Background: Comprehensive genomic profiling (CGP) identifies actionable alterations in two-thirds of metastatic solid tumours, yet real-world treatment implementation remains unknown. We characterised both genomic yield and clinical translation barriers in 111 consecutive patients across 19 tumour types to quantify the precision oncology ‘knowing-doing gap’.
Methods: Out of 114 patients who were initially enrolled in the study, we performed retrospective analysis of 111 consecutive metastatic patients across 19 tumour types, after quality control exclusion, undergoing CGP using the Oncomine Comprehensive Assay Plus (517 genes). Genomic instability was assessed via the genomic instability metric (GIM); actionable alterations were tiered per Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines. Treatment implementation and clinical outcomes were tracked through October 2024 (median follow-up 11.2 months).
Results: Oncogenic alterations were detected in 109 of 111 patients (98.2%), with actionable findings in 72 patients (64.9%: Tier 1 = 32 and Tier 2 = 40). All GIM-high tumours (10/10) harboured homologous recombination repair (HRR) gene alterations. Critically, BRCA1/2 mutations were significantly enriched in GIM-high tumours (50% versus 12%, p = 0.008), whereas non-BRCA HRR genes (ATM, CHEK2, PALB2 and RAD51C/D) showed no association (50% versus 60.6%, p = 0.838). Despite 64.9% actionability, only 10 patients (13.9%) received tier-matched therapy – an 86% attrition rate attributable to clinical deterioration (22%), drug inaccessibility (19%) and financial toxicity (15%). Presumed germline variants were detected in 16.2% but confirmed in only 38.9%. Pharmacogenomic variants guided dose modifications in 29.7% of patients.
Conclusion: CGP demonstrates high diagnostic yield (98.2%) with actionable findings in two-thirds of pan-cancer patients. The differential BRCA1/2-specific association with genomic instability refines homologous recombination deficiency biology for multi-tumour Poly (ADP-ribose) polymerase inhibitor selection. An 86% attrition rate from genomic recommendation to treatment underscores urgent need for infrastructure improvements, including clinical trial access, pharmacogenomic integration and earlier CGP adoption.
