Abstract C120: Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy.

Abstract

Abstract Background: Metaplastic breast cancer (BC) is a treatment-refractory rare type of BC with characteristics similar to claudin-low tumors. Understanding the genomic landscape of metaplastic BC can lead to identification of new therapies. Methods: Patients with metastatic metaplastic BC referred for experimental therapies, who had adequate archival tumor tissue for DNA extraction, had targeted next-generation sequencing (NGS) for 3,769 exons of 236 cancer-related genes and 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation One, Foundation Medicine, MA). Results: NGS results were obtained for 10 women with metaplastic BC (median age 60 years [39-73], median prior therapies for metastatic BC 0 [0-1]). NGS revealed a total of 41 aberrations in 25 genes and all 10 patients had at least 1 molecular aberration (range 1-7, median 4). Of 41 detected molecular aberrations, 17 (41%) included putative activation of the PI3K/mTOR and/or MAPK pathways (PIK3CA [6], PTEN [3], PIK3R1 [1], NF1 [1], EGFR [1], EPHB1 [1], FGF23 [1], FGFR2 [1], HRAS [1], PTPN11 [1]), 13 (32%) loss of cell cycle control (CCND2 [1], CCND3 [1], CCNE1 [1], CDK2 [1], CDKN2A [2], MYC [6], RB1 [1]), 6 (15%) loss of apoptosis (MCL1 [1], NFKBIA [1], TP53 [4]), 2 (5%) aberrant DNA repair (BRCA2 [1], FANCA [1]), 2 (5%) aberrant methylation (KDM6A [1], MLL2 [1]) and 1 (2.5%) aberrant SWI/SNF chromatin remodeling (ARID1A [1]). Of the 10 patients, 9 (90%) received an experimental mTOR targeting therapy combination with temsirolimus, bevacizumab, and liposomal doxorubicin and at the median follow up of 5.8 months, 2 (22%) patients attained a partial response and 3 (33%) had stable disease >/= 4 months. The median progression-free survival was 6.2 months (95% confidence Interval 3.4 - 9.0) Conclusion: Genomic alterations putatively activating PI3K/mTOR and MAPK pathways are common in metastatic metaplastic BC. A combination therapy targeting mTOR demonstrated encouraging activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C120. Citation Format: Filip Janku, Razelle Kurzrock, Thorunn Helgason, Vicente Valero, Francisco Esteva, Jennifer J. Wheler, Daniel D. Karp, Funda Meric-Bernstam, Stacy L. Moulder. Genomic landscape in advanced metaplastic breast cancer and outcomes with mTOR targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C120.