Abstract P4-05-22: A systematic review of the receptor status and genomic landscape of breast cancer brain metastases

Abstract

Abstract Introduction Breast cancer brain metastasis (BCBM) is a growing clinical problem common and one which is associated with significant morbidity and mortality. However the efficacy of systemic treatment is extremely limited and, at present, no systemic therapies are specifically approved for the treatment of BCBM. Given this there is a need to develop treatments. In the era of genomic medicine one avenue is to understand the specific genomic aberrations that are contained within brain metastasis with the aim of developing therapies specifically targeted at these aberrations. Several studies have undertaken DNA sequencing of BCBMs to understand the genomic landscape. The aim of this study was to perform a comprehensive systematic review of these sequencing studies to generate a compendium of genomic aberrations and their actionability, as well as receptor and PAM50 status switching where this was reported. Methods A systematic search of the literature was performed on the Web of Science databases encompassing MEDLINE and with the results screened. Additional potential studies were found by hand searching of the literature. The search terms were “breast AND brain AND metast* AND sequenc*”. Studies were required to be in English, be published before 31st May 2019 and have greater than 3 patients with sequenced BCBMs with data on point mutations of at least one gene contained within the article or supplementary information. Results 11 of 203 (5.4%) literature search results met the requisite inclusion criteria. These studies contained 147 patients (range per study 4-45); of which 111 (76%) had matched pairs of primary BC and BCBM. Paired Oestrogen receptor (ER) and HER2 status was available for 52 and 51 cases respectively. Receptor switching between primary tumour and BCBM occurred as follows: ER+ to ER- 3/16 (19%) compared ER- to ER+ 1/36 (3%); HER2+ to HER2- 3/17 (18%) and HER2- to HER2+ 4/34 (12%). Paired PAM50 data was available for only 20 cases and subtype switching occurred in 11 of 20 (55%) of cases; the biggest switch was from basal-like to normal like occurring in 44% (4 of 9). 160 previously identified genes were found to be mutated in at least 1 BCBM; with 16 genes mutated in >3 BCBM cases (ATR, BRAF, BRCA2, CDH1, EPPKL1, ERBB2, FLT3, ITPR1, KIT, LAMA5, MET, MLH1, PIK3CA, PTEN, RB1, TP53, ZFHX3). The commonest mutated genes were TP53 (n=64 cases), PIK3CA (n=30), MLH1 (n=7), RB1 (n=7) and ERBB2 (n=6). MLH1 was reported as mutated in 7 BCBM cases (actual point mutation only reported in one case). Data on actionability and amplifications will be presented as will differences in the genomic data between the primary and the BCBM where available. Conclusion This systematic review provides an overview of the currently published genomic literature regarding BCBM. It demonstrates that receptor switching is in keeping with previous studies. While PAM50 switching occurs in a significant number of cases and the implications of this for treatment need to be explored. Overall the genes that are mutated in BCBM are similar to those reported in extracranial disease with a number of these being targetable. While the finding of a mutations in MLH1 is a novel finding which warrants further investigation. These data highlight the potential importance of IHC and genomic assessment of BCBM. The value of treatment strategies targeting the actionable mutations need to be explored in the context of clinical trials. PAM50 status switching (Primaries in Rows, Metastases in Columns)LumA (M)LumB (M)HER2 (M)Basal-like (M)Normal-like (M)LumA (P)12200LumB (P)00000HER2 (P)10201Basal-like (P)00054Normal-like (P)00011 Citation Format: Alexander James Morgan, Athina Giannoudis, Carlo Palmieri. A systematic review of the receptor status and genomic landscape of breast cancer brain metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-22.