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Druggable gene alterations in Japanese patients with rare malignancy
Akihiro Ohmoto1, Naomi Hayashi2, Ippei Fukada3
1Division of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Abstract:
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.
Insights
Comprehensive genomic profiling (CGP) reveals druggable alterations in rare cancers, guiding precision oncology. While TP53 and KRAS mutations are less common, ARID1A mutations are more frequent in rare malignancies.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Patients with rare malignancies often lack standard treatments, necessitating precision oncology approaches.
- Next-generation sequencing (NGS) is crucial for identifying actionable targets in rare cancers.
- Defining rare malignancy is essential for targeted therapeutic strategies.
Purpose of the Study:
- To assess the clinical relevance of comprehensive genomic profiling (CGP) in patients with rare malignancies.
- To identify specific gene mutations, fusions, tumor mutational burden (TMB), and microsatellite instability (MSI) in rare cancers.
- To determine the frequency of druggable alterations in rare versus common malignancies.
Main Methods:
- Rare malignancy defined using the Rare Cancers in Europe criteria (<6 cases per 100,000 individuals).
- Analysis of gene mutations, fusions, TMB, and MSI status.
- Druggable alterations identified using established databases (CIViC, MD Anderson Knowledge Base).
Main Results:
- Rare malignancies constituted 45% of cases, with female genital cancers being most common.
- Lower frequencies of TP53, KRAS, and APC mutations, but higher ARID1A mutation rates were observed in rare compared to common malignancies.
- Druggable alterations were found in 25% of rare malignancy patients, a trend higher than in common malignancies (17%).
- BRAF V600E, ERBB2 amplification, PIK3CA E542K, and BRCA1/2 variants were common druggable alterations.
- Five patients with druggable alterations received genome-driven treatment.
Conclusions:
- CGP provides valuable insights into the genomic landscape of rare malignancies.
- Druggable alterations are identifiable in a significant proportion of rare cancer patients.
- Further clinical development is warranted to improve treatment outcomes for rare cancers.
- No significant difference in overall survival was noted between rare and common malignancy groups in this cohort.
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