An Unclassified Tumor — with a Precisely Targeted Therapy

pediatric, precision medicine
Jesus with his mother, Maria.

Early last year, at his home in San Juan, Puerto Rico, Jesus Apolinaris Cruz’s leg hurt so much he could barely sleep. “All day, it was constant pain,” the 13-year-old recalls. His parents took him to two local pediatricians, who examined him, drew blood, and tested his platelets. No diagnosis. Finally, in April 2016, a physician ordered an MRI. No wonder Jesus’s leg hurt: He had a large, cancerous tumor lodged in his hip.

“I gained 20 pounds due to anxiety, but we quickly started to take action,” Maria Apolinaris, Jesus’s mother, says through an interpreter. “We didn’t stand with our arms crossed for very long.”

Thus began a saga that took Jesus and his family from Puerto Rico to Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the cutting edge of cancer therapy. Under a microscope, the exact classification of Jesus’s tumor remains a mystery. But it has shrunk dramatically, thanks to a precision medicine program that uncovered a rare genetic abnormality in the tumor and an experimental therapeutics program with a robust portfolio of clinical trials — including one targeting the same abnormality.

Promising early results of this trial, sponsored by Connecticut-based Loxo Oncology, were highlighted at the annual meeting of the American Society of Clinical Oncology (ASCO).

The road to targeted therapy

Once physicians in Puerto Rico had determined the cause of Jesus’s pain, they referred him to Mark Gebhardt, MD, a pediatric orthopedic surgeon at Dana-Farber/Boston Children’s. Gebhardt brought the case to a multidisciplinary case review team that included pediatric oncologist Katherine Janeway, MD, clinical director of the Solid Tumor Center at Dana-Farber/Boston Children’s.

The team concluded that, because of the tumor’s original size and location, surgery would leave Jesus with lifelong trouble walking and seriously damage his bowel and bladder.

“Because the surgical option was so drastic, and there was no medical option because we couldn’t classify the tumor with a known diagnosis, we decided that the best course was to wait a few weeks for the genetic profiling results,” Janeway recalls.

Like every new patient at Dana-Farber/Boston Children’s, Jesus’s family had been offered the option of having a tumor sample sequenced by pathologists using sophisticated techniques to uncover genetic abnormalities that might aid diagnosis or treatment.

The results carried good news: Jesus’s tumor was driven by a so-called TRK fusion. In the TRK fusion, two genes switch places, which leads the TRK gene to send a constant message to the tumor cells to divide and grow. Janeway likens it to a light switch stuck in the “on” position. This is the abnormality that the Loxo Oncology experimental drug – larotrectinib – targets, essentially turning the light off.

“Loxo Oncology recognized that this gene fusion occurred in childhood tumors,” Janeway says. “They started a clinical trial for children incredibly soon after starting their trial for adults. And very early they developed a liquid formulation for children too young to swallow pills. They should be commended for that.”

Jesus with his father.

Jesus’s tumor is now small enough that a planned operation in July is not expected to cause lasting problems. And, according to the preliminary results presented at ASCO, the vast majority of children with tumors like Jesus’s have also shown a response to larotrectinib.

“Larotrectinib doesn’t break up the fusion. Instead it blocks the resulting signal that tells the cancer to keep growing,” says Steven DuBois, MD, MS, director of experimental therapeutics at Dana-Farber/Boston Children’s and co-lead author of the Loxo Oncology abstract presented at ASCO. “Although it’s too soon to know long-term results or side effects, the early results have shown dramatic responses in patients with an NTRK fusion.”

A bellwether of the future?

As the precision medicine field develops, DuBois adds, researchers are finding that when tumors have signaling abnormalities like TRK and similar fusions, and a targeted drug happens to be available, patients tend to respond well.

“When you make a genetic match like this, it can be transformative,” says Janeway. “Our goal going forward is to have targeted drugs for more and more of our patients.”

Meanwhile, Jesus, his parents, and two older siblings moved to Boston in July 2016 to be close to his medical team. Jesus, who, his mother says, was “just bones” when the family arrived in Boston has gained weight. He is an eighth grader who enjoys drawing, painting, and video games – and not being in pain.

“I always look at the positive side of things,” says Maria Apolinaris. “This has brought us closer together as a family. I can’t complain because my babies are all doing so well. My hope is that they can remove all of Jesus’s tumor and that he can grow and become a man of good.”

Learn more about precision medicine and experimental therapeutics at Dana-Farber/Boston Children’s.