Study identifies risk factors that may lead to secondary cancers

A study using data from the Danish Cancer Registry has identified risk factors among cancer survivors that might help to prevent them from developing new primary cancers, which the study calls secondary cancers. The study also has investigated whether index and second cancers might be linked. The study, from the Danish Cancer Institute in Copenhagen, Denmark, appears in Lancet Oncology (doi:10.1016/S1470-2045(23)00538-7).

Although knowledge about risk factors for the development of a patient’s first cancer, including genetic, immune, and hormonal factors as well as environmental and lifestyle risks (including smoking and alcohol use), is advancing, whether or not these issues also lead to a different cancer diagnosis is understudied. The researchers, led by Trille Kristina Kjaer, PhD, wrote that this study “aimed to investigate absolute and relative incidence of second primary cancer and examine how common etiological exposures for the first cancer were associated with development of a second cancer.”

The study included a cohort of 457,334 patients across Denmark who were diagnosed with cancer between January 1, 1997, and December 31, 2014. Each patient included in the cohort was at least 40 years old. At the time of diagnosis, their year of diagnosis, cohabitation status, income, and comorbidity were also noted, as were their genders: 50.3% (230,150) were male, and 49.7% (227,184) were female. The median age at first primary cancer was 68.3 years. Follow-up for the patients lasted up to 24 years (up to December 31, 2020).

Each patient had survived at for least 1 year after their primary cancer diagnosis had been received.

There were 27 cancer types included for both primary and secondary cancers; the relative risk of developing a new primary cancer during follow-up for the survivors was calculated with Cox proportional hazards regression.

Dr Kjaer says that it is important to note that the study was conducted in a socialized medicine society where citizens have equal access to medical treatment. As for the make-up of the cohort, she adds, “The study includes only adult cancer patients as opposed to many other studies in this field that also include childhood cancer survivors or [feature] only childhood cancer survivors. Also, we were able to take into account the competing risk of death and adjust our results for important confounders such as socioeconomic status and comorbidity.”

The researchers found that for all survivors, the incidence of a new primary cancer increased over time, from 6.3% 5 years after diagnosis to 10.5% at 10 years to 13.5% at 15 years.

Researchers found that survivors of liver, pancreatic, and lung cancer had the lowest 10-year cumulative incidence of a new primary cancer. Lung cancer was also noted to be the most frequent or second most frequent new cancer in survivors of seven of the 10 first primary cancer types associated with the highest incidence of a new cancer diagnosis at 10 years. Men had a higher cumulative incidence of new cancers than women, with the highest rates also noted in people older than 60 years. Finally, the authors observed that strong links in modifiable risk factors (i.e., smoking, alcohol intake, and diets rich in red or processed meats) were noted. Interestingly, survivors of a hormone-related cancer had a lower risk of a new hormone-related primary cancer during follow-up.

Dr Kjaer says that a novel aspect of the study is the focus on both absolute and relative measures of risk for a new primary cancer. “The use of cumulative risk models offers a more straightforward and interpretable presentation of results and will hopefully make it easier to communicate in the cancer clinics to the cancer survivors.”

Catherine M. Alfano, PhD, vice president of cancer care management and research at Northwell Health Cancer Institute in New York, New York, says that studies such as this are important because many countries—especially the United States—lack a complete registry of cancer patient data like the one used in this study for analysis. “Here in the US, we have the Surveillance, Epidemiology and End Results (SEER) registry, but it is far from a complete cohort and it likely incompletely captures subsequent cancer diagnoses in those who already carry a cancer history,” she says. “So, we have an inadequate knowledge base about the incidence and risk factors for subsequent cancers that would inform the care of these survivors.”

Dr Kjaer notes that they presented the risk of a new primary cancer by site as well as the most incidents of new cancers by site. “This makes our findings useful in the planning of surveillance programs. Along the same lines, we show that if the first cancer is associated with a risk factor, for example, smoking or alcohol consumption, that survivor has an increased risk of a new cancer that shares the same risk factors. We cannot adjust for familiar or genetic factors, treatment exposure, or risk factors on the individual level but, still, this underpins the unmet potential for both primary and perhaps also secondary prevention.”

Lidia Schapira, MD, a professor of medicine (oncology) at the Stanford University School of Medicine in Stanford, California, says that the study is important because it makes a substantial contribution to the knowledge base regarding the cumulative risk of developing a second malignancy for adult survivors of cancer. “I am familiar and always impressed by the Danish Registry and I do think it has much to offer to those of us interested in understanding health risks of cancer survivors.” Dr Schapira, who is also the director of the Cancer Survivorship Program at the Stanford Comprehensive Cancer Center, adds that she has collaborated in the past with Danish researchers on similar studies.

Dr Schapira believes that key takeaways from the study include (1) that there is a need for close monitoring for new cancers among highrisk cancer survivors and (2) that cancers related to alcohol, smoking, viruses, and diet apparently are those associated with a greater risk of a second malignancy, possibly in the same organ or in the lung. “A third point,” she adds, “is that interventions to modify these behaviors—smoking cessation is the prime example—can impact this risk and thus should be considered an important component of cancer survivorship care and visits.”

Dr Alfano says that, for her, a key message from this study relates to survivorship or follow-up care. “Follow-up care clinicians should consider the etiology of the original cancer and be aware that the same etiology, be it a risk factor like smoking or a dysregulated system like hormonally derived cancers, is likely placing that cancer survivor at increased risk for other types of cancers with that same etiology.”

Dr Kjaer believes that the results provide new possibilities and relevance for oncologists in the clinic and for cancer survivors and their families. “This knowledge about who has the greatest risk is an important indication of whom we should monitor closely. When advising cancer survivors who may be afraid of developing a second cancer, we can now provide quite precise answers regarding the risk associated with the specific type of cancer they have been treated for.”

She adds, “Second primary cancer occurs with different frequency depending on the site of the first cancer, and we find that there is a a higher cumulative incidence in cancer sites with a relatively good or good survival. To the best of our knowledge, these results are useful in the counselling of patients with cancer and the data provide new evidence for the benefits of personalized survivorship care.”