By Billy Candra 
This groundbreaking finding, emerging from scientists at St. Jude Children’s Research Hospital, represents a significant advancement in understanding the long-term health challenges faced by a growing population of childhood cancer survivors. The study, published in The Lancet Oncology, provides the first population-level quantification of how various factors – specifically pediatric treatment exposures and genetic predisposition – contribute to the risk of developing a second primary cancer, which remains the leading cause of mortality for these long-term survivors. The research leveraged extensive data from two of the world’s most comprehensive childhood cancer survivor studies: the St. Jude Lifetime Cohort Study (St. Jude LIFE) and the Childhood Cancer Survivor Study (CCSS), both headquartered at St. Jude.
A Shifting Landscape: The Rise of Secondary Cancers as a Primary Concern
The landscape of childhood cancer care has been dramatically transformed over the past few decades. Thanks to advancements in chemotherapy, radiation therapy, surgical techniques, and supportive care, survival rates for many childhood cancers have improved remarkably. What was once often a fatal diagnosis is now, in many cases, a treatable condition. This success, however, has brought into sharper focus a new set of challenges: the late effects of cancer treatment. As more children survive into adulthood, clinicians and researchers have observed an increased incidence of chronic health conditions, including cardiovascular disease, endocrine disorders, neurocognitive deficits, and crucially, secondary cancers.
Historically, the focus for preventing and managing these late effects has largely been on the adverse impacts of intensive cancer treatments. While the link between certain therapies and subsequent health issues has been well-established, the relative contribution of other factors, particularly an individual’s genetic makeup, has been less understood at a population level. This St. Jude study addresses this critical knowledge gap, offering a more nuanced and comprehensive understanding of the multifaceted risks involved.
Unprecedented Data: The Foundation of the Discovery
The unparalleled scope and depth of the St. Jude LIFE and CCSS cohorts were instrumental in enabling this research. The Childhood Cancer Survivor Study (CCSS), established in 1994, is a multi-institutional, retrospective, and prospective cohort study of more than 35,000 individuals diagnosed with cancer before age 21 at one of 31 participating institutions across North America between 1970 and 1999. It collects detailed information on initial cancer diagnosis and treatment, as well as long-term health outcomes.
The St. Jude Lifetime Cohort Study (St. Jude LIFE), initiated in 2007, is a comprehensive, institutional follow-up program for all St. Jude patients who were diagnosed with cancer and survived for at least five years. This study provides exceptionally detailed clinical and genetic data, including extensive genetic sequencing, allowing for a deep dive into the biological underpinnings of late effects. Together, these two cohorts comprise over 12,000 survivors with genetic sequencing data, forming the largest survivor cohort in North America, making them an invaluable resource for this type of population-level analysis.
"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," affirmed co-author Greg Armstrong, MD, MSCE, chair of the St. Jude Department of Epidemiology and Cancer Control. The ability to integrate comprehensive treatment histories with detailed genetic information and lifestyle factors across such a vast patient population allowed researchers to disentangle and quantify the individual contributions of these variables to secondary cancer risk.
Quantifying the Risk: Radiation, Genetics, and Chemotherapy
The study meticulously compared data from over 10,000 survivors, analyzing their treatment exposures, genetic information, lifestyle factors, and the subsequent development of a second primary cancer. The findings illuminated a complex interplay of risk factors, with some results challenging conventional wisdom.
Radiation’s Enduring Legacy:
Radiation exposure 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 research documenting the long-term adverse effects of therapeutic radiation. Early cancer treatments, particularly in the mid-to-late 20th century, often involved higher doses and broader fields of radiation, given the limited understanding of its long-term sequelae and fewer alternative treatment options. The detrimental effects of radiation, such as cellular damage and genomic instability, can lead to the development of new malignancies years or even decades after initial treatment.
Awareness of these risks has already spurred a significant evolution in modern oncology. Contemporary childhood cancer treatment protocols have increasingly focused on reducing radiation doses, utilizing highly conformal techniques (like intensity-modulated radiation therapy or proton therapy) to precisely target tumors while sparing healthy tissues, or even eliminating radiation altogether when effective alternative therapies are available. This study provides further robust evidence supporting the continued drive towards minimizing radiation exposure in pediatric cancer care.
The Surprising Influence of Genetics:
While the impact of radiation was stark, the researchers uncovered a more intricate relationship between chemotherapy, genetics, and secondary cancer risk. Depending on the specific type of subsequent cancer, chemotherapy contributed between 8% and 35% of the risk. The late effects of various chemotherapeutic agents, including cardiotoxicity, neurotoxicity, and secondary leukemias or solid tumors, are well-documented.
