Abstract P3-05-03: Metaplastic breast cancers: Genomic profile, mutational burden and TILs

Abstract

Abstract Background: Metaplastic breast cancers (MPBC) are rare, typically triple negative aggressive tumors composed of both, adenocarcinoma and metaplastic elements. Recent evidence that TNBC and MPBC can respond vigorously to immune checkpoint inhibitor therapy (Adams et al, ASCO 2017 and npj Breast Cancer 2017) has prompted the following comprehensive genomic profiling (CGP) and histopathologic assessment of tumor infiltrating lymphocytes (TIL) designed to uncover potential biomarkers of immunotherapy response for MPBC, including mutational burden, Microsatellite Instability (MSI) status and gene amplification of 9p21.4 (or CD274, which includes the PD-L1 locus). Methods: 12,214 locally aggressive, relapsed and metastatic breast malignancies (mBM) were subjected to CGP using DNA extracted from 40 µm of FFPE sections and adaptor ligation-based libraries to a mean coverage depth >650X for up to 315 cancer-related genes. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA. MSI status was determined by an algorithm based on the sequencing results. TIL were assessed on archived H&E tumor sections and enumerated per guidelines established by the TIL Working Group (Salgado, Ann Oncol 2015) in a subset of MPBC with the highest TMB and compared with low TMBC cases. Results: 165 of mBM cases were MPBC (1.4%) and are included in this study. All patients were female with a median age of 60 (range 24-86). 165 of the MPBC cases (100%) harbored a wide variety of GA involving more than 100 individual genes. The most common GA were identified in TP53 (65%), followed by PIK3CA (37%). No cases of MSI hi status (0/103) and only one case with amplification of 9p21.4 (1/165, 0.6%) were observed. Most MPBC had a low mutational burden, with a median TMB of 2.7 mutations/Mb (range 0-39.6). Only 11/165 tumors (6.7%) were found to have a TMB over 10 mutations/Mb, including 3 cases (1.8%) with TMB >20. Tumor sections were available for TIL review from 9/11 cases with highest TMB, as well as 11 control cases with lowest TMB. TIL were more frequently observed in high versus low TMB MPBC, with median TIL percentage of 40 and 20 (range 10-80 and range 10-60), respectively, although this difference was not statistically significant (Wilcoxon rank-sum test, p=0.15). Conclusions: Genomic profiling in the largest cohort of MPBC reported to date confirms that MPBC is enriched for TP53 and PIK3CA mutations and many tumors harbor targetable GA. The frequently observed tumoral PD-L1 expression in MPBC is not based on gene amplification as amplification of 9p21.4 is rare. Most tumors had a low mutation burden, and no significant association of TIL with TMB was observed, suggesting additional processes underlying MPBC immunogenicity. Citation Format: Taff J, Suh J, Singh B, Denkert C, Troxel AB, Ross JS, Adams S. Metaplastic breast cancers: Genomic profile, mutational burden and TILs [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-03.