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Malnutrition is a prevalent problem in patients with cancer and is associated with poor prognosis. The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends the provision of nutritional support and evaluation. This study aims to describe the nutritional management of patients with cancer, including assessment of adherence, from the perspective of both patients and healthcare professionals (HCPs).A cross-sectional descriptive observational study was carried out through two surveys addressed to patients and HCPs.A total of 230 cancer patients and 461 HCPs completed the questionnaire. The survey found 55.0% of patients experienced eating problems during treatment and 64.0% reported sequelae affecting nourishment. However, 60.1% of patients and 42.6% of HCPs indicated that nutritional status is not generally assessed. While 86.6% of HCPs stated that nutritional information is provided to patients, only 33.5% of patients reported having received it. Regarding nutritional adherence, 87.4% of HCPs stated that it is assessed whereas only 49.2% of patients receiving nutritional supplements confirmed this. General discomfort or gastrointestinal problems were the main issues hampering correct adherence perceived by both patients (41.8%) and HCPs (95.4%).Our study demonstrate that different perceptions exist between patients and HCPs about nutritional management in cancer and suggests that in Spain nutritional approach is suboptimal in terms of screening/assessment of malnutrition, nutritional information provided to the patient, nutritional intervention and assessment of adherence to nutritional support. Therefore, measure should be taken to foster the adoption of ESPEN recommendations in clinical practice and to promote nutritional education of HCPs.

Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: Hormone Receptor-positive/HER2-negative (HR+/HER2-neg) (10 patients), pelareorep + letrozole. Cohort 2: HR+/HER2-neg (10 patients), pelareorep + letrozole + atezolizumab. Cohort 3: Triple Negative Breast Cancer (TNBC) (6 patients), pelareorep + atezolizumab. Cohort 4: Hormone Receptor-positive/HER2-positive (HR+/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. Cohort 5: Hormone Receptor-negative/HER2-positive (HR-/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score, a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue was examined for pela replication, and changes to the TME were assessed by imaging mass cytometry (IMC), immunohistochemistry, and T cell receptor sequencing (TCR-seq). Peripheral blood was also examined by TCR-seq. Results: Detailed translational research results will be presented from patients in cohort 1, who received just pelareorep and letrozole. CelTIL score increased in 5/10 patients at day 3 biopsies and 6/10 patients at day 21 biopsies. Preliminary results show high levels of viral replication (>50% of tumor cells) while immunohistochemistry and IMC analysis revealed changes to the TME, with increases in CD8+ T cells and upregulation of PD-L1 at both day 3 and day 21 biopsies. Overall, preliminary data from cohort 1 of AWARE-1 demonstrate pela-mediated priming of an adaptive immune response. (NCT04102618) Citation Format: Luis Manso, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martínez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca González, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena González, Débora Martínez, Laia Paré, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1) [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 PS12-08.

Purpose: We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Vascular normalization can be tracked with 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. We tested the efficacy of the mitochondrial inhibitor ME-344 or placebo added to bevacizumab in early breast cancer. Patients and Methods: Treatment-naïve HER2-negative patients with T > 1 cm (any N) underwent a breast-centered 18F-fluorodeoxyglucose (FDG)-PET (day 1) and received a single dose of bevacizumab (15 mg/kg), followed by a second FDG-PET (day 8). Patients were then randomized (1:1) to Arm A (ME-344 10 mg/kg intravenous on days 8, 15, and 21) or Arm B (placebo). Tumors were biopsied on days 0 and 29. Succinate dehydrogenase enzyme histochemistry (SDH-EHC), confocal microscopy of vessel architecture, and HIF1α staining were performed in pre- and posttreatment biopsies to assess the pharmacodynamics, vessel normalization, and tissue re-oxygenation by bevacizumab, respectively. Results: ME-344 displayed significant biological activity versus placebo: compared with a 186% increase in Arm B, Ki67 decreased by 23.4% from days 0 to 28 in Arm A (P < 0.001) (N = 42 patients). FDG-PET predicted vascular normalization in about one-third of the patients in each arm, which was confirmed using confocal microscopy and HIF1α staining. In the subgroup with vascular normalization, ME-344 induced a Ki67 decrease of 33.4% (placebo: 11.8 increase). SDH-EHC suggested on-target effects of ME-344. Conclusions: ME-344 has significant biological antitumor activity in HER2-negative breast cancer, particularly after induction of vascular normalization and tissue reoxygenation with bevacizumab.

Objectives: an inadequate approach to prevent malnutrition in cancer patients may worsen their quality of life and reduce their response to treatment. This study aims to describe the nutritional management of cancer patients in clinical practice, as well as the opinions of the healthcare professionals (HCPs) involved. Methods: this was an observational, descriptive, cross-sectional study addressed to HCPs in the Spanish healthcare setting. The online questionnaire was designed based on a literature review, one focus group of patients (n = 6), and the experience of the multidisciplinary scientific committee (n = 5), and was distributed by the scientific societies endorsing the study. Results: a total of 461 HCPs answered the survey. Most of them considered that a nutrition expert (95.0 %) is essential for the nutritional management of patients. However, 22.8 % of HCPs did not have access to this expert, and only 49.0 % had received training. Nutritional screening or patient referral for screening was performed by 58.4 % of HCPs. Of the total of HCPs, 86.6 % stated that nutritional information is provided to patients and considered them moderately satisfied with the information received. In malnourished patients or in those at risk of malnutrition, a complete nutritional assessment was performed by HCPs (73.1 %). Most HCPs (87.4 %) reported prescribing or recommending nutritional support if needed, and assessing adherence (86.8 %). Conclusions: despite malnutrition being a common problem in cancer patients, almost half of professionals do not perform any nutritional screening. In addition, patient information and assessment of nutritional adherence appear to be suboptimal.Objetivos: un abordaje inadecuado de la desnutrición en el paciente con cáncer puede conducir a un empeoramiento de su calidad de vida y una respuesta deficiente al tratamiento. El estudio ONA (Oncología, Nutrición y Adherencia) tiene como objetivo describir el manejo nutricional del paciente con cáncer en la práctica clínica, así como las opiniones de los profesionales sanitarios involucrados en el mismo. Métodos: estudio observacional, descriptivo y transversal dirigido a profesionales sanitarios españoles. El cuestionario online fue diseñado a partir de una revisión bibliográfica, un grupo focal de pacientes (n = 6) y un comité científico multidisciplinar (n = 5), y distribuido por las sociedades científicas que avalan el estudio. Resultados: de los 461 profesionales sanitarios participantes, el 95,0 % consideraron fundamental la figura del profesional sanitario con formación específica en nutrición, pero el 22,8 % no tenían acceso a ella y solo el 49,0 % habían recibido formación. El 58,4 % afirmaron realizar el cribado nutricional o derivar al paciente para este fin. El 86,6 % de los participantes indicaron que se informa al paciente sobre aspectos nutricionales y consideraron que este estaba moderadamente satisfecho con la información recibida. En caso de detectarse desnutrición o riesgo de desnutrición, los profesionales afirmaron realizar una evaluación nutricional completa (73,1 %) y, de necesitarse soporte nutricional, este se prescribiría/recomendaría (87,4 %), evaluándose la adherencia al mismo (86,8 %). Conclusiones: a pesar de que la desnutrición es un problema común en el paciente con cáncer, casi la mitad de los profesionales no realizan un cribado nutricional. Además, el proceso de información y evaluación de la adherencia nutricional es subóptimo.

