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OBJECTIVES: We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer. METHODS: This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1-3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013-7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS6) and overall response rate (ORR) by RECIST 1.1 criteria. RESULTS: During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2-100%). The overall PFS6 rate (as binary) was 22% (90% CI: 15.1-100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7-100%) and 38.5% (90% CI: 21.7%-100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug. CONCLUSIONS: The study met its primary endpoint, with a PFS6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients.

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INTRODUCTION: Although targeting human epidermal growth factor receptor 2 (HER2) is a meaningful treatment in HER2-positive breast cancer, ultimately resistance develops. Androgen receptor (AR) expression and immune cell infiltration are thought to be involved in trastuzumab response and may, therefore, be of interest as additional targets for therapy in HER2-positive breast cancer. AIM: To improve insights into the presence among AR expression, immune cell infiltration and HER2, we analysed HER2-positive breast tumours. METHODS: Primary tumours of 221 patients treated with trastuzumab for metastatic disease were selected. HER2 status was centrally confirmed. AR, T-cells (CD3 and CD8), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 immunohistochemical staining and M2 tumour-associated macrophages (TAMs; CD68 and CD163) immunofluorescence were performed. Tumour-infiltrating lymphocytes were evaluated by haematoxylin and eosin staining. RESULTS: Sufficient tumour material was available for 150 patients. Oestrogen receptor was expressed in 51.3% of the tumours and AR in 81.3% of the tumours. AR expression was inversely correlated with M2 TAM (Pearson's r = -0.361, P < 0.001), CD3+ (r = -0.199, P < 0.030) and CD8+ (r = -0.212, P < 0.021) T-cell infiltration. Clustering analysis showed high immune cell infiltration in AR low-expressing tumours, and low immune cell infiltration in AR-high expressing tumours. CONCLUSION: AR expression inversely correlates with immune cell infiltration in HER2-positive breast cancer.

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Model of the our research was the adult male amphibian anura, Pelophylax bergeri, poikilotherm species not considered threatened by the IUCN, sampled in representative sites at different degree. In the first phase, a biochemical characterization of the ADP-ribosylation on the skin of barcoded amphibian anura collected from Matese Lake (clean reference site in CE, Italy) was carried out. Two PARP isoforms were evidence: the first of 66 kDa is localized into nucleus and activated by DNA damage; the second of 150 kDa is in cytoplasm, as demonstrated by biochemical and immunohistochemical analysis. Subsequently, the PARP activity, the quantitative expression of androgen receptor gene, and the levels of arsenic and chromium in skin and testis of frog and soil, water, and sediment collected from sites at different degrees of pollution were measured. A significant variation of PARP activity and androgen receptor expression levels was detected in both tissues of barcoded frogs from Sarno and Scafati, along Sarno River (SA, Italy), suggesting that a PARP activation is correlated to pollution and to steroid-regulated physiology disruption.

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Background: Recent discovery of gene rearrangements have brought a new look to the molecular pathogenesis of cancer. Gene fusions occur in nearly 60% of prostate adenocarcinoma, being the TMPRSS2-ERG one of the most common. Evidence supports the role of ERG fusion in tumorigenesis, progression and invasion via effecting pathways such as WNT, MYC, uPA, PI3K/AKT/PTEN, RAS/RAF/MAPF, NKX3.1, GST-pi and androgen receptor (AR) mediated signaling. Most of the ERG fusions involve 5'-partners androgen responsive. Therefore, we aimed to evaluate AR and ERG fusion protein expression on prostate tissue to find clinicopathological applications and possible role in therapy. Methods: One hundred three samples, including prostate core biopsies and radical prostatectomy specimens, were evaluated for ERG and AR expression by immunohistochemistry (IHC). ERG rearrangement was done by fluorescence in situ hybridization (FISH) on 11 randomly selected cases and correlated with IHC results. Results: From the total of 103 samples, eight (8/103) were benign, fourteen (14/103) had atypical glands, two (2/103) had prostatic intraepithelial neoplasia (PIN), and seventy nine (79/103) showed prostate adenocarcinoma. Forty four (44/79) tumor cases were Gleason score (GS) 6-7 (lower GS), and thirty five (35/79) were GS of 8-10 (higher GS). ERG immunoreaction was observed in 27.8% (22/79) of the tumor cases, showing higher expression in those with lower GS (68.2%, 15/22) compared to higher GS (31.8%, 7/22). Neither benign glands nor PIN stained with ERG. AR expression was observed in 75% of benign samples, 78.5% of atypical glands, 100% of PIN, and in 87.3% of tumor cases with no significant difference based on GS. Co-expression of ERG and AR was evaluated on all the tumor samples. ERG+/AR+ was seen in 77.3% (17/22) of the ERG+ tumor cases, with higher frequency in lower GS (64.7%, 11/17) compared to those with higher GS (35.3%, 6/17). All but five corresponding ERG+ tumor samples were negative for AR. Only 5 samples were ERG-/AR- corresponding to adenocarcinoma GS of 6. Presence or absence of ERG rearrangement was confirmed by FISH and correlated with IHC results. Conclusions: Characterization of ERG status by IHC in prostate tissue has an excellent correlation with FISH. It may also assist in diagnosis since none of the benign glands stained with ERG. Co-expression of ERG+/AR+ in prostate tumor by IHC may suggest gene fusion between ERG and a 5'-partner driven by androgen signaling such as TMPRSS2, which it could represent an important ancillary test for clinical management and development of new therapeutic targets.

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AIM: Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC). METHODS: An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis). RESULTS: Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02). CONCLUSION: Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.

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