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Resumen Objetivo Evaluar el uso de la terapia con beneficio cardiovascular en pacientes con DM tipo 2 previo al ingreso en servicios de medicina interna. Metodos Estudio transversal en un dia de los pacientes con DM tipo 2 hospitalizados en servicios de medicina interna. Se recogieron variables demograficas y antropometricas, datos de laboratorio y utilizacion de farmacos antihiperglucemiantes. La variable desenlace fue la proporcion y los determinantes de uso de inhibidores del cotransportador sodio-glucosa 2 (iSGLT2) y de agonistas del receptor del peptido similar al glucagon tipo 1 (AR-GLP1). Resultados Se incluyeron 928 pacientes pertenecientes a 74 hospitales. La edad media fue 78,9 anos (DE: 10,86), un 50% varones. Un total de 557 (60%) presentaba cardiopatia isquemica, 189 (20,4%) enfermedad cerebrovascular, 293 (31,6%) insuficiencia cardiaca, 274 (29,5%) enfermedad renal cronica y 129 (13,9%) enfermedad arterial periferica. Los antihiperglucemiantes utilizados previo al ingreso fueron: sulfonilureas (5.7%), biguanidas (49.1%), inhibidores de la alfa-glucosidasa (0,2%), pioglitazona (0%), iDPP4 (39%), iSGLT2 (5,8%), AR-GLP1 (2,6%) y analogos de insulina basal (24%). La edad mayor de 75 anos fue el factor determinante principal para no utilizar iSGLT2 (OR ajustada 0,28; intervalo de confianza al 95%: 0,10-0,74; p = 0,039) o AR-GLP1 (OR ajustada 0,09; intervalo de confianza al 95%: 0,02-0,46; p = 0,006). Discusion Una gran proporcion de pacientes ancianos con DM tipo 2 de muy alto riesgo cardiovascular no recibe terapia antihiperglucemiante con farmacos de probado beneficio cardiovascular. El tratamiento mas frecuentemente utilizado fue metformina e iDPP4. Existe un margen de mejora en el tratamiento en esta poblacion de muy alto riesgo.

Background: P led to a meaningful improvement in clinical outcomes when used in combination with endocrine therapy for first- or later-line regimen in HR[+]/HER2[-] MBC. Grade 3-4 neutropenia was the most common adverse event (AE) in the P-containing regimens. Although venous thromboembolic events (VTE) have been rarely reported in registrational trials, a systematic review and meta-analysis of randomized controlled trials demonstrated a higher rate of these AEs. Moreover, rare but severe cases of interstitial lung disease (ILD)/pneumonitis have been observed during post-approval use of P. Here, we present a comprehensive toxicity profile of pts included in the PARSIFAL study, with particular emphasis given to AEs of special interest of the overall safety population. Methods: A total of 486 pts with HR[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse >12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease) were randomly assigned 1:1 to receive P (oral 125 mg/day [d]; 3 weeks on/1 week off) plus either F (intramuscular injection 500 mg/d; d 0, 14, 28, and then every 28 ds) or L (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (de novo/recurrent). Safety assessments included blood analysis and collection of vital signs at screening, d1 of each cycle, and end of treatment/withdrawal. Severity was graded as per the NCI Common Terminology Criteria for Adverse Events v.4.03. Results: The incidence rate of any grade, grade 3-4, and serious AEs was 99.6%, 80.9%, and 29.9%, respectively, in the FP arm, and 99.2%, 78.5%, and 21.1% in the LP arm. Discontinuations due to AEs were 5.4% in the FP arm and 2.1% in the LP arm. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both arms. Febrile neutropenia was reported in 1.2% (3 pts) and 0.4% (1 patient) in the FP and LP arms, respectively. The rate of VTE of any grade was 5.8% (14 pts) in the FP arm and 4.5% (11 pts) in the LP arm (p = 0.531). Among 18 pts who had grade ≥ 3 pulmonary embolism (PE), the incidence reported in the FP and LP arms was 5% (12 pts) vs 2.5% (6 pts), respectively, and many of them (n=16, 88.9%) were unrelated PE. Asymptomatic grade 3 PE was reported in 10 pts of the entire study population on every 3-mo CT scan. Further, in 5 pts PE was detected in the context of progressive disease. Median time from the first dose of study drugs to occurrence of PE was 4.1 mo (range 1.4-32.0 mo) in the FP arm and 7 mo (range 1.8-19.3 mo) in the LP arm. Analysis of baseline characteristics in the whole population revealed that older pts had a significantly increased risk for developing PE (69.5 years [range 47-84 years]; p < 0.01). ECOG performance status, menopausal status, metastatic disease, visceral involvement, number of disease sites, and prior therapies including antithrombotic agents did not significantly increase the risk for developing PE. Grade 3 ILD/pneumonitis was rarely observed in the FP and LP arms (0.8% vs 1.2%, respectively) with no grade 4 AE. Conclusions: First-line treatment with FP and LP for HR[+]/HER2[-] MBC in the PARSIFAL study confirmed the favorable safety profile, with neutropenia representing the most common AE. Although rare, ILD/pneumonitis can be a side effect of P-based regimens. VTE and PE incidence rates were low and consistent with age-specific analyses from PALOMA trials and breast cancer population. Early detection of these AEs may assist in optimizing their management. Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Meritxell Bellet, Florence Dalenc, Miguel J. Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés. Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-17.

