Publications by authors named "Luis Manso"

55 Publications

FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1.

Breast Cancer Res 2021 Feb 12;23(1):21. Epub 2021 Feb 12.

Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.

Background: FGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear.

Methods: FGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied.

Results: FGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models.

Conclusions: FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.
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http://dx.doi.org/10.1186/s13058-021-01398-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881584PMC
February 2021

A study on CNN image classification of EEG Signals represented in 2D and 3D.

J Neural Eng 2021 Jan 8. Epub 2021 Jan 8.

School of Engineering and Applied Science, Aston University, Aston St., Birmingham, West Midlands, B4 7ET, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

Objective The novelty of this study consists of the exploration of multiple new approaches of data pre-processing of brainwave signals, wherein statistical features are extracted and then formatted as visual images based on the order in which dimensionality reduction algorithms select them. This data is then treated as visual input for 2D and 3D CNNs which then further extract 'features of features'. Approach Statistical features derived from three electroencephalography datasets are presented in visual space and processed in 2D and 3D space as pixels and voxels respectively. Three datasets are benchmarked, mental attention states and emotional valences from the four TP9, AF7, AF8 and TP10 10-20 electrodes and an eye state data from 64 electrodes. 729 features are selected through three methods of selection in order to form 27x27 images and 9x9x9 cubes from the same datasets. CNNs engineered for the 2D and 3D preprocessing representations learn to convolve useful graphical features from the data. Main results: A 70/30 split method shows that the strongest methods for classification accuracy of feature selection are One Rule for attention state and Relative Entropy for emotional state both in 2D. In the eye state dataset 3D space is best, selected by Symmetrical Uncertainty. Finally, 10-fold cross validation is used to train best topologies. Final best 10-fold results are 97.03% for attention state (2D CNN), 98.4% for Emotional State (3D CNN), and 97.96% for Eye State (3D CNN). Significance: The findings of the framework presented by this work show that CNNs can successfully convolve useful features from a set of pre-computed statistical temporal features from raw EEG waves. The high performance of K-fold validated algorithms argue that the features learnt by the CNNs hold useful knowledge for classification in addition to the pre-computed features.
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http://dx.doi.org/10.1088/1741-2552/abda0cDOI Listing
January 2021

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials.

Breast Cancer Res Treat 2021 Jan 3. Epub 2021 Jan 3.

Stanford University School of Medicine, Stanford, CA, USA.

Purpose: Abemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2- advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes.

Methods: Exploratory analyses of MONARCH 2 and 3 were performed for 3 age groups (<65, 65-74, and ≥75 years). For safety, data were pooled from both studies; for efficacy, a subgroup analysis of PFS was performed for each trial independently.

Results: Pooled safety data were available for 1152 patients. Clinically relevant diarrhea (Grade 2/3) was higher in older patients receiving abemaciclib + ET (<65, 39.5%; 65-74, 45.2%; ≥75, 55.4%) versus placebo + ET (<65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Nausea, decreased appetite, and venous thromboembolic events were all moderately higher in older patients. Neutropenia (Grade ≥ 3) did not differ as a function of age in the abemaciclib + ET arm (<65, 25.8%; 65-74, 27.4%; ≥75, 18.1%). Dose adjustments and discontinuation rates were slightly higher in older patients. Abemaciclib + ET improved PFS compared with placebo + ET independent of patient age, with no significant difference in abemaciclib treatment effect between the 3 age groups (MONARCH 2: interaction p-value, 0.695; MONARCH 3: interaction p-value, 0.634). Estimated hazard ratios ranged from 0.523-0.633 (MONARCH 2) and 0.480-0.635 (MONARCH 3).

Conclusions: While higher rates of adverse events were reported in older patients, they were manageable with dose adjustments and concomitant medication. Importantly, a consistent efficacy benefit was observed across all age groups.

Clinical Trial Registration: ClinicalTrials.gov: NCT02107703 (first posted April 8, 2014) and NCT02246621 (first posted September 23, 2014).
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http://dx.doi.org/10.1007/s10549-020-06029-yDOI Listing
January 2021

Palbociclib combined with endocrine therapy in heavily pretreated HR/HER2 advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

Breast 2020 Dec 13;54:286-292. Epub 2020 Nov 13.

Hospital Clínico San Carlos, Madrid, Spain. Electronic address:

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated 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 ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia.

Conclusions: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.
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http://dx.doi.org/10.1016/j.breast.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695980PMC
December 2020

Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial.

