Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth

Abstract

Importance: Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging.

Objective: To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer.

Design, setting, and participants: Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer.

Exposures: Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians.

Main outcomes and measures: Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer.

Results: Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening.

Conclusions and relevance: In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.

Figure 1. Overview of the Peds-MiOncoSeq Clinical Study

Flow chart of all patients who were screened and enrolled in the study. The number of patients with successful sequencing and details specifying the tumor type and tissue site are indicated. Two patients declined participation; for the first patient no tissue was available and the family declined research biopsy, while for second patient, cancer was in remission at the time of screening and family chose not to pursue the study using archived tissue. FFPE = Formalin fixed paraffin embedded. * One solid tumor patient was sequenced twice using frozen tissue, ˆ one solid tumor had both his primary and metastatic tumor site sequenced. + One leukemia patient had both bone marrow and malignant pleural fluid sequenced.

Figure 2. Summary results of the Peds-MiOncoSeq study

A matrix representation of selected informative findings from the sequencing results from the Peds-MiOncoSeq cohort. Patients are characterized on the Y axis according to disease type. Molecular aberrations are indicated on the X axis and grouped according to type. The presence of specific mutations, insertion/deletions, amplification/deletions, and gene fusions are indicated by colored blocks. Color-coding of the blocks is indicated in the legend. Data represented in this figure are derived from all 91 patients with completed whole exome as well as transcriptome sequencing of tumors and exome sequencing of germline DNA. Only sequencing findings with biological significance are included. SNV, single nucleotide variant; indel: insertion/deletion.