Jose Pablo Berros

Prognostic Factors in Patients With Advanced Renal Cell Carcinoma

BACKGROUND The purpose of this study was to evaluate prognostic factors in patients with RCC. MATERIALS AND METHODS The expression of several biomarkers were measured by immunohistochemistry (IHC), together with 2 analytic factors (thrombocytosis and neutrophilia), in 135 patients with advanced RCC treated with new targeted drugs (NTDs) (n = 67) and/or cytokines (CKs) (n = 68)-with 23 of the patients who received CKs also receiving NTDs-between July 1996 and February 2010. Relationships with overall survival (OS) and progression-free survival (PFS) were searched for. RESULTS Univariate statistical analysis revealed that high expression of hypoxia-inducible factor-1α (HIF-1α) correlated with poor prognosis in NTD treatment (PFS, 5.4 vs. 13.5, low expression months; P = .033) and CK treatment (PFS, 3.3 vs. 5.7, low expression; P = .003). Overexpression of carbonic anhydrase IX (CAIX) was associated with better prognosis with NTD treatment (OS, 32.1 vs. 7.8 months; P < .001) and CK treatment (OS, 32.9 vs. 5.9 months; P = .001). Positive PTEN was related to good prognosis with sunitinib (PFS, 15.1 vs. 6.5 months; P = .003) and CKs (OS, 13.7 vs. 7.9 months; P = .039). Increased expression of p21 was related to poor prognosis with NTD treatment (PFS, 5.9 vs. 16.8 months; P = .024) and CK treatment (PFS, 3.9 vs. 7.5 months; P < .001) Thrombocytosis was related to poor prognosis with NTDs (OS, 15.9 vs. 26.7 months; P = .007) and CKs (OS, 5.9 vs. 14.3 months; P = .010). Neutrophilia was related to poor prognosis with NTDs (OS, 17.6 vs. 25.4 months; P = .063) and CKs (OS, 5.9 vs. 12.8 months; P = .035). Multivariate analysis revealed that overexpression of CAIX was a favorable prognostic factor independent of PFS (hazard ratio [HR], 0.107; P < .001) and OS (HR, 0.055; P < .001). CONCLUSIONS HIF-1α, PTEN, p21, thrombocytosis, neutrophilia, and CAIX in particular are useful prognostic factors in patients with advanced RCC.

BRAF mutation analysis in circulating free tumor DNA of melanoma patients treated with BRAF inhibitors

BRAFV600E is a unique molecular marker for metastatic melanoma, being the most frequent somatic point mutation in this malignancy. Detection of BRAFV600E in blood could have prognostic and predictive value and could be useful for monitoring response to BRAF-targeted therapy. We developed a rapid, sensitive method for the detection and quantification of BRAFV600E in circulating free DNA (cfDNA) isolated from plasma and serum on the basis of a quantitative 5′-nuclease PCR (Taqman) in the presence of a peptide−nucleic acid. We validated the assay in 92 lung, colon, and melanoma archival serum and plasma samples with paired tumor tissue (40 wild-type and 52 BRAFV600E). The correlation of cfDNA BRAFV600E with clinical parameters was further explored in 22 metastatic melanoma patients treated with BRAF inhibitors. Our assay could detect and quantify BRAFV600E in mixed samples with as little as 0.005% mutant DNA (copy number ratio 1 : 20 000), with a specificity of 100% and a sensitivity of 57.7% in archival serum and plasma samples. In 22 melanoma patients treated with BRAF inhibitors, the median progression-free survival was 3.6 months for those showing BRAFV600E in pretreatment cfDNA compared with 13.4 months for those in whom the mutation was not detected (P=0.021). Moreover, the median overall survival for positive versus negative BRAFV600E tests in pretreatment cfDNA differed significantly (7 vs. 21.8 months, P=0.017). This finding indicates that the sensitive detection and accurate quantification of low-abundance BRAFV600E alleles in cfDNA using our assay can be useful for predicting treatment outcome.