The development of online interactive resources for interpreter training has been at the centre of the agenda in terms of pedagogical assistance and cooperation both for the European Institutions and for their partner universities. Modern videoconferencing systems and online learning technologies provide an excellent alternative to face-to-face classes, offering solutions to the problem of trainers’ availability and engaging learners in synchronous and asynchronous task-oriented activities. In this context, the European Parliament-funded ERITON project was launched in 2014 with the aim of facilitating the dissemination of best practices and enhancing collaboration between EU and non-EU partner universities in the field of conference interpreter training. Forming the strategic core of this project was the use of innovative training methodologies, such as virtual classes and virtual mock-conferences. This paper presents the pedagogical framework of the VCs and discusses the results of an online survey conducted from 2015 to 2017 among students who actively participated in the virtual classes held within the ERITON project. The aim of the survey was to obtain anonymous feedback on the technical set-up of the VCs and on the helpfulness of this format in terms of skill acquisition and progress. The results show that the new medium was well-received and appreciated by respondents, especially since it gave them the possibility to interact in ways and with people that would otherwise be impossible.

This article aims at presenting the reader with a didactic proposal for training higher education interpreting students in entrepreneurial skills by means of introducing a toolkit based on the Blue Ocean Strategy marketing theory. First, the reasons why entrepreneurship is necessary and should thus be an integral part of the interpreting curriculum will be put forward. Second, the Blue Ocean Strategy and its special suitability for the interpreting market will be argued. Third, the transposition of this theory into the interpreting classroom will be explained, with a focus on the approach and development of the lesson plan and didactic materials, which were devised on the basis of a flipped learning teaching methodology. Fourth, the results of the pilot implementation of this toolkit in the dialogue interpreting course Interpretación II: Técnicas de mediación intercultural, a 6 ECTS B.A. in Translation and Interpreting course at the Universidad Pontificia Comillas (Madrid), will be discussed by way of analysing 45 responses to questionnaires designed with the purpose of shedding light on whether perceptions of the interpreting market substantially differ among students who made part of the experimental group that took the Blue Ocean Strategy pilot class (18 subjects) and the control group (27 subjects), who did not receive training in this marketing strategy.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and panchromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Question Which is the optimal endocrine partner (fulvestrant vs letrozole) for cyclin-dependent kinase 4 and 6 inhibitor palbociclib in previously untreated, endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer? Findings In this randomized, open-label, phase 2 trial, 486 patients were assigned in equal numbers to receive palbociclib plus fulvestrant or letrozole. Median investigator-assessed progression-free survival was 27.9 months for fulvestrant-palbociclib vs 32.8 months for letrozole-palbociclib, a difference that was not statistically significant. Meaning Fulvestrant-palbociclib demonstrated no improvement in progression-free survival over letrozole-palbociclib, confirming letrozole as the preferred palbociclib partner in this patient population. This randomized clinical trial investigates fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative breast cancer. IMPORTANCE The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. OBJECTIVE To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. DESIGN, SETTING, AND PARTICIPANTS In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. INTERVENTIONS Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). MAIN OUTCOMES AND MEASURES The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. CONCLUSIONS AND RELEVANCE Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavilypretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/ HER2(-)) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2(-) mBC who had progressed on >= 4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus, This study was sponsored by Biomedical Research Foundation of the Hospital Clinico San Carlos (Madrid, Spain). The study was funded by an investigator sponsored research grant (WI236789) from Pfizer.

The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2+) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34–66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24–54]) or neratinib (33% [95%CI 20–50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR−) tumors had a higher pCR rate than HR+ tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR− patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2+ patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.

Recurrence of Clostridium difficile infection (CDI) has major consequences for both patients and the health system. The ability to predict which patients are at increased risk of recurrent CDI makes it possible to select candidates for treatment with new drugs and therapies (including fecal microbiota transplantation) that have proven to reduce the incidence of recurrence of CDI. Our objective was to develop a clinical prediction tool, the GEIH-CDI score, to determine the risk of recurrence of CDI. Predictors of recurrence of CDI were investigated using logistic regression in a prospective cohort of 274 patients diagnosed with CDI. The model was calibrated using the Hosmer-Lemeshow test. The tool comprises four factors: age (70-79 years and >= 80 years), history of CDI during the previous year, direct detection of toxin in stool, and persistence of diarrhea on the fifth day of treatment. The functioning of the GEIH-CDI score was validated in a prospective cohort of 183 patients. The area under the ROC curve was 0.72 (0.65-0.79). Application of the tool makes it possible to select patients at high risk (> 50%) of recurrence and patients at low risk (< 10%) of recurrence. GEIH-CDI score may be useful for clinicians treating patients with CDI. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

This abstract was withdrawn by the authors.

The purpose of the MERIBEL trial was to evaluate the efficacy and safety of eribulin monotherapy as first-line therapy for patients with aggressive taxane-pretreated HER2-negative metastatic breast cancer with a short disease-free interval. The median time to progression was 4.1 months, and the clinical benefit rate was 26.4%. These results confirm that eribulin represents an effective therapeutic option for this poor-prognosis population. Background: Eribulin has efficacy in patients with progression after >= 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors. Patients and Methods: Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received >= 1 dose of eribulin. Results: The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia. Conclusion: Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC. (C) 2018 Elsevier Inc. All rights reserved.