Breast Cancer Res 2020 11 11;22(1):124. Epub 2020 Nov 11.

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin, 3, 28049, Madrid, Spain.

Background: Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer.

Methods: Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as "non-progressors" if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time.

Results: Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors' tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased T signatures in gene expression studies in baseline-post-bevacizumab-tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating T in non-progressors.

Conclusions: This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing T cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting.

Trial Registration: (www.clinicaltrials.gov): NCT02802098 . Registered on June 16, 2020.
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http://dx.doi.org/10.1186/s13058-020-01362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661209PMC
November 2020

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.

Lancet Oncol 2020 11;21(11):1455-1464

Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Medical Oncology UO Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.

Methods: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data.

Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1).

Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.

Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.
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http://dx.doi.org/10.1016/S1470-2045(20)30450-2DOI Listing
November 2020

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy.

Eur J Cancer 2020 11 23;139:59-67. Epub 2020 Sep 23.

Université Paris Descartes, Paris, France; ARCAGY-GINECO, France.

Background: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo.

Methods: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV).

Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST.

Conclusions: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
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http://dx.doi.org/10.1016/j.ejca.2020.08.021DOI Listing
November 2020

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial.

Clin Cancer Res 2020 Nov 16;26(22):5820-5829. Epub 2020 Sep 16.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.

Patients And Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.

Results: Seventy-one patients were recruited ( = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; = 0.003).

Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0844DOI Listing
November 2020

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer.

Future Oncol 2020 Nov 12;16(33):2763-2778. Epub 2020 Aug 12.

Breast Cancer Unit, Medical Oncology Department, 12 de Octubre University Hospital, HM CIOCC, 28041, Madrid, Spain.

The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.
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http://dx.doi.org/10.2217/fon-2020-0604DOI Listing
November 2020

Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-line chemotherapy.

J Natl Cancer Inst 2020 Aug 8. Epub 2020 Aug 8.

Division of Hematology Oncology, University of California San Francisco, San Francisco, CA, USA.

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.

Methods: Serial CTC data from 469 patients (2,202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs (bCTC), combined CTC status at baseline to the end of cycle 1 (cCTC), and tCTC. Akaike Information Criterion (AIC) was used to select the model that best predicted PFS and OS.

Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (tCTCneg, 56.9% ), low (tCTClo, 23.7%), intermediate (tCTCmid, 14.5%), or high (tCTChi, 4.9%). Patients with tCTClo, tCTCmid and tCTChi patterns had statistically significant inferior PFS and OS compared to those with tCTCneg (P<.001). AIC indicated that the tCTC model best predicted PFS and OS when compared to bCTC and cCTC models. Validation studies in an independent cohort of 1,856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.

Conclusions: We identified four novel prognostic groups in MBC based on similarities in CTC trajectory patterns during chemotherapy. Prognostic groups included patients with very poor outcome (tCTCmid+tCTChi, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be utilized for fine-tuning of CTC-based risk-stratification strategies to guide future prospective clinical trials in MBC.
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http://dx.doi.org/10.1093/jnci/djaa113DOI Listing
August 2020

Impact of the COVID-19 outbreak on cancer patient flow and management: experience from a large university hospital in Spain.

ESMO Open 2020 06;4(Suppl 2):e000828

Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.

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http://dx.doi.org/10.1136/esmoopen-2020-000828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316135PMC
June 2020

Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.

Nat Commun 2020 01 20;11(1):385. Epub 2020 Jan 20.

Department of Medical Oncology, Hospital Clínic de Barcelona, Carrer de Villarroel, 170, 08036, Barcelona, Spain.

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.
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http://dx.doi.org/10.1038/s41467-019-14111-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971277PMC
January 2020

Randomized Phase 0/I Trial of the Mitochondrial Inhibitor ME-344 or Placebo Added to Bevacizumab in Early HER2-Negative Breast Cancer.

Clin Cancer Res 2020 01 9;26(1):35-45. Epub 2019 Oct 9.

Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain.

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 > 1 cm (any N) underwent a breast-centered F-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 ( < 0.001) ( = 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2023DOI Listing
January 2020

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

Oncologist 2019 11 25;24(11):e1024-e1033. Epub 2019 Apr 25.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.

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/m sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m 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 ( = 7, 50%) and NAB150/2w ( = 10, 62.5%) groups than in the NAB100/w ( = 13, 81.3%) or NAB150/w ( = 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 -rs7349683, -rs301927, and -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/m 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.
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http://dx.doi.org/10.1634/theoncologist.2017-0664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853092PMC
November 2019

GEICO1601-ROLANDO: a multicentric single arm Phase II clinical trial to evaluate the combination of olaparib and pegylated liposomal doxorubicin for platinum-resistant ovarian cancer.

