By Billy Candra 
Physicians caring for survivors of childhood cancer later in life must acknowledge that genetic predispositions, alongside the life-saving cancer treatments received, are significant contributors to the risk of developing secondary cancers. This pivotal finding emerges from scientists at St. Jude Children’s Research Hospital, who have for the first time quantified the proportional contributions of various factors to the risk of a second cancer – a critical concern as secondary malignancies represent the primary cause of mortality for long-term childhood cancer survivors. The comprehensive new research leveraged extensive data from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and the Childhood Cancer Survivor Study (CCSS), two of the world’s foremost investigations into the long-term health of childhood cancer survivors, both headquartered at St. Jude. The study’s results were formally published today in the esteemed medical journal The Lancet Oncology, marking a significant advance in understanding and mitigating the long-term health challenges faced by this vulnerable population.
Unraveling the Complex Web of Secondary Cancer Risk
The intricate interplay of factors contributing to secondary cancers in survivors has long been hypothesized, but its precise quantification at a population level remained elusive. "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 the St. Jude Department of Epidemiology and Cancer Control. While the association between treatment exposures and genetics with second cancer risk was previously acknowledged, Dr. Sapkota emphasized the groundbreaking nature of this study: "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 offers unprecedented clarity, enabling more targeted and personalized prevention and screening strategies.
Historically, research has examined how specific treatment exposures, genetic factors, and lifestyle choices individually correlate with an elevated risk of secondary cancers. However, the relative weight and interplay of these elements within a broader survivor population had not been systematically assessed. To bridge this critical knowledge gap, St. Jude scientists undertook a monumental comparative analysis involving more than 10,000 survivors drawn from the St. Jude LIFE and CCSS cohorts. This combined dataset represents the largest survivor cohort in North America, providing an unparalleled foundation for robust statistical analysis. The wealth of information included detailed records of past treatment exposures and their outcomes, comprehensive genetic profiles, documented lifestyle factors, and, crucially, the presence or absence of a secondary cancer diagnosis. This holistic approach allowed researchers to meticulously evaluate the distinct and combined contributions of these diverse factors to the occurrence of subsequent malignancies. Dr. Greg Armstrong, MD, MSCE, chair of the St. Jude Department of Epidemiology and Cancer Control and a co-author on the study, underscored the unique capability of these cohorts. "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," he remarked, highlighting the exceptional data infrastructure at St. Jude.
The Evolving Landscape of Childhood Cancer Survivorship
The journey of childhood cancer treatment has been one of remarkable progress, transforming what was once a near-certain death sentence into a condition with increasingly high survival rates. In the 1970s, the overall five-year survival rate for children with cancer was around 58%. Today, thanks to advances in chemotherapy, radiation therapy, surgery, and supportive care, this figure has soared to over 80%. This triumph of modern medicine, however, has unveiled a new set of challenges: the long-term health consequences for survivors. With an estimated half-million childhood cancer survivors currently living in the United States, and this number steadily growing, understanding and managing late effects, particularly secondary cancers, has become a paramount concern for pediatric oncology and primary care providers alike.
Many childhood cancer survivors face a higher risk of developing a range of chronic health conditions decades after their initial treatment, including cardiovascular disease, endocrine disorders, neurocognitive deficits, and perhaps most alarmingly, secondary malignant neoplasms. These subsequent cancers are not recurrences of the original disease but entirely new malignancies, often linked to the very treatments that saved their lives. For many years, the prevailing wisdom attributed the overwhelming majority of this risk to the intense radiation and chemotherapy protocols employed during childhood. While these treatments are undeniably potent and often necessary, their broad, non-specific targeting can damage healthy cells and DNA, laying the groundwork for future cancerous transformations. This latest St. Jude study provides a crucial refinement to this understanding, introducing a more nuanced perspective that integrates the often-overlooked yet significant role of inherent genetic vulnerabilities.
Quantifying the Risk Factors: Radiation, Chemotherapy, and Genetics
The study meticulously dissected the contributions of various factors to secondary cancer risk. Radiation exposure emerged as the most significant, accounting for approximately 40% or more of the overall risk. This finding aligns with a substantial body of prior research that has extensively documented the long-term adverse effects of radiation, particularly its carcinogenic potential. Historically, radiation therapy was a cornerstone of many childhood cancer treatment regimens, often delivered at high doses to large fields. The implications of this finding are profound, reinforcing the ongoing paradigm shift in modern pediatric oncology. Contemporary therapies have already seen a significant reduction in radiation doses or, in many cases, a complete removal of radiation exposure as other treatment modalities have become more effective and less toxic. This study provides compelling evidence to further support and accelerate these strategic changes in clinical practice, advocating for continued innovation in radiation-sparing protocols.
