Precision medicine of rare tumors: Uncovering the potential actionable targets through genomic profiling

Abstract

Rare tumors constitute a substantial portion of cancer diagnoses, however, research remains limited. To assess the utility of genomic testing for informing treatment decisions, we retrospectively evaluated the landscape of actionable genomic alterations and immune biomarkers in rare tumors. Genomic and clinical data from 42,569 patients with rare tumors, representing 137 cancer types and 15 classification systems, were obtained from public studies available on cBioPortal. Actionability was assessed using the CCBM knowledgebase. In this cohort, TP53 (16.5%), CDKN2A (5.0%), ATRX (4.6%), RB1 (4.2%), and DNMT3A (4.1%) were the most frequently mutated genes. At least one potential actionable biomarker was identified in 24.7% of patients with rare tumors, with considerable variation observed across cancer types (highest in Lung tumors [55.0%] and lowest in Thymic tumors [8.7%]). The actionable rates for approved/national guideline-recommended indications, clinical trial/biological evidence-supported indications, and off-label indications were 8.7% (n=3,713), 5.4% (n=2,292), and 10.6% (n=4,513), respectively. High tumor mutation burden (4.3%, 1,046/24,354) and microsatellite instability (0.9%, 122/13,013) were infrequent in rare tumors, although the former was relatively common in Skin tumors (28.2%, 256/909). Additionally, copy number alterations that potentially indicating actionable proteomic biomarkers, such as CD274 amplification, were detected in 277 patients. Complex cases involving multiple actionable biomarkers (3.8%, n=1,602) and drug resistance mutations (24.2%, n=10,299) were also identified. In conclusion, a significant proportion of patients with rare tumors harbor actionable biomarkers, supporting the recommendation for routine comprehensive genomic profiling. Further, molecular tumor board discussions are advised to interpretate complicated test results.