Abstract PO5-16-01: Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer
Authors: Safonov Anton , Smith Deborah , Ferraro Emanuela , Shen Junchao , Khatri Ishaani , Kumar Rahul , An Julia , Robson Mark , Chandarlapaty Sarat , Boire Adrienne , Schultz Nikolaus , Moss Nelson , Pike Luke , Razavi Pedram 
Published: May 2024

Abstract
Introduction: Recent progress in imaging and therapeutics has led to improvements in the treatment of advanced breast cancer. However, the incidence of brain metastasis (BM) in breast cancer is increasing and continues to be associated with poor prognosis and significant morbidity. Herein, we describe genomic enrichments associated with brain tropism from a large institutional clinico-genomic cohort. Methods: Patients who underwent tumor and matched normal sequencing utilizing hybridization-capture based targeted exonic sequencing (MSK-IMPACT) from April 2014 to March 2023 were included in this analysis; this cohort included 6,377 samples from 5,135 patients. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, copy number changes and structural variants enriched in samples in resected BM specimens (n = 179), compared to primary tumors (n = 2980), stratified by receptor status. Enrichment analysis was conducted using a Fisher exact test for each respective receptor status. Similar analyses were conducted between extracranial metastatic (ECM) sites (n = 3186) and primary tumors, to differentiate the unique genomic features driving the emergence of BM as compared to general metastatic propensity. Multiple hypothesis testing was performed using Benjamini-Hochberg. Further genomic analysis, including allele specific copy number changes and mutational signatures will be reported at the 2023 SABCS meeting. Results: Oncogenic alterations in several genes were found to be enriched in BM samples compared to primary tumor, with an odds ratio exceeding that of the corresponding ECM comparison. For example, in the HR+/HER2- subset (4329 samples from 3476 patients), pathogenic variants in the following genes were enriched in BM:Primary analysis: NF1 (OR 6.4 [2.9 – 13.7], q = 0.001, 15.5% of BM), MYC (OR 3.9 [2.0 – 7.4], q = 0.001, 24.4% of BM), AGO2 (5.2 [2.4 – 10.9], q= 0.002, 15.5% of BM), CDKN2A (OR 3.9 [1.6 – 9.4], q = 0.06, 10.3% of BM), ERBB2 (OR 3.6 [1.5 – 8.6], q = 0.06, 10.3% of BM), RB1 (OR 4.2 [1.5 – 11.4], q = 0.06, 8.6% of BM), TP53 (OR 2.0 [1.1 – 3.5], q = 0.07, 40% of BM). In contrast, ESR1 variants were enriched in BM:Primary (OR 14.0 [6.7 – 28.2], but at the same level as ECM:Primary (OR 12.3 [8.7 – 17.7]). When considering HER2+ tumors (919 samples from 739 patients), only NKX.3 was enriched in the BM:Primary comparison (OR 11.5 [3.2 – 42.3], q = 0.004, 11.6% of BM). Although no TNBC samples met significance thresholds after adjustment for multiple hypothesis testing, CDH1, NTRK1, EGFR, and TP53 emerged as putatively significant. Conclusions: In a large cohort of genomically-profiled breast cancer samples, we find recurrent involvement of genes involved in cell cycle regulation (RB1, CDKN2A, TP53); these have been found to be enriched in brain metastases from other cancer types and are implicated in resistance to common lineage-directed therapies. Our approach also uncovered several targets for which therapies are actively in development (ERBB2, MYC). Further study of genomic evolution of breast cancer in the context of brain metastasis and therapeutic resistance will uncover conserved site-specific genomic changes and will identify novel, rational therapeutic targets.
Citation Format: Anton Safonov, Deborah Smith, Emanuela Ferraro, Junchao Shen, Ishaani Khatri, Rahul Kumar, Julia An, Mark Robson, Sarat Chandarlapaty, Adrienne Boire, Nikolaus Schultz, Nelson Moss, Luke Pike, Pedram Razavi. Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-01.