Introduction Patritumab deruxtecan (U3-1402; HER3-DXd) is a HER3-directed antibody drug conjugate with demonstrated clinically meaningful antitumor activity and acceptable safety profile in heavily pre-treated metastatic breast cancer (BC) with high or low HER3 expression levels (Masuda et al. Cancer Res. 2019; Krop et al. SABCS 2020). Here, we report the interim efficacy and safety data of the TOT-HER3 trial (NCT04610528), the first window-of-opportunity study designed to assess whether a single dose of HER3-DXd may increase immune infiltration during short-term preoperative treatment in early BC. Methods This is a prospective, phase 0, multicenter, single arm trial planned to enroll 80 patients with treatment naïve hormone receptor positive, HER2 negative primary operable BC ≥1 cm by ultrasound. Patients are allocated to one of 4 cohorts based on centrally assessed levels of ERBB3 mRNA by the nCounter platform in a pre-treatment biopsy and receive HER3-DXd administered as a single dose of 6.4 mg/kg. Post-treatment biopsy at C1D21 is obtained to explore primary and correlative endpoints. The primary objective is to evaluate the median change in the CelTIL score (-0.8*tumor cellularity% + 1.3*tumor-infiltrating lymphocytes%) (Nuciforo et al. Ann Oncol. 2018) in paired pre- and post-treatment samples in the overall cohort. Change in CelTIL score and the expression of 67 genes across ERBB3 cohorts and PAM50 subtypes is also explored. Adverse events (AEs) are graded according to CTCAE v 5.0. Results As of April 21 2021, 30 patients (all women) received the study treatment and were evaluable for the primary endpoint. Mean age was 52 years (range 35-77 years); 19 patients were pre- and 11 were post-menopausal. Median tumor size was 20 mm (range 10-60 mm); cN0 70%; mean Ki67 35% (range 10-90%); grade 1-2 67%. According to ERBB3 expression, 6 (20%), 13 (43%), 5 (17%) and 6 (20%) patients were categorized as high, medium, low and ultra-low, respectively. CelTIL score increased, was stable and decreased in 17 (57%), 3 (10%) and 10 (33%) patients, respectively. Overall, a statistically significant increase in CelTIL was observed between paired samples (p=0.028). At C1D21, a total of 12 (44%) patients experienced a response (7 complete and 5 partial response) by clinical palpation. CelTIL significantly changed in responders (p=0.006) but not in patients with stable disease (p=0.61). Baseline ERBB3 levels did not correlate with CelTIL change or clinical response. Moreover, PAM50 subtype distribution was as follows: Luminal A 15 (50%), Luminal B 13 (43%), HER2-Enriched 1 (3.5%), Basal-like 1 (3.5%). CelTIL score did not change significantly between Luminal A and Luminal B tumors. Five (38.5%) Luminal B tumors switched to Luminal A at C1D21. Interestingly, baseline high PAM50 risk-of-recurrence was associated with higher CelTIL score at C1D21 (p=0.002). Patritumab deruxtecan induced high expression of immune-related genes including PD1, CD8a and CD19 and Luminal A signature and suppressed proliferation-related genes. Overall, 29 (97%) patients reported at least one AE and 98% of AEs were grade 1 or 2. The most common AEs were nausea, asthenia, abdominal pain, alopecia, vomiting, diarrhea, neutropenia, increased liver enzymes. A grade 3 treatment-related reversible AST increase occurred in 1 patient. Conclusion In this interim trial analysis, a single dose of patritumab deruxtecan was associated with clinical response and important biological changes irrespective of baseline ERBB3 expression. The safety profile was consistent with that previously reported for the drug. Citation Format: Aleix Prat, Juan M. Cejalvo, Laia Pare, Olga Martínez-Sáez, Mireia Margelí Vila, Claudette Falato, Josefina Cruz, Miriam Arumí de Dios, Maria J Vidal, Juan Antonio Guerra, Ana Maria Luna Barrera, Pablo Tolosa, Francisco Javier Salvador-Bofill, Sonia Pernas, Blanca Gonzáles-Farré, Esther Sanfeliu, Eva Ciruelos, Violeta Serra, Martin Espinosa-Bravo, Yann Izarzugaza, Stephen Esker, Pang-Dian Fan, Guillermo Villacampa, Juan M Ferrero-Cafiero, Tomás Pascual, Mafalda Oliveira. Activity of patritumab deruxtecan, a HER3-directed antibody drug conjugate, in early breast cancer according to ERBB3 expression: Interim analysis results of a window-of-opportunity study (SOLTI-1805 TOT-HER3) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-04.