Predictive factors for response to treatment in patients with advanced renal cell carcinoma

SummaryIntroduction The analysis of predictive factors of response may aid in predicting which patients with advanced renal cell carcinoma (RCC) would be good candidates for systemic treatments. Materials and methods The expression of several biomarkers was retrospectively analyzed using immunohistochemistry (IHC), as well as 2 analytical variables in 135 patients with advanced RCC treated with cytokines (CK) and/or new targeted drugs (NTD). Results 67 patients were treated solely with NTD and 68 with CK (23 also received NTD). Univariate analysis: HIF1α did not correlate significantly with response to these drugs. Overexpression of CAIX was associated with more responses (%) to NTD (64.7 vs. 21.1; p = 0.004) and CK (22.6 vs. 0; p = 0.038). PTEN demonstrated predictive value of response to sunitinib (70.8 vs. 34.1; p = 0.005). p21 was associated with a lower response to sunitinib (35.9 vs. 65.4; p = 0.025). Thrombocytosis was not significantly associated with response to NTD, although it was with CK (0 vs. 20; p = 0.017). Neutrophilia correlated with a lower response to NTD (29.6 vs. 57.5; p = 0.045), although not with CK. Multivariate analysis: Overexpression of CAIX was an independent predictor of significantly higher response to NTD and CK; OR = 8.773 (p < 0.001). Conclusions Our findings highlight the usefulness of CAIX in selecting patients with advanced RCC as candidates for systemic treatment. PTEN and p21 may be important in predicting response to sunitinib. Thrombocytosis and neutrophilia correlate well with response to CK and NTD, respectively.

Prolonged Clinical Benefit of Everolimus Therapy in the Management of High-Grade Pancreatic Neuroendocrine Carcinoma

Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET) are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS) and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR). Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial.

Pegylated Liposomal Doxorubicin and Gemcitabine in a Fixed Dose Rate Infusion for the Treatment of Patients With Poor Prognosis of Recurrent Ovarian Cancer: A Phase Ib Study

Introduction Pegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies. Methods The starting dose of gemcitabine was 1500 mg/m2, 10 mg/m2 per minute, every 2 weeks (±250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m2 every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied. Results Thirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival. Conclusion The recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m2 on day 1, and gemcitabine, 1000 mg/m2 on days 1 and 15 delivered at an FDRI of 10 mg/m2 per minute in 28-day cycles.

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias.

IntroductionFor nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre’s experience with the use of CKs and TKIs in the treatment of patients with advanced RCC.Materials and methodsThis study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival.ResultsNinety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3–4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1–2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82–162] and with TKIs 201 days (65–337) in the firstand 346 days (256–436) in second-line treatment groups. The median overall survival (OS) was 229 days (142–316) and 2,074 days (1,152–2,996) for patients treated with CKs and TKIs.ConclusionsOur results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.

1452PMULTIDISCIPLINARY TREATMENT OUTCOME OF DESMOID-TYPE FIBROMATOSIS (DTF). A REGISTRY-BASED STUDY FROM SPANISH GROUP FOR RESEARCH ON SARCOMA (GEIS)

