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Càncer de pròstata resistent a la castració (CRPC); Cèl·lules tumorals circulants (CTC); Marcadors tumorals Cáncer de próstata resistente a la castración (CRPC); Células tumorales circulantes (CTC); Marcadores tumorales Castration-resistant prostate cancer (CRPC); Circulating tumor cells (CTCs); Tumor markers Background: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. Methods: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. Results: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. Conclusions: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PC. This work was partially financed with the “liquid Biopsy crowdfunding, 2017”. L.M-L. is supported by AECC.

2505 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent, brain penetrant (Kpuu=0.4 in intact rodent), and selective inhibitor of mutated IDH1 protein. Methods: Patients (pts) with relapsed/refractory (R/R) mIDH1 gliomas received olutasidenib 150 mg BID, orally either as single agent (SA) or in combination (CO) with azacitidine in a dose confirmation phase Ib followed by efficacy evaluation phase II study (NCT: 03684811). Results: As of 31-Oct-2019, 29 pts with R/R mIDH1 glioma were treated with olutasidenib as SA (n=24) or CO (n=5). The median age was 45 yrs (range: 23-64) & 62% were male. WHO Glioma Grade (Gr) at study entry was: II (17%), III (52%) & IV (31%). Median number of prior treatments was 2 (1-5); 86% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H (86%), R132L (7%), R132C (3.5%) & unspecified (3.5%). The median duration of olutasidenib treatment for SA & CO was 4.8 (1-11.4) & 1 (0.2-2.3) months, respectively. Fifteen pts discontinued (disease progression [n=12], AE [n=1], withdrew consent [n=1], other [n=1]). For SA, the most common (>25%) TEAEs (all grades, regardless of attribution) were: fatigue (50%), nausea (50%), diarrhea (33%), ALT increase (29%) & headache (29%). For CO, TEAEs that occurred in ≥ 2 pts were: nausea (n=4), fatigue (n=2), neutropenia (n=2), ALT increase (n=2) & AST increase (n=2). There were 2 protocol defined DLTs in the CO cohort, 1 pt with Gr 4 ALT, Gr 3 AST & Gr 3 GGT elevations & 1 pt with Gr 3 ALT elevation. No pts experienced a TEAE of QTcF prolongation. SA best responses are shown in Table; CO pts are too early for response assessment. The median PFS for SA was 8.3 months. Twenty (87%) and 11 (48%) pts were alive and progression-free at 6 & 12 months, respectively. Conclusions: SA olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in glioma pts. Evaluation of CO is ongoing. Updated safety and clinical activity, as well as evaluations of serum/CSF PK/PD will be provided. Clinical trial information: NCT03684811 . [Table: see text]

9505 Background: We report updated safety and efficacy of DM4-conjugated anti-CEACAM5 ADC from the expansion part of the first-in-human study (NCT02187848; Gazzah A et al. J Clin Oncol. 2019;37:15, 9072) in 92 NSQ NSCLC pts. Methods: CEACAM5 expression was assessed by immunohistochemistry on archived tumor samples. Two cohorts of pts have been analyzed: moderate and high expressors, with CEACAM5 expression at ≥2+ intensity between ≥1% to < 50% and ≥50% of the tumor cell population, respectively. SAR408701 was administered at 100 mg/m2 IV every 2 weeks. Tumor assessments were done every 4 cycles (8 weeks). Primary endpoint was overall response rate (ORR). Results: As of January 2020, 92 pts were treated: 28 moderate and 64 high expressors, with median age 62.5 years (31–91; 42.4% of pts ≥65), 51.1% male, 71.7% ECOG PS ≥1; median of 3 prior treatments (1–10 lines) for advanced disease, including anti-tubulin agents (60.9%) and anti-PD1/PD-L1 (75%). In the moderate expressor cohort, 2 confirmed partial responses (PR) were observed (ORR 7.1%). In the high expressor cohort, 13 pts had confirmed PRs (ORR 20.3% [95% confidence interval 12.27%–31.71%]); 27 (42.2%) had stable disease; ORR of 17.8% was observed in 45 pts who had prior anti-PD1/PD-L1. Pts had a median of 7 (1–49) cycles; median relative dose intensity was 0.98. Six pts discontinued due to treatment-emergent adverse events (TEAEs). Most frequent TEAEs (all grades) were asthenia (38.0%), keratopathy/keratitis (38.0%), peripheral neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%). 31 pts had dose modification due to a TEAE, including dose reduction for keratopathy/keratitis in 10 pts. Hematological toxicity included leukopenia (14.4%), neutropenia (4.4%), and thrombocytopenia (13.3%). Grade ≥3 TEAEs occurred in 47.8% of pts and were assessed as drug-related in 15.2%. Conclusions: SAR408701 shows promising antitumor activity in heavily pretreated advanced NSQ NSCLC pts with high CEACAM5 expression. SAR408701 was well tolerated, with minimal hematological toxicity compared to conventional chemotherapy; keratopathy was reversible and manageable with dose modification. These data support the activity of SAR408701 in NSQ NSCLC CEACAM5 high expressors. A phase 3 trial evaluating the activity of CEACAM5-DM4 ADC monotherapy in comparison with docetaxel in NSQ NSCLC CEACAM5 high expressors after failure of standard first line chemotherapy and anti-PD1/PD-L1 is underway. Clinical trial information: NCT02187848 .

