patient and her father
Photo by Rhoda Baer
Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.
In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.
As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.
Investigators described this research in JAMA.
“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.
Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).
The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.
All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.
Actionable findings
Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.
Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).
“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.
“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”
Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.
Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.
Hematologic malignancies
Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)
For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.
A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.
Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.
A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.
Cost and turn-around time
The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.
It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.
“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”