Background: International consensus stresses the preference for endocrine therapies (ET) for the ER[+]/HER2[-] ABC population. However, in real-world, chemotherapy (CT) is an extended practice long before exhausting endocrine options (Swallow E, Curr Med Res Opin. 2014). There is little knowledge on the prognostic factors that drives OS among the ER[+]/HER2[-] population at the time of first line CT for ABC. Methods: The Athena trial assessed safety of different first-line CT & bevacizumab regimens in 2.264 patients (pts) treated between 2006 and 2009 over 34 countries. A total of 1.492 ER/PgR[+]/HER2[-] pts were identified, as 585 TNBC pts (control arm). We adapted the ESMO 2012 guidelines of endocrine resistance to the data collected, considering 5 years the median duration of (neo)adjuvant ET. Endocrine resistance status (ERS) at the time of inclusion was measured by: (1) Progression on ET for Early stage (EEP) [on or within the first year of], and (2) Prior ET for ABC (AEP), whatever the duration or number of endocrine lines. Three ES were pre-defined: Low sensitive (LS): patients with both EEP and AEP criteria; moderately sensitive (MS): either EEP or AEP criteria, and Highly sensitive (HS): neither EEP nor AEP criteria. Other prognostic factors (PF) identified in a prior analysis (Llombart-Cussac A, Breast 2014) were incorporated in a multivariate Cox proportional-hazard model. Results: Median age was 53 years (range 22-93); 5.2% ECOG ≥2 and 28.9% with prior analgesic treatment. ER/PgR positivity were 94.4%/76% respectively. Patients were previously exposed to anthracycline (53.5%) and taxanes (21.4%) for early stage BC. Prior endocrine therapy in (neo)adjuvant and metastatic settings were (65.3%) and (31.8%), respectively. Pts de novo metastatic represented 19.3%, and the median DFI in pts progressing from an early stage was 43.2 mo. Liver involvement was observed in 40.3% of pts and 20.5% presented ≥3 organs involved. The ES for the population was HS: 492 pts (33%), MS: 755 pts (50.6%) and LS: 245 pts (16.4%). After median follow-up of 22.6 months (range: 0.1 to 43.6) and 752 OS events (50.4% of pts), median OS for HS, MS, LS and TNBC groups were >40 mo. (median not achieved), 26.3 (95%CI: 24.5–28.4), 20.1 (95%CI: 17.8–23.9) and 18.3 (95%CI: 16.3–19.7) respectively. 3-years OS survival rates for HS, MS, LS and TNBC were 53.5%, 34.8%, 23.9% and 26.6%, respectively. Multivariate-adjusted hazard ratios of OS for (HS vs LS) and (HS vs MS) were 2 (IC95%: 1.6–2.5) and 1.5 (IC95%: 1.2–1.8). The other PF related with OS were: ECOG≥2 or analgesics or corticosteroids 1.6 (IC95%: 1.4–1.8); liver mets or>2 involved organs 1.4 (IC95%: 1.2–1.6) and adjuvant anthracyline and/or taxane 1.2 (IC95%: 1.1–1.4). Conclusions: Nearly to 40% of ER[+]/HER2[-] ABC pts confronted to first line CT were precluded as highly sensitive to ET, achieving a median OS that doubles the less sensitive groups. Confirmatory studies with post-treatment information may be important to link this benefit to ET. However Endocrine Status may be useful to appropriately characterize or select patients in future first-line CT studies for HER2[-] pts. Citation Format: Llombart A, de la Haba-Rodríguez JR, Gligorov J, Aguirre E, Sampayo M, Cortes J. Prognostic relevance of prior endocrine treatments in overall survival (OS) at the time of first line chemotherapy in ER[+]/HER2[-] advanced breast cancer (ABC) patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-09.

Objective: Endometrial cancer is the second most frequent neoplasm in women with Lynch syndrome (LS). We sought to assess whether analyzing women with endometrial cancer would identify families with LS not identified with current clinical criteria. Methods: We included women diagnosed with endometrial cancer younger than 50 years and also older if they had a family cancer history associated with LS. In blood samples obtained, we analyzed mutations in mismatch repair (MMR) genes, as well as protein expression by immunohistochemistry and microsatellite instability (MSI) in tumour tissue. Results: A total of 103 patients were enrolled. We detected 14 pathogenic mutations and 4 genetic variants of unknown clinical significance in MMR genes. We found MSI in 41.66% of the women with a pathogenic mutation. In this group, 76.92% showed loss of at least one MMR protein. Women with mutations were younger at diagnosis, but all of them had a family history compatible with LS. Conclusions: Analysis of the MMR genes, in particular MSH6, seems to be appropriate in women with endometrial cancer and a family history of tumours associated with LS.

1007 Background: The CDK4/6 inhibitor palbociclib (P) in combination with letrozole (L) has become a standard first-line treatment for patients (pts) with luminal metastatic breast cancer (MBC) (PALOMA-1 & 2 trials). Meanwhile, the anti-estrogen fulvestrant (F) showed to be superior to anastrozole in the same population (FALCON trial). We aimed to identify the best endocrine agent to combine with P in this first-line scenario. Methods: A total of 486 pts with ER[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease) were randomly assigned (1:1 ratio) to receive P (oral 125 mg/day [d]; 3 wks on/1 wk off) plus F 500 mg/d (I.M Days 0, 14, 28, and then every 28 d) or PL (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (“de novo”/recurrent). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. 254 events were needed with 80% power to detect a hazard ratio (HR) ≤0.7 in favor of PF (2-sided α = 0.05). Results: By March 9th, 2020, 256 PFS events occurred. Pts characteristics were well balanced. Median age was 62 years (range: 25–90), 56.6% were ECOG 0, 40.7% had “de novo” metastatic disease, 48% had visceral disease, and 43.6% with ≥3 organ sites involved. At median follow-up of 32 mo, median PFS was 27.9 mo (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 mo (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for pts with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). No differences were observed in ORR or CBR between arms. Grade ≥3 adverse events were similar in both arms, being neutropenia and leukopenia the most frequent. No treatment-related deaths were reported. Conclusion: This study was not able to identify an improvement in PFS for PF over PL in patients with endocrine-sensitive ER[+]/HER2[-] MBC. As both arms demonstrated comparable 4 years-OS, PF is a reasonable alternative to PL in this setting. Clinical trial information: NCT02491983 .

