Abstract 2116: Genomic landscape of 1007 pan-cancer brain metastases.

Abstract Background: The pan-cancer genomic landscape of brain metastases (BM) has not been well-characterized. Herein, we evaluate genomically profiled BM tumor samples and additional sequenced tumor samples from other sites to further understand disease evolution. Methods: We analyzed BM specimens from 1007 patients who underwent craniotomy between 2014 and 2024. Targeted sequencing was performed with MSK-IMPACT, a next-generation sequencing assay which detects genomic alterations in up to 505 genes. The FACETS algorithm was used to estimate tumor purity, fraction of genome altered (FGA) and whole-genome duplication (WGD) status. We analyzed matched sample pairs from patients who had additional sequenced tumor samples resulting in 227 primary-BM (P-BM) pairs, 189 extracranial metastasis-BM (ECM-BM) pairs and 60 BM-BM pairs. One pair per patient was selected for each category based on maximum purity. For paired comparisons, the Wilcoxon signed-rank test was used to compare continuous features and McNemar’s test was used to compare WGD, with Benjamini-Hochberg p-value adjustment. The Jaccard index was computed to assess mutational concordance between pairs. Private mutation analysis was limited to genes with driver mutations in 5 pairs in each P-BM/ECM-BM group. Results: Median intracranial progression-free survival (iPFS) and overall survival (OS) from craniotomy were 11.3 and 25 months, respectively. The most frequent histologies in the cohort were non-small cell lung cancer (NSCLC; n = 360), breast (n = 181), and melanoma (n = 128). The genes with the highest proportion of oncogenic alterations were TP53 (62.0%), CDKN2A (25.0%), TERT (23.4%), KRAS (19.7%), and ERBB2 (12.3%). At least one structural variant or mutation was shared by 88.1% of P-BM pairs, 90.0% of ECM-BM pairs and 98.3% of BM-BM pairs. The mean number of shared driver mutations was 2.48 for P-BM pairs, 2.43 for ECM-BM pairs and 4.02 for BM-BM pairs. In a pan-cancer paired analysis, FGA, WGD and tumor purity were higher in BM in P-BM pairs (q 0.01 for all) and in ECM-BM pairs (q 0.01 for all). FGA and purity were higher in BM for P-BM pairs in upper gastrointestinal (GI) and NSCLC (q 0.01), and in ECM-BM pairs for NSCLC (q 0.01). By histology, in P-BM pairs, lower GI (n = 22) had the highest mean Jaccard index (J = 0.71) and prostate cancer (n = 10) had the lowest (J = 0.33), while in ECM-BM pairs melanoma (n = 23) had the highest (J = 0.77) and sarcoma (n = 9) had the lowest (J = 0.36). TP53 was the most commonly mutated gene in both P-BM (n pairs = 147, shared proportion = 0.816) and ECM-BM pairs (n pairs = 111, shared proportion = 0.869). Mutations in NFE2L2 and KMT2B were most commonly private to the BM in P-BM pairs (4/6 and 5/8 pairs with driver mutations private to BM, respectively), while NF1 mutations were most often BM-private in ECM-BM pairs (4/7). Conclusion: There is a high degree of concordance in alterations between P-BM and ECM-BM pairs. Alterations more commonly private to BM warrant further investigation. Citation Format: Ramzi Homsi, Henry Walch, Roshal Patel, Anna Skakodub, Emily Miao, James Lee, Chengcheng Gui, Mitchell Parker, Zachariya Yazdani, Michel A. Padilla Mazzeo, Claire Cooper, Kyle Sporn, Brandon Imber, Yao Yu, Jessica Wilcox, Nelson Moss, Ahmet Turan Ilica, Rabih Bou-Nassif, Joseph Stember, Christopher Jackson, Connor Kinslow, Gustav Cederquist, Caleb Lareau, Helena A. Yu, Soo Ryum Yang, Pedram Razavi, Joseph Chan, Kenny Kwok Hei Yu, Walid Khaled Chatila, Nikolaus Schultz, Luke R. Pike. Genomic landscape of 1007 pan-cancer brain metastases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2116.