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Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.

Purpose: Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3 years of luteinizing hormone-releasing hormone analogues. Methods and Materials: A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score >= 8 (77.3%), prostate-specific antigen level >20 ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT + 9 weekly cycles of docetaxel + 3 years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5 years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. Results: No difference between the arms of the study was found in biochemical recurrence (93.4% at 60 months for arm A vs 85.3% for arm B; P = .3297). PFS at 60 months was 93.4% and 83.7% in arms A and B, respectively (P = .2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level

Aim: We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen. Patients & methods: Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients. Results: CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007–0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7–15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3–4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively). Conclusion: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

e17582 Background: Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for the treatment of mCRPC patients (pts) after failure to docetaxel. Despite its proven efficacy, there is variability in the response, progression-free survival (PFS) and overall survival (OS) of pts. Changes in the genetic constitution of the individual such as the SNPs could explain this variability. The aim of this study was to evaluate the impact of certain SNPs in cabazitaxel activity. Methods: Clinical data from 67 mCRPC pts treated with cabazitaxel between March 2011 and October 2016 were collected. DNA was isolated from formalin fixed paraffin-embedded tumor samples. 56 SNPs in 5 genes related with metabolism and/or mechanism of action of cabazitaxel (CYP3A4, CYP3A5, ABCB1, TUBB1, CYP2C8) were chosen based on their Minor Allele Frequency, linkage disequilibrium and information from dbSNP and analyzed by TaqMan OpenArray (Lifetech). The presence/absence of mutant alleles of the selected SNPs was correlated with clinical features, progression free survival (PFS) and overall survival (OS) of prostate cancer. Chi-square test and Kaplan-Meier with log-rank test were used for statistical analyses. Results: The median age was 61 years (range 44-82). 56.7% (n = 38) had a Gleason score ≥8 and 94% had received docetaxel in first line. Type of response to cabazitaxel was associated with median OS (Partial response = 24.35 months, Stable disease = 11.16 months, Progression disease = 5.8 months; p= 0.045). Univariate analysis, showed worsed OS at 1 year for wild type status of SNP rs151352 (OR = 4, 95%CI 1.27-12.58, p= 0.029). In addition, two SNPs (rs11773597, rs1202186) were associated with radiological response to cabazitaxel ( p= 0.031 and p= 0.030 respectively). Other 7 SNPs (rs11773597, rs2235040, rs1045642, rs1419745, rs1202170, rs6949448, rs11572093) were associated ( p

The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers., This investigation was funded by FEDER, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III (FIS) through projects Nos PI11/01862 and PI11/02571, and by the Consejería de Salud de la Junta de Andalucía through project No PI-0338. The authors wish to express their gratitude to G Ortiz Ferron (CIC, University of Granada, Spain) for his skillful assistance with cytometry experiments.

Background Cabazitaxel is used in the treatment of metastatic prostate cancer. It is not a substrate of P-glycoprotein, which is involved in cellular detoxification of chemotherapeutic agents and in the expulsion of drugs at blood-brain barrier. Our objectives are to test Cabazitaxel in vitro in malignant neural cell lines such as glioblastoma, anaplastic glioma and neuroblastoma, and to find any predictor of response that allows us to select potential responder patients in glioblastoma multiforme and other neural tumors. Methods Cell lines A172 (glioblastoma, p53 wild type), LN229 (glioblastoma, p53 mutated), SF268 (anaplastic glioma, p53 mutated) and SK-N-SH (neuroblastoma, p53 wild type) were cultured in 48-well plates and increasing doses of Cabazitaxel were tested (0.1, 0.5, 1, 5, 10, 25, 50, 100μM). After 48hours of treatment, the proliferation values were studied by spectrophotometric assays. Also, gene expression studies of the MMR complex (miss-match repair) were performed by RT-qPCR for the primers of MLH1, MSH2, MSH3, MSH6, PMS2 genes. We also analyzed the expression of CD133 marker by RT-qPCR assays. A PCR study with Bisulfite kit was carried out to detect the promoter methylation of MGMT. Results IC50 values at 48hours were 13.76μm in SF268, 6.77μm in SK-N-SH, 2.88μm in LN 229 and 1.34 in A172. The expression values of MMR complex proteins were significantly higher in line A172 (relative value 1), followed by line LN229 (0.25) and negative in lines SK-N-SH and SF268. The methylation of MGMT promoter was positive in lines A172 and LN229. Finally, the expression of CD133 was higher in A172 (0.6), followed by LN229 (0.4), SK-N-SH (0.2) and SF268 (0). Pearson correlation coefficient for the relationship between CD133 expression and IC50 values is -0.96. Conclusions 1. Glioblastoma, anaplastic glioma and neuroblastoma cell lines have a high sensitivity to Cabazitaxel in vitro. 2. Cell lines with MGMT methylation and MMR expression (A172 and LN 229) are the most sensitive. Of them, line A172 presents a p53 wild type, and therefore, a greater sensitivity to Cabazitaxel. 3. The expression of CD133 correlates inversely with the values of IC50 to Cabazitaxel, and may also be a predictor of response. Legal entity responsible for the study UGR. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