Lynch syndrome (LS) is an autosomal dominant condition characterized by an increased risk of hereditary colorectal, endometrial, ovarian, pancreatic, urinary tract, and gastric cancer. It is estimated that around 5% of all endometrial cancer (EC) cases are due to an inherited predisposition, of which LS might be the most frequent. The lifetime risk of developing EC in women with LS ranges between 40% and 71% depending on the type of mutation. In many cases, this risk may even exceed their risk of developing colon cancer. Moreover, in 60% of these women, EC will be the first primary malignancy diagnosed and the sentinel diagnosis of the syndrome. Therefore, it is essential to identify which women with EC have LS in order to allow implementation of individualized screening and preventive strategies.

Improved understanding of risk of recurrence (ROR) is needed to reduce cases of recurrence and more effectively treat breast cancer patients. The purpose of this study was to examine how a gene-expression profile (GEP), identified by Prosigna, influences physician adjuvant treatment selection for early breast cancer (EBC) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice. A prospective, observational, multicenter study was carried out in 15 hospitals across Spain. Participating medical oncologists completed pre-assessment, post-assessment, and follow-up questionnaires recording their treatment recommendations and confidence in these recommendations, before and after knowing the patient’s ROR. Patients completed questionnaires on decision-making, anxiety, and health status. Between June 2013 and January 2014, 217 patients enrolled and a final 200 were included in the study. Patients were postmenopausal, estrogen receptor positive, human epidermal growth hormone factor negative, and node negative with either stage 1 or stage 2 tumors. After receiving the GEP results, treatment recommendations were changed for 40 patients (20%). The confidence of medical oncologists in their treatment recommendations increased in 41.6% and decreased in 6.5% of total cases. Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results (p Though this study does not include evaluation of the impact of GEP on long-term outcomes, it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection. Patients’ anxiety about the selected adjuvant therapy decreased with use of the GEP.

Purpose: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients. Experimental Design: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations. Results: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients. Conclusions: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants. Clin Cancer Res; 20(5); 1158–68. ©2014 AACR.

BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

Background & Aims We investigated whether patients with multiple serrated polyps, but not meeting the World Health Organization criteria for serrated polyposis syndrome, and their relatives have similar risks for colorectal cancer (CRC) as those diagnosed with serrated polyposis. Methods We collected data from patients with more than 10 colonic polyps, recruited in 2008–2009 from 24 hospitals in Spain for a study of causes of multiple colonic polyps. We analyzed data from 53 patients who met the criteria for serrated polyposis and 145 patients who did not meet these criteria, but who had more than 10 polyps throughout the colon, of which more than 50% were serrated. We calculated age- and sex-adjusted standardized incidence ratios (SIRs) for CRC in both groups, as well as in their first-degree relatives. Results The prevalence of CRC was similar between patients with confirmed serrated polyposis and multiple serrated polyps (odds ratio, 1.35; 95% confidence interval [CI], 0.64–2.82; P = .40). The SIR for CRC in patients with serrated polyposis (0.51; 95% CI, 0.01–2.82) did not differ significantly from the SIR for CRC in patients with multiple serrated polyps (0.74; 95% CI, 0.20–1.90; P = .70). The SIR for CRC also did not differ significantly between first-degree relatives of these groups (serrated polyposis: 3.28, 95% CI, 2.16–4.77; multiple serrated polyps: 2.79, 95% CI, 2.10–3.63; P = .50). Kaplan–Meier analysis showed no differences in the incidence of CRC between groups during the follow-up period (log-rank, 0.6). Conclusions The risk of CRC in patients with multiple serrated polyps who do not meet the criteria for serrated polyposis, and in their first-degree relatives, is similar to that of patients diagnosed with serrated polyposis.

Background and study aims: Endoscopic surveillance in patients with multiple colorectal polyps aims to reduce colorectal cancer (CRC) incidence and mortality, as well as the need for colorectal surgery. The aim of this study was to determine the risk of developing CRC or the need for surgery during endoscopic surveillance in a cohort of patients with multiple (10-100) colorectal polyps. Patients and methods: This was a multicentrer, longitudinal, observational study in 15 CRC high risk clinics in Spain, carried out between January 2009 and December 2010. Patients who were included in the EPIPOLIP trial and had at least 1 year of follow-up were included in the study. The primary outcome of interest was the incidence of CRC at least 1 year following the initial colonoscopy. The secondary outcome was the need for colorectal surgery. Results: A total of 265 patients were followed for a median of 3.8 years. Patients underwent a median of 5 colonoscopies, and 17 patients (6.4 %) were diagnosed with CRC. A total of 32 patients (12.1 %) underwent surgery, including 15 (5.7 %) for prophylaxis without a diagnosis of CRC. The corresponding incidence density rates for CRC and colorectal surgery were 1.4 (95% confidence interval [CI] 0.7 to 2.1) and 2.7 (95 % CI 1.7 to 3.6) per 100 patient-years, respectively. Only the presence of symptoms at first colonoscopy was independently associated with CRC diagnosis (hazard ratio [HR] 7.7, 95% CI 1.1 to 59.3) and colorectal surgery (HR 4.6, 95% CI 1.02 to 20.6). Conclusions: Patients with more than 10 neoplastic polyps required frequent colonoscopies within a short follow-up period. More than 10% of patients required colorectal surgery within 4 years, more than half for incident CRC.