6544 Background: The KEYNOTE-048 study (Burtness, at al. Lancet 2019;394:1915–28) led to approval of PE in combination with 5-FU/plat for first-line (1L) treatment of head and neck squamous cell carcinoma (HNSCC). The Phase I INDUCE-1 study (NCT02723955) has shown that GSK609±PE has a manageable safety profile in patients (pts) with advanced solid tumors (Hansen, at al. Annals of Oncology 2018;29[suppl_8]:viii404) and that GSK609 combined with PE has anti-tumor activity in pts with anti-PD-1/L1-naïve HNSCC (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). To evaluate the safety of GSK609±PE in combination with 5-FU/plat, we initiated additional safety cohorts. Methods: Pts eligible for GSK609+5-FU/plat had a diagnosis of advanced selected solid tumors and ≤5 prior lines of systemic therapy. Pts eligible for GSK609+PE+5-FU/plat had a diagnosis of recurrent or metastatic 1L HNSCC deemed incurable by local therapies. 5-FU/plat was administered every 3 weeks (Q3W) for 4-6 cycles (Burtness, at al. Lancet 2019;394:1915–28); GSK609 24 or 80 mg ±PE 200 mg were administered Q3W for up to 2 years/35 cycles or until disease progression or unacceptable toxicity. Results: Twenty-nine pts were enrolled in the 5-FU/plat safety cohorts: 10 pts in the GSK609+5-FU/plat cohort and 19 pts in the GSK609+PE+5-FU/plat cohort. With GSK609+5-FU/plat, 9/10 (90%) pts experienced ≥ 1 adverse event (AE). Of 32 AEs of any grade, 9 were Grade ≥3 and 3 were serious AEs (SAEs). Two of the 3 SAEs were related to study treatment (oral mucositis and febrile pancytopenia). With GSK609+PE+5-FU/plat, 18/19 (94.7%) pts experienced ≥ 1 AE. Of 119 AEs of any grade, 24 were Grade ≥3 and 15 were SAEs. Of the 15 SAEs, 11 were related to study treatment (febrile neutropenia [n=4], colitis [n=2], diarrhea [n=1], vomiting [n=1], acute kidney injury [n=1], cardiac chest pain [n=1] and lung infection [n=1]). For all cohorts, no Grade 5 AEs were observed. For 10 pts evaluable for confirmed best overall response in all cohorts, 2 pts had partial response, 6 pts had stable disease and 2 pts were nonevaluable. No difference in GSK609 exposure was observed relative to GSK609 monotherapy. Conclusions: The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted. Clinical trial information: NCT02723955 .

