Breast cancer is the cancer with the most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients vs. 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based on the expression levels of five microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the overexpression and downregulation of proteins differently expressed in the serum of breast cancer patients vs. that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue, and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a, miR-497, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of miR-125b, miR-29c, miR-16, miR-1260, and miR-451 was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of miR-16 with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and the potential use of the predictor here described are discussed.

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from a range of in-vitro and in-vivo models of metastatic prostate cancer (mPC) revealed a high contribution of tumor material to EV-loaded DNA/RNA. Findings were validated in a cohort of longitudinal plasma samples collected from mPC patients during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA genomic features recapitulated matched-patient biopsies and associated with clinical progression. We developed a novel approach to enable the transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptomic profile in mPC EV-RNA is enriched for tumor-associated transcripts when compared to same patient blood RNA and healthy individuals EV-RNA, and reflect early on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.

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TPS209 Background: Multiple lines of evidence suggest a crosstalk between androgen receptor (AR) signaling and DNA damage repair (DDR) in prostate cancer. Co-targeting both pathways in mHNPC can result in a clinically relevant synergistic effect. ZZFIRST trial is evaluating the combination of TALA –a poly(ADP-ribose) polymerase inhibitor– and EZ –an AR signaling inhibitor– in mHNPC patients. Methods: This is a multicenter, open-label, randomized, investigator-initiated phase 2 clinical trial. Men aged ≥18 years with histologically confirmed mHNPC, an ECOG performance status of 0-1, and a prostate-specific antigen (PSA) ≥4 ng/mL at enrolment are eligible. Patients must have not received previous systemic treatment for locally advanced or mHNPC. A total of 54 patients will start treatment with EZ 160 mg/day for 2 28-day cycles in addition to standard androgen-deprivation therapy (ADT). Patients are then randomized and stratified based on homologous recombination gene alterations on a 1:2 ratio to either continue EZ 160 mg/day, or to receive EZ 160 mg/day plus TALA 0.5 mg/day. In both arms, patients will continue ADT throughout the trial. Treatment will continue until progressive disease (PD) or unacceptable toxicity. PSA will be determined every 4 weeks and radiological tumor extend will be assessed at screening and every 8 weeks for the 6 initial months of treatment and every 12 weeks thereafter until PD. Primary endpoint is PSA-complete response defined as the percentage of patients with PSA < 0.2 ng/mL at 12 months of therapy. Secondary endpoints include PSA-complete response at any time point and at month 7, PSA response ( < 4 ng/ml) at 7 and 12 months, PSA-progression-free survival (PSA-PFS), radiologic PFS, time to castration resistance based on PSA-PFS and rPFS, and overall survival. Safety will be assessed as per NCI-CTCAE 5.0. Exploratory endpoints include analysis of transcriptional changes in AR and DDR pathways and assessment of genomic signatures on tumor and liquid biopsies collected at baseline, 4 weeks, and PD. An imaging sub-study of whole-body diffusion weighted MRI will help to further study antitumor activity and drug resistance mechanisms. This trial was opened to accrual in July 2020. Currently 44 patients have been enrolled (with 37 randomized by cycle 3 day 1) out of 54 expected. Analysis will be assessed with the exact binomial test. At least 11 patients must maintain PSA < 0.2 ng/mL by 12 months of therapy among 32 evaluable patients in the combination arm to justify further investigation of this strategy. A drop-out rate of 10% has been considered. Clinical trial information: NCT04332744.