5053 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. SIOG guidelines (Droz, Eur Urol 2017) recommend that fit elderly pts should receive the same treatment as younger patients. Evidence of the optimal treatment sequence in this patient subpopulation is lacking. Methods: We evaluated the outcome of elderly (≥ 75 years [yrs]) pts treated in the prospective PROREPAIR-B cohort study (NCT03075735). We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS) and progression-free survival (PFS) to 1L-therapy following PCWG2criteria. Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included local therapy, Gleason Score, stage IV at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (Hb; ≤LNL), albumin (≤LNL) and ECOG PS. Results: 419 pts were included in the study. Of these, 137 (32,7%) had age ≥ 75 yrs. 48 (35%) received docetaxel and 88 (64.2%) had Abi/Enza as first-line therapy. Of the 121 pts that progressed on 1L-therapy, 30 (24.8%) did not receive 2L therapy. Choice of 2L-therapy was: Doc in 37 (30,6%), Abi/Enza in 38 (31.4%), Cabazitaxel in 9 (7.4%) and Radium-223 in 7 (5.8%) pts. Pts treated with 1L-Doc had higher rates of visceral metastases (22.9% vs 5.7%; p=0.003), high ALP (68.8% vs 43.2%; p=0.004) and low Hb (12.5% vs 3.4%). PFS to 1L-therapy was longer for Abi/Enza than for Doc treated pts (9.6 vs 8.3m; HR: 0.52; p=0.001). The pattern of disease progression (PSA, radiographic, clinical) was similar in Doce and Abi/Enza treated pts. No difference between pts treated with initial Abi/Enza vs Doc was observed in OS (28.2 vs 24.8m; HR:1.18; p=0.474). No significant OS differences were observed in the MV model. Conclusions: No differences in OS were observed between treatment sequences starting with Doc vs Abi/Enza in pts ≥ 75 yrs. Pts treated with 1L-Doc had worse baseline prognostic features. Age should not be considered as a factor for treatment choice in elderly mCRPC pts based on treatment outcome.

264 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. Evidence suggests a degree of cross-resistance between agents, which may impact the efficacy of subsequent lines of therapy. Evidence on the optimal treatment sequence is lacking. Methods: We evaluated the outcome of patients (pts) treated with 1L Doc, Abi or Enza in the prospective PROREPAIR-B cohort study. We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS), progression-free survival (PFS) to 1L-therapy (PCWG2) and PFS2 (time from initiation of 1L-therapy to progression on second-line [2L] therapy). Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included age (≥75 years), local therapy, Gleason Score, metastases at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (≤LNL), albumin (≤LNL) and ECOG PS. Results: 406 pts received 1L-Doce (N=188) or Abi/Enza (N=218). Pts receiving Doc were younger (p=0.002), had higher rates of visceral metastases (17.6 vs 8.7%; p=0.008), ALP (52.1% vs 40.4%; p=0.018), LDH (48.1% vs 31.2%; p

Prostate tumors are the most frequent malignant cancer among men. In recent years, we have seen a significant progress in the knowledge of the carcinogenesis of prostate cancer, leading to the development of effective drugs in this scenario. Prostate cancer patients had no effective therapeutic alternatives after docetaxel failure, limiting their survival rates. However, new drugs have markedly improved this. Cabazitaxel, a new generation taxane, has shown improved patient survival, despite the disease progression seen after docetaxel treatment. Herein, we present the case of a prostate cancer patient with poor prognosis and lung metastases in < 6 months postdocetaxel treatment. The patient was treated with cabazitaxel, achieving a long and maintained response. Later, on developing a new progressive disease, the patient was retreated with cabazitaxel, achieving a partial response and obtaining a widespread survival and clinical benefit. We currently have no predictive response factors to establish the most appropriate therapeutic sequence. Close monitoring of these patients is of paramount importance to detect early disease progression and try a new line of treatment, while the patient still has the chance to respond.

