Abstract P3-07-36: Immune related gene expression signatures predict benefit of letrozole over tamoxifen in BIG 1-98
Authors: Willis S , Gray KP , Regan MM , Rae JM , Kammler R , Young B , Ditzel HJ , Lyng MB , Colleoni M , Viale G , Leyland-Jones B 
Published: May 2016

Abstract
Background: The prognostic significance of increased levels of CD8+ tumor infiltrating lymphocytes(TILs) in ER- breast cancer has been described. We sought to identify possible immune-related biomarkers for predicting benefit from letrozol(LET) or tamoxifen(TAM) for recurrence in ER+ breast cancer.
Patient and Methods: We used Illumina DASL Assay to measure gene expression in FFPE primary breast cancers from a subset of postmenopausal patients enrolled in the BIG 1-98 randomized phase 3 trial comparing 5 years LET (n=344) vs TAM (n=381) as adjuvant endocrine therapy. Gene sets (n=1910) that represent cell states and perturbations within the immune system from the Human Immunology Project Consortium were used in an exploratory analysis to identify possible predictive signatures.
Results: We identified five distinct gene signatures from previously reported laboratory experiments associated with immune cell differentiation that are highly predictive of benefit (reduced breast cancer recurrence risk) of LET over TAM, each with gene signature p-values&lt;1E-5 and signature-by-treatment interaction p&lt;1E-6. The signatures predict a similar pattern that patients at low-risk score benefit from LET and patients with high-risk score appear to have an advantage with TAM after 5 years. The gene signatures originate as a result of being differentially expressed in the following previously reported experiments. [RAP2A EEF2K TRAF3IP2 GPR37L1 DDX54] down regulated comparing TLR3 and TLR9 agonists in dendritic cells. [RPA1 DUSP4 NUDT18 ZFYVE28] up regulated in comparison of T follicular helper versus Th17 cells. [MAPK15 CCR4 SORCS2 RAMP1 SH3PXD2A] up regulated in regulatory T cell versus CD4+ T cells. [NDUFA6 GIMAP1 CPNE3 ST3GAL6 CCDC88A] down regulated in comparison of untreated CD8+ dendritic cells versus treated with IFNG. [GPN1 COX17 CUL2 CDSA] down regulated in naïve vs stimulated CD8 T cells after 48 hours. We further investigated the signatures using Hungarian Academy of Sciences (HAS) cohort (Gyorffy B 2010), which is a collection of smaller published affymetrix cohorts combined into a larger ER+, TAM treated cohort (n=700). One signature was not tested because two genes were not present in the affymetrix cohort. Three of the remaining four signatures gave informative prognostic results in the HAS cohort, and the signature associated with differentiation of CD8+ dendritic cells was highly prognostic with HR=0.36 (0.26-0.49) p=1E-11.
Conclusion: The role of selective estrogen receptor modulators on immune response has been well described, where TAM has been shown to prevent differentiation and activation of dendritic cells (Naibandian 2005). Similarly, it has been shown that MET inhibitors negatively regulate neutrophils suggesting that anti-MET drugs in cancer could impact immune response (Finisquerra 2015). These findings suggest that if TAM is a negative regulator of immune response why in the ATAC clinical trial, the combination therapy of anastrozole plus TAM were not significantly different from TAM alone were anastrozole was superior. With the increasing importance of understanding the role of immune response on outcome and the use of combination therapies the assessment of TILs in the neoadjuvant setting will be critical for guiding therapy.
Citation Format: Willis S, Gray KP, Regan MM, Rae JM, Kammler R, Young B, Ditzel HJ, Lyng MB, Colleoni M, Viale G, Leyland-Jones B. Immune related gene expression signatures predict benefit of letrozole over tamoxifen in BIG 1-98. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-36.