Introduction: Obesity results in PD1-mediated T-cell dysfunction in preclinical models and improved outcomes from ICI. We wanted to validate this clinical association in a prospective cohort of pts receiving PD1/L1 inhibitors across multiple CT and investigate the potential impact of CF, such as age and concomitant medications (CM) that may interact with obesity. Methods: Clinicopathological data from 310 pts treated with ICI at VHIO phase 1 Unit from Aug'12 to Jul'18 were investigated. Frequent CM included metformin (M), statins (S) and others. Associations between different variables and progression-free survival (PFS) were assessed with univariable and multivariate Cox regression models and survival data were calculated by the Kaplan-Meier method. Tumor types were stratified by proven PD1/L1 inhibitor efficacy versus unknown PD1/L1 sensitivity. Results: Out of 310 pts, median age was 59.8 years (y), 54.2% were male and most frequent tumor type was melanoma (19.4%) and lung (13.2%). In univariate models, pts with BMI>25 kg/m2 (n=147, 47%) had increased PFS (3.5 months [m], CI95% 2.8-5.5) as compared to those with BMI Citation Format: Analía Azaro, Alejandra Ivars, Ignacio Matos, Omar Saavedra, Itziar Gardeazabal, Juan Martin-Liberal, Cinta Hierro, María Vieito, Irene Braña, Cristina Viaplana, Guillermo Villacampa, Gemma Sala, María Alsina, Ana Callejo, Helena Verdaguer, Guillem Aegiles, Ana Oaknin, Eva Muñoz, Rodrigo Dienstmann, Elena Garralda. Validation of body mass index (BMI) as a prognostic factor in patients (pts) treated with immune checkpoint inhibitors (ICI) across multiple cancer types (CT) and the impact of confounding factors (CF) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B050. doi:10.1158/1535-7163.TARG-19-B050

Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas. Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812–9. ©2018 AACR.

Circulating tumor cells (CTCs), proposed as major players in cancer dissemination, have demonstrated clinical prognostic significance in several cancer types. However, their predictive value remains unclear. Here we evaluated the clinical utility of six CTC markers (tissue specific and epithelial to mesenchymal transition transcripts) both as prognostic and predictive tools in metastatic colorectal cancer (mCRC) patients. CTCs were immunoisolated from blood in 50 mCRC patients at baseline and at 4 and 16 weeks after treatment onset. Expression levels of GAPDH, VIL1, CLU, TIMP1, LOXL3 and ZEB2 were determined by qualitative polymerase chain reaction and normalized to the unspecific cell isolation marker CD45. At baseline, median progression-free survival (PFS) and overall survival (OS) for patients with high CTC markers were 6.3 and 12.7 months, respectively, versus 12.7 and 24.2 for patients with low CTC markers (PFS; p = 0.0003; OS; p = 0.044). Concerning response to therapy, PFS and OS for patients with increased CTC markers along treatment were, respectively, 6.6 and 13.1 months, compared with 12.7 and 24.3 for patients presenting CTC markers reduction (PFS; p = 0.004; OS; p = 0.007). Of note, CTC markers identified therapy-refractory patients not detected by standard image techniques. Patients with increased CTC markers along treatment, but classified as responders by computed tomography, showed significantly shorter survival times (PFS: 7.8 vs. 13.2; OS: 14.4 vs. 24.4; months). In conclusion, we have generated a CTC marker panel for prognosis evaluation and the identification of patients benefiting or not from therapy in mCRC. Our methodology efficiently classified patients earlier than routine computed tomography and from a minimally invasive liquid biopsy.

3015 Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) > 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347. [Table: see text]

2580 Background: There have been important changes in early drug development units with an unprecedented increase of immune-oncology (IO) trials. Currently at the Vall d’Hebron Institute Oncology (VHIO) close to 50% of our Phase 1 trials (Ph1t) portfolio includes IO drugs, while from 2011 to 2015 more than 80% of our trials assessed targeted agents (TA). We wanted to investigate whether this swift had a positive impact on patient (pts) outcome. Methods: We performed a retrospective analysis of the pts treated with IO and TA at VHIO Ph1t Unit from Jun’11 to May’18. Only patients treated with IO in ≥ 2nd line were included (and without an approved IO therapy as per standard-of-care) and those with TA classified as tiers II-III-IV by the ESMO scale for clinical actionability of molecular targets ESCAT (which also represents unapproved indications). The aim of this study was to compare overall survival (OS) for the two cohorts. Given the non-randomized nature of the study a propensity score weighting (PSW) was used to control for selection bias in treatment effect estimation. Results: Out of 545 eligible pts, 281 (51.5%) received TA and 264 (48.5%) IO, with unadjusted median OS (mOS) of 7.7 months (m) and 9.2m, respectively. In univariate analysis, OS was associated with tumor type, number of previous treatment lines, regimen (monotherapy vs combination), and clinical-laboratory prognostic factors (Vioscore: albumin < 3.5 g/dl; LDH > upper limit of normal; neutrophil/[leukocytes minus neutrophils] ratio (dNLR) > 3; more than 2 sites of metastasis; and presence of liver metastasis) (p < 0.05). After adjusting for these factors in a PSW model, the IO group showed statistically significant longer OS with HR = 0.75 (CI95% 0.65 – 0.86, p < 0.0001). The In a stratified analysis by tumor type we found no significant heterogeneity in the relative benefit of IO over TA. Conclusions: In real world data from our Ph1t population, treatment with IO was associated with longer OS than treatment with TA, even after adjusting for known prognostic factors and treatment selection biases. These results suggest that the likelihood of patient benefit with IO therapies in Ph1t is increasing.