Future Sci OA 2019 Feb 10;5(2):FSO370. Epub 2019 Jan 10.

Department of Medical Oncology, Clinica Universitaria de Navarra, Madrid, Spain.

Response to polyadenosine diphosphate ribose polymerase () inhibitors in platinum-resistant ovarian cancer and in the absence of mutations is very low. Combining PARP inhibitors with other agents might overcome this lack of activity. Here we describe the rationale and design of GEICO1601-ROLANDO (resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubin; NCT03161132). ROLANDO is a Phase II single-arm multicenter trial in which patients are treated with a combination of olaparib and pegylated liposomal doxorubicin (PLD) in platinum-resistant epithelial ovarian, primary peritoneal, or Fallopian tube cancer regardless of the  mutation status. The primary end point is progression-free survival at 6 months. Other secondary end points are response rate, disease control rate, quality of life and overall survival.
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http://dx.doi.org/10.4155/fsoa-2018-0107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391624PMC
February 2019

Proteomics characterisation of central nervous system metastasis biomarkers in triple negative breast cancer.

Ecancermedicalscience 2019 15;13:891. Epub 2019 Jan 15.

Biomedica Molecular Medicine SL, 28049 Madrid, Spain.

Background: Breast cancer (BC) is the most frequent tumour in women. Triple negative tumours (TNBC)-which are associated with minor survival rates-lack markers predictive of response to anticancer drugs. Triple negative tumours frequently metastasise to the central nervous system (CNS).

Objective: The main objective of this study was to study differences in tumour protein expression between patients with CNS metastases and those without this kind of spread, and propose new biomarkers.

Methods: A retrospective study was performed. Targeted proteomics and statistical analyses were used to identify possible biomarkers.

Results: Proteins were quantified by a targeted proteomics approach and protein expression data were successfully obtained from 51 triple negative formalin-fixed paraffin-embedded samples. ISG15, THBS1 and AP1M1 were identified as possible biomarkers related with CNS metastasis development.

Conclusions: Three possible biomarkers associated with CNS metastases in TNBC tumours were identified: ISG15, THBS1 and AP1M1. They may become markers predicting the appearance of CNS infiltration in triple negative BC.
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http://dx.doi.org/10.3332/ecancer.2019.891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369972PMC
January 2019

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper.

Crit Rev Oncol Hematol 2019 Feb 19;134:39-45. Epub 2018 Dec 19.

Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease.

Methods: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV, those with < 5 CTCs as Stage IV Survival was analyzed using Kaplan-Meier curves and the log rank test.

Results: For all patients, Stage IV patients had longer median overall survival than those with Stage IV (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV vs. 18.7 months Stage IV, p < 0.0001). Moreover, patients with Stage IV disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location.

Conclusions: We confirm the identification of two subgroups of MBC, Stage IV and Stage IV, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.
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http://dx.doi.org/10.1016/j.critrevonc.2018.12.004DOI Listing
February 2019

Safety of eribulin as third-line chemotherapy in HER2-negative, advanced breast cancer pre-treated with taxanes and anthracycline: OnSITE study.

Breast J 2019 03 8;25(2):219-225. Epub 2019 Feb 8.

Medical Oncology Department, Hospital 12 De Octubre, Madrid, Spain.

Eribulin is active and safe in heavily pre-treated metastatic breast cancer patients. Few safety data have been published in third line. We aimed to report the specific safety profile on third line beyond taxanes and anthracyclines in advanced breast cancer (ABC). A multicenter phase II, prospective study was conducted in anthracyclines and taxanes pre-treated HER2-negative ABC, programmed to receive eribulin as third-line chemotherapy. Adverse events (AEs) were assessed and classified according to CTCAE. In addition, efficacy, in terms of overall survival (OS) and progression-free survival (PFS), and the dynamics of circulating tumor cells (CTCs) during treatment were assessed. 59 patients fulfilled the criteria. All but one showed AEs with a cumulative number of 598 AEs. The most frequent grade 3/4 drug-related AEs were neutropenia (1.7%), febrile neutropenia (0.5%), leukopenia (0.5%), alopecia (0.5%), asthenia (0.3%), elevated gamma glutamyl transferase levels (0.2%), and respiratory tract infection (0.2%). Median PFS was 4 months (95% CI 3.1-5.9) and median OS was 13.6 months (11.8-not reached). The mean number of CTCs in peripheral blood was significantly reduced from baseline to cycle 2 (16.8 vs 5.4 CTCs; P < 0.001). Median OS was significantly longer in <5 baseline CTC patients compared to ≥5 baseline CTC patients (13.1 months [95% CI: 11.8-not reached] vs 12.5 months [95% CI: 7.6-not reached]; P = 0.045). A significant correlation (P = 0.0129) was observed between CTC levels at cycle 2 and death when CTCs were analyzed using cox regression. Eribulin chemotherapy is effective and safe as third line in advanced HER2-negative breast cancer. CTC levels correlate with overall survival.
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http://dx.doi.org/10.1111/tbj.13199DOI Listing
March 2019