Background This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. Materials and Methods This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. Results Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients’ experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. Conclusion The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 Implications for Practice The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

Globally, intracranial pressure (ICP) monitoring use in severe traumatic brain injury (sTBI) is inconsistent and susceptible to resource limitations and clinical philosophies. For situations without monitoring, there is no published comprehensive management algorithm specific to identifying and treating suspected intracranial hypertension (SICH) outside of the one ad hoc Imaging and Clinical Examination (ICE) protocol in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial. As part of an ongoing National Institutes of Health (NIH)-supported project, a consensus conference involving 43 experienced Latin American Intensivists and Neurosurgeons who routinely care for sTBI patients without ICP monitoring, refined, revised, and augmented the original BEST:TRIP algorithm. Based on BEST:TRIP trial data and pre-meeting polling, 11 issues were targeted for development. We used Delphi-based methodology to codify individual statements and the final algorithm, using a group agreement threshold of 80%. The resulting CREVICE (Consensus REVised ICE) algorithm defines SICH and addresses both general management and specific treatment. SICH treatment modalities are organized into tiers to guide treatment escalation and tapering. Treatment schedules were developed to facilitate targeted management of disease severity. A decision-support model, based on the group's combined practices, is provided to guide this process. This algorithm provides the first comprehensive management algorithm for treating sTBI patients when ICP monitoring is not available. It is intended to provide a framework to guide clinical care and direct future research toward sTBI management. Because of the dearth of relevant literature, it is explicitly consensus based, and is provided solely as a resource (a "consensus-based curbside consult") to assist in treating sTBI in general intensive care units in resource-limited environments.

Background A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela) in combination with paclitaxel (PTX) versus PTX alone.1 Given that pela is an intravenously delivered immuno-oncolytic reovirus, we hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, we are conducting together with the SOLTI group the AWARE-1 study (a window-of-opportunity study of pela in early breast cancer), which is currently enrolling and for which initial translational research results are presented. Methods AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole; Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HER2+/HR+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HER2+/HR- (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score [2], a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, and changes to the TME are being assessed by immunohistochemistry and T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results Detailed TCR-seq results from peripheral blood and tumor tissue are presented for the ten-patients enrolled into Cohort 1 who received pela and letrozole. In tumor tissue, T cell clonality increased in day 21 biopsies relative to baseline biopsies, with similar increases in T cell fraction (the number of T cells) in the majority of patients. In general, most of the tissue-expanded T cell clones were also seen in the peripheral blood. Conclusions Overall, these preliminary data from cohort 1 of AWARE-1 demonstrate that pela mediates priming of a T cell-based immune response that occurs both systemically and within breast cancer tissue. Trial Registration NCT04102618 Ethics Approval This study was approved by the Spanish Health Authority, protocol number 2018-003345-42. References Bernstein V, et al. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213. Breast Cancer Res Treat 2018;167(2):485-493. Nuciforo P, et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol 2018;29(1):170-177.

Background: Antiangiogenic agents have shown activity in breast cancer; however their use should be optimized. One potential solution is designing rational combinations based on blocking specific mechanisms of resistance. We previously published that tumors exposed to bevacizumab (BEV) can either experience vascular pruning (followed by increased tumor hypoxia) or vascular normalization (followed by a switch to mitochondrial metabolism). FDG-PET can monitor which pattern is occurring as early as 8 days after the first dose (Mol Oncol; 10: 704-18). We have also shown that when vascular normalization occurs, tumors become highly sensitive to mitochondrial inhibitors (Cell Rep 2016; 15: 1-14). ME-344 is a mitocondrial respiration inhibitor that has recently completed phase I. We sought to test the pharmacodynamic effects of ME-344 and its effects in Ki67 and cleaved caspase 3 (CC3) after single-dose BEV in treatment-naive early HER2-negative breast cancer patients, and whether the effects are restricted or not to those patients experiencing vascular normalization as predicted by FDG-PET. Trial design Placebo-controlled, two-arm, randomized, multicentric phase 0 trial. Treatment-naive HER2-negative breast cancer patients undergo a breast FDG-PET and a baseline tumor biopsy (frozen and paraffinized cores), followed by a single (15 mg/kg) BEV dose. FDG-PET is repeated on day +8. Patients are then randomized to three ME-344 (10 mg/kg) doses or placebo (days +8, +15 and +22). A second biopsy is then harvested, ending trial procedures. Patients can then follow surgery or neoadjuvant treatment according to their physician's criterion. Serial paraffinized biopsies are used to measure Ki67 and CC3; frozen biopsies are used for measuring mitochondrial activity with SDH enzymo-histochemistry (EHC) and assessing vessel architecture. Toxicity is graded with NCI CTC AE V4.03 criteria. Eligibility criteria 1) Women >18 year old; 2) diagnosed of HER2-negative breast cancer; 3) patients must be treatment-naive; 4) ECOG 0/1; 5) lack of neuropathy; 6) primary tumor > 1cm . Specific aims Primary: 1) To study the effects in cell replication and cell death as a surrogate measure of efficacy of ME-344 added to BEV in treatment-naive breast cancer. 2) To determine if FDG-PET accurately detects patients experiencing vascular normalization early after BEV dosing. 3) To observe the effects of ME-344 in mitochondrial activity at the tumor level by performing SDH EHC. 4) To assess if ME-344 efficacy (measured by changes in CC3 and Ki67) is restricted or not to those patients experiencing vascular normalization and mitochondrial switch. Secondary: 5) To study the tolerability of the combination of BEV plus ME-344. Statistical methods The sample size is calculated on the basis of the expected change in Ki-67 staining in the primary tumors in patients receiving ME-344 (-10% on average). With an α and β errors of 5% and 20% respectively, the minimum number of patients necessary to observe a 10% decrease is 20 per arm. Changes in CC3, KI67, SDH activity and FDG-PET SUV will be compared with intra-subject measurements and Z-scores. Accrual: 13 of 40 planned patients. Contact: acsalgado86@gmail.com Citation Format: Cortes A, Apala JV, Malon D, Guerra J, Gion-Cortes M, Manso L, Hornedo J, Gonzalez-Cortijo L, Mouron S, Quintela-Fandino M. CNIO-BR-009 trial: Targeting mitochondrial metabolism with ME-344 in breast cancer upon bevacizumab-induced vascular normalization: A phase 0 randomized clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-02.

Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, and atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint is CelTIL score [2], a metric for quantifying changes in tumor cellularity and the number of tumor infiltrating lymphocytes (TILs), where an increase in CelTIL score has been associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, changes to the TME by immunohistochemistry (IHC), PD-L1 expression by the Ventana SP142 assay used as the atezolizumab companion diagnostic, and T cell clonality by T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results: Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4]. Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer. References: [1] Bernstein, V., et al. Breast Cancer Res Treat, 2018. 167(2): p. 485-493. [2] Nuciforo, P., et al. Ann Oncol, 2018. 29(1): p. 170-177. [3] Mostafa, A.A., et al. Cancers (Basel), 2018. 10(6). [4] Lee, J., et al. Cancer Research, 2020. 80(16 Supplement): p. 2206-2206. Citation Format: Luis Manso, Fernando Salvador, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan M. Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose L. Alonso, Alejandro Martínez, Rafael Villanueva, Juan A. Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez-Farre, Grey A. Wilkinson, Thomas C. Heineman, Gerard Nuovo, Houra Loghmani, Matt Coffey, Azucena Gonzalez, Débora Martínez, Laia Paré, Tomás Pascual, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT191.

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial. Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes. Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value. Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432–41. ©2016 AACR.

The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. Patients and methods: Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). Results: A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). Nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. Conclusion: Combined treatment with nintedanib (200 mg/bid) plus letrozole (2.5 mg/day) effectively suppressed FGFR1 and aromatase activity, and these respective doses can be used as starting doses in any subsequent trials. However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions, MQF is a recipient of the following grants: AES - PI16/00354 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF) and B2017/BMD3733 - Call for Coordinated Research Groups from Madrid Region - Madrid Regional Government - ERDF funds. RC is a recipient of the following grants: AES PI17/01865 and PIE15/00068 by the ISCIII and co-funded by the European Regional Development Fund (ERDF). This study was partially funded by Boehringer-Ingelheim. CRIS Contra el Cancer Foundation contributed with a generous donation to this study

ObjectivesTo estimate the prevalence of disabling chronic pain (DCP) in Spanish adults, to analyse its characteristics, to determine its multimorbidity and to identify its associated factors.Settings2011 Andalusian Health Survey, a cross-sectional population survey based on face-to-face home interviews.Participants6507 people aged 16 years or older and living in Andalusia, Spain.OutcomesThe response variable was disabling chronic pain. Multivariate multinomial logistic regression models were used to analyse the association of factors with disabling chronic pain. The sample design was considered throughout the statistical analysis.ResultsThe prevalence of disabling chronic pain in the Spanish adult population was 11.36% (95% CI 11.23 to 11.49), while that of non-disabling chronic pain was 5.67% (95% CI 5.57 to 5.77). Disabling chronic pain was associated with high multimorbidity (especially in women (51%) and in the elderly (70%) with three or more additional chronic diseases), as well as with disadvantaged social status (such as female gender (OR=2.12), advanced age (OR10-year increase=1.28), unemployment (OR=1.33), manual work (OR=1.26), low income (OR=1.14) and reduced emotional social support (OR=1.04)). Other influential factors were tobacco consumption (OR=1.42), sleeping ≤7 hours (OR=1.2)], environmental or work conditions (OR=1.16) and quality of life (ORmental=1.21, ORphysical=2.37).ConclusionsThe population with disabling chronic pain was associated with multimorbidity, vulnerable social status and an impaired quality of life. In contrast, the population with non-disabling chronic pain showed almost no differences when compared with the population without chronic pain. The association between DCP and mental disorders highlights the need for psychosocial services in the management of chronic pain.

// Miguel Quintela-Fandino 1 , Nora Soberon 2 , Ana Lluch 3 , Luis Manso 4 , Isabel Calvo 5 , Javier Cortes 6, 7 , Fernando Moreno-Anton 8 , Miguel Gil-Gil 9 , Noelia Martinez-Janez 7 , Antonio Gonzalez-Martin 10 , Encarna Adrover 11 , Raquel de Andres 12 , Gemma Vinas 13 , Antonio Llombart-Cussac 14 , Emilio Alba 15 , Silvana Mouron 1 , Juan Guerra 16 , Begona Bermejo 3 , Esther Zamora 6 , Jose Angel Garcia-Saenz 8 , Sonia Pernas Simon 9 , Eva Carrasco 17 , Maria Jose Escudero 17 , Ruth Campo 17 , Ramon Colomer 18 , Maria A. Blasco 2 1 Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain 2 Telomeres and Telomerase Group, Molecular Oncology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain 3 Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain 4 Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain 5 Medical Oncology Department, Hospital de Monteprincipe, Madrid, Spain 6 Medical Oncology Department, Hospital Vall d´Hebron, Barcelona, Spain 7 Medical Oncology Department, Hospital Ramon y Cajal, Madrid, Spain 8 Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain 9 Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain 10 Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain 11 Medical Oncology Department, Hospital General de Albacete, Albacete, Spain 12 Medical Oncology Department, Hospital Lozano Blesa, Zaragoza, Spain 13 Medical Oncology Department, Institut Catala d'Oncologia-Hospital Dr. Josep Trueta, Girona, Spain 14 Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain 15 Medical Oncology Department, Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain 16 Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain 17 GEICAM, Madrid, Spain 18 Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain Correspondence to: Miguel Quintela-Fandino, email: mquintela@cnio.es Maria A. Blasco, email: mblasco@cnio.es Keywords: telomere length, critically short telomeres, breast cancer, weekly paclitaxel, toxicity Received: October 25, 2016 Accepted: January 27, 2017 Published: February 21, 2017 ABSTRACT Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres ( 21.9% CSTs) had 2-fold higher number of neuropathy ( P = 0.04) or fatigue ( P = 0.019) episodes and >3-fold higher number of myalgia episodes ( P = 0.005). The average telomere length was unrelated to the incidence of side effects. The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.

Thromboembolic disease (VTE) is a very important cause of morbidity and mortality in cancer patients, with a recurrence rate of 10-17% in patients treated with anti-vitamin K and 6-9% in low molecular weight heparin (LMWH). This case reflects the recurrence of VTE, differential diagnosis in the presence of pleural effusion+fever and the management of central venous catheter-associated thrombosis (CVC).

