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Purpose Both venous and arterial thrombotic events (VTE/AT) can be associated with immune checkpoint inhibitors (ICI). However, there is a paucity of information apropos patients in routine clinical practice. Methods/patients Retrospective, multicenter study promoted by the Thrombosis and Cancer Section of the Spanish Society of Medical Oncology (SEOM). Individuals with kidney or bladder cancer who initiated ICI between 01/01/2015 and 12/31/2020 were recruited. Minimum follow-up was 6 months (except in cases of demise). The primary objective was to calculate the incidence of ICI-associated VTE/AT and secondary objectives included to analyze their impact on survival and identify variables predictive of VTE/AT. Results 210 patients with kidney cancer were enrolled. The incidence of VTE/AT during follow-up (median 13 months) was 5.7%. Median overall survival (OS) was relatively lower among subjects with VTE/AT (16 months, 95% CI 0.01–34.2 vs. 27 months, 95% CI 22.6–31.4; p = 0.43). Multivariate analysis failed to reveal predictive variables for developing VTE/ AT. 197 patients with bladder were enrolled. There was a 9.1% incidence rate of VTE/AT during follow-up (median 8 months). Median OS was somewhat higher in patients with VTE/AT (28 months, 95% CI 18.4–37.6 vs 25 months, 95% CI 20.7–29.3; p = 0.821). Serum albumin levels p Conclusions There appears to be no association between developing VTE/AT and ICI use in patients with renal or bladder cancer. Serum albumin levels are a predictive factor in individuals with bladder cancer.

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.

463 Background: Real-world evidence on la/mUC management in Europe is limited. This study describes patient (pt) characteristics, treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Methods: A retrospective chart review was conducted using electronic medical records from 9 university hospitals in Spain. The study population included all pts aged ≥18 y with a first diagnosis/record of la/mUC from 1/1/2015–12/31/2020 (study period). Date of first la/mUC record/diagnosis during the study period was the index date. Pts with urachus carcinoma or other nonurothelial cancers were excluded. Pt characteristics are described for the full study population. Treatment patterns, survival, and la/mUC-associated HCRU are described for the follow-up cohort: a subset of the study cohort with a first la/mUC diagnosis/record from 1/1/2015–6/30/2020 (ie, to allow for ≥6 mo follow-up). Pts were followed from index date to death, loss to follow-up, or end of study. Median overall survival (OS) and progression-free survival (PFS; evaluated in a real-world setting) were determined using Kaplan–Meier curves. Time to progression, excluding pts who died and were censored at death, was also estimated. HCRU included inpatient admissions, outpatient visits, and emergency visits. Results: Overall, 903 pts were included. Median age at la/mUC diagnosis was 70 y; 79.6% were men. Most (71.0%) had ≥1 comorbidity, most commonly cardiovascular disease (54.2%). Primary tumor sites were the bladder (83.7%), urethra (7.0%), and upper tract (6.6%). De novo la/mUC (41.9%) was the most common initial UC diagnosis. In the follow-up cohort (n = 829), median follow-up was 12.7 mo. Most (84.7% [n = 702]) pts received first-line (1L) systemic treatment; of these, 46.9% (n = 329) received second-line (2L) and 16.6% (n = 116) received third-line (3L) therapy. Chemotherapy was the most common treatment (1L: 77.8% [n = 546]; 2L: 49.8% [n = 164]; 3L: 74.1% [n = 86]), followed by PD-1/L1 inhibitors (1L: 28.3% [n = 199]; 2L: 47.7% [n = 157]; 3L: 19.0% [n = 22]). From index la/mUC diagnosis, estimated median (95% CI) OS was 18.8 (17.5–21.5), PFS was 9.9 (8.9–10.5), and time to progression was 12.7 (11.3–14.6) mo. From the start of 1L, 2L and 3L therapy, estimated median (95% CI) OS were 16.9 (14.3–18.9), 11.6 (9.6–14.3), and 9.9 (7.9–12.6) mo. For HCRU, 71.8% (n = 595) of pts had ≥1 outpatient visit (mean: 2.2/mo), 56.6% (n = 469) had ≥1 inpatient admission (0.4/mo; median duration: 8.0 d), and 56.5% (n = 468) had ≥1 emergency visit (0.4/mo). Conclusions: This retrospective study of university hospital data describes pt characteristics and real-world treatment patterns, survival, and HCRU for pts with la/mUC in Spain. Advances in immunotherapy are shifting the treatment landscape for targeted groups of pts with la/mUC, but a need remains for innovative treatments that could improve pt outcomes.

