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.
To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer.
Design, Settings and Participants
An observational, consecutive case series (May 2012–October 2014) of 102 children and young adults (mean age, 10.6; median age, 11.5, range: 0–22 years) with relapsed, refractory, or rare cancer at a single major academic medical center.
Each participant underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing along with genetic counseling. Results were discussed in a multi-disciplinary Precision Medicine Tumor Board (PMTB) and recommendations were reported to treating physicians and families.
Main Outcomes and Measures
Proportion of patients with potentially actionable findings (PAF), results of clinical actions based on integrative clinical sequencing (ICS), and estimated proportion of patients or their families at risk for future cancer. PAF was defined as any genomic findings discovered during sequencing analysis that could lead to a 1) change in patient management by providing a targetable molecular aberration, 2) change in diagnosis or risk stratification or 3) provides cancer-related germline findings, which inform patients/families about a potential future risk of various cancers;
We screened 104 patients and enrolled 102 patients of which 91 (89%) had adequate tumor tissue available to complete sequencing and only these patients were included in all subsequent calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Overall, 42 (46%) patients had PAFs which changed patient management including, 54% (15/28) with hematological malignancies and 43% (27/63) with solid tumors. Overall, individualized actions were taken in 23 of the 91 (25%) patients and families based on actionable ICS findings, including change in treatment in 14 (15%) and genetic counseling for future cancer risk in 9 (10%) patients. 9/91 (10%) of these personalized clinical interventions resulted in ongoing partial clinical remission of 8–16 months duration or help sustain complete clinical remission of 6–21 months duration. All 9 (10%) patients and families with actionable incidental genetic findings agreed to formal genetic counseling and screening.
Conclusions and Relevance
In this single center case series of children and young adults with relapsed or refractory cancer, incorporation of data from integrative clinical sequencing into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling in a small proportion of patients. The lack of a control group limited our ability to judge whether better clinical outcomes were achieved compared to standard care.