NEW YORK – Preliminary findings from almost 600 pediatric cancer cases profiled by the Texas KidsCanSeq study so far suggest germline exome sequencing can uncover clinically informative variants in pediatric cancer cases, without causing a rash of unnecessary recommendations by physicians treating the children.
The KidsCanSeq study is open to all children with newly diagnosed or recurrent solid tumors in or outside of the central nervous system, as well as those with lymphomas or rare histiocytic disorders, explained Sharon Plon, co-leader of a pediatric cancer program at Baylor College of Medicine and director of Texas Children's Hospital's Cancer Genetics Clinical and Research Programs.
Plon presented the findings from the National Cancer Institute- and National Human Genome Research Institute-funded effort at the American College of Medical Genetics and Genomics annual meeting on Thursday. The work falls under implementation research being done by the Clinical Sequencing Evidence-Generating Research consortium.
At half a dozen participating sites across Texas, KidsCanSeq has enrolled 72 pediatric oncologists so far, along with 628 pediatric cancer patients and their parents. Many of the children and families participating in the study have Hispanic ancestry, Plon said, noting that the team is working to reach diverse individuals and populations or locations that have been medically underserved in the past.
The KidsCanSeq investigators are offering germline testing to all of the participants, including targeted panel sequencing on pediatric cancer-related genes, exome sequencing, and parental genetic testing on suspicious variants, when possible. In a subset of the pediatric cases that appeared to be particularly high-risk, they also did targeted sequencing on tumor samples, combined with additional array, RNA sequencing, or exome sequencing data, as needed.
The team has analyzed germline exome sequences for 578 of the pediatric cancer patients, Plon noted, distinguishing between cases with non-significant germline findings, including variants of uncertain significance (VUS), and those with germline profiles that contained diagnostic, carrier, or secondary, non-cancer-related findings.
With the help of a structured email format designed by the study's lead genetic counselor, the investigators shared significant germline findings with the pediatric oncologists participating in the study, alerting them to the addition of germline results to patients' electronic medical records and outlining the implications and recommended actions or guidelines associated with the germline variants identified.
From surveys sent to the pediatric oncologists after significant and subsequent non-significant germline findings, the team got a sense of the medical recommendations made in response to the germline profiles, if any, and insights into the level of genetics training that the oncologists had.
As of the end of February, for example, 30 participating oncologists completed 157 surveys related to germline test results from 204 cases, including 88 pediatric cases with diagnostic or carrier findings.
In more than one-quarter of the cases described in these surveys, the pediatric oncologists reported one or more medical recommendations based on the available germline data. That was particularly true when the germline tests uncovered cancer-related pathogenic or likely pathogenic variants. In contrast, VUS findings were far less likely to prompt new medical recommendations.
The medical recommendations spurred on by the germline genetic profiles often included referrals to genetics specialists or another medical specialty, Plon reported, though imaging, additional genetic testing, or testing referrals for the patients' relatives also occurred.
Based on their current results, the researchers have not seen signs that germline test results are prompting a flurry of additional laboratory testing or imaging requests, she added, in part because the structured email communications shared with oncologists may help to rein in unnecessary testing related to VUS results.
"Oncologists frequently recommended follow-up with genetics professionals for patients and/or family members after return of reports with significant findings," she and her coauthors noted in an abstract accompanying the presentation, noting that the findings so far "do not support concerns about the potential of germline testing for all pediatric cancer patients to generate extensive downstream laboratory or imaging costs."