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

Bladder cancer is the fourth most common cancer in men and the ninth most common in women in the Western world. The management of bladder carcinoma requires a multidisciplinary approach. Optimal treatment depends on several factors, including histology, stage, patient status, and possible comorbidities. Here we review recent findings on the treatment of muscle-invasive bladder carcinoma, advanced urothelial carcinoma, upper tract urothelial carcinoma, non-urothelial carcinoma, and urologic complications arising from the disease or treatment. In addition, we present the recommendations of the Spanish Oncology Genitourinary Group for the treatment of these diseases, based on a focused analysis of clinical management and the potential of current research, including recent findings on the potential benefit of immunotherapy. In recent years, whole-genome approaches have provided new predictive biomarkers and promising molecular targets that could lead to precision medicine in bladder cancer. Moreover, the involvement of other specialists in addition to urologists will ensure not only appropriate therapeutic decisions but also adequate follow-up for response evaluation and management of complications. It is crucial, however, to apply recent molecular findings and implement clinical guidelines as soon as possible in order to maximize therapeutic gains and improve patient prognosis.

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

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

Multidrug resistance is one of the major obstacles to the successful treatment of non-small cell lung cancer (NSCLC). An ability to identify molecular markers of drug resistance in peripheral blood cells in order to better target treatment would therefore be extremely useful in selecting therapy protocols for patients. The aim of the present study was to evaluate whether expression of resistance genes (MDR1, MRP3 and LRP) can predict clinical outcome in NSCLC patients treated with paclitaxel and carboplatin.Peripheral blood samples were obtained from lung cancer patients before and after chemotherapy and expression of the resistance gene in polymononuclear cells was detected by real-time reverse-transcription polymerase chain reaction. The results were correlated with treatment response and overall survival, which was calculated according to the Kaplan-Meier method.MDR1 expression levels in PMNs rose rapidly within 24 h post-administration of paclitaxel and carboplatin, whereas MRP and LRP expression levels remained unchanged. However, no significant correlation was observed between MDR1 expression and the patients' survival or treatment response.Modulation of MDR1 gene expression in PMNs after lung cancer treatment with paclitaxel and carboplatin cannot be used as a prognosis marker in these patients.

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...

e13056 Background: VTE is a common complication in HGG; however, it´s incidence remain uncertain. KS is the only validated predictive model to gauge cancer patient´s cancer risk for developing VTE....

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.

TPS2110 Background: Recurrent GBM has a very poor prognosis and there is an unmet need for new treatment options. EGFR is an attractive therapeutic target for GBM, due to high rates of amplifcation...

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...