Pain is a frequent symptom in the evolution of the cancer patient, often acquiring chronic character as a consequence of the progression of the disease. More than 70% of patients are not under control. In this case review we will expose the management of different types of pain, side effects and education, taking also into account the fragility of the elderly patient.

Pain is a frequent symptom in the evolution of a cancer patient, affecting 70% of them in terms of decreasing quality of life. Treatment should adapt to type and intensity of pain in order to optimize analgesic control. In this case report we will review different pain types with the use of questionnaires, emphasizing the importance of side effects (constipation), their etiology (

Introduction: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. Methods: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). Results: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. Conclusions: The combination allows the delivery of full-dose intensity, while efficacy seems promising.

Context Patients and caregivers participate in decision-taking, and their views should be considered in the preparation of Clinical Practice Guidelines (CPGs). We involved them in the development of a CPG on the safe use of major opioids. Objective To identify the values and preferences of patients and caregivers on the use of opioids and the desired outcomes, to investigate motives for the acceptance/rejection of opioid therapy, and to evaluate their beliefs and information about these drugs. Methods A qualitative study was conducted using semi-structured interviews in an Andalusian population of terminal patients and caregivers (N = 42). Study variables included the role, diagnosis, and adherence to treatment. Content and validity analyses were performed. Results Less than one-third of participants recognized the term opioid. Among these, false beliefs were held related to the addictive nature of these drugs, their exclusive use in terminal cases and at the end of life, and their association with premature death. The information received was very general: it was known that they are “useful for pain,” and some were informed about the administration route, composition, and habituation. Participation in decision making was usually limited to reporting symptoms to the physician. Conclusion These patients and caregivers demonstrated a preference for pain alleviation by opioid treatment and gave negative assessments on adverse digestive effects that can cause this treatment to be abandoned. They expressed interest in receiving more information and in participating in therapeutic decision making, and they reported erroneous beliefs and a lack of information about the effects of these drugs.

3100 Background: We have shown that when Aas induce vascular normalization (VN), tumors escape upregulating mitochondrial metabolism. Mitochondrial inhibition with ME344 induced synergy with various Aas. We also found that VN could be traced by showing a 10% decrease in tumor FDG-PET SUV from day (d) 0 to d8 of Aa. We studied the activity of adding ME344 or placebo to Bev (Ki67 decrease) in E-HERNEBC in a phase 0 randomized trial. As a secondary objective we measured the activity of the combination in patients (Pts) showing VN according to FDG-PET. Methods: Untreated E-HERNEBC Pts with T > 1cm, any N, M0 underwent a baseline FDG-PET (d1) and received a single dose of Bev (15mg/kg) prior to randomization (1:1) to arm A (FDG-PET on d8 followed by ME344 10 mg/kg IV on d8, d15 and d21) or Arm B (FDG-PET on d8 followed by placebo on d8, d15 and d21). Tumors were biopsied on d0 and 28. A 40 Pts sample size was powered to detect a 30% relative difference between arms in digitally acquired Ki67 decrease from d0 to d28 (alpha 0.05, beta 0.2). Results: Arm A: 20 Pts; Arm B: 21 Pts. Baseline characteristics were in arm A vs B: age 58.4(41.5-75.3) vs 53.6(39-82.8); T1(30%)/T2(60%)/T3(10%) vs T1(52%)/T2(48%)/T3(0%); N0(80%)/N1(20%) vs N0(81%)/N1(19%); ER+(75%)/TNBC(25%) vs ER+(71.4%)/TNBC(28.6%); Ki67 31.6% (3.6%-70%) vs 25.2% (1.2% - 81.5%). PET-SUV decreased > 10% from d0 to d8 in 6/20 (arm A) and 6/21 (arm B) Pts. Two G3 adverse events (blood pressure) were reported (1/arm) and deemed related to Bev. Results of the primary endpoint: table. Conclusions: ME344 showed significant biologic activity, enhancing the effect in Ki67 decrease vs placebo when added to Bev in E-HERNEBC. The activity was greater in TNBC. A trend for greater activity in patients experiencing VN according to FDG-PET was observed. Clinical trial information: NCT02806817. [Table: see text]

Background: Obesity and physical inactivity are poor prognostic indicators for breast cancer (BC). Cardiorespiratory fitness (VO2max) is a good predictor of survival. Despite preserved LVEF, cardiorespiratory function is impaired in women with breast cancer after the completion of adjuvant therapy. International organizations recommend at least 150 minutes per week of moderate-vigorous physical activity (MVPA). Some studies show that a minority of cancer survivors are meeting the PA recommendations. A limitation of physical activity (PA) research has been the use of self-reported measures. Eligibility criteria: 1) Age 18-79, 2) Able to walk a mile, 3) More than one year from diagnosis, 4) More than 3 months since the last therapy, 5) No evidence of disease. Aims: Objective assessment of physical activity in breast cancer survivors. Adherence to international recommendations. Material and methods: PA was evaluated through accelerometry (600 minutes per day, 5 days per week, 2 week-end days were required to consider as valid accelerometry values). Cardiorespiratory fitness was assessed through the “one-mile test”. Results: 92 women (W) with BC history were included. 86 W were evaluable for accelerometry. 85 W were evaluable for VO2max. Age: 54.02 years (33-77), BMI: 27.89 (SD 8.89), waist perimeter: 89.74 cm (SD 17.37), median time from diagnosis 3.94 years, treatment with anthracyclines 55 W (63.9%), radiotherapy 69 W (80.23%). Accelerometry (86W): Average weekly time MVPA 351.14 min/wk (SD: 168.98). 76 (88%) met international recommendations of PA. Women previously treated with anthracyclines (47 W; 340.25 min/wk), radiotherapy (59 w; 343 min/wk) and both (48 W; 331 min/wk) exercised less than women who did not receive these therapies (8 W; 386 min/wk). This association was not statistically significant. Average VO2max was 24.8 ml/kg/min (SD: 7.6).There was a significant effect of anthracyclines for VO2 max. Women not treated with anthracyclines had a VO2max: 26.41 whereas treated W had VO2max 22.08 ml/kg/min. Discussion: A cohort of Spanish women met international recommendations of PA when it was objectively assessed. This cohort exhibited a poor cardiometabolic and cardiorespiratory profile. Previous exposure to anthracyclines predicted a poorer cardiorespiratory fitness. Specific research to investigate the role of exercise to mitigate that dysfunction in breast cancer survivors is warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-17.