Prostate cancer is the most common cancer in men worldwide. To improve future drug development and patient management, surrogate biomarkers associated with relevant outcomes are required. Circulating tumour cells (CTCs) are tumour cells that can enter the circulatory system, and are principally responsible for the development of metastasis at distant sites. In recent years, interest in detecting CTCs as a surrogate biomarker has ghiiukjrown. Clinical studies have revealed that high levels of CTCs in the blood correlate with disease progression in patients with prostate cancer; however, their predictive value for monitoring therapeutic response is less clear. Despite the important progress in CTC clinical development, there are critical requirements for the implementation of their analysis as a routine oncology tool. The goal of the present review is to provide an update on the advances in the clinical validation of CTCs as a surrogate biomarker and to discuss the principal obstacles and main challenges to their inclusion in clinical practice.

The accuracy in the diagnosis of metastatic colorectal cancer (mCRC) represents one of the challenges in the clinical management of patients. The detection of circulating tumour cells (CTC) is becoming a promising alternative to current detection techniques, as it focuses on one of the players of the metastatic disease and it should provide with more specific and sensitive detection rates. Here, we describe an improved method of detection of CTC from mCRC patients by combining immune-enrichment, optimal purification of RNA from very low cell numbers, and the selection of accurate PCR probes. As a result, we obtained a logistic model that combines GAPDH and VIL1 normalized to CD45 rendering powerful results in the detection of CTC from mCRC patients (AUROC value 0.8599). We further demonstrated the utility of this model at the clinical setting, as a reliable prognosis tool to determine progression-free survival in mCRC patients. Overall, we developed a strategy that ameliorates the specificity and sensitivity in the detection of CTC, resulting in a robust and promising logistic model for the clinical management of metastatic colorectal cancer patients.

4068Background: HER2 status is a predictive biomarker to response to trastuzumab in metastatic gastric adenocarcinomas. However, relatively little is known about the role of HER2 and HER3 in the no...

3032Background: HPD with ICIs has been recently described as progression disease (PD) by RECIST with a ≥ two-fold increase in tumor growth rate experimental vs. reference. However, the implementati...

Introduction: Over 2 years we have adapted our VHIO molecular prescreening program (PreScr) to identify genomic alterations in tumors of patients (pt) eligible for phase 1 clinical trials (Ph1) testing NOTCH inhibitors. This retrospective study aims to assess the prevalence of NOTCH pathway alterations in tumors and how this information was used to select therapies and to develop the PreScr. Methods: From Jan/2015 to Dec/2016, 1,832 pt had formalin-fixed, paraffin-embedded tumor samples (TS) analyzed for mutations (mut) using a customized developed Amplicon-Seq panel of 61 cancer-related genes (including FBXW7 [50% exon coverage], NOTCH1 [hotspots 5% exon coverage], NOTCH4 [hotspots 3% exon coverage]) run in Illumina MiSeq; 191 (TS) for Copy Number Alterations (CNAs) using a panel of 59 genes (including NOTCH1-4) run in NanoString NCounter; and 481 (TS) for gene expression using a panel of 26 genes (including NOTCH 1-4) run in Nanostring NCounter. NOTCH1-2 gene amplifications (ampl) were validated by FISH. Results: Tumor types samples were colorectal (CRC) n=468 (25%), lung (LC) n=273 (15%), breast (BC) n=176 (10%), gynecologic (GYNC) n= 111 (6%), head and neck (H&N) n=95 (5%), urinary (UC) n=91 (5%), brain primary tumors n= 34 (2%), and others n=513 (28%). Overall, FBXW7 mut were detected in 28 cases (GYNC 4.5%, CRC 3.7%, UC 2.2%, H&N 1%, others 0.6%). Most frequent co-occurring mut were TP53 (n=15) and APC (n=11). We found no mutations in NOTCH1 or NOTCH4. NOTCH2ampl (≥ 6 copies) were found in 3 cases (biliary tract 20%, BC 4.3%). We found no CNAs in NOTCH1/3/4. Outlier high expression (normalized z-score > 4) of NOTCH family genes was detected in a variety of tumor types, including LC (NOTCH2/3), CRC (NOTCH1/2), BC (NOTCH3/4), UC (NOTCH3/4), and salivary gland (NOTCH1). Five pt were treated with Notch Gamma-secretase inhibitors in clinical trials (4 pt with FBXW7 mut and 1 pt with NOTCH2 ampl). Conclusion: We found a low prevalence of NOTCH pathway alterations in metastatic pt for Ph1 clinical trials. In order to increase the sensitivity for NOTCH mut detection, we will increase exon coverage of NOTCH genes. In parallel, outlier high expression data will be used to guide enrichment in future clinical trials. Our results reveal the challenges faced in an evolving PreScr to the NOTCH targeted therapy development. Citation Format: Analia Azaro, Susana Aguilar, Rodrigo Dienstmann, Irene Braña, Cinta Hierro, María Ochoa de Olza, Juan Martin-Liberal, María Vieito, Ignacio Matos, Paolo Nuciforo, Josep Tabernero, Jordi Rodon, Ana Vivancos, Elena Garralda. Evolving molecular prescreening program to identify genomic alterations in the NOTCH pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B075.

