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Therapeutic alternatives in advanced urothelial carcinoma are limited, especially in advanced lines, with only a few drugs having demonstrated relevant clinical benefit. This article discusses about a young patient with significant cardiovascular comorbidities, already treated with recommended first- and second-line drugs, and suffering from liver metastases. Despite the known poor prognosis of this disease and the few supporting data, given his peculiar clinical history, we opted to treat him with a third-line gemcitabine rechallenge with a notable response on his liver lesions. We present an intriguing case, both in terms of the therapeutic sequence and the disease course.

Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.

705 Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]

PARP inhibitors (PARPi) have recently emerged as a new treatment option for several solid tumors, including metastatic castration-resistant prostate cancer (mCRPC). However, several grade 3–4 adverse events have been reported during PARPi administration, leading to limitations in treatment adherence. Herein, we conducted a meta-analysis aimed at analyzing the incidence rate of commonly reported grade 3–4 adverse events, dose reduction, and treatment discontinuation in mCRPC patients treated with PARPi monotherapy. Incidence rate with 95% confidence intervals (CIs) of grade 3–4 toxicities, dose reduction, and treatment discontinuation were calculated. Six trials involving 752 mCRPC patients were available for the meta-analysis. According to our results, anemia was the most frequently observed grade 3–4 toxicity (24.1%), and dose reduction (26.9%) and treatment discontinuation (14.1%) were common events during PARPi treatment. Clinicians should carefully consider these risks, especially taking into account that the use of PARPi in mCRPC patients is expected to rise in the near future.

Background: With hormonal agents quickly expanding as novel therapeutic options in nonmetastatic castration-resistant prostate cancer (nmCRPC), the toxicity profile of enzalutamide, apalutamide, an...

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

e16545 Background: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to >400 spots (mean 240; >400 in 7 samples) and intratumoral T/CD4 cells from 4 to >400 spots (mean 168; >400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to >400 spots (mean 175, >400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (

Background: On February 23rd the first case of SARS-CoV-2 infection was diagnosed at the University Hospital Trust of Verona, Italy On March 13th, the Oncology Section was converted into a 22 inpatient beds COVID unit and we had to reshape our organization and personnel to face the SARS-CoV-2 epidemic, while maintaining our oncological activity Methods: We tracked down oncological activity from January 1st to March 31st, 2020, in relationship to the organizational changes implemented and in comparison to the same period of 2019 We also recorded cases of SARS-CoV-2 infections observed in oncology health professionals and hospital admissions of active oncology patients for SARS-CoV-2 infection Results: Progressive restrictions in patients', visitors', and caregivers' access to the inpatient and outpatient facilities of the Oncology section and organizational changes were adopted early on during the epidemic peak Since March 13th, segregated personnel teams were created, one dedicated to the COVID unit and a "clean" one dedicated to oncological patients, resulting in an overall 40% and 43% reduction in oncology-dedicated medical and nursing/auxiliary staff, respectively As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations, and specialty visits in the period January-March 2020 was 8%, 6%, and 3%, respectively;based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11 Patient's acceptance of adopted measures was very high (see abstract by Tregnago D) Overall, 8/85 (9%) health professionals tested positive for SARS-CoV-2 (no hospital admissions and no treatment required) and 7/525 (1 3%) active oncology patients were admitted for SARS-CoV-2 infection (of whom, 2 died of infection-related complications) Conclusions: A minimal (

Background: The health emergency caused by the SarS-Cov-2 pandemic has a strong impact on oncological patients' (pts) life. The purpose of this study is to explore the emotional impact and pts' perception experienced who accessed to our Oncology section at University Hospital and Trust of Verona (Italy) regarding these rules. Method(s): An questionnaire was designed by our Psycho-Oncology service and administered to all pts accessing to our outpatient facilities during a 21-days period (April 9th - April 30th, 2020). Two main areas were investigated: i) organizational aspects and ii) awareness about infection risks, protective strategies, and new rules adopted (14 items, plus demographic data). Percentage of relevant answers to questionnaire items are reported with 95% confidence intervals (95% CI). Result(s): Among 241 respondents, fear of accessing hospital facilities and that chemotherapy treatment could increase the infection risk was reported to be quite high or high in 34% (95% CI: 29-41%) and 27% (95% CI: 21-33%), respectively. Awareness of disease-related risks of infection and strategies to reduce them was "very clear" or "fairly clear" [83% (95% CI: 78-88%) and 93% (95% CI: 90-96%), respectively]. Availability of medical personnel to be contacted while not in hospital was perceived as "very high". Almost all pts felt that organizational measures were clearly expressed (98%, 95% CI: 96-100%) and mainly obtained through the information received at the triage (73%, 95% CI: 67-79%). Overall acceptance of these measures was very high (>70%). Of note, the acceptance of phone-based follow-up and visits were perceived as "not very adequate" or "absolutely not adequate" by 17% (95% CI: 12-22 %) and 18% (95% CI: 13-23%) of respondents, respectively. Conclusion(s): Herein, we report among the first real-life experiences about oncological pts' perception of infection risks and their level of acceptance of protective measures during SarS-Cov-2 pandemic. A timely and thoughtful measures adoption, the coordinated efforts of all figures involved in cancer care and an effective communication strategy to share the necessary risks and sacrifices with pts/caregivers, can lead to effective protection of oncological pts. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Copyright © 2020