2552Background: Our preclinical data show that one mechanism of acquired resistance to anti-angiogenic therapy involves hypoxia correction, measured by decreased SUV ( ↓ SUV) on FDG-PET followed by...

Resumen En las ultimas decadas, las politicas sanitarias de los paises desarrollados y los profesionales estan orientando sus actividades hacia el ciudadano como eje del sistema sanitario. Los ciudadanos, a su vez, demandan un papel activo en la toma de decisiones relacionadas con su salud. En este contexto, el desarrollo y la utilizacion de guias de practica clinica (GPC) se estan orientando tambien como instrumento de encuentro entre politicas, ciudadanos y profesionales, lo que plantea no pocas dificultades metodologicas y operativas. El objetivo de este trabajo es proporcionar pautas generales que ayuden a los distintos actores en la incorporacion de los pacientes para el desarrollo de las GPC y adaptarlas a una version de pacientes (GPC-P). Se ha realizado una revision estructurada de documentos metodologicos sobre GPC y documentos orientados a la elaboracion de GPC-P o similares. Tras la sintesis de informacion, se proponen tres areas de desarrollo (contenidos, diseno y evaluacion) y dos ambitos en la participacion del paciente en GPC: como un miembro mas del grupo que elabore la guia y/o como miembro del grupo de la elaboracion de la GPC-P. El proceso de participacion de ciudadanos no es sencillo, requiere planificacion y sensibilidad de los implicados, pero no cabe duda que anade valor en la implantacion de las GPC.

Antecedentes Se conoce bastante del perfil de los hiperfrecuentadores (HF) y los costes de sus demandas, pero su opinion sobre los motivos de su conducta ha sido poco investigado. Objetivos Identificar las razones autopercibidas de la conducta de los HF. Diseno Analisis cualitativo de transcripciones registradas en video de reuniones con grupos focales. Emplazamiento Dos centros de salud del Servicio Sanitario Publico de Andalucia en Sevilla. Participantes Participaron 12 mujeres y 15 varones, 9 personas entre 45 y 65 anos y 18 mayores de 65 anos, con una media de 55 visitas al centro en el ultimo ano. Los grupos fueron realizados en Sevilla entre el 26 de noviembre y el 12 de diciembre de 2003. Metodo Analisis inductivo de las trascripciones de entrevistas de grupos focales. Resultados Las razones principales de los HF para acudir a atencion primaria son la percepcion de problemas (psicologicos, fisicos) junto con la creencia de encontrar ayuda efectiva en los servicios sanitarios. Factores como la relacion con los profesionales o la organizacion de los servicios se perciben como factores que predisponen dificultan o facilitan la utilizacion, y un apoyo familiar o social escaso se considera importante para buscar ayuda en atencion primaria. Conclusiones Los servicios sanitarios deberian tener en cuenta estos motivos autopercibidos al disenar e implementar sistemas de apoyo para utilizar la demanda de forma mas racional y efectiva, basandose en nuevas tecnologias (informacion y consultas por internet y telefono) y en la cooperacion de otros profesionales (farmaceuticos, enfermeras).

The objective of the study is to compare the efficacy of electro-acupuncture with placebo-acupuncture for the treatment of shoulder pain. This study comprised of a prospective, randomized, placebo controlled trial, with independent evaluator set in a Public primary care clinic in Spain. The participants are patients aged from 25 to 83 years with shoulder pain. Patients were randomly allocated to two treatments over eight weeks, with electro-acupuncture or skin non-penetrating placebo-acupuncture, both able to take diclofenac if needed for intense pain. Primary outcome measure was the difference between groups in pain intensity (visual analogue scale-VAS). Secondary outcomes were differences between groups in pain intensity measured by Lattinen index, in range of motion (goniometer), functional ability (SPADI), quality of life (COOP-WONCA charts), NSAIDS intake, credibility (Borkoveck and Nau scale) and global satisfaction (10 points analogue scale). Assessments were performed before, during and three and six months after treatment. At six month follow-up after treatment the acupuncture group showed a significantly greater improvement in pain intensity compared with the control group [VAS mean difference 2.0 (95% CI 1.2-2.9)]. The acupuncture group had consistently better results in every secondary outcome measure than the control group. Acupuncture is an effective long-term treatment for patients with shoulder pain (from soft tissues lesions) in a primary care setting.

