Abstract PD5-07: Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts
Authors: Yuan Y , Yost SE , Chang C-W , Yoh KE , Johnson RM , Schmolze D , Liang J , Hutchinson KE 
Published: May 2019

Background: Prognosis for triple-negative breast cancer (TNBC) patients remains poor, due in part to the lack of effective targeted therapies in the advanced setting. Emerging clinical data indicates reduced efficacy of immune checkpoint inhibitors in heavily pre-treated TNBC, but the underlying mechanisms are poorly understood. To better understand the immune phenotypic evolution of paired TNBCs, we studied the genomic and transcriptomic profiles of tumors from patients undergoing treatment for TNBC.

Methods: We analyzed primary and recurrent TNBCs from 55 poor-risk patients, including 44 paired primary-metastatic samples and 11 paired metastatic tumors. FoundationOne® and RNAseq was successful on 89 specimens and 97 specimens, respectively. In addition to somatic alterations, FoundationOne® provided tumor mutational burden (TMB). From RNAseq, we ascertained the TNBC molecular subtypes, and the mRNA expression of immune-related genes. Stromal tumor-infiltrating lymphocytes (stromal TILs), recurrence-free survival, and overall survival were also studied.

Results: From FoundationOne® sequencing, a mutational landscape typical of TNBCs was observed across both primary and recurrent disease specimens, with TP53 mutated in 82.0% of specimens, and BRCA1 and BRCA2 mutated in 4.5% and 16.9% of specimens, respectively. Sample profiles revealed minimal shifts in copy number alterations and TMB over time, however, notable TNBC subtype shifts were observed between primary and recurrent tumors. These included an increase in the Lehmann/Pietenpol-defined basal-like 1 phenotype (BL1, 12.8% to 20.9%), an increase in the mesenchymal phenotype (M, 12.8% to 20.9%), and a significant decrease in the immunomodulatory phenotype (IM, 27.1% to 2.3%). Similarly, tumors exhibited a downward shift in gene expression delineating the Burstein-defined basal-like immune-activated phenotype (BLIA, 37.0% to 14.3%). Composite expression of immunomodulatory gene signatures representative of Th1/Th2 responses, IFNg-related inflammation, M1/M2 macrophage activation and suppression, etc., was decreased in the recurrent tumors compared to the primaries (p = 0.01), and histopathology-derived percent stromal TILs were significantly decreased in the recurrent TNBCs (p = 0.02). However, higher stromal TILs (≥30%) were not associated with improved overall survival when measured in primary specimens (p = 0.15), or with the time from relapse to death when measured in recurrent specimens (p = 0.65) in this cohort of immunotherapy-naïve patients.

Conclusion: In this retrospective study of paired TNBCs, significant transcriptomic phenotype shifts were observed as patients progressed, while only minor genomic shifts were seen. Selective immune profiling showed significantly reduced TILs and immune-activating gene expression signatures in recurrent TNBCs, which may explain the lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to understand the proteomic landscape shifts in TNBCs over time and to identify novel targeted agents appropriate for recurrent disease.

Citation Format: Yuan Y, Yost SE, Chang C-W, Yoh KE, Johnson RM, Schmolze D, Liang J, Hutchinson KE. Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-07.