MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research

Abstract

Purpose: We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy.

Experimental design: Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs.

Results: Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation.

Conclusions: We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a diverse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res; 22(15); 3810-20. ©2016 AACR.

Figure 1

Total and expressed single nucleotide variants (SNVs) in tumor samples. Red bars indicate expressed somatic SNVs, turquoise bars denote gene not expressed, and green show the reference allele only was expressed. Horizontal dotted lines show the previously reported mean of total exomic SNVs by tumor diagnosis in literature. The black triangle represents a relapsed or refractory tumor sample. MM, malignant melanoma; TCC, transitional cell carcinoma; NET, neuroendocrine tumor; OS, osteosarcoma; FN-RMS, fusion-negative rhabdomyosarcoma; FP-RMS, fusion-positive rhabdomyosarcoma; US, undifferentiated sarcoma; DSRCT, desmoplastic small round cell tumor; MEC, myoepithelial carcinoma; CCS, clear cell sarcoma; SS, synovial sarcoma; MRT, malignant rhabdoid tumor; WT, Wilms tumor; ACC, adrenocortical carcinoma; ASPS, alveolar soft part sarcoma; MTC, medullary thyroid carcinoma; IMT, epithelioid inflammatory myofibroblastic sarcoma; RCC, renal cell carcinoma; PM, peritoneal mesothelioma.

Figure 2

Landscape of Pediatric and Adolescent Young Adult Solid Tumors of Index Cases. At the top are the clinical characteristics, including change in diagnoses indicated by a vertical arrow; the diagnostic abbreviations are the same as in Figure 1 with the addition of EWLS for Ewing-like sarcoma. Fusion genes, somatic SNVs, copy number alterations in known cancer consensus genes, and germline alterations in cancer genes and American College of Medical Genetics (ACMG) genes are color coded as shown.

Figure 3

Comparison of Somatic SNVs in relapsed tumors and across metastases in the exome. A minimum threshold of 10 total reads, 3 variant reads, and a variant allele frequency of ≥ 10% in the tumor DNA was used. Somatic SNVs common to the paired metastatic or relapsed tumors are shown in red bars, indicating a common origin. Unique SNVs seen in each sample are shown in light blue bars.