Background: Delaying/overcoming resistance to ET in HR-positive HER2-negative BC patients (pts) is a major need to futhrt improve safe and efficacious treatment options. F is a selective estrogen receptor (ER) downregulator currently indicated for the treatment of HR-positive metastatic BC in postmenopausal women with disease progression following anti-estrogen therapy. In FIRST trial F 500mg improved median time to progression (TTP) over anastrozole (23.4 vs 13.1 months, respectively) in untreated metastatic BC. P is a selective reversible inhibitor of cyclin-dependent kinase 4/6. FDA granted its accelerated approval based on progression-free survival (PFS) in combination with letrozole for postmenopausal women with ER-positive and HER2-negative advanced BC as initial ET (PALOMA-1). In another study, after progression to ET, P in combination with F resulted in longer PFS than F alone (PALOMA-3). The high median TTP achieved with F alone (FIRST) coupled with the significant benefit of adding P to F (PALOMA-3) suggest that F 500mg in combination with P in the first-line setting may significantly improve long-term disease control. Trial Design:This is an international, randomized, double-blind, multicentre phase II study comparing F 500mg in combination with P vs F 500mg plus placebo as first line therapy in postmenopausal women with HR-positive, HER2-negative metastatic BC who have received ≥5 years of adjuvant ET for early disease and remained disease free for >12 months following its completion or have “de novo” metastatic disease. HR and HER2 status will be based on central testing on the most recent tumour biopsy. Patients will be randomized 1:1. The primary objective is to compare the efficacy of both treatment arms in terms of PFS at 1 year according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator assessment. As secondary efficacy objectives,PFS, Objective Response Rate (ORR), Clinical Benefit Rate (CBR), Overall Survival (OS), and 1-year and 2-year survival probabilities, have been considered. Other secondary objectives include the comparison of safety, tolerability and health-related quality of life between the treatment arms. As exploratory objectives, the identification of promising biomarkers related with response to study therapy and primary/acquired drug resistance. Pts will be stratified by the site of disease (visceral vs non-visceral) and disease presentation at study entry (recurrent disease vs metastatic “de novo”). With a sample size of 190 pts, the analysis would have 80% power to detect a difference between both treatment arms, assuming PFS proportions of 0.545 and 0.695, respectively. This study is sponsored by GEICAM and Cancer Trials Ireland (formerly ICORG) is also participating. Recruitment started in February 2016 with 14 pts included. Analysis of the primary endpoint is planned for Q1 2018. ClinicalTrials.gov identifier:NCT02690480. Citation Format: Moreno F, Martínez-Jañez N, Garau I, Guerra JA, Alarcón J, Bermejo B, Gonzalez-Cortijo L, Bueno C, Lao J, Bezares S, Rosell L, Blanch A, Caballero R, Carrasco E, Rojo F, Martín M, O'Connor M, Hernando A, Albanell J. A phase II study to compare fulvestrant (F) 500mg plus placebo versus (vs) F 500mg plus palbociclib (P) as first line treatment for postmenopausal women with hormone receptor (HR)-positive advanced breast cancer (BC) sensitive to endocrine therapy (ET). “The FLIPPER study” (GEICAM/2014-12) [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 OT3-02-07.

Background : Given our preclinical data showing synergy between dovitinib and paclitaxel in preclinical models we conducted this phase I trial aiming to define the recommended phase II-dose (RP2D) on the basis of toxicity and pharmacodynamic criteria while searching for genetic variants that could sensitize patients to the regimen under study. Patients and methods A 3+3 escalation schedule was adopted. Seriated FGF23 and dovitinib and paclitaxel pharmacokinetic profiles were determined along a single-agent dovitinib “priming-phase” followed by a dovitinib + paclitaxel combination phase. RECIST 1.1 criteria and NCI CTCAE V.4.0 were used. In fresh pre-treatment tumor biopsy samples, FGFR1, 2 and 3 amplifications were revealed by FISH probes; 32 missense variants were genotyped in tumors and peripheral blood mononuclear cells with Taqman genotyping assays (FGFR1-3 and RET). Constructs encoding for wild-type and variant genes associated with clinical benefit were transfected into HEK-293 cells for preclinical experiments checking constitutive activation and dovitinib sensitivity of the variants. Results twelve patients were recruited in three dose-levels. At level 1B (200 mg dovitinib 5-days-on/2-days-off plus 60 mg/m 2-week of paclitaxel) more than 50% FGF23 upregulation was observed and no dose-limiting-toxicities (DLTs) occurred. The most frequent toxicities were asthenia, neutropenia, nausea/vomiting and transaminitis. Two patients with progressive disease prior to trial inclusion achieved prolonged disease stabilization. Both had the germline variant G2071A in the RET gene, which led to constitutive activation of the protein product and Y-905 phosphorylation, both in transfectants and in patients with the alteration. This variant was sensitive to dovitinib; in addition both patients experienced progression upon medication withdrawal. Conclusions Level 1B was the RP2D as it provided adequate pharmacodynamic exposure to dovitinib. The G2071A germline variant act as a genetic modifier that renders different tumors sensitive to dovitinib.

PURPOSE To evaluate the impact of the selection criteria that are used in current high-dose consolidation chemotherapy (HDCT) trials on the outcome of high-risk breast cancer patients treated with conventional adjuvant chemotherapy. PATIENTS AND METHODS From 1975 to 1995, 265 breast cancer patients at our institution showed involvement of ten or more positive axillary lymph nodes. Of these, 171 received standard adjuvant combination chemotherapy, but not HDCT consolidation, and were the subjects of our study. One hundred twenty-eight patients met the standard selection criteria for HDCT with hematological support (< 60 years, no significant concomitant disease, and no progression during adjuvant treatment), whereas 43 did not. Clinical outcome was analyzed by using disease-free survival (DFS) and overall survival (OS) as endpoints. To provide an assessment of the short-term efficacy of HDCT, we also evaluated the outcome in a cohort of 39 patients from the last 4 years who met the criteria for, and were actually treated with, HDCT after adjuvant chemotherapy. RESULTS With a median follow-up of 4.4 years (range, 0.7 to 17.2 years), 112 of the 171 patients have had a relapse, and 87 have died. The estimated 5-year DFS was 32.3%, and OS was 49.4%. DFS was significantly higher for patients who met the HDCT criteria (36.6% at 5 years) than for those who did not (15.8% at 5 years; P < .05). OS was also significantly more favorable in patients meeting HDCT criteria (55.4% at 5 years) than in patients not meeting HDCT criteria (22.7% at 5 years; P < .01). We performed a multivariate analysis to adjust for other potential prognostic factors and found that meeting the HDCT criteria and having undergone locoregional radiotherapy were the only significant independent predictors for DFS and OS. Finally, we compared the outcome of the 128 patients who met the HDCT criteria and were treated with conventional adjuvant chemotherapy only with that of the 39 patients who met the criteria and who actually underwent HDCT, and we did not observe significant differences in the DFS or OS between these groups. CONCLUSIONS Meeting HDCT inclusion criteria is an independent indicator of favorable prognosis in high-risk breast cancer patients. The selection of patients by these criteria may explain, at least in part, the promising short-term results of nonrandomized adjuvant HDCT trials in high-risk breast cancer.

TPS615Background: In a 290 HRPBC patient series we found a 7.9% of cases harbouring FGFR1 amplification, associated to a 5.5-fold increase in relapse risk. In vitro data with a panel of 5 HRPBC cel...

