Abstract 4626: A TRIM24-like mutational signature predicts worse relapse-free survival (RFS) and overall survival (OS) in patients (pts) with metaplastic breast cancer (MpBC)

Abstract

Abstract Background: TRIM24 is a multifunctional, epigenetic PHD/Bromodomain protein that negatively regulates p53, via an E3-ubiquitin ligase RING domain, and co-regulates transcription. Over-expression of TRIM24 in murine mammary epithelium results in the development of carcinosarcomas that bear close histologic resemblance to human MpBCs and are characterized by a distinct genomic signature. Here, we investigate the association between the presence of a TRIM24-like mutational signature and clinical outcomes in a cohort of human MpBCs. Methods: 20 archived samples of human MpBC with annotated clinical data underwent whole exome sequencing. In parallel, we sequenced 7 spontaneously arising carcinosarcomas from a TRIM24 overexpressing mouse model. To compare the mutations with those seen in the human MpBCs, we grouped them into pathways and created a signature of pathway activation seen in TRIM24-driven tumors. Median RFS and OS were estimated using the Kaplan-Meier method and compared between pts with and without a TRIM24-like mutational signature. Results: Baseline clinical characteristics are summarized in Table 1. Of the 20 MpBC pts, 5 had a TRIM24-like mutational signature and the remaining 15 pts did not. There were no statistically significant differences in baseline characteristics between the 2 groups. Median RFS for pts with a TRIM24-like mutational signature was 9 months (95% confidence interval [CI]: 8-undefined months). Median RFS for pts without a TRIM24-like mutational signature has not been reached (log-rank, p=0.0149). Median OS for pts with and without a TRIM24-like mutational signature was 17 months (95% CI: 10-undefined months) and 147 months (95% CI: 22-undefined months), respectively (log-rank, p=0.0402). Conclusion: In this cohort, pts with MpBCs that exhibit a TRIM24-like mutational signature had worse RFS and OS. This finding should be confirmed in larger, prospective studies. Table 1: Baseline Clinicopathological Characteristics by TRIM24 StatusTRIM24-like (n=5)Non TRIM24-like (n=15)p valueAge at diagnosis - Median (years, interquartile range)55 (50-61)56 (47-66)0.965Clinical Tumor SizeMean (cm, standard deviation)4.2 (1.5)3.4 (1.6)0.383Clinical Nodal StatusNegative - n (%)3 (60)11 (73)0.570Positive - n (%)2 (40)3 (20)Unknown - n (%)01 (7)ER/PR StatusNegative - n (%)5 (100)14 (93)1.000Positive - n (%)01 (7)HER2 StatusNegative - n (%)5 (100)15 (100)NAPositive - n (%)00HistologySpindle Cell - n (%)4 (80)7 (47)0.319Matrix-producing - n (%)1 (20)8 (53) Citation Format: Clinton Yam, Aundrietta Duncan, Jeffrey T. Chang, Michael Z. Gilcrease, Vrutant V. Shah, Michelle Barton, Stacy L. Moulder. A TRIM24-like mutational signature predicts worse relapse-free survival (RFS) and overall survival (OS) in patients (pts) with metaplastic breast cancer (MpBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4626.