ABSTRACT Aim: We analyzed retrospectively data about treatment outcome with existing treatments in DTF. Methods: Descriptive analysis of data related to diagnosis and treatment from all DTF was collected in patients (p) between Sept. 1999 and Nov. 2013 in 26 hospitals of GEIS . Ethics committee approval was obtained. Results: 185 patients. Age: median 37 years (6-85) .63.2% female .Median time lapse from first symptom to diagnosis: 4 months(m). Location : trunk wall 81p (43.8%), extremities 50p (27%), retroperitoneum 10p (5.4%), Gastro-intestinal 16p (8.6%), Head/neck 6p( 3.2%), others 6p(3.2%), 2p (1.1%) missing . 20p (11%) presented a second neoplasia (throughout the whole process). Median tumor size: 8 cm(range 1-96). 3 p (1.6%) presented distant peritoneal disease. First treatment : No treatment 6p (2.7%), Surgery (S) alone 144 p ( 77.8%, 3p >1), S+radiotherapy (RT) 7p (3.7%), S+ chemotherapy (CT) 2 p (1.08%), S+hormonetherapy (HT) 3p (1.62%), S +HT+ Non steroidal antiinflammatory drug (NSAID)+Tirosin-kinasa inhibitor(TKI) 1p (0.54%), CT 5p (2.7%), RT 3p ( 1.6%),NSAID 5p (2.6%), HT 2p (1.08%), TKI 1p(0.54%), HT+NSAID 6p (2.7%). 128p (69.2%) became free of disease, in 49p (26.5%) residual disease remained . 61p (33%) progressed. Median Progression free survival (PFS) :109 m (95%CI 44.6-175.1).Multivariate analysis for PFS: extended/radical surgery(p=0.000) and tumor size Response to CT /other treatments CT treatment Other treatments (TKI, HT, NSAID) p % p % PR 12 30.7 4 7.4 SD 15 38.4 31 55.3 PD 3 7.6 10 17.8 NE 4 10.2 6 10.7 NA 5 12.8 5 8.9 Total 39 100 56 100 PR: partial response; SD: stable disease; PD: progressive disease; NE: non evaluable; NA: non available data. Conclusions: Surgical quality and tumor size seems to play a relevant role in predicting PFS in DFT. Other sistemic treatments showed meaningful activity in progressive disease. Disclosure: All authors have declared no conflicts of interest.

430PGEINOFOTE: SAFETY AND ACTIVITY ANALYSIS OF THE USE OF FOTEMUSTINE (FT) IN DIFFERENT SCHEDULES IN PROGRESSIVE GLIOBLASTOMA (GB) IN SPAIN

ABSTRACT Aim: Previous studies showed that FT may be useful as treatment in recurrent GB. The present study evaluate the activity and toxicity of FT in recurrent malignant GB patients in the clinical setting in Spain. Methods: Patients (age >18 years) with GB that was progressive (first or second recurrence) after prior standard radiotherapy plus temozolomide (TMZ) chemotherapy were eligible for the study. Patients were scheduled to receive FT in different schedules (Addeo vs others). Tumor response was assessed by MRI every 8-12 weeks. The primary end point was safety; secondary points included progression free survival (PFS), overall survival (OS). We analyze the differences between Addeo schedule (A) vs others (O) and 1° recurrence (1°R) vs 2° recurrence (2°R) in terms of safety and activity. Results: 84 patients were assessed; all of them began FT previously Nov 31, 2012. There were 46 males, and the median age was 56 years (ranged from 30 to 73). The median KPS was 70 (40-100). A schedule was used in 60 pts (71.4%). FT in first recurrence was used in 39 pts (46.2%) and 45 pts (51.2%) in second recurrence. The median PFS was (A 1°R / O 1°R/ A 2°R / O 2°R) 3.11/2.41/3.04/2.84 months, the median OS was (A 1°R / O1°R/ A 2° R / O 2°R) 6.15/5.29/4.36/3.87 months . The most common toxicities include thrombocytopenia and neutropenia. There were no statistical differences in Grade III or IV toxicities in relation with the type of schedule (A vs O) nor the 1° or 2° R (17%-7%). The patients received more frequent A schedule than O in 1°R or 2° R. No differences between A vs O in terms of clinical benefit, PS improve or less dexametasone use. Time to response: patients in A schedule spent less time to get the better response than patients with O schedules, whenever we use FT (no significant differences). Conclusions: FT has modest activity for recurrent GB with acceptable toxicity, regardeless the type of schedule. Probably, A get better response in less time than O schedules. Disclosure: All authors have declared no conflicts of interest.

Abstract C41: BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors.