BACKGROUND: Clinical efficacy and safety of T-DM1 for the treatment of HER2-positive MBC has been assessed in several phase II and III trials and is now considered the standard of care in taxane-and trastuzumab-progressing patients. However, although T-DM1 has shown encouraging antitumor activity in the advanced setting, several strategies to improve T-DM1 efficacy are currently evaluated, including the combination with non-pegylated liposomal doxorubicin (NPLD), considering that: i) doxorubicin is one of the most active chemotherapeutic agents against HER2-positive breast cancer; ii) the combination of doxorubicin and trastuzumab induces synergistic antitumor activity in HER2-overexpressing preclinical models; and iii) liposomal formulations of doxorubicin have a reduced risk of developing cardiac toxicity. OBJECTIVES: The primary objective of this trial is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and NPLD in patients with HER2-positive MBC naïve of anthracyclines and previously treated with trastuzumab and a taxane. The secondary objectives include 1) safety, with special emphasis on cardiac safety evaluated by left ventricular ejection fraction, high-sensitivity troponin I and B-type natriuretic peptide (BNP) levels, 2) pharmacokinetics, 3) antitumor activity, and the 4) role of single nucleotide polymorphisms of HER2 gene for developing cardiotoxicity. TRIAL DESIGN: This is a dose-finding, open-label, non-randomized and multicenter phase I clinical trial of T-DM1 at a fixed dose of 3.6 mg/kg IV in combination with three different dose levels (DL) of NPLD (45, 50, and 60 mg/m2) IV administered on Day 1 every three weeks. The trial follows a modified dose escalation scheme with a 3+3 design.A total of three patients will be included in the first cohort and observed for dose-limiting toxicities (DLTs) during the first two cycles of treatment. If none of these patients experiences a DLT, three other patients will be treated at the next DL. However, in case of at least one patient experiences a DLT, three more patients will be treated at the same DL. The MTD will be defined as the highest DL at which ≤1 of six patients experiences a DLT during the first two cycles of treatment. An expansion cohort of six additional patients at the MTD will be included. ELIGIBILITY: Anthracycline-naïve patients with HER2-positive MBC and up to two prior chemotherapy regimens in the advanced setting who previously were treated with trastuzumab and a taxane. ECOG performance status of 0-1. Adequate organ and cardiovascular function with LVEF ≥ 55%. RECIST v1.1 evaluable disease. ACCRUAL: A total of 12-24 patients will be enrolled at four sites in Spain and France. Recruitment was opened on September 2015. To date, four patients (three at DL1 and one at DL2) have been recruited. Citation Format: López-Miranda E, Brain E, Saura C, Gligorov J, Dubot C, Dieras V, Suter TM, Aguirre E, Perez-García JM, Llombart A, Cortés J. Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-03.

Importance Cutaneous lupus erythematosus (CLE) can be severe and treatment resistant. B-cell depletion therapy (BCDT) with rituximab is well recognized in organ involvement in systemic lupus erythematosus (SLE), but its efficacy in cutaneous manifestations is less well established. Objective To evaluate the outcomes of BCDT in CLE and its clinical subtypes in the setting of associated SLE. Design, Setting, and Participants This single-center, retrospective, cohort study was performed at the adult tertiary referral Rheumatology Department of University College London Hospital, London, United Kingdom, from January 1, 2000, through March 31, 2016, with 12-month follow-up completed on March 31, 2017. Adult patients with carefully classified CLE and mucocutaneous British Isles Lupus Assessment Group (BILAG) grade A or B who were treated with rituximab BCDT were selected from a prospective database of 709 patients with SLE. Data were analyzed from April through December 2017. Main Outcomes and Measures Clinical response was examined at 6 and 12 months after treatment for CLE and its subtypes acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and nonspecific LE (NSLE). A complete response was defined as achieving BILAG grade D; partial response, BILAG grade C; stable disease, no change; and disease flare, change from BILAG grade C or D to grade A or B. Results A total of 50 patients with SLE were eligible for inclusion; mean (SD) age at diagnosis was 26.9 (12.1) years, and 49 (98%) were women. Twenty-one patients had ACLE; 6, SCLE; 10, CCLE; and 11, NSLE (including 2 with concurrent ACLE and CCLE). Overall, at 6 months, 38 patients (76%) improved their mucocutaneous BILAG grade A or B status, including 20 (40%) with a complete response. At 12 months, 28 of 46 patients (61%) maintained this response, including 24 (52%) with a complete response. Two of 6 patients (33%) with SCLE showed a complete response at 6 and 12 months. Five of 12 patients (42%) with CCLE showed a complete response at 6 months, and 5 of 11 (45%), at 12 months. Fifteen patients (30%) required further rituximab therapy within 12 months for cutaneous involvement. Conclusions and Relevance B-cell depletion therapy using rituximab appears effective in patients with SLE and severe active CLE; however, outcomes are variable in those with SCLE and CCLE subtypes.