2581 Background: Several FGFR and ligand (11q) alterations have been described in cancer. While FGFR fusions are recognized biomarkers of response to FGFRinh, it is still unclear to what extent FGFRamp, FGFR mRNA high expression (mRNAh) or FGFRmut predict sensitivity in the clinic. Methods: Retrospective analysis of pts with molecularly-selected FGFRamp/mRNAh/mut tumors treated with FGFRinh in phase 1 trials at our institution. Mut were detected with IlluminaÒ or Foundation OneÒ. FGFR1-2amp were analyzed by in situ hybridization and mRNA levels by qRT-PCR or nCounterÒ. Clinical benefit (ClinBen) was defined as any tumor shrinkage plus disease control for ³ 4 months (m). Time to progression (TTP) was defined as time between start of FGFRinh and end for any cause. Results: From 2011 to 2016, 36 pts with FGFRamp(25)/mRNAh(5)/mut(6) received an FGFRinh (irreversible- [11 cases (c)] or reversible-FGFR1-4inh [23 c], isoform-specific FGFRinh [3 c] or combo with PI3Kinh [1 c]). Median age 55 yrs (34-76); median prior palliative lines was 3 (0-8); tumor types: breast (17), colorectal (3), esophagus (3), liver (3), lung (3), others (7). Median TTP was 1.67 m (CI 95%; 1.40-2.87). In the FGFRamp/mRNAh population (30), 7 pts achieved ClinBen (23%). 4 out of these seven pts had mRNAh (1 FGFR2amp breast with FGFR2 mRNAh, 1 bladder FGFR3 mRNAh and 2 liver FGFR4 mRNAh without known amp), and 2 pts harboured 11q co-amplification (1 FGFR2amp breast, 1 FGFR2amp head and neck). There was no correlation between ClinBen and level of FGFRamp in the overall population (p = 0.51) or in the breast cancer group (p = 0.29). Of 6 FGFRmut pts, one with bladder cancer had ClinBen (clonal oncogenic FGFR3 S249C). The remaining 5 unresponsive FGFRmut pts had subclonal events, some of these FGFRmut were of unknown functional significance, and had coexisting oncogene mut in MAPK or PI3K pathways. Conclusions: Our results suggest that ClinBen with FGFRinh in the FGFRamp setting is enriched in pts with high mRNA expression and/or ligand co-amplification, and in the FGFRmut population may be dependent on clonality and functionality of the event and co-existence of driver mut.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Background]: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. [Methods]: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. [Results]: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. [Conclusions]: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing., ISCIII PI11/00873; Fundación Asociación Española Contra el Cancer (AECC), Grupos Estables 2011; InveNNta (Innovation in Nanomedicine), co-financed by the European Union (EU) through the Operational Programme for Cross-border Cooperation, Spain-Portugal (POCTEP 2007-2013), European Regional Development Fund (ERDF); Helse Vest, Research Council of Norway, Norwegian Cancer Society and Harald Andersens legat (H.B.S.); L. Alonso-Alconada is recipient of fellowship from the Basque Government (Spain).