Background: BRAF mutation is present in 50% of metastatic melanoma patients. Treatment with BRAF inhibitors improves survival of BRAF mutant melanoma patients, with a median progression free survival time of 6 months. Twenty percent of patients are refractory to BRAF inhibitors, and others have early resistance development. Pretreatment analysis of BRAFV600 mutation in cell free DNA from serum or plasma could help to select patients for BRAF inhibitor treatments. We have investigated the sensitivity of the assay and its predictive value. Methods: Analysis of BRAFV600 mutation was performed in cell free DNA (cf DNA) from serum and plasma of 22 metastatic melanoma patients before starting a BRAF inhibitor treatment. Results: Six patients were women, median age was 62 years old (58-81). Four patients (18%) had complete response to treatment. Eleven patients (50%) had partial response to treatment. Two patients (9%) had progression disease as their best response. Median progression free survival time (PFS) for patients with complete response, partial response, stable disease and progression disease were: not reached, 4.6 months, 3 months and one month, respectively (p<0.00001). Twelve patients (54.5%) had BRAF positive analysis pretreatment in serum/plasma. From BRAF serum/plasma positive patients 1 had CR (8%) and 7 PR (58%). From BRAF serum/plasma negative patients: 3 (30%) CR and 4 (40%) PR. Median PFS for patients treated with BRAF inhibitors was 3.5 months for BRAF serum/plasma positive patients and 13.57 months for BRAF serum/plasma negative patients (p=0.026) Conclusion: BRAFV600 serum/plasma analysis is a good predictor of survival for patients treated with BRAF inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C41. Citation Format: Maria Gonzalez Cao, Salvador Martin Algarra, Eva Munoz, Clara Mayo de las Casas, Jose Luis Manzano, Javier Cortes, Miguel Angel Molina-Vila, Jose Pablo Berros, Leticia De Mattos-Arruda, Miguel Sanmamed, Alvaro Gonzalez, Carlos Alvarez, Niki Karachaliou, Rafael Rosell. BRAFV600 serum/plasma analysis: Predictive value of survival in melanoma treated with BRAF inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C41.

Protein BIII-tubulin expression as a prognostic and/or predictive factor of response to docetaxel in patients with hormone-refractory prostate cancer.

84 Background: Docetaxel is a standard treatment for hormone-refractory prostate cancer. Preclinical-clinical studies suggest that the determination of the BIII-tubulin is associated with response to taxanes. This study analyzes the role of that subunit of microtubules in prostate biopsies of patients with HRPC treated with docetaxel. METHODS Thirty two patients with prostate biopsy who received docetaxel in first-line chemotherapy between 2006 and 2011 were included in this retrospective cohort analysis. The clinic-pathological characteristics, PSA response, progression-free survival (PFS) and overall survival (OS) were collected. The findings were correlated with the overexpression of BIII-tubulin protein measured by immunohistochemistry techniques (IHC) with a purified and monoclonal Ac mouse. RESULTS The median age and Karnofstky index (KI) were 68 years (range 49-77) and 80% (60-90) respectively. Five patients (15.6%) had received only one anti-hormone treatment, fifteen (46.8), two and twelve (37.5) more than two lines. Twenty patients (62.5) had only one metastatic localization. The median of PSA value before the docetaxel treatment was 302 (4-3745). With a median of eight cycles (3-10) of docetaxel (75mg/m2/ /3s) 41% of patients achieved biochemical response with a median PFS and OS of 4.9 and 19.6 months respectively. Moderate-intense overexpression of BIII-tubulin was identified in five patients (15.6) and minimal or absent in 27 (84.4). In univariate analysis, over-expression was correlated with KI, but not with Gleason score. PSA responses to docetaxel was observed in four patients (80%) with over-expression compared with 20% of those with minimal or absent BIII-tubulin staining. The median PFS and OS for patients with over-expression was 8.6 and 20 months respectively compared to 4.3 and 17 months for those with minimal or absent BIII-tubulin. CONCLUSIONS Over-expression of BIII-tubulin in tumor prostate tissue, applying the present technique is unusual. Its presence appears to be related with higher biochemical response to docetaxel and improvement in PFS and OS. These findings are discordant with those previously published.