For cancer survivors, recurrence is a real and ever-present concern. But while the threat of cancer coming back following treatment looms large for many, survivors are also at increased risk of a new, unrelated cancer known as “second cancer.”
According to the National Cancer Institute, nearly one in five cancers diagnosed today occurs in an individual with a previous diagnosis of cancer.
Furthermore, these “second cancers” are a leading cause of morbidity and mortality among cancer survivors.
Recently researchers at St. Jude Children’s Research Hospital discovered that there are certain factors that offer clues into a survivor’s risk of a second cancer, specifically genetics and the type of cancer treatment they received.
What is second cancer?
The American Cancer Society defines second cancer as “a new cancer that’s unrelated to any previous cancer diagnosis.” In short, a completely different type of cancer.
A second cancer can occur in the same organ or area of the body as the first cancer – such as a different type of colorectal cancer – or develop in an entirely different organ or tissue.
The Study
Scientists at St. Jude Children’s Research Hospital used data from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and Childhood Cancer Survivor Study (CCSS) – collectively the largest survivor cohort in North America, housed at St. Jude – to examine how survivors’ genetics and cancer treatment contribute to the risk for secondary cancers.
“We found the burden of second cancer in survivors of childhood cancer is largely contributed by pediatric treatment exposures and genetic predisposition,” said corresponding author Yadav Sapkota, PhD, St. Jude Department of Epidemiology and Cancer Control, in a press release. “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.”
For the study, which was published in The Lancet Oncology, the St. Jude team compared over 10,000 survivors from St. Jude LIFE and CCSS. The dataset included treatment exposures and outcomes, genetic information, lifestyle factors, and the presence or absence of a second cancer. This information allowed the researchers to evaluate the role of these factors in the occurrence of second cancers.
“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,” said co-author Greg Armstrong, MD, MSCE, St. Jude Department of Epidemiology and Cancer Control chair.
Key Findings
Perhaps unsurprisingly, radiation exposure was the most significant contributor to secondary cancer risk, accounting for approximately 40% or more of the risk, and further supporting a growing body of evidence that shows that radiation has long-term negative impacts on health.
But less straightforward among the team’s findings was the risk associated with chemotherapy and genetics.
Depending on the cancer type, chemotherapy contributed anywhere from 8% to 35% of second cancer risk. Not unlike radiation therapy, the potential long-term effects of chemotherapy have been well documented. However, the role of genetic predisposition in second cancer risk among survivors had not been studied as closely.
In order to better understand the relationship between genetic predisposition and second cancer risk, St. Jude researchers examined “hundreds of common genetic variants previously associated with developing cancer in the general population.” These variants, which comprise what is known as a polygenic risk score, in addition to some rare genetic variants, were studied in relation to second cancers in St. Jude LIFE and CCSS participants.
This polygenic risk score approach revealed that depending on the cancer type, polygenic risk score contributed to 5% to 37% of the risk of second cancer.
“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,” said co-author Yutaka Yasui, PhD, 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.”
“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,” Sapkota said.
The researchers found that lifestyle factors, such as diet and exercise, contributed to the risk of second cancer much less than expected, accounting for only 1% to 6% of second cancer risk. However, they noted that survivors in the study were relatively young, primarily in their 20s and 30s, in which case, “lifestyle factors did not yet have enough time for effects to become apparent.”
“We know healthy lifestyle choices are important for survivors,” Sapkota said. “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.”
Care Implications for Survivors of Childhood Cancer
The study’s authors believe that the findings should inform the overall treatment plan and follow-up care of young survivors – from more regular and intense cancer screenings for those with a strong genetic predisposition to ensuring patients have access to information, such as genetic and lifestyle risk factors, so they can better advocate for themselves.
“Historically, we have paid attention to survivors’ treatment exposures when determining second cancer risk,” Sapkota said. “Our study suggests that we need to better account for genetic predisposition in this population.”
“Second cancers remain the leading cause of mortality for childhood cancer survivors,” Sapkota added. “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.”