[Abstract] BACKGROUND: Based on the TROPIC study results, cabazitaxel was approved for the management of metastatic castration-resistant prostate cancer (mCRPC) progressing on or after docetaxel. METHODS: This multi-centre program provided early access to cabazitaxel to patients with mCRPC before its commercialization. Safety data from 153 Spanish patients receiving cabazitaxel 25 mg/m(2) i.v. Q3W, plus oral prednisone/prednisolone 10 mg daily, are reported. RESULTS: Median age of patients was 70 years (26.8% ≥ 75 years), 94.1 and 26.8% had bone and visceral metastasis, respectively. Most had an Eastern Cooperative Oncology Group ≤ 1 (88.9%) and had received a median of 8.0 cycles of last docetaxel treatment. The median of cabazitaxel cycles and cumulative dose were 6.0 (Interquartile range [IQR]: 4.0; 8.0) and 148.9 (IQR: 98.2; 201.4) mg/m(2), respectively. Adverse events (AEs) possibly related to cabazitaxel occurred in 143 (93.5%) patients. The most frequent grade ≥ 3 AEs were neutropenia (n = 25, 16.3%) and asthenia (n = 17, 11.1%). Febrile neutropenia and grade ≥ 3 diarrhea occurred in 5.2% of the patients each. There were five (3.3%) possibly treatment-related deaths, mainly infection-related. G-CSFs were used in 114 (74.5%) patients, generally as prophylaxis (n = 107; 69.9%). Grade ≥ 3 peripheral neuropathy and nail disorders were uncommon. CONCLUSIONS: Cabazitaxel administration, in a real-world setting, is tolerated by Spanish patients with mCRPC, and the AEs are manageable.

229 Background: Novel agents, such as abiraterone (A), cabazitaxel (CZ), and enzalutamide are currently available for the treatment of docetaxel (D)-treated metastatic castration resistant prostate cancer (mCRPC). The sequencing approach following D progression is still unknown. We now explore which factors are driving sequencing decisions in routine clinical practice in Spain. Methods: A prospective multicenter national observational descriptive study collecting data of 2nd line (L) treatments in mCRPC patients to analyze responses and progression to 1stL D. Results: 149 patients have been recruited from July 2013 to January 2015. Median age was 72 (48-89). Median D cycles was 6 (1-24), and median dose: 75 mg/m2 (30-75). 24 patients (16%) required dose reduction. The reasons for D ending were treatment completion (40%, n = 60), toxicity (15.3%, n = 23), progression (radiological, biochemical, clinical; 42%, n = 63), or others (2.7%, n = 4). 67% (n = 100) of the patients received A, 25% (n = 44) CZ, and 8% (n = 5) other treatments as 2ndL. From those who completed or progressed to D (n = 123), 2ndL initiation was mainly determined by two progression criteria (2C; biological and radiological), followed by one progression criteria (1C). This was independent of the 2ndL treatment chosen, and it was observed in similar ratios in both A (2C: 50%, n = 39; 1C: 37.2%, n = 29) and CZ (2C: 62.5%, n = 25; 1C: 27.5%, n = 11). Nevertheless, A was predominantly given when patients progressed after D ending, whereas CZ was mostly given when progressing during D (Table 1). Conclusions: A is the 2ndL treatment of choice in routine clinical practice in Spain, independent of the type and time of progression. CZ is preferentially used in patients progressing during D treatment. [Table: see text]

e15537 Background: No standard regimen exists for second line treatment of mTCC patients. Taxanes have shown some activity in this setting. Cbz, is a novel semi-synthetic taxane never tested before...

e15597 Background: The IMRCC prognostic model for mRCC treated with VEGF-targeted agents (Heng, JCO '09) has been externally validated (Heng, Lancet Oncol '13), however, pt treated with Pz were not...

