Abstract P5-07-04: Comprehensive analysis of the gene rearrangements within 822 breast cancer brain metastases reveals an enrichment of cyclin dependent kinase 12 rearrangements in HER2-positive brain metastases
Authors: Bhogal Talvinder , Sokol Ethan , Ramkissoon Shakti , Giannoudis Athina , McGregor Kimberly , Clark Allison , Razis Evangelia , Bartsch Rupert , Huang Richard , Palmieri Carlo 
Published: March 2022

Introduction:. Breast cancer (BC) brain metastases (BM) are a growing clinical problem as survival for metastatic BC improves. Genomic analyses of BM are key to developing more targeted therapeutic interventions. In this study we explored the gene rearrangements of BM and compared these to a cohort of non-paired local breast cancers (BCs) and non-CNS metastasis (N-CNS). Methods:. We analyzed 822 BMs and compared them to 11,988 local, breast-biopsied BCs and 15,516 N-CNS (samples unpaired) profiled with comprehensive genomic profiling (CGP) (Foundation Medicine, Cambridge, MA, USA) examining all classes of alterations in at least 324 genes. The prevalence of individual gene rearrangements within the BM was compared to those within BC and N-CNS cases. Further analysis was undertaken by classifying BM, BC and N-CNS specimens with respect to their oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status, available for a subset of samples. Results:. CGP identified 307 rearrangement events in BMs impacting 169 genes. Twenty genes exhibited recurrent rearrangement events with a prevalence greater than 0.5% in either the BM, BC or N-CNS. 10 of these 20 genes were significantly more prevalent within the BM specimens vs. BC and N-CNS (p&lt;0.05). The 10 significant genes and their prevalence in BM were as follows: CDK12 (3.53%, 29/822), RB1 (1.95%, 16/822), ETV6 (1.70%, 14/822), FANCA (0.73%, 6/822), PALB2 (0.73%, 6/822), ATR (0.61%, 5/822), CTNNA1 (0.61%, 5/822), FBXW7 (0.61%, 5/822), KDM5C (0.61%, 5/822) and MSH6 (0.61%, 5/822). BMs were enriched with CDK12 rearrangements (3.53%, 29/822) as compared to the BC (0.86%, 103/11,988; p=4x10-9) and N-CNS specimens (0.68%, 105/15,516; p=2x10-11). CDK12 rearrangements had a significantly higher propensity within HER2+ BM (14.59%, 27/185) as compared to the HER2+ BC (7.80%, 86/1,102; p=0.0046) and HER2+ N-CNS (7.87%, 94/1,194; p=0.0048). Further analysis by receptor status is outlined in Table 1. Conclusion:. These data demonstrate that overall rearrangements are uncommon in BMs. However, we identified that the most common rearrangement involves CDK12 which has a relatively high prevalence in HER2+ BMs compared to HER2+ primary BCs and N-CNS. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BM secondary to breast cancer.

The prevalence of CDK12 rearrangements within BM, BCs, and other N-CNS in different sub-types of BC.SubtypePrevalenceP-valueBM BCN-CNSBM vs. BCBM vs. . N-CNSAll3.53%. (29/822)0.86%. (103/11,988)0.68%. (105/15,516)3.55x10-91.85x10-11HER2+(irrespective of ER status)14.59%. (27/185)7.80%. (86/1,102)7.87%. (94/1,194)0.00460.0048HER2+, ER-15.29%. (13/85)10.53%. (6/57)1.96%. (1/51)0.460.02HER2+, ER+13.64%. (9/66)7.14%. (6/84)10.20%. (5/49)0.270.77HER2-, ER-0.67%. (2/298)0.17%. (1/585)0.69%. (2/291)0.261.00HER2-, ER+0.00%. (0/212)0.16%. (1/641)0.00%. (0/634)1.001.00

Citation Format: Talvinder Bhogal, Ethan Sokol, Shakti Ramkissoon, Athina Giannoudis, Kimberly McGregor, Allison Clark, Evangelia Razis, Rupert Bartsch, Richard Huang, Carlo Palmieri. Comprehensive analysis of the gene rearrangements within 822 breast cancer brain metastases reveals an enrichment of cyclin dependent kinase 12 rearrangements in HER2-positive brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-04.