These are some of the questions that we set out to answer when we launched the Zero Childhood Cancer Program (ZERO), a joint initiative of Children’s Cancer Institute and the Kids Cancer Centre at Sydney Children’s Hospital. ZERO is now a national cancer precision medicine program for all young people with high-risk cancer, involving all eight pediatric oncology treatment centers in the country. We developed a national molecular tumor board, which attracts a large multidisciplinary team, including ~50 clinicians, scientists, genetic counselors and bioinformaticians to identify the optimal evidence-based treatment options based on a patient’s comprehensive molecular profile. In 2015, when we launched ZERO, the prevailing attitude was that whole genome sequencing (WGS) was too expensive, too complex to analyze, inappropriate given the expected low numbers of mutations, and that clinicians would drown in molecular data with hundreds of variants of uncertain significance. But we hypothesized that the benefits of WGS outweighed these concerns and that it would, together with RNA sequencing, provide the most comprehensive insights into the molecular underpinnings of each patient’s tumor, which would have high clinical utility. The launch of the Illumina HiSeq X Ten platform reduced the cost of WGS ~5-fold and we set ourselves the task of developing approaches to perform genomic analysis, coupled with customized analysis platforms to enable a national team of child cancer experts to rapidly distill this information into clinically meaningful, actionable data. Fast-forward to 2020, and in our Nature Medicine paper we report the first national precision medicine program for young people with high-risk cancer, based on WGS and RNA sequencing from 247 children. Given the recent data showing the importance of methylation data in refining diagnoses of brain tumors, we added this platform to the pipeline. We found that this combined comprehensive molecular platform resolved the molecular basis of over 90% of tumors, changed diagnosis (with implications for patient management) in 5% and led to personalized treatment options in 71% of patients. In 16% of families, we identified a cancer predisposition variant in their germline DNA, which was not known in 60% of cases and has implications for cancer risk in the family. When patients were treated with their recommended targeted therapies, 31% had an objective response and a further 40% achieved prolonged stable disease. In all categories, these findings were far higher than expected at the outset of this study and suggests that precision medicine based on a comprehensive molecular profiling strategy is both feasible and effective. The study shows that comprehensive genomic analysis is a key part of the path forward to deciphering the molecular puzzles presented by high-risk pediatric cancer. Equally, the sometimes bewildering genomic complexity of tumors shows there is so much more to discover.

From: Professor Michelle Haber, Professor Glenn Marshall, Associate Professor David Ziegler, Associate Professor Mark Cowley, Associate Professor Paul Ekert.