4525 Background: Treatment of mTCC progressing to cisplatin is an unmet need. Prognostic factors (PF) for worse overall survival (OS) are ECOG >0, Hb

15 Background: Docetaxel improves survival in patients (pts) with metastatic hormonosensitive prostate cancer (PC) and castration-resistant prostate cancer. The objective of this phase IIb trial was to assess the activity of low dose docetaxel concurrent with radiotherapy plus standard hormonal treatment in pts with high risk localized CaP. Methods: High-risk localized CaP was defined by ≥ 1 of the following criteria: T3-T4, Gleason score (GS) ≥ 8, PSA > 20 ng/mL, pN+. Pts were randomly assigned to either arm A (LH-RH analogs every 3 months for 3 years and radiotherapy 73.8 Gy [1.8 Gy x 41 fractions] or 74 Gy [2Gy x 37 fractions]) or arm B (LH-RH analogs every 3 months for 3 years, radiotherapy and concurrent weekly docetaxel at 20 mg/m2 for 9 weeks). Chemotherapy was started one week before of radiotherapy. Primary endpoint was PSA relapse according to the Phoenix definition. The planned number of pts was 130 to detect a 15% difference with a power of 80% and an alpha of 0.05 (two-sided). Results: From 12/2008 to 9/2012, 130 pts were accrued (Arm A: 64, Arm B: 66). Median age was 68 years (61-73). Patients had T3-T4 (82.6%), GS ≥ 8 (76.3%), PSA > 20 ng/mL (26.9%) and pN+ (18.9%). All characteristics were well-balanced between arms. Median dose of radiotherapy was 74 Gy (72–74.8) in arm A, and 73.8 Gy ( 72-75.6) in arm B. 75.7% of pts received the planned 9 treatments of docetaxel and median number of cycles delivered per patient was 9. After a median follow-up of 29.6 months (9.6-40.2), most common grade 1/2 toxicities (arm A and arm B) were: cystitis ( 12.5% vs 8.3%), diarrhea (35.9% vs 70%), proctitis (12.5% vs 13.3%), rectal tenesmus (3.1% vs 23.3%), asthenia (23.4% vs 61.6%) and dysuria ( 28.1% vs 30.0%). Toxicity G3/G4 diarrhea was reported in 8.3% of pts in arm B and 0% in arm A. G3/G4 lymphopenia occurred less often in arm A than in arm B (3.1% vs 23.3%). %). There was no toxicity-related death. Conclusions: The QRT SOGUG phase IIb trial met its accrual target and shows that concurrent weekly docetaxel can be administered with standard doses of radiotherapy and without increasing toxicity profile. Clinical trial information: 2008-003554-14.

Aim: Cabazitaxel (Cab) is a novel tubulin-binding taxane active in preclinical models against docetaxel-sensitive and resistant tumors. Cab is approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure; however, its activity against other cancers remains unexplored. SOGUG 2011-04 is a phase II clinical trial designed to explore the efficacy of Cab in advanced genitourinary TCC after progression to a platinum-based regime. As part of this trial, a pharmacogenetic study to identify single-nucleotide polymorphisms (SNPs) predictive of Cab toxicity and response was conducted. Methods: DNA was extracted from blood samples from 45 patients in this trial. Nine key SNPs in genes involved in the pharmacokinetic and pharmacodynamic pathways of Cab (CYP3A4 rs35599367; CYP3A5 rs776746; CYP2C8 rs11572080 and rs1113129 ABCB1 rs1045642, rs1128503 and rs2032582; TUBB1 rs6070697 and rs463312) were genotyped using standard techniques. Logistic regression was used to study toxicity and response, and Cox regression to analyze progression free survival (PFS) and overall survival (OS), using an additive genetic model. Preliminary results are presented. Results: CYP3A5 rs776746 (splicing defect) protected against gastrointestinal (GI) toxicity (OR = 0.06, 95%CI = 0.007-0.63, P = 0.018) and was associated with reduced PFS (HR = 4.4, 95%CI = 1.6-11.7, P = 0.0032). Adjusting for patient prognosis, according to Bellmunt's classification, did not change the results. Furthermore ABCB1 rs1128503, rs1045642 and rs2032582 were associated with the total number of Grade 3-4 toxicity events (P values of 0.009, 0.041, and 0.043, respectively, multivariable analysis). TUBB1 Q43P missense polymorphism was associated with reduced OS (P = 0.0023) although only three patients carried this variant. Conclusions: Polymorphisms in CYP3A5 may define a subset of patients with decreased Cab activity resulting in less GI adverse events and shorter PFS. Additionally, variation in ABCB1 may be associated with the severity of Cab toxicity. These results need to be validated in larger and independent series but suggest potential markers for Cab treatment optimization. * This study has been supported by an unrestricted educational grant of Sanofi-Aventis to the Spanish GU Oncology Group (SOGUG) Disclosure: I. Duran: has participated in compensated Advisory Boards for Sanofi-Aventis; M. Climent: has participated in compensated Advisory Boards for Sanofi-Aventis. All other authors have declared no conflicts of interest.

