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Toward Precision Therapy for Children with Cancer: An Interview with Dr. Javed Khan

, by NCI Staff

Credit: National Cancer Institute

Based on the results of a new study, NCI is launching a clinical program called ClinOmics, which will use genomic approaches to help guide the treatment of patients with cancer who are treated at the NIH Clinical Center.

In this interview, Javed Khan, M.D., of NCI’s Center for Cancer Research (CCR), discusses the promise and the challenges of genome-based therapy for children and adults with cancer.

How would you define precision medicine for children and young adults with cancer?

Precision medicine refers to the use of DNA sequencing and other types of “Omic” analysis to match patients with the most appropriate therapies. A goal is to identify individuals whose tumors have a patient-cancer specific abnormality for which a targeted therapy exists. For example, children with acute lymphoblastic leukemia who have a genetic abnormality known as the Philadelphia chromosome are treated with the targeted drug imatinib (Gleevec®).

Do many doctors use genomic data when selecting treatments for young patients with cancer?

Some doctors at certain hospitals are making clinical decisions based on information gained from profiling a patient’s tumor, but this is largely done on an ad hoc basis. We are still in the early days of genome-based therapy for pediatric patients, though the field is advancing rapidly.

You co-authored a new NCI study testing the use of genome-guided therapy for children and adolescents with cancer. What did you learn?

Our pilot study tested the feasibility of using genomic testing of blood and tumor to identify genetic alterations that could inform decisions about treatment for 59 children and young adults with refractory or relapsed cancer.

Among this group, approximately 50 percent had clinically “actionable” mutations in the tumor—that is, genetic changes in the person’s own tumor that changes the patient’s diagnosis, or that may be targeted with FDA-approved drugs or agents being tested in existing clinical trials. Twenty-four (41 percent) of these patients had a mutation that could be targeted by an approved or investigational therapy. Remarkably, 12 percent of the patients were found to have a significant germline mutation that might be relevant to the development of cancer and important in managing the care of the patient and his or her family.

We concluded that a comprehensive genomics analysis is not only feasible, but that it has the potential to improve the care of both adults and children with cancer. And it was on the basis of this experience that we are launching the CCR ClinOmics program.

Can you please tell us about NCI’s new ClinOmics program?

It’s a state-of-the-art comprehensive genomics platform for testing all patients with cancer—both children and adults—who are being treated at the National Institutes of Health (NIH) Clinical Center. For each patient, several types of genomic testing will be done in a CLIA-certified laboratory, and the results will be entered into the patient’s electronic medical record. The patient’s medical team can access the test results and potentially use the information to help select therapies for the patient.

Which kinds of genomic testing will you do?

We will sequence DNA from a patient’s tumor, which can show genetic alterations that occurred during the patient’s lifetime. These are called somatic changes. We will also sequence DNA from each patient’s germ cells, which can reveal genetic changes that the person may have inherited. In addition, we will perform additional genomic analyses such as whole-transcriptome sequencing (RNAseq) to identify actionable fusion genes and expressed mutations that may be targeted for therapy.

Who decides which genetic changes might be relevant to treatment?

Two panels of NCI experts, one for somatic changes and the other for germline changes, will review each patient’s genomic test results to determine whether there are actionable genomic alterations. These findings will be entered into the patient’s electronic medical record for the medical team to review.

Why is this program being established now?

The technology has advanced to the point where the tests are reliable and can be used to make clinical decisions. Another consideration is the turnaround time for results. The test results are currently available to physicians in a secure format within 4 weeks. As technology advances, the turnaround time will soon be as short as 2 weeks.

How will patients at NCI be enrolled in the program?

Principal investigators in the CCR will open clinical protocols that will use the ClinOmics program for patients with adult and pediatric tumors. Patients already being treated at the NIH Clinical Center will need to be enrolled in a clinical protocol at the Clinical Center to participate.

What are some challenges associated with genome-based therapy for children with cancer?

Recent studies have shown that, although large amounts of genomic data can be generated from pediatric patients, most of these data cannot now be translated into recommendations for a treatment. Studies have also suggested that pediatric tumors may have fewer mutations than adult tumors and, as a result, may have fewer actionable genetic alterations. However, our study and others have shown that children and young adults with refractory, metastatic, or relapsed cancers have a higher number of actionable mutations.

Is resistance to targeted cancer therapies a problem for pediatric patients?

Yes. In both children and adults, tumors change over time, and drugs may stop working as tumors acquire new genetic alterations. Resistance can develop very quickly. To address the problem of drug resistance, future clinical trials are going to have to evaluate immune-based or combination therapies—even for those patients whose tumors harbor a genetic alteration for which a targeted therapy already exists.

Will the ClinOmics program help contribute to advances in cancer research?

The program will create a repository for tumor tissue collected from patients that can be used for research purposes. This will allow investigators to develop cancer models such as patient-derived xenografts, or PDXs. In addition, patients in the program will be followed over time. This means that in the future we will be able to ask detailed research questions about these patients, such as whether certain genetic changes were associated with a response to specific therapies.

Javed Khan, M.D., Deputy Chief, Genetics Branch, NCI’s Center for Cancer Research

Is there a primary message about genome-guided therapy for young patients and their families?

It’s really important for patients with life-threatening cancers to have their tumors and normal cells profiled by genomic tests. I think these tests should be standard of care for all patients with high-risk cancers, and this will be the case for those who come to NCI. That may seem like a strong statement, but I think most experts would agree that we are heading in that direction.

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