Abstract P2-08-17: Tumor inflammation signature (TIS), intrinsic subtypes and chemo-endocrine score (CES) in metastatic triple-negative breast cancer (mTNBC): A SOLTI biomarker program study
Authors: Pascual T , Pernaut C , Tolosa P , Galvan P , Bárcena C , Vidal M , Manso L , Adamo B , Dueñas M , Muñoz M , Chic N , Gonzalez-Farre B , Villagrasa P , Ciruelos E , Prat A 
Published: May 2019

Abstract
Background: The TIS is a clinical research gene expression-based assay that enriches for response to anti-PD1 monotherapy in multiple cancer-types (Ayers et al. JCI 2017). However, the expression of the TIS in mTNBC and its relationship with other biological classifications and overall survival (OS) is currently unknown.
Methods: A comprehensive RNA-based characterization of 45 patients with mTNBC treated at 2 SOLTI sites was performed. RNA from metastatic biopsies was analyzed on the nCounter system using the Breast Cancer 360TM panel, which includes 752 breast cancer-related genes, including the TIS and the PAM50 and TNBCtype subtype classifications. The 1ary objective was to estimate the proportion of TIS-high tumors (defined as a score above its median expression in the PanCancer TCGA dataset) within PAM50 Basal-like disease. 2ary objectives were 1) to explore TIS distribution across the other molecular subtypes, 2) to evaluate the distribution of the PAM50 and TNBCtype subtype classifications in mTNBC, 3) to explore the association between OS and TIS, subtypes and 38 additional signatures tracking multiple tumor biological processes. OS was defined as the time from the date of metastatic diagnosis to death or last follow-up. Descriptive statistics, log-rank tests and univariate cox models were performed using R code.
Results: Most tumor samples (77.3%) were obtained at first recurrence or diagnosis of metastatic disease. Metastatic biopsies were obtained from 10 different sites, being skin (31.3%), breast (22.2%) and lung (8.9%) the most frequent. PAM50 subtype distribution was as follows: Basal-like (73.3%), Luminal A (13.3%), HER2-enriched (11.1%) and Luminal B (2.2%). Similarly, all the TNBCtype subtypes were identified: Mesenchymal (MSL, 48.8%), Basal-like Immune-activated (31.2%), Luminal Androgen Receptor (LAR, 15.6%) and Basal-like Immune-Suppressed (4.4%). The vast majority of non-Basal-like tumors were identified as LAR or MSL (81.8%). The proportion of TIS-high within Basal-like disease was 73% (95% confidence interval [CI] 59-84%) and similar to the proportion of TIS-high within TNBC from TCGA (70%, CI 61-78%). The proportion of TIS-high was similar across the PAM50 and TNBCtype molecular subtypes. The median OS was 25.3 months (CI 19.2-36.8). TIS, PAM50 and TNBCtype subtypes were not found associated with OS. Among the 41 biological classifications, expression of 6 signatures were found significantly associated with OS: CES (hazard ratio [HR] 0.44; p=0.015), Basal-like score (HR=5.52; p=0.011), FOXA1 (HR=0.83; p=0.014), mast cells (HR=0.77; p=0.017), differentiation score (HR=0.63; p=0.039) and Luminal A score (HR=0.27; p=0.039). Compared to tumors with a CES-low score, tumors with a CES-high score were found enriched for luminal-related genes, including AR.
Conclusions:˜50% of mTNBC tumors are PAM50 Basal-like and are enriched for the TIS. Future studies should determine the ability of this biomarker to predict response to anti-PD1 monotherapy or in combination with chemotherapy. In addition, mTNBC with a high luminal-profile or CES might help identify patients who might benefit from anti-androgen therapies alone or in combination with immunotherapy.
Citation Format: Pascual T, Pernaut C, Tolosa P, Galvan P, Bárcena C, Vidal M, Manso L, Adamo B, Dueñas M, Muñoz M, Chic N, Gonzalez-Farre B, Villagrasa P, Ciruelos E, Prat A. Tumor inflammation signature (TIS), intrinsic subtypes and chemo-endocrine score (CES) in metastatic triple-negative breast cancer (mTNBC): A SOLTI biomarker program study [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 P2-08-17.