In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ³5 at baseline presented worse PFS and OS than those with

e14604 Background: Stage II colon cancer has a 5 year survival over 80% that is only marginally improved by the use of adjuvant treatments, so the decision of starting an adjuvant treatment, especi...

e15068 Background: Adjuvant radio-chemotherapy with 5- FU bolus, McDonald regime is the standard adjuvant treatment due to it has shown significant benefit in OS and DFS over surgery alone at a non...

5603 Background: Although there has not been a direct comparison between neoadjuvant chemotherapy followed by chemoradiation with chemoradiation alone, neoadjuvant chemotherapy is active in squamous cervical cancer. Methods: In this one arm phase II trial we accrued 25 patients from 2007 to 2012 diagnosed with squamous cervical cancer deemed poor candidates to initial chemoradiation (decided by a multidisciplinary committee). Patients had > 18 years of age, PS 0-1, adequate organ function an gave informed consent. They received neoadjuvant paclitaxel and cisplatin (80 and 33 mg/m2 respectively) on days 1,7, 15 of every 28 for two cycles and then external radiation in 1.8 Gy/ fraction with concurrent weekly cisplatin 40 mg/m2followed by brachytherapy in 5-6 applications. Dose intensity and toxicity was accrued, and both after neoadjuvant and chemoradiation patients were evaluated by RECIST 1.1 criteria for response with CT scan and pelvic MNR. Results: Baseline characteristics of the patients are listed in Table. 24 patients were evaluable for efficacy and safety. Response rate after neoadjuvant chemotherapy was 84 % (complete and partial responses in 24 and 60% of patients, respectively), without progression disease. Response rate after radiochemotherapy was 93 % (complete and partial responses in 52 and 41% of patients, respectively). After a mean of 29 months of follow up, 11 patients (45%) thus far have developed recurrent disease. Median progression-free survival and overall survival were 33 (23- 42) and 34+ m (29 – not reached). Treatment was well tolerated, without toxicities grade 3-4. Conclusions: Our weekly cisplatin-paclitaxel neoadjuvant regimen has been feasible and very effective in terms of dose delivery, tolerance and radiological responses without compromising definitive treatment with chemoradiation. If this approach is superior than the standard chemoradiation alone in this population should be explored in a randomized trial. [Table: see text]

e16095 Background: CRPC remains a therapeutic challenge, although in recent years the introduction of new agents has allowed an improvement in overall survival of these patients. In the literature there are few data on the use of cyclophosphamide in this context. The current study was designed to evaluate the efficacy and toxicity of the metronomic oral administration of a combination of cyclophosphamide and prednisone in patients with CRPC, not candidates for docetaxel or after progression to it. Methods: We retrospectively evaluated the medical records of all patients with metastatic CRPC who were treated with prednisone and cyclophosphamide in our institution. Patients had been previously treated with a docetaxel-containing regimen or were not considered candidates for taxanes, because of important comomorbidities or poor Performance Status (PS). Results: Data from 40 patients treated with cyclophosphamide 50 mg/day vo and prednisone 5 mg bid from January 2010 to December 2012 has been analyzed. Baseline characteristics of the patients are listed in the Table. 36 patients were evaluable for efficacy and toxicity. The PSA response rate (RR) was 30%, with partial responses in 7/40 patients. The clinical benefit (stabilization disease + RR) was 52%. Median progression-free survival was 13 weeks (95% CI 13.2 – 14.5). Median overall survival was 46 weeks (95% CI 26.4 – 65.9). The overall 1-year and 2-year survival were 32% and 8 %, respectively. The treatment was safe and well tolerated. Anemia (grade 0-3) was observed in a third of all patients. Conclusions: In this study in patients with a poor prognosis, metronomic oral cyclophosphamide plus prednisone have demonstrated efficacy with excelent tolerance. Oral cyclophosphamide is an interesting alternative to consider in patients non candidates for intravenous chemotherapy. [Table: see text]

