Abstract PD7-07: Somatic alterations in primary tumors of patients (pts) with metastatic breast cancer (MBC) may predict likelihood of brain metastasis
Authors: Kabraji Sheheryar , Li Yvonne Y. , Hughes Melissa E. , Gupta Hersh V. , Buckley Lauren , Files Janet L. , Mohammed-Abreu Ayesha , Feeney Anne-Marie , Kirkner Greg , Patel Ashka , Garrido-Castro Ana C. , Barroso-Sousa Romualdo , Bychkovsky Brittany , Meyerson Matthew , Tolaney Sara , Dillon Deborah A. , Johnson Bruce , Winer Eric , Cherniack Andrew , Lin Nancy U. 
Published: March 2023

Abstract
Background: Despite advances in treatment options, outcomes remain poor for many pts with breast cancer brain metastases (BCBMs). Identifying genomic predictors of brain metastasis from primary tumors could lead to better stratification of pts at risk and drive the development of preventative strategies. The objective of this study was to describe the landscape of genomic alterations in primary tumors from pts with MBC who subsequently did or did not develop BCBMs.
Methods: We performed a case control study to identify somatic alterations in primary tumors associated with a higher incidence of brain metastases. We reviewed outcomes for 2562 unique MBC patients from a single institution who underwent targeted next-generation DNA sequencing of &gt; 280 cancer-related genes (OncoPanel) from their tumor between July 1, 2013 and December 31, 2020. Pts were included in this analysis if they had at least 2 years of follow-up from date of metastatic diagnosis and OncoPanel testing on a primary breast tumor. We compared single nucleotide variants (oncogenic or likely oncogenic), copy number variation (amplification and deep deletions) and tumor mutation burden in the primary tumors of pts in this cohort. Copy number variation was corrected for Panel version and tumor purity. Wilcoxon rank sum test and Fisher exact test was used to compare genomic differences between groups. False discovery rate was used to correct for multiple hypothesis testing and q &lt; 0.1 was considered significant
Results: A total of 369 pts were included in the final analytic cohort. Of these, 115 were diagnosed with brain mets (cases, BM group) and 224 were not (controls, nBM group). The BM group was enriched for patients with HER2-positive breast cancer (33 vs 12.5%), consistent with previous work. In the whole cohort, the most common and clinically significant somatic alterations (oncogenic single nucleotide variants or copy number high amplification or two copy deletion) are shown in Table 1. When adjusting for subtype there were no significantly enriched SNVs in BM vs nBM group. When adjusting for subtype, FGFR1 amplification was significantly enriched in hormone receptor positive HER2 negative (HR+ HER2-) patients with BM (log2 odds ratio 1.22, q &lt; 0.1). Tumor mutation burden was not significantly different in primary tumors between the BM and nBM groups (median TMB 7.3 vs 6.1, Wilcoxon p = 0.08).
Pathway analysis combining all subtypes revealed that RTK_RAS pathway (log2 odds ratio 1.64, q value &lt; 0.1) and TP53 pathway (log2 odds ratio 1.15, q value &lt; 0.1) gene sets were significantly enriched in the BM group. When controlling for subtype, pathway analysis revealed that RTK_RAS pathway gene set was significantly enriched in HR+ HER2- BM group (log2 odds ratio 1.36 q &lt; 0.1).
Conclusions: In this case control series of patients with metastatic breast cancer with or without brain metastases, we found that primary tumors that are enriched for somatic alterations in the RTK_RAS and TP53 pathway may be associated with higher risk of developing brain metastases. Further validation in larger cohorts is warranted.
Table 1. Frequency of somatic alterations in primary tumor by brain metastasis outcome.
Citation Format: Sheheryar Kabraji, Yvonne Y. Li, Melissa E. Hughes, Hersh V. Gupta, Lauren Buckley, Janet L. Files, Ayesha Mohammed-Abreu, Anne-Marie Feeney, Greg Kirkner, Ashka Patel, Ana C. Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Matthew Meyerson, Sara Tolaney, Deborah A. Dillon, Bruce Johnson, Eric Winer, Andrew Cherniack, Nancy U. Lin. Somatic alterations in primary tumors of patients (pts) with metastatic breast cancer (MBC) may predict likelihood of brain metastasis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-07.