Therapeutic targeting of HER2-CBR heteromers in HER2-positive breast cancer.

Proc Natl Acad Sci U S A 2019 02 7;116(9):3863-3872. Epub 2019 Feb 7.

Department of Biochemistry and Molecular Biology, Complutense University, 28040 Madrid, Spain;

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CBR. We show that HER2 physically interacts with CBR in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ-tetrahydrocannabinol (THC) disrupts HER2-CBR complexes by selectively binding to CBR, which leads to () the inactivation of HER2 through disruption of HER2-HER2 homodimers, and () the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CBR transmembrane region 5 mimicked THC effects. Together, these findings define HER2-CBR heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.
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http://dx.doi.org/10.1073/pnas.1815034116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397550PMC
February 2019

Late Administration of Trastuzumab Emtansine Might Lead to Loss of Chance for Better Outcome in Patients with HER2-Positive Metastatic Breast Cancer.

Breast Care (Basel) 2018 Aug 13;13(4):277-283. Epub 2018 Jul 13.

Medical Oncology Department, Salamanca Clinic University Hospital, Salamanca, Spain.

The optimal sequence of anti-human epidermal growth factor receptor 2 (HER2) therapies in metastatic breast cancer (MBC) is still undetermined. Physicians must therefore make decisions based on clinical trials and their own experience for the best treatment sequence in these patients. The objective of this review is to summarize the efficacy and safety data for trastuzumab emtansine (T-DM1) in patients with MBC. Additionally, the concept of 'loss of chance for a better outcome' is investigated. It applies to patients who are not receiving the best possible treatment for their disease. Physicians should strive to offer the best possible care, although getting optimal results in each individual patient is not guaranteed. Lastly, the number of patients with MBC lost per treatment line is evaluated. We conclude that both concepts reinforce the importance of giving the most active treatments as soon as possible in the course of disease to secure the longest possible survival for HER2-positive MBC patients.
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http://dx.doi.org/10.1159/000488794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170918PMC
August 2018

Long-term response to first-line bevacizumab-based therapy in patients with metastatic breast cancer: results of the observational "LORENA" study.

Onco Targets Ther 2018 17;11:5845-5852. Epub 2018 Sep 17.

Department of Medical Oncology, Hospital Universitario Cruces, Barakaldo, Spain.

Background: Randomized controlled trials of the first-line combination of bevacizumab and chemotherapy in patients with metastatic breast cancer (MBC) have shown improvements in tumor response and progression-free survival (PFS).

Objective: The aim of this ambispective, observational study (LORENA) was to describe the clinical characteristics of long-term responders to bevacizumab-based therapy.

Patients And Methods: This study consisted of a retrospective and a prospective phase. During the retrospective phase, patients with HER2-negative MBC who were treated with bevacizumab-based first-line therapy were included. During the prospective phase, patients with PFS of ≥12 months were treated according to routine clinical practice procedures. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed.

Results: In total, 148 women were included (median age: 50 years; range: 29-81 years). The mean duration of exposure to bevacizumab was 18 months. The majority of patients experienced objective response (complete: 23%; partial: 57%). Median PFS was 22.7 months and median OS was 58.2 months. In multivariate analyses, patients receiving maintenance hormonal therapy (MHT) had longer PFS (=0.002; hazard ratio [HR] =1.8) and OS (=0.009; HR=2.0), while patients not previously treated with taxanes had longer OS (<0.0001; HR =3.3). No unexpected adverse events were observed.

Conclusion: The results of this study suggest, that among long-term responders, first-line bevacizumab-based therapy is more effective in patients who had not been previously treated with taxanes, and that MHT provides additional therapeutic benefits by extending PFS and OS.
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http://dx.doi.org/10.2147/OTT.S170303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149976PMC
September 2018

In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer.

