Pediatric cancers and precision medicine: The feasibility question

precision cancer medicine personalized medicine pediatric oncology childhood tumors
What is precision cancer medicine all about? See the full infographic at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

A family walks into their oncologist’s office and sits down. Their son’s care team is there, ready to discuss the sequencing report they received about the tumor in his leg.

“We think we have something,” the oncologist says. “We found a known cancer-associated mutation in one gene in the tumor. There’s a drug that targets that exact mutation, and other children and adults whose tumors have this mutation have responded well. We’ll have to monitor your son closely, but we think this is a good option.”

This hypothetical conversation, while common in adult oncology, happens rarely (if at all) on the pediatric side. This kind of personalized, genomics-driven medicine (where the genetic alterations in a patient’s tumor drive therapy, not the tumor’s location) isn’t a standard approach for childhood cancers yet.

Note that I said yet. The door to personalized pediatric genomic cancer medicine is cracking open, in part because three recent papers — including one out of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center — are starting to convince the field that clinical genomics can indeed be done in pediatric oncology.

Matching children to treatment: It’s not that easy

In their quest to make personalized cancer medicine a reality for children, pediatric oncologists are butting up against several obstacles, such as:

  1. Targetable mutations are rare in pediatric tumors
  2. Pediatric tumors are rare period, which means relatively little sequencing data are available on childhood cancers
  3. Few targeted drugs are available to children in either approved or experimental form, due to age requirements or lack of appropriate formulations (e.g., pill versus liquid)

Before these obstacles can even be addressed, though, there’s the question of whether it’s readily possible to take a tumor sample from a child, sequence it, find a clinically actionable genetic alteration and return that information to the treating oncologist.

Every study, every paper is all part of one big story about bringing precision medicine to children with cancers.“Pediatric oncology has lagged behind adult oncology when it comes to incorporating targeted drugs and genomic testing or tumor profiling into treatment,” says Katherine Janeway, MD, clinical director of the Solid Tumor Center at Dana-Farber/Boston Children’s. “[W]e’re starting to understand how to carry out clinical sequencing in pediatric oncology and which patients might benefit from it.”

Janeway should know, as she’s the lead author on a new paper in JAMA Oncology reporting the results of the Individualized CAncer Therapy (iCat) trial, a four-center study intended to show the feasibility of clinical sequencing in pediatric oncology.

The study team sequenced tumor samples from 100 patients with relapsed or treatment-resistant pediatric solid cancer against a panel of known cancer-associated alterations in 305 genes. If there was a match, and a relevant drug was available either in a clinical trial or in an age-appropriate, FDA-approved formulation, the team sent the patient’s treating oncologist an iCat recommendation. The team also sent back any information about mutations suggesting a change in diagnosis or hinting that the patient might have a cancer presdisposition syndrome (and should seek genetic counseling).

iCat study precision cancer medicine personalized medicine pediatric oncology childhood cancer
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In all, the team made 31 iCat recommendations, meaning that for 31 percent of trial participants, the sequencing data turned up a clinically actionable mutation. In addition, 12 patients’ tumors yielded sequence data pointing to a new diagnosis or a predisposition to cancer.

“We designed the study such that if we could make an iCat recommendation for 14 percent of participants, we could say that clinical sequencing was feasible,” Janeway noted in a statement. “We exceeded this benchmark.”

During follow-up, they learned that three of those patients received the recommended treatment, though none of the three responded. Among the other 28, reasons for not following the recommendation included a) the patient was ineligible for or could not otherwise access a relevant clinical trial, b) the patient was responding well to current therapy, or c) the patient had died.

Janeway notes that while the low response rate is a concern, with our current level of knowledge, we don’t really know how best to implement genomic-based treatment in children.

“It’s not always clear whether the link between a given gene variant and drug will hold up when you move into the clinic,” she explains. “We need to know more about outcomes so that we can appropriately counsel families about what might happen if they take a precision medicine approach.”

Is precision possible?

The iCat paper joins a growing body of evidence in favor of incorporating sequencing into pediatric oncology care, at least among children with relapsed tumors:

Together, these and other studies are fueling a significant expansion of personalized medicine studies in childhood cancer. Already there’s the Genomic Assessment Informs Novel therapy (GAIN) consortium study, a 12-center follow-up to iCat that Janeway and her colleagues launched last fall. And sometime this year, the National Cancer Institute will add a pediatric arm to its Molecular Analysis for Therapy Choice (MATCH) trial, a “basket” trial that puts patients and treatments together based on tumor sequencing data.

“There’s a lot more going on than any one study would suggest,” Janeway says. “Every study, every paper is all part of one big story about bringing precision medicine to children with cancers. If we do this kind of sequencing and we do it right, I’m confident we’ll find new treatment opportunities.”

Learn more about personalized medicine in pediatric oncology at Dana-Farber/Boston Children’s Cancer. And visit the Thriving blog to read about a young patient who is now a brain tumor survivor thanks to precision cancer medicine.