e20708 Background: Malignant bowel obstruction is a complex syndrome that needs a multidisciplinary management and a better definition of prognostic risk factors. Methods: Information of patients with known history of cancer, admitted for a first episode of suspected malignant bowel obstruction, between 2008 and 2010 with consultation by a medical oncologist or palliative care specialist was reviewed and epidemiological variables like sex, age, localization, histology, and clinical stage treatments received, presence of infiltrating abdominal tumors, and peritoneal carcinomatosis were recorded at diagnosis and at the time of admission. Results: The basal characteristics of the 115 patients are resumed in the Table. At admission patients had in their majority known stage IV disease (75%) with previous evidence of peritoneal carcinomatosis in 63% of cases and of intra abdominal infiltrating masses in 49%, but only half of the patients were receiving active chemotherapy. Nearly all patients presented symptoms like pain (98%) and nausea (91%), followed by vomit and abdominal distension and a deterioration of their performance score (9% PS0-1, 43% PS2, 33% PS3, 13% PS4). Palliative prognostic index (PPI) altered items were mainly oral intake (64%) and edema (21%). They were treated with antisecretors (octreotide 58%, butylscopolamine 26%), anti-emetics, (ondasetron 65%, metoclopramide 46%) neuroleptics (60%), corticosteroids (59%) and analgesics (opioids in 66%). Conclusions: The episode of obstruction could be resolved in a median of 12 days in more than half of our patients(59%), this led to an acceptable rate of outpatient management of 61%, nerveless the prognosis of this patients is still very poor. with a median survival from the moment of obstruction of only 42 days and a rate of reobstruction of 52%. [Table: see text]

7549 Background: CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly docetaxel (D) and cisplatin (C) and thoracic radiotherapy. Methods: 50 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 > 1.1, V20 < 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 14,5 months. Results: The p characteristics were: mean age 59,1 years (34-75); male/female 44/6; squamous/adeno/large cell carcinoma: 52%/34%/14%; stage IIIAN2 14 p (28%) and stage IIIB 36 p (72%). All p were evaluable for response and toxicity. RR: 4 CR, 36 PR (RR 80%; 95% CI:69-91), 4 SD (8%) and 6 PD (12%). The median PFS was 13 months (95% CI:8-18) and median OS was 19 months (95% CI:14-24). The PFS and OS at 1/2 years were 52%/30% and 79%/40% respectively. A total of 50 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 2/16; anemia 12/0; nausea/vomiting 28/2; diarrhea 22/4; there were two episodes of febrile neutropenia. Main toxicities per p in CChRT (D-C doses: 192, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28/6; anemia 60/0; esophagitis 52/4 and pneumonitis 34/0; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p. Conclusions: CChRT with bi-weekly docetaxel and cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.

Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream and, concordantly, the presence of these Circulating Tumor Cells (CTC) is associated with a poor prognosis. In this work, the molecular characterization of CTC from mCRC patients was approached, with the aim of understanding their biology and improving their clinical utility in the management of colorectal cancer patients. For this, EpCAM-based immunoisolation of CTC was combined with whole transcriptome amplification and hybridization onto cDNA microarrays. Gene expression data from mCRC patients, once the background of unspecific immunoisolation from a group of controls had been subtracted, resulted in 410 genes that characterized the CTC population. Bioinformatics were used for the biological interpretation of the data, revealing that CTC are characterized by genes related to cell movement and adhesion, cell death and proliferation, and cell signalling and interaction. RTqPCR on an independent series of mCRC patients and controls was used for the validation of a number of genes related to the main cellular functions characterizing the CTC population. Comparison between primary carcinomas and lung and liver metastases further involved the CTC-genes in the promotion of metastasis. Moreover, the correlation of CTC-gene expression with clinical parameters demonstrated detection and prognosis significance. In conclusion, the molecular characterization of CTC from mCRC patients and the identification of diagnostic and prognostic biomarkers represent an innovative and promising approach in the clinical management of this type of patients.

10534 Background: Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream, being this Circulating Tumor Cells (CTC) the principal source of the further metastasis. Clinically, the presence of CTC is associated with poor prognosis and there exists a clear necessity for more specific and efficient chemotherapies in the treatment of mCRC. Our aim was to overcome this adverse scenario through the massive molecular profiling of the CTC population isolated from mCRC patients. Methods: CTC’s were magnetically isolated by using anti-EpCAM coupled magnetic beads from 6 mCRC patients and 3 healthy controls. The presence of CTCs was evaluated by citokeratins 8, 18 and 19 staining. RNA from CTCs was amplified by a whole transcriptome amplification system (WTA) and resulting material was hybridized onto gene expression arrays. Bioinformatics were used to array analysis. Selected genes were validated by RT-qPCR. Results: 410 transcripts were found to specifically characterise the CTC population after array signals comparison between mCRC patients and controls. Gene-gene interaction analysis generated networks related with cell migration, adhesion or apoptosis resistance. Gene ontology revealed similar functions. Signalling pathways such as RhoA, PKA, ILK, integrins or actin cytoskeleton signalling were found as relevant in CTCs. Eleven genes (TGFB1, APP, TIMP1, CD9, CLU, ITGB5, LIMS1, RSU1, VCL, BMP6 and TLN1) were validated by real-time PCR in 20 mCRC patient and 10 control samples. All genes showed a significantly higher expression in patients (p

