NEW YORK – Researchers at the Children's Hospital of Philadelphia (CHOP) are advocating for increased NTRK fusion testing in pediatric cancer patients after finding in a recent study that such alterations tend to occur more frequently in children than adults, and that knowledge of such fusions can help definitively diagnose patients and inform therapeutic strategy in earlier disease settings.
Currently, there are two US Food and Drug Administration-approved treatments for adult and pediatric patients whose tumors have NTRK fusions, larotrectinib (Bayer's Viktrakvi) and entrectinib (Genentech's Rozlytrek). These drugs are available to patients with refractory or unresectable tumors who harbor such fusions after they have exhausted other options. That means physicians typically screen for NTRK fusions in patients when their disease is in advanced stages.
However, based on the results of a study published this month in JCO Precision Oncology, CHOP researchers believe NTRK fusion testing has broad clinical utility and should be done more readily in pediatric cancer patients. In this study, the researchers explored the prevalence of NTRK fusions in a large cohort of young cancer patients and catalogued the wide variety of tumor types these rearrangements show up in, as well as the tumor types in which they are less likely to occur, the range of NTRK fusion partners, and the clinical outcomes of patients with these tumor markers.
The researchers found that knowing pediatric cancer patients' NTRK fusion status can help definitively diagnose their tumors, which are often exceedingly rare, provide information about their clinical prognosis, and inform personalized treatment strategies.
"The identification of these NTRK fusions has facilitated precision cancer diagnosis and TRK inhibitor–targeted therapy," Li and colleagues concluded in their paper. "Our experience highlights the clinical utility of screening NTRK fusions for all pediatric tumors."
In the study, researchers profiled 1,347 pediatric tumors from 1,217 patients using custom DNA and RNA next-generation sequencing panels. They found that 2.2 percent of all pediatric tumors profiled had NTRK fusions. The incidence was slightly higher for patients with solid tumors, with 3 percent harboring NTRK fusions in this study.
Marilyn Li, a lead author of the study and director of cancer genomic diagnostics at CHOP, said her team's research is the first "solid evidence" of the higher prevalence of NTRK fusions in pediatric cancers. "It is somewhat surprising to see and important to know the much higher frequency in pediatric tumors compared to adult ones and [that it is a] higher frequency than what we thought," Li said.
In a 2018 study of NTRK fusions in adults, researchers found 0.31 percent of adult cancers harbored these rearrangements based on an analysis of 13,467 adult tumors in The Cancer Genome Atlas Program. That study also analyzed pediatric tumors from the St. Jude PeCan database and reported a similar rate, 0.34 percent, harboring NTRK fusions.
However, Li noted that study may have yielded a lower rate of NTRK fusions because the St. Jude database may include more pediatric tumor types that do not or very rarely harbor NTRK fusions, such as leukemia and neuroblastoma.
The difference in prevalence of NTRK fusions between adult and pediatric cancers identified by Li's group is likely due to the fact that such markers tend to show up in certain tumor types that are more common in young people. "The prevalence is lower in adults likely due to the low prevalence of NTRK fusions in common adult cancers, such as lung cancer and colorectal cancer," Li explained, while tumors that occur more often in children, such as those studied in her research, appear more likely to have NTRK fusions.
The researchers found NTRK fusions across many different pediatric cancer types, with the highest occurrence (13 percent) in papillary thyroid cancer. NTRK fusions were also found in 1.9 percent of central nervous system tumors, 1.8 percent of non-central nervous system tumors and non-papillary thyroid carcinoma solid tumors, and less than 1 percent of hematologic cancers.
Li and colleagues also discovered that in younger patients, parts of the NTRK gene can fuse with parts of a variety of other genes. They used the CHOP Cancer Fusion Panel, which is able to identify known and new fusion proteins associated with 110 cancer genes, to catalog these NTRK fusion partners.
In thyroid cancers, the researchers found both NTRK1 and NTRK3 fusions in 10 patients. Although the data are limited, they concluded that "the presence of an NTRK fusion may have diagnostic, prognostic, and therapeutic significance … and may hold clinical utility for stratifying surgical and medical care." A 2018 trial studying larotrectinib in solid tumors with NTRK fusions showed two patients with advanced thyroid cancer remaining progression free for more than seven months.
The patients with central nervous system tumors who had NTRK fusions had either gliomas or mixed neuronal glial tumors, the researchers found. These patients also exclusively harbored NTRK2 fusions. Most of the patients in this cohort underwent surgery to remove their tumor, but the study authors suggested they may benefit from a TRK inhibitor as an adjuvant treatment to prevent recurrence.
Knowing that a patient's tumor had an NTRK fusion also helped clinicians diagnose it. In the study, the discovery of an NTRK fusion confirmed an already known diagnosis, helped rule out other possible diagnoses, or changed the diagnosis. For example, one patient was initially thought to have a mucoepidermoid carcinoma, but the diagnosis was changed to secretory carcinoma based on the detection of an ETV6-NTRK3 fusion and further immunohistochemical analysis.
In five patients, a definitive diagnosis was made because an NTRK fusion was able to provide a rationale for excluding certain tumor types. "There are pediatric tumors [in which] we have never seen an NTRK fusion, such as neuroblastoma and medulloblastoma," Li said. "If the diagnosis is not clear, NTRK fusion testing should be considered."
The study identified several tumor types that did not have any NTRK fusions, including neuroblastomas, medulloblastomas, Wilms tumors, atypical teratoid or rhabdoid tumors, hepatoblastomas, osteosarcomas, Ewing sarcomas, and rhabdomyosarcomas.
These tumors comprised about one-third of the study cohort. The researchers did not rule out NTRK fusions ever occurring in these tumors, but concluded that they are likely rare.
Although there are now FDA-approved TRK inhibitors that require testing patients for NTRK fusions, such analysis is still not as widespread as it should be in pediatric oncology, in Li's view. There are several reasons why more young cancer patients are not tested for NTRK fusions, from physician's lack of awareness of which tumors commonly harbor the alterations to access to next-generation sequencing testing and insurance coverage, Li said. However, she urged that most pediatric cancers should be tested for NTRK fusions, whether they have metastatic or earlier-stage disease.
While the study was not focused on the treatment of patients with NTRK fusions, Li highlighted the experience of one patient with unresectable, infantile fibrosarcoma with a SPECC1L-NTRK3 fusion, who was treated with larotrectinib to shrink the tumor. Doctors initially couldn't resect the tumor because it would have caused significant damage to the patient's upper arm, where the tumor was located, but after several cycles of neoadjuvant treatment with larotrectinib, they were able to surgically remove the tumor. They continued to treat this patient with larotrectinib, and six months after surgery, scans showed no signs of residual or recurrent disease.
This case suggested to Li and her colleagues that other pediatric cancer patients could benefit from TRK inhibitors after surgery to stave off recurrence.
There are ongoing clinical trials, including one at CHOP, that are evaluating TRK inhibitors in a wide range of pediatric cancer patients. The Phase II trial at CHOP is studying larotrectinib in several pediatric cancers with NTRK fusions but in earlier stages, rather than when the tumor is metastatic or unresectable.
The investigators have not presented results from this clinical trial, but in Li's research, the limited number of patients with NTRK fusions who were treated with TRK inhibitors have responded and none have become resistant to treatment.
"It is important for the treating physician to know the prevalence [of NTRK fusions]," she said, emphasizing that they can be found in a broad spectrum of pediatric cancers and urging physicians to consider an NTRK fusion test for any "tumors that could possibly harbor an NTRK fusion."