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Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD

Background: TMPRSS2-ERG is a genetic alteration specific of prostate cancer, present in primary tumors and maintained under castration resistant prostate cancer (CRPC) progression. It results in androgen-driven overexpression of ERG, which is involved in resistance to taxanes in preclinical models. In prior work, we found that TMPRSS2-ERG expression in blood correlated with docetaxel resistance in metastatic CPRC. Here, we investigated if TMPRSS2-ERG expression in primary tumors predicts taxanes resistance in CPRC and the potential impact of prior second-line hormonal manipulations with abiraterone (A) or enzalutamide (E). Methods: Patients with metastatic CRPC treated with taxanes were included. Formalin-fixed paraffin-embedded (FFPE) tumors and peripheral blood mononuclear cells (PBMCs) fraction were tested for TMPRSS2-ERG by RT-qPCR. FFPE from hormone-sensitive disease (primary diagnosis) were retrospectively obtained. PBMCs were prospectively collected prior taxane initiation. TMPRSS2-ERG expression was tested by RT-qPCR. TMPRSS2-ERG detection was correlated with taxane response and clinical outcome. Results: A total of 84 tumor samples from 74 patients were included: 65 (87.3%) treated with docetaxel, 19 (25.7%) with cabazitaxel and 10 (13.5%) with both. Forty-six tumor samples (54.7%) were TMPRSS2-ERG+ and 38 (45.2%) TMPRSS2-ERG-. Overall, no correlation between tumor TMPRSS2-ERG expression and taxanes response or clinical outcome was observed. In 42 (50%) samples matched tumor and PBMC samples were available at the time of this analysis: 23 (54.7%) had detectable TMPRSS2-ERG on tissue and 11 (26.2%) on PBMCs fraction. In 27 patients, taxanes were administered as a first-line therapy and in 15 after A or E progression. TMPRSS2-ERG was detected in PBMC from 8 (29.6%) and 3 (20%) patients without or with prior A or E. In patients without prior A or E, TMPRSS2-ERG expression in primary tumors predicted a lower median PSA-PFS (5.5 vs 10.1 months for TMPRSS2-ERG+ vs -, respectively; p Conclusions: The role of TMPRSS2-ERG in taxane resistance may be different according to prior exposure to second-line hormone-therapy in CRPC. Prior androgen receptor inhibition may result in TMPRSS2-ERG downregulation and/or activation of alternative mechanisms of resistance. Further data according to this hypothesis will be presented. Citation Format: Mercedes Marín-Aguilera, Òscar Reig, Natalia Jiménez, Iván Victoria, Lydia Gaba, Sandra López, Javier Prato, Maria Verónica Pereira, Teresa Vilella, Montserrat Domenech, Josep Badal, Albert Font, Juan José García-Mosquera, Olatz Etxaniz, Cristina Carrato, Cristina Suárez, Joan Carles, Fabriccio Racc, Pedro Luis Fernández, Aleix Prat, Begoña Mellado. TMPRSS2-ERG predictive value for taxanes resistance according to prior second-line hormonal manipulations in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2777. doi:10.1158/1538-7445.AM2017-2777