The great promise of precision oncology programs lies in the potential of linking the specific genomic features of a tumour, to therapies that can directly or indirectly target these. The ZERO Childhood Cancer Program (ZERO) is Australia’s national precision medicine program for childhood cancer. ZERO has demonstrated that precision guided therapy is associated with improved survival of children diagnosed with high-risk cancers, by identifying therapeutic options that would otherwise go unrecognised.
However, one of the roadblocks preventing use of these therapies is the common situation of finding a novel genomic feature that is suspected of being a cancer driver and of being targetable, or encountering more familiar oncogenic lesions in an atypical tumour context. In such instances, the lack of direct clinical experience or preclinical data about the biological and therapeutic significance of the lesion means that often, the targeted therapies are not used even when there is a chance the patient can benefit. These are lost therapeutic opportunities.
One way to address this issue is to establish an experimental program that can rapidly develop models to study individual genomic lesions and determine, at the bench, whether a genetic aberration is oncogenic and how it can be therapeutically targeted. This will be illustrated using unique variants encountered in the ZERO program, and how studying rare or individual variants still provides more general insights into the biology of childhood cancers and the use of targeted therapies. Moreover, we contend that understanding the biology of rare or individual mutations can recover lost therapeutic opportunities, providing clinicians and families with more information on which to base treatment decisions.