BACKGROUND: Olaparib is a well-tolerated oral PARP inhibitor. Olaparib has shown promising monotherapy activity in patients with germline mutations in BRCA genes and cancers that exhibited a failure in DNA repair mechanism. The aim of this trial is to evaluate the efficacy of olaparib as single agent in non-BRCA MBC patients whose tumors exhibit an homologous recombination deficiency (HRD) signature. TRIAL DESIGN: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive oral olaparib 300 mg twice a day during 28 days cycles until progression or unacceptable toxicity. HRD signature will be evaluated with one tumor tissue-based test: FMI Lynparza HRR. The stage I principal selection criteria are: (1) Confirmed non-BRCA triple negative locally advance (LA) or MBC; (2) HRD signature; (3) one to three previous lines for the MBC and prior taxanes exposure; (4) RECIST v1.1 evaluable disease. In stage II the study will be extended to patients with luminal subtype and confirmed non-BRCA LA or MBC with HRD signature. The primary goal is to evaluate the efficacy of olaparib monotherapy. Primary endpoint are the clinical benefit rate (CBR), defined as the percentage of patients who experienced overall response (as best response) or stable disease ≥24 weeks in accordance with RECISTv1.1. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CBR ≤5% while targeting an improvement of the CBR to ≥20% would be an optimal approach to evaluation of the study strategy. At first stage, ≥1 patient with clinical benefit among 17 patients will be necessary to continue. At the study end, ≥5 subjects with clinical benefit out of 35 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 39 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. We anticipate a 40% of screened TNBC and 25% of luminal (RH-positive HER2-negative) non-BRCA patients will exhibit HRD signature. Therefore, we expect to screen 48 patients in the 1st stage and 80 patients in the 2nd stages to accomplish with the accrual goal (a total of 128 patients screened). Secondary objectives include (1) efficacy measures: objective response rate (ORR), progression-free survival (PFS) and overall survival; (2) the assessment of HRD signatures agreement and validity to predict clinical benefit and overall response; and (3) safety-related outcomes. Citation Format: Elena Aguirre, Kepa Amillano, Alfonso Cortés, María José Juan, Antonia Márquez, Manuel Ruiz, Sonia Servitja, Ander Urrutikoetxea, Antonio Llombart, José Perez, Javier Cortes. A two-stage Simon Design phase II study for NOn-BRCA metastatic BReast cancer (MBC)patients with homologous recombination deficiency treated with OLAparib single agent.(NOBROLA study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT165.

Background: HER2-negative metastatic breast cancer (MBC) patients with central nervous system (CNS) involvement previously treated with a local therapy had very few possibilities of disease response with conventional systemic treatments. Liposomal irinotecan (nal-IRI) is a novel formulation of irinotecan. It has shown promising activity in patients with CNS involvement. The aim of this trial is to evaluate the efficacy of nal-IRI as single agent in HER2-negative MBC patients with CNS progression following local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy. Trial design: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive intravenous nal-IRI in a fixed dose of 60 mg/m2 expressed as irinotecan hydrochloride trihydrate salt on day 1 of a 14-day cycle until progression or unacceptable toxicity. The principal selection criteria are: (1) HER2-negative inoperable MBC with CNS involvement; (2) prior local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy; (3) prior treatment with taxanes; (4) at least one measurable brain lesion according to RECIST v1.1 criteria. The primary objective is to evaluate the efficacy of naI-IRI monotherapy. Primary endpoint is the CNS overall response rate (ORR), defined as the percentage of patients who experienced complete (CR) and partial response (PR) (as best response). It will be assessed in accordance with the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CNS ORR ≤5% while targeting an improvement of the CNS ORR to ≥15% would be an optimal approach for evaluating the study strategy. At least 2 responders among 23 patients will be necessary to proceed to the second stage. At the study end, ≥6 responders out of 56 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 63 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. The secondary objectives include safety-related outcomes and efficacy measures: CNS clinical benefit rate (CR, PR and stable disease [SD] ≥12 weeks), ORR according to a CNS volumetric parameter (CR, PR and >65% reduction of CNS lesion), clinical benefit rate (CR, PR and SD ≥24 weeks), progression-free survival and overall survival. Trial registration: NCT03328884. Date of registration: November 1st, 2017. First patient included: July, 05th 2017. Citation Format: Javier Cortés, David Paez, José Manuel Pérez García, Salvador Blanch Tormo, Kepa Amillano Parraga, Manuel Ruiz Borrego, Antonio Antón Torres, María Fernández, Emilio Alba Conejo, Miguel Ángel Seguí Palmer, Joan Dorca Ribugent, Rafael López López, Mireia Margelí Vila, Elena Aguirre, Antonio Llombart. Multicenter open-label, phase II trial, to evaluate the efficacy and safety of liposomal irinotecan (nal-IRI) for progressing brain metastases in patients with HER2-negative breast cancer (The Phenomenal Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT154.

En la actualidad, el dolor es considerado como el quinto signo vital. El objetivo del trabajo fue determinar la efectividad de un programa educativo para el personal de enfermería sobre manejo de dolor en pacientes con problemas crónicos degenerativos y quirúrgicos. El método usado fue el diseño pre-experimental con pretest-postest. La población de estudio estuvo integrada por personal de enfermería (42) de dos instituciones de salud de segundo nivel de atención, del sector público. Se utilizó el cuestionario Conocimiento y Actitudes Respecto al Dolor. La media de respuestas correctas del conocimiento pretest fue de 50.9 (DE = 9.65), valor mínimo de 28.1 y máximo 78.1; y en el postest la media fue de 70.4 (DE = 10.9) valor mínimo de 40.6 y máximo 90.6. Posterior a la intervención educativa, se encontró mayor conocimiento en el personal de enfermería (t (41)= - 12.98; P < 0.001). El estudio de intervención educativa del personal de enfermería fue efectivo para mejorar el conocimiento sobre el manejo del dolor en los pacientes, ya que los primeros brindaron una mejor atención y cuidados, posteriores a la intervención educativa, no obstante, este fue insuficiente para la mayoría del personal participante.

Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated.

This Phase 1 study aimed to determine the recommended Phase 2 dose of LY2334737, an oral gemcitabine prodrug, when combined with standard dose docetaxel treatment in patients with advanced solid tumors. Pharmacokinetics (PK) and antitumor activity were additionally evaluated.Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily (QD) for 14 days, followed by a 7-day drug-free period. Docetaxel was given at 75 mg/m(2) every 3 weeks (q3w). Cycles were repeated until progressive disease (PD) or unacceptable toxicity.Of 22 patients recruited, all Caucasian, 7 received an LY2334737 dose of 10 mg/day, 10 received 20 mg/day, 5 received 30 mg/day. Nineteen patients discontinued due to PD, 2 due to adverse events, 1 due to investigator decision. Dose-limiting toxicities: 2× febrile neutropenia (G3), 2× fatigue (1× G2, 1× G3), 1× neutropenia (G4). The maximum tolerated dose (MTD) was identified to be 10 mg/day. Two patients achieved partial response, 10 patients stable disease. Enrollment was stopped after unexpected hepatic toxicities were observed with LY2334737 QD for 14 days per cycle in another study of Japanese patients. PK data were consistent with the first-in-man study of LY2334737 and did not reveal any drug-drug interaction between LY2334737 and docetaxel.Combination of LY2334737 at doses up to 30 mg/day QD for 14 days per cycle with docetaxel 75 mg/m(2) q3w resulted in an undesirable toxicity profile and a low MTD of 10 mg/day. Alternative treatment schedules of LY2334737 should be explored.

Background & Aims We investigated clinical and molecular differences between the different phenotypes of serrated polyposis syndrome (SPS) and the frequency of mutations in BRAF or KRAS in polyps from patients with SPS. Methods We collected data on clinical and demographic characteristics of 50 patients who fulfilled the criteria for SPS. Polymerase chain reaction and sequence analysis were used to identify BRAF and KRAS mutations in 432 polyps collected from 37 patients; we analyzed CpG island methylator phenotypes in 272 of these polyps. Results Fifteen patients (30%) had type 1 SPS and 35 had type 2 SPS. There were no significant differences in age at diagnosis, sex, smoking frequency, body mass index, or colorectal cancer predisposition between groups of patients, or in the pathologic or molecular characteristics of their polyps. A familial history of colorectal cancer or colonic polyps was reported more frequently by patients with type 2 SPS. BRAF mutations were found in 63% of polyps and KRAS mutations were found in 9.9%; 43.4% of polyps had the CpG island methylator phenotype–high phenotype. A per-patient analysis revealed that all patients had a BRAF or KRAS mutation in more than 25% of their polyps; 84.8% of patients had a mutation in BRAF or KRAS in more than 50% of their polyps. Conclusions Except for a greater likelihood of familial history of colorectal cancer or colonic polyps in patients with type 2 SPS, we found no significant demographic, pathologic, or molecular differences between types 1 and 2 SPS. All patients had a BRAF or KRAS mutation in at least 25% of their polyps.

TPS625Background: Palbociclib (P) is a cyclin-dependent kinase inhibitor approved for the treatment of ER+/HER2- locally advanced (LA) or MBC and, in combination with endocrine therapy, was shown t...

in 32 (15.4%) AJ and 22 (0.5%) NAJ (p=0.0001); among AJ this variant was significantly associated with a diagnosis of CRC (OR: 2.6 [95% CI: 1.1-5.8]). Conclusion: Overall, the frequency of pathogenic APC or MUTYH mutations increases with adenoma count and is lower in AJ compared to NAJ. The low yield of comprehensive MUTYH testing in AJ suggests this gene plays a small role in AJ with polyposis and that other genes may be responsible for the polyposis phenotype in Ashkenazim. The higher prevalence of the APC*R332X mutation in AJ compared to NAJ suggests R332X may be a founder mutation. This should be further explored through haplotype analysis. Finally, we propose that increased colorectal screening be considered in Ashkenazim who have the I1307K variant and report a personal history of colorectal adenomas.

• Purpose: The immune response is altered in patients with neoplasms. Immunosuppression has important consequences in patients with melanoma. The aim of this study was to assess quantitative immune alterations in melanoma patients.. • Material and methods: We obtained a peripheral blood sample in EDTA from 86 melanoma patients (63 of them disease-free and 23 with distant disease). Total leukocytes and lymphocytes, B lymphocytes (CD19), types CD3, CD4, CD8 lymphocytes, and NK lymphocytes (CD56) were counted by determining the surface markers by flow cytometry, using a Coulter Epics Elite (Coulter Corp.). IgA, IgG, IgE and IgM were assayed by nephelometric methods employing a Hyland PDQ laser nephelometer. • Results: We found significant differences between disease-free patients and those with active disease with regard to lymphocytes total count (median: 2251.57 vs. 1783.04/mm 3 , p=0.010), NK lymphocytes (CD56) (149.54 vs. 115.2/mm 3 , p=0.016), and IgA levels (241.59 vs. 300.55 mg/dl, p=0.044), when taken as continuous variables. When considering each parameter as a discontinuous variable, only changes in absolute lymphocyte count retained an statistical difference depending on the presence or absence of active disease, 73.9% of the patients with active metastatic disease having a lymphocyte count below 2000 cells/mm 3 versus only 36.5% of the disease-free patients (c2 Pearson=9.476, df=1, p=0.002). The median survival for the 46 patients with absolute lymphocyte count above 2000 cells/mm 3 was 965 days (DF=65.03, IC 95%=792.72-1090.30) versus 441 days (DF=75.61, IC 95%=292.81-589.19) for the 40 patients with absolute lymphocyte count below 2000 cells/mm3 (log rank=4.54, df=1, p=0.0331). • Conclusions: There are significant differences in some lymphocyte populations and IgA levels between patients with metastases and disease-free patients. Melanoma patients with absolute lymphocyte levels above 2000 cells/mm3 have a longer survival than those with a lymphocyte count below 2000 cells/mm 3 .