While the impact of radiation was relatively straightforward to quantify, the researchers uncovered more intricate relationships concerning chemotherapy and genetic predisposition. Chemotherapy, depending on the specific type of cancer and the agents used, contributed between 8% and 35% of subsequent cancer risk. The potential late effects of chemotherapy, ranging from organ damage to increased risk of secondary leukemias and solid tumors, have been thoroughly described in the medical literature. However, the contribution of genetic predisposition to secondary cancer risk in survivors has been comparatively less recognized and quantified. The St. Jude team sought to bridge this knowledge gap by comprehensively examining hundreds of common genetic variants previously associated with cancer development in the general population, a measure known as a polygenic risk score (PRS), alongside a careful analysis of rare genetic variants. They then correlated these genetic markers with the incidence of secondary cancers among the St. Jude LIFE and CCSS participants. This sophisticated polygenic risk score approach revealed that, contingent on the specific type of secondary cancer, genetic predisposition accounted for a substantial 5% to 37% of the total risk.
This finding challenges conventional wisdom in the field. As Dr. Yutaka Yasui, PhD, from the St. Jude Department of Epidemiology and Cancer Control and a co-author, explained, "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." Yet, within the specific context of childhood cancer survivors, and particularly for estimating their risk of certain types of subsequent cancers, these scores "may provide useful information in conjunction with therapy exposures." Dr. Sapkota further emphasized the paradigm-shifting nature of this discovery: "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 revelation underscores the critical need to integrate genetic profiling into the comprehensive risk assessment for survivors.
Intriguingly, lifestyle factors, encompassing elements such as diet and exercise, demonstrated a much smaller contribution than might have been anticipated, accounting for a mere 1% to 6% of secondary cancer risk. However, the researchers offered a crucial caveat: the survivor cohort primarily comprised individuals 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 manifest. Dr. Sapkota clarified, "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 highlights that while lifestyle’s direct impact on secondary cancer risk may be limited in younger survivors, its overall importance for general health and other late effects remains undisputed.
Changing the Paradigm of Care for Childhood Cancer Survivors
The implications of this research are profound, necessitating a fundamental re-evaluation of how healthcare providers assess and manage long-term risks for childhood cancer survivors. "Historically, we have paid attention to survivors’ treatment exposures when determining second cancer risk," Dr. Sapkota observed. "Our study suggests that we need to better account for genetic predisposition in this population." This shift implies moving beyond a purely treatment-centric risk model to one that incorporates an individual’s inherent genetic vulnerabilities.
For survivors identified with a strong genetic predisposition to specific cancers, alongside their treatment history, this could translate into more aggressive and personalized surveillance strategies. Such strategies might include more frequent and intense cancer screenings, utilizing advanced imaging techniques (e.g., MRI, specialized ultrasound), or specific biomarker tests tailored to their particular genetic risk profile. The goal is to detect a second cancer at its earliest, most treatable stage, significantly improving prognoses. Furthermore, arming survivors with a comprehensive understanding of their unique combination of treatment-related, genetic, and lifestyle risk factors empowers them to engage more proactively with their healthcare providers, advocating for the necessary specialized screening and follow-up care.
Broader Impact and Future Directions
This study is poised to catalyze a significant shift in clinical guidelines and public health initiatives. Organizations like the American Cancer Society and the Children’s Oncology Group (COG) have long provided guidelines for survivor follow-up, primarily based on treatment exposures. The St. Jude findings suggest that these guidelines may need to be augmented to incorporate genetic risk stratification. This would necessitate increased funding for genetic testing and counseling services for survivors, as well as educational programs for primary care physicians and oncologists to help them interpret and apply complex genetic information in clinical practice.
The implications extend beyond clinical care to policy and research. Policy makers may need to consider how to ensure equitable access to advanced genetic screening and personalized follow-up care for all survivors, regardless of socioeconomic status. For researchers, this study opens new avenues for investigation. Further refinement of polygenic risk scores, identification of additional rare genetic variants, and longitudinal studies tracking the long-term impact of lifestyle factors as survivors age will be crucial. The insights gained could also inform the development of novel, less genotoxic chemotherapeutic agents and radiation techniques, further reducing the burden of secondary cancers for future generations of survivors.
"Second cancers remain the leading cause of mortality for childhood cancer survivors," Dr. 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 research not only provides a clearer roadmap for personalized care but also reaffirms St. Jude’s commitment to not only curing childhood cancer but also ensuring the highest possible quality of life for its survivors.
Authors and Funding
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.
