Abstract 4331: Comprehensive analysis of copy number variation and sensitivity to targeted therapy in renal cell carcinoma using in-house cancer gene panel testing

Abstract

Abstract Purpose: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are the main drugs used to treat metastatic renal cell carcinoma (mRCC), but there are no effective biomarkers to determine their use. In this study, we aimed to identify factors that correlate with staging of RCC and drug sensitivity to mRCC based on the results of an in-house cancer gene panel test at Fujita Health University. Methods: 133 patients with RCC (70 non-metastatic RCC and 63 mRCC). DNA was analyzed for mutations in 143 cancer genes using the PleSSision Rapid cancer gene panel test. NextSeq2000 was used as the next-generation sequencer. From the curated reports obtained, factors including each gene mutation information and the correlation between copy number (CN) variation (CNV) cluster analysis information, clinicopathological information, and therapeutic response to ICI or TKI was examined. In this study, the therapeutic response was evaluated with RECIST1.1 and complete response and partial response were determined as objective response (OR). The endpoint was progression-free survival 2 (PFS2) defined as the interval between first-line treatment and the second relapse. Result: Mutational analysis showed no difference in the pattern of genetic variation with or without metastasis. CNV analyses showed a marked trend toward a decrease in CN on homologous recombination repair genes in a part of mRCCs. Cluster analysis of CNV information for each gene in response to TKI treatment in mRCC revealed multiple regions of decreased or increased CN. The main regions of increased CN were shown to be those formed by CN gain of oncogenes on chromosomes 7 and 12. Detailed analysis of this hot spot showed that when the cutoff value of sum of CN for KRAS, ERBB3, CDK4, and MDM2. for chromosome 12 set to 9, 8 (72.7%) of 11 patients with CN 9 or higher were in OR group, while 4 (7.7%) of 52 patients with CN less than 9 were in OR group, showing a significant difference between the two groups (P < 0.001). Similarly, when the cutoff value of sum of CN for EGFR, MET, and BRAF for chromosome 7 set to 8, 5 (83.3%) of 6 patients with CN 8 or higher were in OR group, while 7 (12.3%) of 57 patients with CN < 8 were in OR group, showing a significant difference between the two groups (P < 0.001). On the other hand, genetic markers predicting susceptibility to ICI could not be identified. Kaplan-Meier analysis showed that the group of patients with higher CN values for either chromosome 7 or 12 had better PFS2 after TKI treatment than the group of patients with lower CN values for either chromosome 7 or 12 (P < 0.001). Conclusion: Our results from in-house cancer gene panel tests successfully showed an association between RCC progression and cancer-related gene alterations. Furthermore, the results showed the possibility of predicting TKI treatment sensitivity in mRCC by focusing on CN gain of oncogenes in specific chromosomal regions. Citation Format: Akhito Takeuchi, Mayu Takeda, Eiji Sugihara, Yoshinari Muto, Sachio Nohara, Shigeki Tanishima, Kenji Zennami, Kiyoshi Takahara, Tetsuya Tsukamoto, Ryoichi Shiroki, Hideyuki Saya, Makoto Sumitomo. Comprehensive analysis of copy number variation and sensitivity to targeted therapy in renal cell carcinoma using in-house cancer gene panel testing. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4331.