In the Zero Childhood Cancer Program, a PMT with 17 RMS patients (11 fusion-positive (FP) and six fusion-negative (FN) patients) out of 252 pediatric and AYA high-risk cancer patients; dysregulation of Cyclin D–CDK4/6 axis associated genes, including overexpression of CDK4, CDKN2A/B, CCND3 or CCNE1; and CNVs of CDK4, CDKN2A/B, CCND2, or CCND3 were identified as therapeutic response biomarkers for CDK4/6 inhibition in ~45% of FP patients and in ~30% of FN RMS patients. Here, CCND3 is linked to cancer.