or targeted interventions for those at highest risk.
"Second cancers remain the leading cause of mortality for childhood cancer survivors," Dr. Sapkota reiterated, underscoring the urgency of this research. "Now that we have quantified the contributions of treatment, genetics and lifestyle to the risk of secondary disease, we have a better understanding of where to focus efforts to prevent, detect and treat these cancers, and hopefully extend these survivors’ lives."
This groundbreaking research from St. Jude Children’s Research Hospital, published in The Lancet Oncology, serves as a powerful testament to the ongoing commitment to improving the lives of childhood cancer survivors. By illuminating the critical role of genetics alongside treatment exposures, it provides a roadmap for more personalized, proactive, and ultimately, more effective long-term care, offering renewed hope for a healthier future for this resilient population.
The study’s first author is Achal Neupane, of St. Jude. The study’s other authors are Siddhant Taneja, Jennifer French, Matthew Ehrhardt, Tara Brinkman, Rachel Webster, Jun Yang, Kirsten Ness, Melissa Hudson, Gregory Armstrong, Leslie Robison and Yutaka Yasui; St. Jude; Qi Liu; University of Alberta; Cindy Im, Lucie Turcotte and Joseph Neglia; University of Minnesota; Monica Gramatges, Baylor College of Medicine; Rebecca Howell, University of Texas MD Anderson Cancer Center and Smita Bhatia; University of Alabama at Birmingham. The study was supported by grants from the National Cancer Institute (R01HL173881, R01CA216354, R21CA261833, U24CA55727, U01CA195547 and CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.
