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e13072 Background: Bone Metastases (BM) are still the main cause of morbidity and morbility in cancer patients because of their complications defined as skeletal-related events (SREs).SREs reduce pts quality of life and are associated with an increasing in social and health costs. At present, data concerning BM are mainly obtained retrospectively from monocentric experiences. Methods: We performed a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 month (m)'s follow-up who were registered in a prospective BM database (BMDB). Detailed information on patients at first diagnosis of BM was recorded in a custom-built software system, updated every 6 m by participating centres and reviewed by the coordinator centre.All pts have signed an informed consent. Results: Since October 2014,618 pts with BM from solid tumors were enrolled of whom 220 have BC as primitive site with a 6 m follow-up. Median age was 62 y (range 26-86). Median Follow up was 34 m (6-149). At enrolment 109 (50%) had only BM and 109 (50%) pts had concomitant visceral and BM. Median time to first BM was 47 m (range 0-312) in Bone only disease and 78.6 m in pts with visceral bone metastases. Disease Free interval (DFI) was different according to BC molecular subtypes and stage. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.56, 95% confidence interval [CI]:1.1-2.3) (p = 0.002), basal-like (2.50, 95% CI:1.1-6.0) (p = 0.043), and HER2-enriched tumors (1.37, 95% CI:0.78-2.4) (p = 0.273). DFI for pts with stage I disease at diagnosis of primary BC was longer than that for stage III pts (median 67.2 m, 95%CI:53.1-96.1, vs. 58.1 m, 95%CI:41.9-73.4), with a HR of 1.84 (95% CI:1.1-3.0) (p = 0.015) for the stage III group, and 0.98 (95% C.I.:0.6-1.5) (p = 0.930) for the stage II group. During BM disease, 98 pts had at least 1 SREs . Zoledronate was used in 69.1% and Denosumab in 28.3% of cases. First line treatment was hormone-based (n = 105, 50.7%) chemo-based therapy (n = 80, 38.7%) and chemo+ormono based (n = 20, 9.7%). During follow up progression disease occurred in 167 pts. Median progression-free (mPFS) and overall survival calculated from metastatic disease diagnosis (mOS) were 15.1 m (95%CI 12.6-18.4) and 66.8 m (95%CI 52.1-79.2),respectively. Conclusions: This study presents prospective data about a cohort of BC pts enrolled at the first BM occurrence and followed over the time, extrapolated by the multicentric observational BMDB in order to better understed the clinical history of breast cancer and bone metastases.

e17030 Background: Urothelial carcinoma (UC) accounts for 90% of cases of bladder cancer. In advanced UC diagnosis, skeletal involvement is frequent. Here we report the establishment of a primary culture of bone metastasis (BM) from High Grade UC derived from 81 years-old patient with a previous diagnosis of papillary urothelial cancer in 2016. After 2 years, patient relapsed to bone and visceral sites and because of poor clinical condition, patient underwent palliative best supportive care. Methods: Patient-derived bone metastatic cell culture was obtained from a surgical specimen. Tumor cells were isolated by collagenase digestion. Cells were seeded on in vitro 2D plates or into 3D collagen scaffolds composed of bovine collagen type I. The establishment of tumor cell isolation was confirmed through the evaluation of cytomorphologic features and positive pan-citokeratin staining. Then, drug treatments was performed and cell survival was evaluated. The study was approved by Ethical Committee and patient signed an informed consent. Results: After a long-term culture, we were able to isolate from a 3D scaffold a tumor clone that successfully growth until passage 20. Stabilized cells generate spheroid-like aggregates, recreating acinar-structures typical of the primary papillary urothelial tumor. Next, we treated cells with: Gemcitabine (Gem), Carboplatin (Carbo), Docetaxel, Carbo+Gem and Bone targeted drugs (Zoledronic Acid and Denosumab). The most effective treatment was Gem+Carbo, in particular 24% of survival in 2D platform and 87% on 3D collagen scaffold. For all treatments, cells cultured on 3D scaffold were more resistant to drugs, mimicking more closely the in-vivo condition. Conclusions: We were able to isolate and establish a BM primary culture from UC using a 3D in-vitro collagen scaffold. This system can recreate microenvironmental conditions more similar to in-vivo ones and it promoted the isolation of tumor cell clones from stromal components of the heterogeneous primary culture. This cell line could be useful to investigate the molecular and genetic profile in order to identify promising molecular targets and to better understard the natural history of BM from UC.