Nat Commun 2018 08 29;9(1):3501. Epub 2018 Aug 29.

Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, 28029, Madrid, Spain.

Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC.
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http://dx.doi.org/10.1038/s41467-018-05742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115463PMC
August 2018

Microbiome and Allergic Diseases.

Front Immunol 2018 17;9:1584. Epub 2018 Jul 17.

Research Laboratory and Allergy Unit, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Universidad de Málaga, ARADyAL, Malaga, Spain.

Allergic diseases, such as respiratory, cutaneous, and food allergy, have dramatically increased in prevalence over the last few decades. Recent research points to a central role of the microbiome, which is highly influenced by multiple environmental and dietary factors. It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. It has been described at some extent changes in environment and nutrition produce dysbiosis in the gut but also in the skin, and lung microbiome, inducing qualitative and quantitative changes in composition and metabolic activity. Here, we review the potential role of the skin, respiratory, and gastrointestinal tract (GIT) microbiomes in allergic diseases. In the GIT, the microbiome has been proven to be important in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells. In the lung, the microbiome may play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis and psoriasis. Thus, the microbiome can be considered a therapeutical target for treating inflammatory diseases, such as allergy. Despite some limitations, interventions with probiotics, prebiotics, and/or synbiotics seem promising for the development of a preventive therapy by restoring altered microbiome functionality, or as an adjuvant in specific immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2018.01584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056614PMC
July 2018

Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study.

Gynecol Oncol 2018 09 27;150(3):471-477. Epub 2018 Jul 27.

Oncology Institute of Southern, Switzerland, Bellinzona.

Background: Tumor Treating Fields (TTFields) are an anti-mitotic therapy comprising continuous delivery of low-intensity alternating electric fields at intermediate frequencies to the tumor region by a home-use medical device.

Methods: The INNOVATE (EF-22) Study was a phase 2, single arm clinical trial, which tested the safety and efficacy of TTFields (200 kHz) in combination with weekly paclitaxel (weekly for 8 weeks and then on days 1, 8, 15 of each subsequent 28 day-cycle; starting dose 80 mg/m) in 31 patients with recurrent, platinum-resistant ovarian carcinoma. The primary endpoint was safety and secondary endpoints included OS, PFS and RR.

Results: Median age was 60 (range: 45-77), 24 patients (77%) had serous histology, 16 patients (52%) ECOG score 0 and 15 (48%) ECOG 1, the median number of prior chemotherapy lines was 4 (range: 1-11). All patients received prior platinum-based chemotherapy and 30 (97%) received prior taxanes. No serious adverse events related to TTFields were reported. There was no increase in grade 3-4 adverse events compared to the frequency of such events reported in the literature with single agent weekly paclitaxel. Twenty-six patients (84%) had the expected TTFields-related dermatitis but only one patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25%) had partial response and the clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%.

Conclusion: TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase 3 trial.
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http://dx.doi.org/10.1016/j.ygyno.2018.07.018DOI Listing
September 2018

A Spiking Neural Model of HT3D for Corner Detection.

Front Comput Neurosci 2018 1;12:37. Epub 2018 Jun 1.

Laboratory of Robotics and Artificial Vision, Department of Computer and Communication Technology, University of Extremadura, Cáceres, Spain.

Obtaining good quality image features is of remarkable importance for most computer vision tasks. It has been demonstrated that the first layers of the human visual cortex are devoted to feature detection. The need for these features has made line, segment, and corner detection one of the most studied topics in computer vision. HT3D is a recent variant of the Hough transform for the combined detection of corners and line segments in images. It uses a 3D parameter space that enables the detection of segments instead of whole lines. This space also encloses canonical configurations of image corners, transforming corner detection into a pattern search problem. Spiking neural networks (SNN) have previously been proposed for multiple image processing tasks, including corner and line detection using the Hough transform. Following these ideas, this paper presents and describes in detail a model to implement HT3D as a Spiking Neural Network for corner detection. The results obtained from a thorough testing of its implementation using real images evince the correctness of the Spiking Neural Network HT3D implementation. Such results are comparable to those obtained with the regular HT3D implementation, which are in turn superior to other corner detection algorithms.
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http://dx.doi.org/10.3389/fncom.2018.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992504PMC
June 2018

Exosomes: Definition, Role in Tumor Development and Clinical Implications.