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.MethodsThis survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2–positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher’s exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options.ResultsThis is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2–positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients’ planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.ConclusionOur study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan&ndash, Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51&ndash, 10.88) and 11.57 months (95% CI 10.90&ndash, not reached (NR)) as second-line and 11.38 months (95% CI 5.79&ndash, NR) and NR (95% CI 11.51&ndash, NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib&ndash, nivolumab and 25.64 months and NR with nivolumab&ndash, cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39, 95% CI 1.24&ndash, 4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04&ndash, 2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33, 95%CI, 1.16&ndash, 4.69, p = 0.018) and Hb levels (HR = 3.12, 95%CI 1.18&ndash, 8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72, 95%CI 1.04&ndash, 7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.

e17081 Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was assessed at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to bNLR. NLR was defined as neutrophil / lymphocyte (cutoff = 3) and ΔNLR the difference between NLR at 2nd cycle and bNLR (median as cutoff = 1.1). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd (67%), 3rd (22%) and > 3rd (11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. bNLR was available in 404 patients: bNLR < 3 (54%) correlated with statistically significant longer PFS [11.4 vs 5.4 months; HR 1.69 (1.33-2.15)] and OS [46.2 vs 17.2 months; HR 2.37 (1.72-3.26)] (both p< 0.001), with similar ORR (35% vs 30%, p= 0.28) but higher DCR (71% vs 52%, p< 0.001). ΔNLR was available in 360 patients: ΔNLR < 1.1 (73%) correlated with a statistically significant improvement of PFS [11.2 vs 4.9 months; HR 1.53 (1.16-2.03), p= 0.03], OS [Not Reached vs 19.7 months; HR 1.83 (1.28-2.61), p= 0.001], ORR (37% vs 23%, p= 0.011) and DCR (68% vs 53%, p= 0.008). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bNLR and ΔNLR with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bNLR and early ΔNLR with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.

Background The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Methods Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between ‘pure’ or ‘mixed’ histology ILC and Ki67. Results At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8 %, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21 %); 10-years DFS and OS were 75.1, 66.5, and 30.2 % (p = 0.01) and 84.3, 76.4 and 59 % (p = 0.003), for patients with a Ki67 21 %, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85 %, OS 100 %). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with ‘pure’ ILC performed worse than ‘mixed’ histology. Conclusions Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with ‘pure’ ILC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0325-z) contains supplementary material, which is available to authorized users.

Background The aim of this analysis was to develop and validate a prognostic model for advanced breast cancer (ABC) with luminal subtype based on the combination of clinical, pathological and therapeutic predictors to provide a practical tool to evaluate patients' prognosis. Methods Clinical and pathological data were retrospectively correlated to progression-free and overall survival (PFS/OS) using a Cox model. Significant treatment variables were adjusted with the propensity score analysis. A continuous score to identify risk classes was derived according to model ratios. The performance of the risk-class model was tested for post-progression survival (PPS) and conditional survival (CS) as well. Results Data from 335 patients (3 institutions) were gathered (median follow-up 58 months). At multivariate analysis Ki67, Performance Status (PS) and number of metastatic sites were significant predictors for PFS, whereas Ki67, PS, brain metastases, PFS after 1st-line therapy, number of chemotherapy lines, hormonal therapy and maintenance were significant predictors for OS. The hormonal maintenance resulted to be prognostic after adjustment with propensity score analysis. A two-class model significantly differentiated low-risk and high-risk patients for 2-year PFS (31.5% and 11.0%, p 0.0001 ), and 3-years OS (57.1% and 4.8%, p 0.0001 ). A three-class model separated low risk, intermediate-risk, and high-risk patients for 2-year PFS (40.8%, 24.4%, and 11.0%, p 0.0001 ) and 3-year OS (68.1%, 24.8%, and 4.8%, p 0.0001 ). Both models equally discriminate the luminal ABC prognosis in terms of PPS and CS. Conclusions A risk stratification model including ‘ easy-to-obtain ' clinical, pathological and therapeutic parameters accurately separates luminal ABC patients into different risk classes.

TPS596 Background: Urothelial cancer (UC) is the ninth most common cancer worldwide, this tumour has a poor prognosis when in advanced stage. Cisplatin-based chemotherapy is considered the most effective treatment but more than 50% of patients are considered not eligible ( cis-unfit) for this regimen and have a median survival of only 6-9 months. In the past years, the most used chemotherapy regimen for cis-unfit patients was the combination of carboplatin and gemcitabine. Two single arm studies tested the anti-PD-L1/PD1 monoclonal antibodies atezolizumab and pembrolizumab and reported a response rate of 25% with good safety profile in an unselected population for PD-L1 expression. Recently, atezolizumab alone showed longer OS compared to carboplatin-gemcitabine regimen. Avelumab is another fully human anti-PD-L1 IgG1 antibody already tested in urothelial and in other cancers with a promising safety and efficacy profile. Methods: The single arm, phase II ARIES trial (NCT03891238), aims to evaluate the activity and efficacy of avelumab in patients with metastatic or locally advanced UC considered cis-unfit with PD-L1 expression ≥5%. Overall survival is the primary endpoint. Cis-unfit definition includes at least one of the following characteristics (i) ECOG-Performance status=2; (ii) creatinine clearance