New Tool Better Predicts Subsequent Cancers in Child Survivors

An e-health cancer predisposition screening tool increases by over 50% the likelihood of predicting the development of subsequent malignant neoplasms (SMNs) in childhood cancer survivors, show results from a nested, case-controlled study.

“We consider that all pediatric oncology patients should be screened [with this tool] at diagnosis or at any time in follow-up to determine the likelihood of an underlying CPS [cancer predisposition syndrome] and for SMN risk prediction,” say the authors.

The screening tool ― based on McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) ― can be downloaded for free.

The team was led by Noelle Cullinan, MD, at the Hospital for Sick Children, Toronto, Ontario, Canada. The study was published online in August in the Journal of Clinical Oncology.

In a related editorial, published online on September 2, Roya Mostafavi, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, and Kim Nichols, MD, Danny Thomas Place, Memphis, Tennessee, agree with the authors.

SMNs represent a leading cause of non-relapse-related death among 5-year survivors of initial childhood cancer. SMNs account for roughly 50% of all non-relapse-related deaths in this patient group, the authors point out.

“Development of decision support tools such as the MIPOGG is one important step in the right direction,” the editorialists comment.

Major advantages of the tool are that it requires only a few minutes to complete and the information is generally readily available. In addition, it can lower costs by enabling clinicians to prioritize patients who are most likely to benefit from a genetics referral, and it can be used sequentially over the trajectory of a child’s care.

However, a positive MIPOGG result doesn’t tell practitioners which cancer a patient is most likely to have and thus cannot guide clinicians as to which surveillance strategy to follow. “Without a patient’s germline genetic information, it will be challenging for providers to determine if, when and how to monitor for SMN,” the authors note.

The editorialists conclude that “childhood cancer survivors scoring positive on the MIPOGG should be triaged for genetics evaluation and when appropriate, germline genetic testing, to inform cancer surveillance and/or risk-reducing measures.”

Cases vs Controls

The study involved a cohort of 13,367 patients who were diagnosed with or were treated for a primary cancer before the age of 18 years. Of these, 317 patients (2.4%) developed an SMN (case patients). They were matched to 1569 chidlhood cancer survivors who did not develop an SMN (control patients).

The median age at the primary cancer diagnosis was 7.9 years among the case patients and 7.6 years among the control patients. The median age on SMN development was 18.3 years.

The median time between primary cancer diagnosis and SMN was 11.2 years, although almost one third of these patients developed an SMN after 15 or more years.

The team conducted a multivariable model analysis that controlled for exposure to chemotherapy and radiation treatment for the primary cancer.

It showed that an MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio, 1.53; 95% CI, 1.06 – 2.19).

Prediction of SMN development was better for patients who had survived a central nervous system (CNS) tumor or a solid tumor, compared to patients with hematologic malignancies, as well as for patients who did not undergo radiotherapy during the treatment of their primary malignancy.

For patients who had had a CNS tumor, those whose MIPOGG output was “yes” were 2.9 times more likely to develop an SMN in comparison with those whose MIPOGG output was “no,” the authors note.

Although the tool improved the prediction of a secondary cancer by 53% overall, for the patients who had had a solid tumor as their primary disease, this increased to 63%.

“Considering that MIPOGG refers approximately 30% of children with cancer for CPS evaluation, this study demonstrates that the case referral rates in this cohort are higher than anticipated,” the investigators observe.

They also feel that the MIPOGG can act as a surrogate for CPS prediction in healthcare settings in which there is limited access to genetic testing. In settings in which genetic testing is easily accessible, the MIPOGG can help to prioritize patient referrals for CPS evaluation.

Although enthusiastic about the potential for the new tool, the editorialists point out a few limitations to the study. “None of the patients [in this study] underwent germline genetic testing,” Mostafavi and Nichols observe. Thus, it’s not known whether the childhood cancer survivors who were recommended for a genetics referral did in fact have an underlying CPS. “Conversely, it is unclear whether those who were not recommended for a genetic referral were truly free of an underlying predisposition,” they add.

However, data from another study support the idea that a positive MIPOGG output is likely a surrogate for the presence of an underlying germline mutation. Those data come from 3000 childhood cancer survivors participating in the St. Jude Lifetime Cohort Study. They show that carriers of germline cancer predisposing gene mutations did develop an SMN at a significantly higher rate.

The study was funded by the Pediatric Oncology Group of Ontario Research Unit and other organizations. Cullinan has disclosed no relevant financial relationships. Nichols owns stock in Incyte and receives research funding from Incyte/Novartis and Alpine Immune Sciences.

J Clin Oncol. Published online August 12, 2021. Full text, Editorial

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