Cancer Microenviron 2018 Jun 3;11(1):13-21. Epub 2018 May 3.

Medical Oncology Service, University Hospital 12 de Octubre (Madrid, Spain), Avda Córdoba S/N, 28041, Madrid, Spain.

Exosomes are microvesicles released by cells in both physiological and pathological situations. They are surrounded by a lipid bilayer with proteins derived from the origin cell, and contain a variety of molecules, such as nucleic acids. They represent an emerging mechanism of intercellular communication, and they play an important role in the pathogenesis of cancer, stimulating proliferation and aggressiveness of cancer cells, inducing a microenvironment favorable to tumor development and controlling immune responses. Because of the growing understanding of the potential implications of extracellular vesicles in the development of malignancies, research on exosomes, and its role as a diagnostic and therapeutic tool, constitutes nowadays a very exciting and promising field.
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http://dx.doi.org/10.1007/s12307-018-0211-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008261PMC
June 2018

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

Lancet Oncol 2018 06 26;19(6):812-824. Epub 2018 Apr 26.

Breast Cancer Unit and Gynaecological Tumours, Ramon y Cajal University Hospital, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Baselga Oncology Institute, Quiron Group, Madrid and Barcelona, Spain. Electronic address:

Background: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer.

Methods: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual.

Findings: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia.

Interpretation: The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials.

Funding: Polyphor.
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http://dx.doi.org/10.1016/S1470-2045(18)30147-5DOI Listing
June 2018

Special issue on cognitive robotics.

Cogn Process 2018 05 16;19(2):231-232. Epub 2018 Apr 16.

University of Extremadura, Caceres, Spain.

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http://dx.doi.org/10.1007/s10339-018-0863-8DOI Listing
May 2018

MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.

J Clin Oncol 2017 Nov 2;35(32):3638-3646. Epub 2017 Oct 2.

Matthew P. Goetz, Mayo Clinic, Rochester, MN; Masakazu Toi, Kyoto University, Kyoto, Japan; Mario Campone, Institut de Cancerologie de l'Ouest, Angers Cedex; Olivier Trédan, Centre Léon Bérard, Lyon; Nawel Bourayou, Eli Lilly, Paris, France; Joohyuk Sohn, Yonsei Cancer Center, Seoul; In Hae Park, National Cancer Center, Goyangsi, South Korea; Shani Paluch-Shimon, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Jens Huober, University of Ulm, Ulm, Germany; Shin-Cheh Chen, Chang Gung University Medical College, Taipei, Taiwan; Luis Manso, Hospital Universitario 12 de Octubre; Susana Barriga, Eli Lilly, Madrid, Spain; Orit C. Freedman, Durham Regional Cancer Centre, Oshawa, Ontario, Canada; Georgina Garnica Jaliffe, Grupo Médico CAMINO S.C., Mexico City, Mexico; Tammy Forrester, Martin Frenzel, and Ian C. Smith, Eli Lilly, Indianapolis, IN; and Angelo Di Leo, Hospital of Prato, Prato, Italy.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.
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http://dx.doi.org/10.1200/JCO.2017.75.6155DOI Listing
November 2017

Integrating planning perception and action for informed object search.

Cogn Process 2018 May 14;19(2):285-296. Epub 2017 Aug 14.

RoboLab - Robotics and Artificial Vision Laboratory, Escuela Politécnica de Cáceres, Universidad de Extremadura, Avd. de la Universidad s/n, 10071, Badajoz, Spain.

This paper presents a method to reduce the time spent by a robot with cognitive abilities when looking for objects in unknown locations. It describes how machine learning techniques can be used to decide which places should be inspected first, based on images that the robot acquires passively. The proposal is composed of two concurrent processes. The first one uses the aforementioned images to generate a description of the types of objects found in each object container seen by the robot. This is done passively, regardless of the task being performed. The containers can be tables, boxes, shelves or any other kind of container of known shape whose contents can be seen from a distance. The second process uses the previously computed estimation of the contents of the containers to decide which is the most likely container having the object to be found. This second process is deliberative and takes place only when the robot needs to find an object, whether because it is explicitly asked to locate one or because it is needed as a step to fulfil the mission of the robot. Upon failure to guess the right container, the robot can continue making guesses until the object is found. Guesses are made based on the semantic distance between the object to find and the description of the types of the objects found in each object container. The paper provides quantitative results comparing the efficiency of the proposed method and two base approaches.
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http://dx.doi.org/10.1007/s10339-017-0828-3DOI Listing
May 2018