e19505 Background: Although its mortality has decreased in the last years, neutropenic fever is still one of the most important oncological emergencies. Methods: We have assessed the epidemiological data on patients admitted or evaluated for neutropenic sepsis in a third level cancer center from January 2009 to December 2010. Results: We have found 68 patients who had at least one episode of febrile neutropenia, of them 66% were male and 34% female, and the mean age was 59 years. The performance status was 0 and 1 in 80% of patients and only 19% percent had serious comorbilities such as renal dysfunction, cirrhosis, diabetes mellitus or chronic pulmonary disease. 36% of our patients had a high risk neutropenic fever per MASCC criteria. The majority of patients were lung cancer (31%) breast cancer (22%); and gastrointestinal cancer (28%) and 53% where treated with palliative intention. The episodes of febrile neutropenia were more frequent in patients in first line of treatment (72%) and first cycle of any treatment (42%). 8% of patients were treated with chemorradiation and 35% of the patients were receiving prophylaxis with GCSF. There was no found the source of the infection in 45% of patients. 25% had positive cultures. The porcetaje of infections with gram-positive and-negative was very similar. Patients were treated with a combination of amikacine and ceftacidime in 63% of times, further addition of vancomicine or antifungical therapies were only needed in minority of patients, 88% percent of patients received granulocyte stimulating factors. The mean duration of the neutropenia was of 2 days. Following chemotherapy treatment doses were reduced in 44% of patients and delayed in 26%. Thirteen percent of patients received secondary prophylaxis with GCSF, treatment regimen changed was changed in only 2% of patients and 29% received no further treatment. Conclusions: The mortality rate was of 3%, and the time of hospitalization was short (mean of 7 days). Febrile neutropenia remains a serious complication that we have to decrease.

e14733 Background: Biliary tract tumours are rare and often poor prognosis cancers that comprise cholangiocarcinomas, ampullary tumours and gallbladder cancers. Methods: Medical Electronic Records for patients diagnosed between January 2008 and December 2010 and treated at a medical oncology unit were reviewed, and clinical and epidemiological data for patients were retrieved. Results: We have found 28 patients with a distribution with a clear majority of men (60%), with a median age of 66 years (range 45-80).Patients were mostly metastatic (85%) at diagnosis and the majority of patients had intrahepatic cholangiocarcinoma (60%) as diagnosis and debuted with large intrahepatic masses and metastatic disease.Those with tumours arising outside the liver (40%) had obstructive jaundice (28%) or cholangitis (26%) at diagnosis and needed in most cases biliary stenting (33%).Six patients had PS2 at diagnosis and received gemcitabine monotherapy. Only one patient remaining progression free at 6 months and none of them received treatment at progression, the mean PFS was of 5.3 months and the OS was of 8.3 months.Of 22 patients with good performance status, 12 of them with a mean age of 60 years received polychemotherapy with GEMOX or CDDP-gem with PFS of 7. 3 months and OS of 12. 3 months.The other 10 patients (with a mean age of 65 years) received gemcitabine as monotherapy with a PFS of 7. 9 months and a OS of 11. 4 months.Eight patients were treated with second line therapy with no responses and a mean of PFS of 2 months, OS was not superior to patients who did not receive second line treatment. Conclusion: Our patients with biliary tract tumours had a mean progression free survival of 8.2 months and a mean overall survival of 12.3 months with 5 patients remaining progression free more than 20 months after beginning treatment. This survival data are compatible with those reported in recent clinical trials although we did not find improvements in survival with polychemotherapy and second line therapies. Conclusions: Taken as a whole our patients with biliary tract tumours had a mean progression free survival of 8.2 months and a mean overall survival of 12.3 months with 5 patients remaining progression free more than 20 months after beginning treatment.