Druggable gene alterations in Japanese patients with rare malignancy

Without a current standard of care, patients with rare malignancy are subjected to precision oncology with next-generation sequencing to identify a course of treatment. We sought to establish the clinical relevance of comprehensive genomic profiling (CGP) among patients with rare malignancy. Rare malignancy was defined using the Rare Cancers in Europe definition (<6 cases per 100,000 individuals). We analyzed gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Level A gene alterations, categorized using Clinical Interpretations of Variants in Cancer and MD Anderson Knowledge Base for Precision Oncology, were considered druggable. Rare malignancy accounted for 149 (45%) cases, with female genital cancers (32%) most common. Among the rare malignancy cases, we identified a lower frequency of mutation in TP53 (41% vs. 60%, P<0.001), KRAS (13% vs. 43%, P<0.001) and APC (3% vs. 25%, P<0.001), and a higher frequency of ARID1A mutation (14% vs. 6%, P=0.03), as compared with common malignancies. TMB-high and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 37 patients with rare malignancy; this percentage tended to be higher than that for patients with common malignancies (25% vs. 17%, P=0.08). Common druggable alterations were BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variant. Five of the 37 patients with druggable alterations received genome-driven treatment. There was no significant difference in overall survival between the rare and common malignancy groups. Our results provide clues for future clinical development and treatment success among Japanese patients with rare cancers.