However, the contribution of genetic predisposition to secondary cancer risk in survivors was less widely recognized and proved to be a critical revelation. The researchers investigated this predisposition by examining hundreds of common genetic variants previously linked to cancer development in the general population, aggregated into what is known as a polygenic risk score (PRS), as well as some rare genetic variants. A polygenic risk score is a sophisticated measure that combines the effects of many common genetic variants, each contributing a small amount to an individual’s overall risk for a particular disease. By summing these small effects across the genome, a PRS can provide a more comprehensive estimate of genetic susceptibility than looking at single gene mutations in isolation.
The polygenic risk score approach revealed that, depending on the cancer type, genetic predisposition contributed significantly, ranging from 5% to 37% of the risk for a second cancer. This finding underscores that an individual’s inherited genetic blueprint plays a substantial role alongside their treatment history.
"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," stated corresponding author Yadav Sapkota, PhD, from the St. Jude Department of Epidemiology and Cancer Control. This statement highlights the paradigm shift the study introduces, suggesting that an individual’s inherent biological susceptibility may be as, or even more, influential than certain treatment modalities for specific secondary cancers.
Co-author Yutaka Yasui, PhD, also from the St. Jude Department of Epidemiology and Cancer Control, commented on the utility of PRS: "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. 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." This suggests that while PRS may not be universally applicable for all diseases in the general population, their predictive power increases significantly when combined with specific risk factors, such as intensive childhood cancer treatments.
Lifestyle Factors: A Nuanced Role at a Young Age
In contrast to radiation, chemotherapy, and genetics, lifestyle factors such as diet and exercise appeared to contribute much less to secondary cancer risk in this cohort, accounting for a modest 1% to 6% of the risk. This finding, however, comes with an important caveat: the survivors included in this study were primarily in their 20s and 30s. At this relatively young age, the long-term cumulative effects of lifestyle choices on cancer development may not yet have fully manifested.
Dr. Sapkota clarified this point: "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 underscores the ongoing importance of promoting healthy habits for survivors, even if their direct impact on secondary cancer risk at younger ages is less pronounced than other factors. The benefits of a healthy lifestyle for overall well-being and reducing other late effects remain undeniable.
Transforming Clinical Care: A New Era of Personalized Risk Assessment
The implications of this research for the clinical care of childhood cancer survivors are profound and far-reaching. "Historically, we have paid attention to survivors’ treatment exposures when determining second cancer risk," Sapkota noted. "Our study suggests that we need to better account for genetic predisposition in this population."
This calls for a fundamental shift towards a more personalized approach to long-term follow-up care. Instead of a one-size-fits-all screening protocol based primarily on treatment history, future guidelines could incorporate genetic risk assessment. Survivors identified with a strong genetic predisposition, in addition to specific treatment exposures, could receive more frequent, intensive, or tailored cancer screenings. This proactive approach could lead to earlier detection of secondary cancers, at a stage when they are more amenable to treatment, thereby improving prognosis and extending lives.
For patients, this research empowers them with crucial knowledge. Survivors armed with an understanding of their unique combination of treatment-related, genetic, and lifestyle risk factors can better engage with their healthcare providers, advocating for the specific screenings and preventative measures relevant to their individual risk profile. This enhanced patient-provider dialogue is essential for optimizing long-term health outcomes.
Broader Impact and Future Directions
"Second cancers remain the leading cause of mortality for childhood cancer survivors," Sapkota reiterated. "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 study paves the way for a new generation of risk stratification models that integrate clinical data with genomic information. Future research will likely delve deeper into specific genetic variants and their interactions with different types of treatments, potentially leading to the development of highly precise predictive tools. The ultimate goal is to move towards true precision medicine for childhood cancer survivors, where risk assessment, prevention strategies, and surveillance protocols are individually tailored to maximize health and longevity.
The findings also highlight the ongoing importance of long-term follow-up clinics, like those at St. Jude, which are dedicated to monitoring the health of survivors and conducting research to improve their quality of life. As the number of childhood cancer survivors continues to grow, understanding and mitigating the risks of secondary cancers will remain a paramount public health challenge, and studies like this one are critical steps toward ensuring a healthier future for these resilient individuals.
The study’s first author is Achal Neupane, of St. Jude. The study’s other authors include Siddhant Taneja, Jennifer French, Matthew Ehrhardt, Tara Brinkman, Rachel Webster, Jun Yang, Kirsten Ness, Melissa Hudson, Gregory Armstrong, Leslie Robison, and Yutaka Yasui from St. Jude; Qi Liu from the University of Alberta; Cindy Im, Lucie Turcotte, and Joseph Neglia from the University of Minnesota; Monica Gramatges from Baylor College of Medicine; Rebecca Howell from the University of Texas MD Anderson Cancer Center; and Smita Bhatia from the University of Alabama at Birmingham. The study received support from grants from the National Cancer Institute (R01HL173881, R01CA216354, R21CA261833, U24CA55727, U01CA195547, and CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.