e23542 Background: Soft tissue sarcomas (sts) represent a rare group of solid neoplasm of mesenchymal origin with a 1% incidence of all adult cancers. Liposarcoma and leiomyosarcoma (L-sarcoma) are the most common histotypes. The current first-line treatment for advanced/metastatic L-sarcomas is represented by anthracycline based-regimens. Second-line therapy options include trabectedin, eribulin, ifosfamide, gemcitabine and dacarbazine. In particular, the activity of trabectedin, a tetrahydroisoquinoline molecule, as well as its mechanism of action is not completely elucidated. Methods: The study involved six patient affected L-sarcoma. Patient-derived primary cultures were established after patient surgical treatment. Primary cells were cultured in standard monolayer culture and 3D collagen-based scaffolds. In order to gain inside into the mechanism of action of the drugs, genomic-, chemobiogram, proteomic-, cytometer and in silico analysis were performed. Results: The results confirmed the preservation of tumor gene expression in 3D culture model compared to standard monolayer culture. In particular 3D culture system was able to resemble the patient gene expression of TGFb, SLUG, SNAIL, MMP9 compared to 2D. In silico analysis showed an upregulation of COL1A1 gene, the extracellular matrix component of the present 3D model, in sts compared to other tumors. Pharmacological analysis displayed an increased sensitivity to trabectedin in all the 3D L-sarcoma primary culture compared to 2D culture system, while this was not observed with the other drugs. As previous preclinical evidences suggested that trabectedin mechanism of action include the impairing of ECM proteolytic degradation mediated by tumor cells, we think that its high observed sensitivity depend on the presence of collagen in our 3D- model. Conclusions: These results were suggestive of the losing credibility of monolayer standard culture for pharmacology studies and highlight the promising role of 3D patient-derived culture model for the study of sts biology. Moreover these results shed the light on the potential role of ECM in the mechanism of action of trabectedin in L-sarcomas. The work points out the role of this tumor microenvironment component in predicting response to trabectedin and provide the rationale for better stratifying patients which will be candidate for this drug. Further researches are needed to confirm these evidences.

4611 Background: Neuroendocrine neoplasms (NENs) are a rare subgroup of tumors with challenging management due to their unpredictable and heterogeneous behaviour. The identification of clinically useful biomarkers is a top priority need in this disease. The negative notch regulator DLL3 has gained increasing attention in small cell lung carcinoma, large cell neuroendocrine carcinoma and neuroendocrine prostate cancer, confirming the tumor suppressor function of Notch-1 signaling in neuroendocrine cells. Methods: A retrospective immunohistochemical analysis of DLL3, PD-L1 and RB1 was performed on FFPE samples from 43 patients with gastroenteropancreatic (GEP)-NENs and correlated with clinical characteristics. Results: DLL3 was expressed in high-grade (G3) GEP-NENs. The presence of DLL3 was significantly associated with poorly differentiated NEC (77.8% positive tumors), while none of the patients with well-differentiated NET expressed this marker. Expression of DLL3 was correlated with loss of RB1 and negative 68Ga-PET/CT scan. The 85.7% of DLL3- positive tumors showed loss of RB1 expression, while only 1 out of 35 DLL3- negative tumors had RB1 loss. DLL3 was expressed in 75% of patients with negative 68Ga-PET/CT, while only in 25% of patients with positive 68Ga-PET/CT scan. The presence of DLL3 was negatively associated with PFS and OS. Median PFS was 41.9 months in DLL3-negative patients versus 7.9 months in DLL3-positive patients; median OS was 72.9 months in DLL3-negative patients versus 11.7 months in DLL3-positive patients. No correlation was found with DLL3 and PD-L1 expression. The presence of PD-L1 was not associated with any clinical characteristics. Conclusions: DLL3 is expressed in high grade GEP-NENs and is associated with loss of RB1, negative 68Ga-PET/CT scan and unfavourable clinical outcome. The presence of DLL3 discriminates poorly differentiated NEC from well-differentiated NET. DLL3 could represent the ideal prognostic factor to stratify patients with GEP-NENs and a candidate therapeutic target in NEC patients.

e16181Background: Neuroendocrine Neoplasia (NEN) incidence increases with age above all at 70 years-old. This population is usually underestimated in clinical trials and because of co-morbidities a...

e18054Background: Hematologic markers of inflammation have been shown to be prognostic in different malignancies. Also in head and neck squamous-cell carcinoma (HNSCC) a prognostic role has been de...

e13075Background: BM are still the main cause of morbidity and morbility in cancer patients, mostly due to their complications defined as skeletal-related event (SRE). SRE reduce patients’quality o...

e23190Background: Patient-derived specimens are an invaluable resource to study cancer in particular in rare tumors as Soft Tissue Sarcomas, for which several subtypes exist, that are not all cover...