2028 Background: We compared the efficacy and safety of treatment with TMZ or TMZ+BEVprior to and concomitant with radiotherapy in unresectable(GBM) patients. Methods: Between December 2009 and Apr...

Background: Bevacizumab has efficacy in first-line treatment of advanced colorectal cancer. The overall response with Bevacizumab is low in some studies. Not know the ideal method of assessing response to therapy with bevacizumab. Metabolic imaging of tumor viability with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and simultaneous anatomic localization provided by low-dose non-enhanced computed tomography (CT), can be obtained in a combined modality FDG-PET/CT scan. The purpose of this study was to evaluate the possible contribution of FDG-PET/ CT as a surrogate marker to evaluate treatment response in patients with metastatic colorectal cancer (mCRC) who had been treated with bevacizumab and standard chemotherapy. Methods: Retrospective analysis of 28 patients with advanced colorectal cancer who had been treated in the Hospital Universitario Virgen de las Nieves in Granada. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin or irinotecan based regimens. FDG-PET/CT scans were performed before the start of the treatment and after six cycles of therapy. Results were compared to concurrent contrast-enhanced CT. Response to treatment was determined according to RECIST size criteria obtained from data from thin (3-5mm) slice CT, and changes in uptake of 18F-FDG uptake on PET. Results: A total of 28 patients were evaluated. Overall, 22 patients had favorable response to treatment, and only 6 had progression of disease. Complete response (CR) was evident on FDG-PET in 6/28 (21,4%) patients whereas only 5 were deemed CR by CT and partial response (PR) in 15/28 (64,3%) with both techniques. Similarly, only 1/ 28 (3,6%) lesion appeared stable by FDG-PET and CT criteria. Progression of disease (PT) was evident on FDG-PET in 6/28 (21,4%) patients whereas only 5 were deemed PT by CT. There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.81, P

TPS4672 Background: Advanced transitional cell carcinoma of the urothelium (TCCU) on progression after previous cisplatin-based combination is generally an incurable disease. The appropriate management of these patients is still an unmet need. Many drugs have shown modest or no activity in previous phase 2 trials. Population heterogeneity in these studies emerges as one of the key determinants that could explain the variable outcomes. Recently, in a phase III study in this setting, prognostic factors (PF) for overall survival were identified (Bellmunt J et al, JCO 2010). Taxanes are active drugs in 2nd-line metastatic TCCU. Cabazitaxel (C) is a semi-synthetic taxane that is a poor substrate for the multidrug resistance system. C could be a valid alternative in this patient population. Methods: This is an open label phase II study of C in patients (pts) with advanced or metastatic TCCU who have progressed within 12 months after receiving a 1st-line platinum based chemotherapy. There are three treatment arms as patients will be assigned to one of three groups previously defined based on the presence of 0, 1 or 2-3 PFs as defined by Bellmunt et al. The activity of C will be assessed separately in each group and overall. The primary endpoint is response rate (RR) evaluated according to RECIST 1.1, a maximum of 35 pts are needed in each subgroup (maximum number of pts required: 105). Secondary objectives are RR in the whole population, toxicity, progression-free survival and overall survival. In addition, an external validation of the prognostic model proposed by Bellmunt will be conducted, as well as a pharmacogenomic study in order to better define the toxicity profile of the drug and the potential responders.