97 Background: Multidrug resistance (MDR) phenotype is the major cause of chemotherapy failure. It has been related to several proteins expression: P-glycoprotein (PgP), MRP family, LRP, and BCRP. We study the resistance pattern induced after paclitaxel and carboplatin in non-small cell lung cancer (NSCLC). Methods: We used 5 different cell lines. A549 and A427 cell lines were derived from lung epithelial carcinoma. NODO line was obtained from lung carcinoma metastases, and 3 cell lines derived from other tumours: gastric cancer (GAS), seminoma (SEM), breast cancer (MCF7). The cell lines were exposed to paclitaxel, carboplatin, and the combination of both drugs. The concentrations we used were similar to the plasma concentrations observed in patients treated previously. Results: A549 cell line did not show basal expression of MDR1, but a weak basal expression of MRP3 was observed. After chemotherapy, we observed that paclitaxel induced MDR1 and carboplatin induced MRP3. The combination of both drugs induced MDR1 and MRP3 expression, however, when paclitaxel is associated to carboplatin, MRP3 expression did not increase significantly. A427 cell line did not show basal expression of MDR1 and MRP3. Paclitaxel induced MDR1 and carboplatin induced MRP3. The association of both drugs increased significantly the expression of MDR1, and very few the expression of MRP3. NODO cell line did not show any basal expression. Paclitaxel induced MDR1 and carboplatin induced MRP3. Cell lines derived from other tumours not show any basal expression. Paclitaxel induced MDR1 in all cell lines. Carboplatin did not induce MDR1, nor MRP3 in GAS cell line. Conclusions: Plasma concentrations of paclitaxel induced MDR1 expression but not MRP3 in lung cancer and other tumours derived cell lines. Carboplatin produced overexpression of MRP3 but not MDR1 in the same cell lines. The combination of both drugs at plasma concentrations was not able to activate a new resistance mechanism in the studied cell lines, but improve the resistance mechanism induced by each one of the drugs individually.

96 Background: Non-small cell lung cancer (NSCLC) is sometimes chemoresistant and does not respond to treatment; several factors are involved in the development of chemoresistance, such as multidrug resistance (MDR) phenotype, mainly. Methods: We studied MDR1 gene expression in peripheral blood PMN of 23 patients with NSCLC, advanced stages in most of the cases, who had not received treatment previously, before (hour 0) and after (hour 6) paclitaxel-carboplatin treatment. RNA was obtained from PMN pellet by means of the protocol of trizol. RNA was checked with agarose gels, and later RT-PCR technique was carried out using specific primers. Expression levels were randomly distributed, so that overexpression under 3 was considered low level of expression, and overexpression above 4 was considered high level of expression. Results: After treatment, we found overexpression of MDR1 in 22 patients. High levels were found in 11 patients, and low levels were observed in the other 11 patients. No relation was found between this fact and the treatment response or survival rate. No significant differences in expression were found in the other variables: gender, tobacco habit, weight loss at the diagnosis, tumour staging, and tumor histology. Conclusions: We can conclude that MDR1 expression in peripheral blood is not a predictive factor for treatment response nor a prognostic factor of the disease. Despite these results, further studies are necessary on molecular biology of NSCLC in order to try to establish subgroups of patients based on genetic profiles, in which the use of microarrays could be very useful.

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.

e13036 Background: Multidrug resistance (MDR) phenotype is the major cause of chemotherapy failure. The relationship between the expression of these markers and chemotherapy resistance is clear. We study the resistance pattern induced after treatment with paclitaxel, carboplatin in non small cell lung cancer (NSCLC). Methods: We used 5 different cell lines. A549 and A427 cell lines were derived from lung epithelial carcinoma. The NODO line was obtained from lung carcinoma , and 3 cell lines derived from other tumours . The cell lines were exposed to paclitaxel, carboplatin, and the combination of both drugs. The concentrations we used were similar to the plasma concentrations observed in patients treated previously. Results: A549 cell line did not show basal expression of MDR1, but a weak basal expression of MRP3 was observed. After chemotherapy, we observed that paclitaxel induced MDR1and carboplatin induced MRP3. The combination of both drugs induced the expression of both cell lines, however, when pacl...

