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5040 Background: TMPRSS2-ERG fusion gene is a common driver of prostate cancer. The PREMIERE study is a phase II, single arm open-label, multicentre, clinical trial designed to analyse the predictive/prognostic value of TMPRSS2-ERG in first-line chemo-naïve mCRPC patients treated with enzalutamide. Methods: We centrally evaluated TMPRSS2-ERG in diagnostic samples using PCR, FISH and IHC for ERG. Among exploratory biomarkers we included plasma DNA, AR copy number by ddPCR and CTC by AdnaTest. PCWG2 criteria were used for outcome evaluation. We correlated TMPRSS2-ERGand other exploratory biomarkers with mCRPC outcomes. Results: Ninety eight patients with median age 77 y (range 59-95), ECOG 0/1 (54/46%) with mts located in bone (82%), LN (48%) and visceral (17%). With a median FU of 37.3 months, PSA response was PSA50: 82% and PSA90: 53%; median PSA-PFS was 13.7m (95%CI 10.2-19.0), Rad-PFS 26.7m (95%CI: 22.0-NA) and OS 37.5m (95%IC: 33.7-NA). TMPRSS2-ERG was detected in 32 pts (33%), AR gain in 11 pts and CTCs in 35 pts. No differences were observed based on TMPRSS2-ERG status for PSA response (PSA50: 81% vs 83%; p=0.8), PSA-PFS (median 12.8 vs 14.7m; HR 0.98; 95%CI 0.58-1.67; p=0.95), Rad-PFS (median 28.4 vs 26.4m; HR 1.02; 95% 0.53-1.96, p=0.95) or OS (median 36.9 vs 38.1m; HR 1.23; 95%CI 0.69-2.21, p=0.48). Plasma AR gain was associated with worse PSA-PFS (median 4.2 vs 14.7 m; p<0.0001), Rad-PFS (median 3.6 vs 28.4m; p<0.0001) and OS (median 12.7 vs 38.1m; p<0.0001). Plasma DNA and CTCs were also associated with worse outcome. Multivariate analyses of exploratory biomarkers are included in the table. Conclusions: The fusion gene TMPRSS2-ERG is not predictive nor prognostic on enzalutamide treatment in first-line chemo-naïve mCRPC patients. Plasma AR gain and CTCs are strong independent biomarkers associated with adverse outcome. Multivariate analysis of exploratory biomarkers. Clinical trial information: NCT02288936. [Table: see text]

5052 Background: Circulating tumor cells (CTCs) enumeration using CellSearch correlates with clinical outcome in prostate cancer, but is limited for gene expression analysis. AdnaTest ProstateCancer is a commercially available CTC immune-enrichment and PCR-related detection method that allows gene expression studies (Antonarakis E, NEJM 2014). It has demonstrated incremental detection of CTCs in patients with no CTCs identified by CellSearch (Samoila A, ASCO 2013) but needs to be clinically qualified. There is a strong need for studies to assess the association with the clinical outcome in CRPC. Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC pts were recruited in 16 institutions. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma AR (Grande E, ASC0 2017 #) and CTC characterization (Grande E, ESMO 2016). Outcome measures included PSA-PFS (sPFS), radiographic PFS (rPFS) and OS. Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-eight patients had CTC blood samples available. CTCs were detected at baseline, 12 weeks and progression in 36% (35/98), 27% (26/95) and 78% (32/41), respectively. The CTC conversion rate (positive to negative after 12 w) was 43% (15/35). All CTC conversions had ≥50% decline in PSA (15/15) whereas only 35% (7/20) of pts with persistent CTCs. At first interim analysis, with a median follow-up of 10.6 months, detection of CTCs at baseline was associated with worse sPFS (median, 7.59 m versus NR, HR, 3.67; 95% CI 1.90-7.10; P < 0.001), rPFS (median, 12.9 m versus NR; HR, 7.61; 95% CI, 2.80-20.64; P < 0.001) and OS (medians NR, HR, 9.51; 95% CI, 1.11-81.52; P = 0.0398). CTC positive pts were less likely to have a ≥90% decline in PSA (OR, 2.88; 95% CI, 1.13-7.72; P = 0.02). Conclusions: CTC detection using AdnaTest is associated with an adverse outcome in chemotherapy-naïve asymptomatic or oligo-symptomatic mCRPC pts. Clinical trial information: NCT02288936.

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Background: Endocrine resistance is a major cause of therapeutic failure in metastatic breast cancer (MBC). The information provided by DNA sequencing of plasma cell free DNA (cfDNA) and by the analysis of circulating tumor cells (CTC) may be useful to determine the occurrence and type of endocrine resistance. However, different levels of concordance between cfDNA and CTC, and also between liquid biopsy and tissue biopsy, have been reported. Thus, the best strategy for performing DNA sequencing in the setting of therapeutic decisions for luminal MBC patients is not well defined. The purpose of this study was to determine the concordance between DNA sequencing data from CTC, cfDNA, metastasis, and primary tumor in endocrine-resistant luminal MBC.Methods: Using the same panel (10 genes) we performed simultaneous sequencing of cfDNA, CTC, metastases and primary tumor in 38 patients with luminal MBC. CTC isolation was performed with an Epcam-based immunomagnetic system. Concordance of DNA sequencing data of the different types of sample was analyzed and correlated with clinical data. Results: CTC were detected in 21% of the patients. The rate of detection of genetic alterations was 87.5% for CTC, 61.5% for cfDNA, 63.2% for metastasis and 67.7% for primary tumor, and involved mainly TP53, PIK3CA, ESR1 and AKT1. A higher number of mutations was found in cfDNA of MBC patients with progressive disease (p=0.02) and the same trend was observed for endocrine resistance (p=0.08), especially for PIK3CA, ESR1 and AKT1 mutations. Global concordance was low to intermediate between CTC and cfDNA, but significantly higher between CTC and metastasis. Concordance also varied according to the specific genetic alteration, with no ESR1 mutations detected in CTC and with a low concordance for PIK3CA and AKT1 mutations between CTC and cfDNA samples.Conclusions: DNA sequencing of different types of tumor samples (cfDNA, CTC, metastasis and primary tumor) may provide different rates of genomic alterations detection in luminal endocrine-resistant MBC. A moderate to low concordance, with discordances depending both on the clinical situation and on the sequenced gene, support the complementarity of the different samples, with cfDNA and metastatic tissue as the preferred sources of tumor DNA.