Genomic Sequencing Shows Benefit for Children With Cancer

Veronica Hackethal, MD

September 03, 2015

Incorporating genomic sequencing and genetic counseling could benefit children with rare, relapsed, or refractory cancer, according to investigators.

The study was published in the September 1 issue of JAMA.

"We showed that comprehensive DNA and RNA sequencing on pediatric oncology patients can be done and can have an impact clinically for individual patients and in cases where targeted gene panels might have challenges," said lead author Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor.

"This shows the real potential of precision medicine in clinical practice. In about half the patients, we identified a clinically actionable alteration, and in about 10% of patients, we identified a cancer-related incidental finding that suggested the need for genetic counseling and screening," he reported.

Precision medicine emphasizes personalized care based on individual variation. Integrative sequencing can be of benefit in hard-to-cure diseases, like pediatric cancer; it can identify genomic changes that can aid diagnosis, predict outcomes, and help in the selection of therapy. Bringing these new technologies into clinical practice is the next step.

This shows the real potential of precision medicine in clinical practice.

This study comes on the heels of an adult program called MiOncoSeq, which was established in 2011 at the University of Michigan. The program looked at the feasibility of using integrative clinical sequencing in adults with advanced cancer. In 2012, Peds-MiOncoSeq was established, with similar objectives in relapsed, refractory, or rare pediatric cancer.

Dr Chinnaiyan and his colleagues began their ongoing observational study in May 2012. All 102 children and young adults enrolled (average age, 10.6 years) had relapsed, refractory, or rare cancer.

The study used germline DNA and tumor DNA and RNA sequencing, rather than whole-genome sequencing. Members of a multidisciplinary precision medicine tumor board discussed results weekly and made recommendations to families and physicians.

Actionable findings were defined as sequencing results that could lead to a change in patient management, diagnosis, risk stratification, or patient or family counseling.

Of the 91 patients (89%) whose tumor tissue was adequate for sequencing, 28 (31%) had hematologic malignancies and 63 (69%) had solid tumors.

Sequencing revealed actionable findings in 42 patients (46%) — 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.

Of the 91 patients, 23 (25%) received individualized actions. Fourteen (15%) had a change in treatment and nine (10%) received genetic counseling because findings indicated future cancer risk.

In nine of 91 patients (10%), personalized treatment changes contributed to a partial clinical remission of 8 to 16 months or to a complete clinical remission of 6 to 21 months. Treatment changes did not succeed in five patients (5%).

Average turnaround time was 54 days. The main reasons for delays were related to waits for bioinformatics analysis and the next board meeting.

Integrative clinical sequencing cost an estimated $6000 per patient.

"The next step is to develop a sequencing and analysis platform that has a faster turnaround time, is scalable to handle higher patient volumes, and is more cost-effective," Dr Chinnaiyan explained.

"Sequencing by use of targeted gene panels is already being adopted for clinical practice for certain cancer types," he pointed out. "With improvements in the technology and decreases in cost and time for analysis, we believe more comprehensive approaches to sequencing tumors will be adopted as precision medicine evolves."

First Study to Show Benefit in Childhood Cancer

"The major strength of the study is its coverage of a relatively large number of patients in the childhood cancer setting. It's really the first study that tests the hypothesis that precision medicine can benefit children with cancer," said John Maris, MD, who, along with his colleagues from the Children's Hospital of Philadelphia, wrote an accompanying editorial.

Dr Maris said he agrees with Dr Chinnaiyan that the next step is to improve turnaround times, and pointed out that these technologic barriers are "quickly being solved."

Although sequencing tests should not cost much more than an MRI or other commonly used diagnostic tests, the cost of the drugs is a "huge challenge to the field right now," according to Dr Maris.

Probably the most important challenge, he continued, lies in developing drugs that can target these mutations and proving that drugs targeting specific mutations work in specific diseases. For example, a mutation that appears in melanoma might not behave like one that shows up in neuroblastoma, he explained.

Major challenges in pediatric oncology also include a lack of information on pediatric dosing and a lack of clinical trials involving children.

A major issue is that "we're talking about very, very small subsets of patients," Dr Maris emphasized. "I think the traditional way to develop drugs for cancer in general, and for children in particular, needs to be completely rethought. That's going to require innovation in the pharmaceutical industry, the US Food and Drug Administration, and in academia in order to be successful."

Because this study did not have a control group, it could not be determined whether the clinical outcomes that occurred were better because of the intervention or whether they would have occurred during standard care.

Dr Chinnaiyan — a Howard Hughes Medical Institute Investigator, an A. Alfred Taubman Scholar, and an American Cancer Society professor — reports serving on the advisory board of Paradigm Diagnostics, a nonprofit tumor sequencing company of the University of Michigan. Dr Maris and his coauthors have disclosed no relevant financial relationships.

JAMA. 2015;314: 881-883, 913-925. Editorial, Abstract


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