Purpose: Posttranslational modifications are known to be altered in cancer cells, and loss of selected histone acetylation and methylation marks has recently been shown to predict patient outcome in human carcinoma. Materials: Since January 2002 to June 2005, 107 women with breast cancer and 108 control subjects were recruited. A sensitive SYBR green methylation-specific PCR quantitative technique was used to analyze the utility of circulating DNA with CpG island hypermethylation of APC, RAR-β, E-cadherin, ESR1 and 14-3-3σ gene promoter regions as breast cancer biomarkers. Sera were collected in 107 operable breast cancer patients (pts) previously surgery and in 60 of those pts after treatment. Respect controls, 34 had benign breast disease and 74 with no evidence of breast disease Results: Mean serum values of methylated ESR1 and 14-3-3σ gene promoters significantly differed between breast cancer patients and healthy controls (p = 0.0112 for ESR1 and p= 0.0047 for 14-3-3- σ). When their results were combined, it was found that hypermethylation of these two genes differentiated between breast cancer patients and healthy controls (p≤0.0001) with a sensitivity of 81% (95% confidence interval: 72—88%) and specificity of 88% (95% CI: 78—94%). Presence of methylated ESR1 in serum of breast cancer patients was associated with ER-negative phenotype (p = 0.0179); and presence of methylated 14-3-3-σ was associated with T3-4 stage (OMS) (p< 0.05) and nodal positive status (p< 0.05). We observed lower methylated ERS1 or 14-3-3-σ values after surgery, respect pretreatment levels, but without an overall statistically significant difference. With a median follow up of 6 years, we found that patients with a significant decrease of sera methylated levels of both genes after surgery had better time to progression an overall survival respect patients without this observation Conclusions: These results also suggest that this panel of genes detected in ductal lavage and blood specimens could be useful to biomarkers for early detection breast cancer. These findings cast some doubts on the utility for early cancer diagnosis of highly sensitive techniques to identify hypermethylation of specific gene promoters in DNA extracted from serum. Although numerous issues remain to be resolved, the quantitative measurement of circulating methylated DNA is a promising tool for cancer risk assessment.

e13648 Background: To determine whether estrogen receptor (ER) (+) and ER (-) status relates to epigenetic changes in breast cancer-related genes and to correlate with molecular breast cancer subtypes. Methods: From January 2002 to June 2005, we quantified methylation levels ERS1 gene in serum of 92 pts breast cancer. A PCR quantitative technique was used to analyze levels of methylation gene. We also examined and correlationed the expression of ESR1 AND HER2+ in tumors by immunohistochemistry with molecular phenotype. Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement (N0;63%,N1;30%,N2;7%), tumor size (T1;58%, T2;35%, T3;4%, T4;4%) and grade (G1;20%, G2;37%, G3;30%). Of the cases, 37pts (40%) were Luminal A (LA), 32pts (33%) Luminal B (LB), 14pts (15%) triple-negative (TN), and 9pts (10%) HER2+. The methylated ESR1 in serum was significantly associated with ER(-) in breast tumors >80% (p=0.0179). Methylation ESR1 was preferably associated with TN (80%) and HER2+ (6...

e13151 Background: NSCLC is frequently chemoresistant. Multidrug resistance phenotype is involved in the development of chemoresistance. It has been related to several proteins expression, like P-glycoprotein (mdr1 gene). We examined whether elevated mdr1 expression levels in peripheral blood mononuclear cells (PBMC) predict treatment response. Methods: We studied mdr1 gene expression in PBMC of 23 patients with NSCLC, advanced stages in most of the cases, who had not received treatment previously. Blood extraction of 5ml was made to each patient before (hour 0) and after paclitaxel-carboplatin chemotherapy (hour 6). The mdr1 gene expression levels were assessed by quantitative reverse transcription polymerase chain reaction. Results: After treatment, we found mdr1 overexpression in 22 patients. Expression levels were randomly distributed, so that overexpression under 3 was considered low level of expression, and overexpression above 4 was considered high level of expression. High levels were found in 11 ...

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.

3146 Background: The molecular profile of a cancer may give information pertinent to response to chemotherapeutic agents. Vascular endothelial growth factor is a endothelial mitogen, survival facto...