e19072 Background: The gene expression profile in peripheral blood samples from lung cancer patients is a potential predictor to treatment response. Methods: The study has been developed using 10 healthy volunteers as the control group and 10 lung cancer patients (stage IV). Written informed consent was obtained being the protocol approved by the local Clinical Research and Ethics Committee. Peripheral blood samples were obtained from lung cancer patients before (T0) and after treatment (T15d). RNA from peripheral blood samples was extracted and purified selecting 28S/18S ratios>1.5 to obtain cDNA and cRNA for hybridization of the 20,000 genes included in Human 20K CodeLink. An array from each participant was obtained in duplicate. For each array, 2 μg of cRNA was compared to 2 μg of healthy cRNA.. Significant genes were found using Significance Analysis of Microarrays which uses repeated permutations of the data. Results: The selected genes were expressed >3-fold with a false discovery rate =0.05. Before treatment (T0) when patients were compared to healthy volunteers there was an increase in the expression of: histone 1 H4c, transforming growth factor beta 2, endothelial cell growth factor 1 (platelet-derived), glucose-6-phosphatase catalytic 2, Relaxin 3 receptor 1, Insulin-like growth factor binding protein 2, RAS-like family 11 member B, and ELK4. After treatment (T15d), when each lung cancer patient's results were compared to their own before treatment results (T0), there was an increase in the expression of: Bcl2, myosin light polypeptide 4; interferon alpha-inducible protein 27; interferon gamma receptor 1; RASSF5, ARHGEF6, IGFBP5, tumor protein p53 inducible nuclear protein 1, peroxisome proliferative activated receptor gamma. Conclusions: The data presented identifies biologically relevant over-expressed genes in lung cancer. A validation of these results and the analysis of the genes that identify patients who will respond positively to erlotinib treatment is being carried out. No significant financial relationships to disclose.

14041 Background: Preoperative CT improves survival in esophageal cancer. 50% of patients (pts) do not respond to cisplatin+5-FU (C+F). The reduction of fluorodeoxyglucose uptake after 14 days (d) of CT predicts clinical response (rsp). Our objective was to measure the rsp (rsp) rate after CT adjusted according to PET rsp. Methods: Eligible pts were ≥ stage II esophageal cancer and able to tolerate CT. By adjusting CT according to PET rsp, we expected an increase of rsp rate by 25%. Taking into account a confidence level of 90%, an error β of 20% and a minimal error of 15% (even with such a high error rate the data will exceed the standard results), we calculated a sample size of 23 pts. All underwent esophagoscopy, computed tomography and PET scan prior to C (100mg/m2 d1) +5-FU (1,000mg/m2 d1–5). If PET rsp after first cycle (uptake decreased ≥ 35%), we continued up to third C+F cycle, then if endoscopy rsp: C+F + concurrent radiation only if stage II or III. If no endoscopy rsp, surgery only if stage II or III. On the other hand, if the pts had no rsp in PET after first C+F cycle they continued with 2 cycles of docetaxel (35mg/m2 d 1 & 8) and irinotecan (50mg/m2 d 1 & 8) (D+I) every 21 d and then if endoscopy rsp: radiation + docetaxel only if stage II or III. If no endoscopy rsp, surgery. Results: Since 2/04, 23 pts have been enrolled. Location: 2 cervical, 4 upper thoracic, 7 mid-thoracic, 10 GE junction. PET stage: 7 IIA, 6 IIB, 2 III, 2 IVA, 6 IVB. Up-staging with PET in 6 pts, down-staging in 4 pts. Histology: 10 Adenocarcinoma, 13 squamous carcinoma. Improved swallowing function: from a total of 12 PET responders, 9 had a clinical rsp after C+F, 3 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 16/23 (70%). Endoscopy rsp (frequent inaccuracy by overstaging): from a total of 12 PET responders, 6 had a clinical rsp after C+F, 6 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 13/23 (57%). Conclusion: Our results suggest that it is possible to significantly increase the percentage of pts who respond to induction CT adjusted according to PET in esophagogastric cancer before concurrent chemoradiotherapy or esophagectomy, or both. No significant financial relationships to disclose.