Abstract P2-09-13: Molecular characterization of tumors from metastatic TNBC patients treated with atezolizumab (atezo)
Authors: Molinero L , Chang C-W , Udyavar A , Fasso M , O'Hear C , Emens L , Cruz C , Hegde P , Schmid P 
Published: February 2018

Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited treatment options. Atezolizumab (atezo) is a humanized monoclonal antibody that inhibits the binding of PD-L1 to PD-1 and B7.1. Atezo has demonstrated promising activity in the mTNBC cohort of the phase 1 PCD4989g study. Clinical activity was previously linked to higher PD-L1 expression by IHC (ORR: 13% vs 5%) and TILs (ORR: 13% vs 7%) (Schmid et al., AACR 2017, NCT01375842). Here we characterize molecular features of tumors from atezo-treated patients and explore their potential association with clinical activity.

Methods & Results: Molecular characterization of pre-treatment tumor tissue was performed to investigate potential biological mechanisms associated with the clinical activity of atezo in mTNBC. DNA mutational analysis of tumors from 78 patients was performed with the Foundation Medicine One panel. Median tumor mutation burden (TMB) was 4.6 Mut/Mb (CI 95% 3.604 - 5.405). TMB was not associated with either TILs or immune biomarkers by IHC (PD-L1 or CD8) or with clinical activity (ORR, PFS or OS). The prevalence of loss of heterozygosity or mutations in TP53 or BRCA1/2 in this mTNBC cohort was 65%, 95%, and 10%, respectively. None of these genomic alterations were associated with clinical activity to atezo. RNA-Seq based analyses were performed in tissue from 96 patients. PAM50 profiling classified these tumors as 84% basal-like, 9% HER-2-enriched, 4% luminal A and 2% luminal B. TNBC subtyping (Burstein et al., CCR 2015) classified 42% of the tumors as basal-like (BL) immune activated (BLIA), 35% BL immune suppressed (BLIS), 17% luminal androgen receptor (LAR) and 2% mesenchymal (MES). Histopathology immune biomarkers TILs, PD-L1 and CD8 were highest in BLIA, intermediate in LAR and lowest in BLIS. ORRs by RECIST 1.1 were highest in BLIA and LAR, and lowest in BLIS and MES (17.5%, 18.8%, 0% and 0%, respectively). Although univariate analysis showed that the BLIA subgroup had significantly longer PFS and OS, multivariate analysis showed an association for both the BLIA and LAR subgroups with improved PFS and OS. High expression of pre-specified B- and T-cell RNA signatures were significantly associated with better ORR, PFS, and OS.

Conclusion: Comprehensive molecular characterization of tumors from this non-randomized phase 1 mTNBC cohort showed a low TMB. Mutations in BRCA1/2, TP53, or loss of heterozygosity did not impact atezo clinical activity. Clinical benefit from atezo was enriched in BLIA and LAR TNBC subtypes, both representing tumors with a rich tumor immune microenvironment.

Citation Format: Molinero L, Chang C-W, Udyavar A, Fasso M, O'Hear C, Emens L, Cruz C, Hegde P, Schmid P. Molecular characterization of tumors from metastatic TNBC patients treated with atezolizumab (atezo) [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 P2-09-13.