La quimioterapia en cáncer de pulmón no microcítico avanzado consigue un pequeño pero consistente beneficio así como paliación de síntomas relacionados con el cáncer. En la actualidad, el tratamiento en 1ª línea se basa en dobletes con fármacos de 3ª generación con o sin platino. Las terapias dirigidas se muestran prometedoras por su actividad y tolerancia. La aplicación de la genómica es hoy también una vía de investigación. Actualmente, se pueden considerar segundas, terceras o más líneas de tratamiento, y también una administración individualizada para performance status 2 o ancianos. Existen diferencias relacionadas con el sexo, desde su causa a los resultados. Ciertamente, estamos avanzando en el tratamiento del cáncer de pulmón no microcítico, aunque lentamente. La investigación de fármacos más eficaces, la selección de pacientes basada en factores clínicos y la biología del tumor, y la óptima combinación de las diferentes modalidades terapéuticas, son la prioridad de los ensayos del futuro. Chemotherapy has a place in the treatment of advanced non-small cell lung cancer achieving a palliation of the disease-related symptoms and a small but consistent survival benefit. At present, the first line treatment is based on third generation drugs doublets with or without platinum. Targeted therapies seem promising because of their activity and tolerance. Application of genomics to non-small cell lung cancer therapy represents also an interesting research way for personalized treatments. Second, third and more lines of treatment have to be considered, as well as adequate individualized treatments for performance status 2 and elderly patients. Sex-related differences have been determined in causation and results. Advances in the treatment of non-small cell lung cancer have certainly been achieved, although slowly. Investigation of more efficient drugs, selection of patients based on clinical factors and tumor biology, and the optimal way to combine the different therapeutic modalities, are to be the priority for future trials.

10787 Background: Patients with breast cancer in which sentinel lymph node biopsy is histologically negative for tumor cells, have a low probability of having involvement of additional regional lymph nodes. Lymph node dissection may be avoided in these cases. Methods: Ninety-six consecutive patients with invasive breast cancer and tumour size less than 2 centimeters by mammography, had lymphoscintigraphy with colloidal 99Tc and radioisotope-guided sentinel lymph node biopsy in the University Hospital of Zaragoza from 1999 to 2005.Pathological assessment included serial sections of the sentinel lymph node with immunohistochemistry for cytokeratins in selected cases. Results: Sentinel lymph node biopsy was negative in 57 patients. There were 56 females and 1 male. Median age was 57 years (range 24–87). Median pathological tumor size was 15 mm (range 5–31). Location of the sentinel lymph node was axillary in 47patients, internal mammary in 0 patients, and both in 10 patients. Median number of resected lymph nodes was 2 (range 1–4). With median follow-up of 33 months, no local or systemic relapses have occurred. Conclusions: Avoidance of regional lymph node dissection is safe in patients with breast cancer and histologically negative sentinel lymph node biopsy. No significant financial relationships to disclose.

20119 Background: The activation of Tyrosin Kinase Receptors (RTKs) produces several effects about cellular response. These are membrane receptors that bind differentiation signals, grow factors and cellular mediators. The interaction with their ligand causes the phosphorilation and internalization in the endosome. By a metabolic way, these receptors are degradated into the proteasome to small peptides that are expressed over the cellular surface joined to MHC class I mollecules, getting a better immunogenic recognition of the tumor cells. It is known that the bigger expression of the tyrosin kinase receptors in tumors is associated with an aggressive phenotype. For example overexpression of ephA2 or EGFR. Our study is based in the demostration of the overexpression of other receptors in renal cell cancer, a tumour with a disappointing response with treatment in advanced stages. On this way we can use them as targets for monoclonal antibodies and for citotoxic lymphocites CD8 stimulated that will join to peptides presented in MHC class I after the proteasomic degradation. Methods: We use Western-Blot for identifying the overexpressed RTKs in relation to normal tissue and as a reference the expression of beta-actin, that is present in every cells. The cells are from 5 murine renal cell cancer lines, (thanks to Hillman Cancer Center Institute, University of Pittsburgh. Pennsylvania. USA). The control is a murine cell line that is very similar to normal renal tissue (HK). We calculate the ratio of expression compared with the expression of normal tissue with an statistical analysis. Results: HER-2, VEGFR-2, Met, Ron-beta are overexpresed in renal cell cancer in a murine model, as EGFR (epidermic growing factor receptor). Conclusions: Met may be excellent therapeutic and inmunologic target and in selected cases of renal cell cancer. It’s known that EGFR and VEGFR are also good targets. Future research about these targets will get new options of combined immunotherapy (vaccines and monoclonal antibodies). No significant financial relationships to disclose.

798 Background: AT is one of the most active chemotherapy regimens for BC. This study was designed to evaluate clinical and pathological response rates and toxicity of neoadjuvant AT in patients wi...