422 Background: VTE is common in cancer patients, but there is limited data in patients with UTT. We previously demonstrated that non-urothelial histology, cardiovascular disease (CVD) or CVD risk factors or renal dysfunction increased VTE risk in metastatic UTT. In this study, we assessed the frequency and risk factors for VTE in localized disease. Methods: Data was collected via an electronic data capture platform from 29 centers. Patients diagnosed with < cT2, > N1, or M1 disease at diagnosis were excluded. Patients without a date of diagnosis, last follow up, or VTE data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis, excluding VTEs diagnosed in the metastatic setting. Chi-squared analyses were used to assess differences in VTE rates for various patient, therapy, and tumor-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Results: 1131 patients were eligible for analysis. Perioperative chemotherapy was utilized in 46.9% (530/1131) of patients. 70.8% (801/1131) underwent definitive surgical intervention. There were 64 VTEs (cumulative incidence 5.7%). Treatment with chemotherapy (p = 0.609) or surgery (p = 0.886) did not increase VTE risk. In the univariate analysis, non-urothelial histology (p = 0.025), CVD or CVD risk factors (p = 0.004), renal dysfunction (p = 0.023), and radiation to the primary tumor (p = 0.048) were statistically significant factors. Multivariate analysis demonstrated that non-urothelial histology and CVD or CVD risk factors were associated with increased VTE risk (table). Conclusions: The VTE incidence of 5.7% in localized disease is lower than our previously reported rate in the metastatic setting (8.2%). Consistent with our findings in metastatic UTT, non-urothelial histology and CVD or CVD risk factors increase VTE risk in localized disease. Additional analyses to control for baseline demographics in patients treated with surgery and chemotherapy will be performed. [Table: see text]

261 Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naïve mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalemia and PSA response. Changes in HbA1c values were minimal and observed in 16 (10.7%) pts. Conclusions: These data suggest that P 5 mg BID, which is approved in combination with AA, and DEX 0.5 mg QD, are effective in preventing ME-associated AEs, and that P 2.5 mg BID and P 5 mg QD can be safely used with appropriate monitoring. The suggestion of a higher PSA response rate with DEX 0.5 mg QD arm warrants further validation. Clinical trial information: NCT01867710. [Table: see text]

4524 Background: Neoadjuvant cisplatin-based chemotherapy (Neo) improves outcomes in MIUC. However, the benefit achieved with Neo correlates with pathologic downstaging and patients with residual d...

4561 Background: Metastatic Chromophobe renal cell carcinoma (mChRCC) is a rare entity with no specific targeted therapy recommended. We aim to assess the outcome of targeted therapy (TT) in a larg...

4512 Background: GC has been adopted as a standard neoadjuvant regimen for MIBC, supported by practice guidelines, despite a lack of prospective (randomized) data in this setting. Given the histori...

4525 Background: Most studies reporting outcomes of pts with metastatic UC are derived from clinical trial data, potentially limiting the breadth/generalizability of the findings. To explore patterns of care/outcomes in “real world” pts, we initiated an international retrospective cohort study. Methods: Data were collected via an electronic data capture platform from 23 centers. Eligible pts had UC (at least muscle-invasive) and were initially evaluated from 1/1/2006-1/1/2011. Parameters were subjected to regression analysis to identify prognostic variables. Results: By 12/18/12, 1905 pts were enrolled. Among 1077 with metastatic UC, median age was 67 (IQR 60-75), 80% were male, 87% had bladder primary tumors, and 33% received perioperative chemotherapy. Only 758 (70%) received 1st-line chemotherapy for metastatic UC: cisplatin-based (51%), carboplatin-based (29%), non-platinum single-agent (16%), and non-platinum multi-agent (4%). The median survival from date of diagnosis of metastatic UC was 5.2 months (95% CI 4.4-6.5) and 16.1 months (95% CI 15.1-17.5) for pts who did and did not receive 1st-line chemotherapy, respectively [13.9 months (95% CI 12.78-14.98) from start of chemotherapy for latter group]. Among pts receiving 1st-line chemotherapy, univariable analysis revealed gender, primary tumor site, removal of primary, creatinine clearance, LDH, and hgb were not significantly associated with survival whereas smoking status, performance status, perioperative chemotherapy, metastatic sites, study site and chemotherapy regimen were. The multivariable analysis is shown in the Table. Conclusions: The current analysis identifies previously unrecognized prognostic factors in an international cohort of “real world” pts with metastatic UC treated with 1st-line chemotherapy. A large subset of pts with metastatic UC receives no chemotherapy. [Table: see text]