As cancer survival rates improve, a new challenge is coming into sharper focus: what happens after the first cancer is treated. A large population-based study drawing on decades of U.S. registry data offers one of the most comprehensive looks yet at the risk of subsequent primary cancers (SPCs)—and reveals a complex, evolving landscape shaped by age, sex, and generational exposure. The work was published in PLOS Medicine.
Using data from more than 3.3 million individuals diagnosed with a first primary cancer between 1975 and 2019, investigators from the Virginia Commonwealth University (VCU) School of Medicine analyzed nearly 30 million person-years of follow-up, identifying more than 510,000 second cancers. Their findings, based on Surveillance, Epidemiology, and End Results (SEER) registries, show that SPC risk is not static but varies significantly depending on when patients were born, how old they were at diagnosis, and the type of cancer they initially had.
“We have follow-up guidelines after treatment for the primary cancer, but we don’t really know what risk profile these patients fall into for another cancer,” said Susan Hong, MD, who co-directs a cancer survivorship outcomes research program at VCU and co-directed the study. “They’re not average-risk individuals—but they’re not necessarily at extremely high risk across the board either. That’s where it becomes very nuanced and complex.”
Age and sex drive risk—but not uniformly
The analysis confirmed that SPC incidence increases with age at first cancer diagnosis, rising substantially in both men and women, though more steeply in males. Among women, rates climbed from 915 per 100,000 person-years at ages 35–39 to 1,980 at ages 75–79; in men, the increase was from 1,228 to 2,945.
But these patterns were not consistent across all cancer types. For breast cancer survivors, the risk of developing a second cancer remained relatively stable regardless of age at diagnosis—a finding that surprised the investigators.
“I was kind of surprised that the risk of subsequent cancer didn’t vary by age among breast cancer survivors,” said Hui Cheng, PhD, the study’s lead analyst. “I thought older patients would have higher risk, but that wasn’t necessarily the case.”
By contrast, survivors of lung and bladder cancers and melanoma showed a clear age-related increase in SPC risk, suggesting that surveillance strategies may need to differ significantly by index cancer type.
Cohort effects point to environmental and behavioral drivers
One of the study’s most striking findings emerged from its age–period–cohort modeling: SPC risk peaked among individuals born between 1935 and 1945, then declined in more recent birth cohorts—with notable exceptions.
Researchers observed rising risks among female lung cancer survivors and male bladder cancer survivors, even as overall SPC incidence declined in more recent decades. The cohort-specific patterns hint at underlying environmental or behavioral exposures that vary across generations.
“We observed higher risk in cohorts born in the ’40s and ’50s,” Cheng said. “If we think back, those individuals were young adults during peak tobacco use, which may be a contributing factor. But we don’t have individual-level smoking data, so we can’t confirm that directly.”
This limitation underscores a key challenge of large registry-based studies: while they offer statistical power and long-term follow-up, they often lack granular data on treatment exposures, genetics, and lifestyle factors.
Treatment advances and unintended consequences
The findings also reflect the dual-edged nature of cancer treatment progress. As therapies improve and patients live longer, the window for developing late effects—including second malignancies—widens.
“We’re doing so well treating primary cancers, and people are living longer,” Hong said. “But we also need to think about what risk profile these patients fall into over time.”
Radiation therapy and certain chemotherapies are known contributors to secondary malignancies, with risks often emerging 10 to 15 years after exposure. Yet without detailed treatment data, the current analysis cannot disentangle these effects.
Instead, the study serves as what investigators describe as a “hypothesis-generating” effort—mapping broad patterns that can guide more targeted research.
Toward risk-stratified survivorship care
“We’re trying to figure out how to risk-stratify patients and pay attention to their long-term health care needs without overreacting or underreacting,” Hong said.
In practice, that could mean more intensive surveillance for older survivors of certain cancers, while maintaining consistent monitoring across age groups for others, such as breast cancer.
The findings also highlight gaps in the current survivorship infrastructure—particularly for adult-onset cancers. While pediatric oncology has long benefited from coordinated long-term follow-up systems, similar frameworks are less developed for adult survivors.
“There’s been a long-standing effort to follow childhood cancer survivors, but we don’t have that kind of system in place for adults,” Hong noted. “Now that we’re seeing more cancers in younger adults, we need to think about how to address decades of survivorship.”
A starting point for deeper investigation
Ultimately, the study raises as many questions as it answers. Why do certain cohorts carry higher risks? How do treatment regimens, genetics, and lifestyle interact to drive SPC development? And which risk factors are modifiable?
The research team is already looking ahead to studies that can incorporate more detailed patient-level data, with a focus on identifying actionable prevention strategies.
“We’re very interested in understanding what factors are associated with better or worse outcomes—especially modifiable risk factors,” Cheng said.
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