Ashleigh J Sullivan, Dong-Anh Khuong-Quang, Anita Villani, Marie Wong-Erasmus, Sarah Trinder, Loretta M S Lau, Paulette Barahona, Ann-Kristin Altekoester, Megan Rumford, Kimberly Dias, Chelsea Mayoh, Noemi A Fuentes-Bolanos, Eliza K Courtney, Sam El-Kamand, Louise Cui, Angela Lin, Scott Davidson, Kyoko E Yuki, Nicholas Sanders, Jordan Staunton, Sophie Jessop, Shampavi Sriharan, Frank Alvaro, Antoinette Anazodo, Kanika Bhatia, Martin Campbell, Steve Foresto, Nicholas G Gottardo, Maria Kirby, Seong Lin Khaw, Neevika Manoharan, Geoff McCowage, Andrew S Moore, Wayne Nicholls, Matthew O'Connor, Bhavna Padhye, Anne L Ryan, Leanne Super, Paul J Wood, Janene Davies, Colleen D'Arcy, Andrew J Gifford, Michael Rodriguez, Katherine M Tucker, Mark Pinese, Paul G Ekert, Michelle Haber, Vanessa Tyrrell, Toby N Trahair, Glenn M Marshall, Adam Shlien, Mark J Cowley, David S Ziegler
The role of comprehensive genomic profiling for therapeutic decision-making is established in high-risk pediatric cancers, but its utility in rare and diagnostically challenging tumors is unclear. Here we report 123 non-high-risk patients enrolled in the Australian ZERO Childhood Cancer Program for diagnostic uncertainty, clinician request to address a specific molecular query, or other rare tumors. Comprehensive multi-omic profiling led to a change in diagnosis in 17.9% (22/123) of patients, with overall diagnostic utility in 35% (43/123). Molecular queries were resolved in 97.6% (40/41). Multi-omic results informed conventional management in 20.3% (25/123). Precision-guided therapy was recommended in 67.5% (83/123), and administered in 36.1% (30/83), with an objective response or prolonged (>6 months) stable disease in 88.9% of evaluable cases (16/18). Findings were confirmed in an independent cohort from the Canadian KiCS program (n=41). In conclusion, in rare and diagnostically challenging pediatric tumors, multi-omic profiling improved diagnostic accuracy and informed clinical management, supporting its integration into routine care.