In the last decades the health policies of developed countries and those of professionals are directing their activities towards the citizen as the focal point of the health system. The citizens also demand an active role in health related decision-making processes. In this context, the development and use of clinical practice guidelines (CPGs) are instruments of encounter between policies, citizens and professionals but they create many methodological and operational difficulties. The objective of this work is to provide general guidelines to help the different players to incorporate patients in the development of CPGs and to adapt the patient CPG version (CPG-P). A structured review has been carried out on methodological documents on CPGs and documents oriented towards the production of CPG-P (or related documents). After analysing the information, we propose three areas of development (contents, design and evaluation) and two areas for the participation of patients in CPGs: patients as a members of the guideline development group and/or as members of the CPG-P development group. The process of participation of citizens is not a simple one, it requires planning and sensitivity to those involved, but there is no doubt that it adds value to the introduction of CPGs.

1029 Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound form of paclitaxel commonly used in various tumor types. Its main toxicity is neuropathy; however, it has not been clinically...

Summary Background: The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m 2 and cisplatin was administered at a dose of 100 mg/m 2 on day 1, every 21 days. Results: Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%-82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3-4 in 54% of the patients, and thrombocytopenia grade 3-4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m~/week, and 31 mg/nr/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7-13), 17 patients are still alive and nine have died. The median overall survival is 12 months. Conclusion: This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.

Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound form of paclitaxel that is thought to exploit natural albumin pathways to enhance the selective uptake and accumulation of paclitaxel at the site of the tumour, thus reducing its diffusion to normal tissues. Nab-P has been approved for the treatment of metastatic breast cancer patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Toxicity profile of Nab-P is well characterized with significantly less haematological toxicities compared with conventional paclitaxel (P). Nab-P derived grade III neuropathy is short-lasting and more reversible than conventional P-derived neuropathy, probably due to absence of Cremophor solvent, or due to P itself. However there is still a lack of clinical and physiological characterisation of Nab-P induced neuropathy. The Current used tools for early detection and continuous evaluation of neurotoxicity are not optimal. Most used toxicity scales are limited, as they do not provide a detailed information of the severity of the neuropathy, its impact on quality of life, or physiopathology mechanisms. In addition, an inter-individual variability exists in terms of neurotoxicity predisposition when taxanes are used; it seems to be related to polymorphic differences in genes implicated in transport and metabolism of these drugs. Specific aims: Primary objective is to characterize neurotoxicity according to Total Neuropathy Score (TNS) and electromyographic changes. Secondary endpoints are determine the rate of neuropathy chemo-induced, the predictive value of some genetic variants (SNPs) for the development of neuropathy, clinical activity, toxicity profile and safety of treatments and quality of life (EORTC QLQ-C30 and CIPN20). Trial design: Phase II open-label randomised clinical trial with four parallel arms: a) conventional paclitaxel 80 mg/m2 on days 1, 8 and 15; b) Nab-P 100 mg/m2 on days 1, 8 and 15; c) Nab-P 150 mg/m2 on days 1, 8 and 15; d) Nab-P 150 mg/m2 on days 1 and 15. Study treatments will be administered in a 28-day cycle until progression disease, intolerable toxicity or investigator's decision. Eligibility criteria: Women >18 years, with cytological or histological confirmation of HER2-negative breast cancer, metastatic disease, not prior chemotherapy for advanced disease, no prior grade > 1 neuropathy from any cause, measurable or evaluable disease, ECOG >2 and adequate bone marrow, renal and hepatic functions. No Relevant comorbidities. Statistical methods: This is an exploratory safety study to better characterize neurotoxicity in patients treated with Nab-P compared toP. Therefore no formal sample size or power calculations will be performed. We expect to recruit 60 patients, 15 in each treatment arm, in 18 months. Recruitment will start on October 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-05.

4613 Background: Trastuzumab(T) exhibits activity in human gastric cancer cells that overexpress HER2/neu. We previously reported a 13.5% HER2/neu overexpression/amplification in AGC or gastroesofageal junction (GEJ) cancers (Grávalos C, et al. J Clin Oncol 24, 18S, 200s, abstr # 4089). We designed a phase II trial to determine the efficacy and tolerability of T and cisplatin(C) in pts with ACG with HER2/neu overexpression/amplification. Exploratory objectives include analysis of c-erbB-2 extracellular domain and correlation of the results with histological erB-2/neu overexpression and with clinical response Methods: Chemo-naïve pts with adenocarcinoma histopatologically confirmed, HER2/neu overexpression/amplification, measurable, no operable, locally advanced or metastatic AGC, age ≥ 18, ECOG ≤ 2, FEVI ≥ 50% and adequate organ function were eligible. Prior adjuvant radiotherapy or/and chemotherapy were allowed. Immunohistochemistry (IHC) was performed using herceptest. A fluorescence in situ hybridization (FISH) assay was done when IHQ was = 2. HER2/neu expression was considered negative if IHC= 0, 1 or IHC=2 and FISH -; and positive if IHC=2 and FISH + or IHC=3. T 8 mg/kg d1 (loading dose in first cycle) and 6 mg/kg (maintenance doses) and C 75 mg/m2 d1 were administered every 21 days until progression, unacceptable toxicity or withdrawal inform consent Results: 21 pts has been included. 17 are evaluable. 16 were men. Median age 66 (50–78). ECOG 0/1: 5/12. Histological subtypes were: 50% intestinal, 25% diffuse and 25% unknown. 56% had gastric localization and 44% GEJ. 16 pts had metastases (59% liver, 47% lymph nodes, 23% peritoneum, 17% lung, and 24% others). Prior treatment: 5 pts underwent surgery and 2 had adjuvant chemotherapy. Median cycles 2 (1–14). Efficacy: 6 (35%) pts achieved response (1/5 CR/PR), 3 (17%) stabilization (52% control disease = RC + PR+SD), 4 pts with progression disease, 4 pts too early Tolerance: There was no grade 4 toxicity. Main grade 3 adverse events included: asthenia (3 pts), nauseas/vomiting (3), diarrhea (2), hiporexia (2) and neutropenia (1) Conclusions: Trastuzumab and cisplatin is a well tolerated regimen with a promising activity. The study is ongoing and an update will be presented at the meeting. No significant financial relationships to disclose.