Publications by authors named "Jon Zugazagoitia"

29 Publications

  • Page 1 of 1

An Open Source, Automated Tumor Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer.

Clin Cancer Res 2021 Jun 4. Epub 2021 Jun 4.

Department of Pathology, Yale School of Medicine.

Purpose: Although tumor infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple negative breast cancer (TNBC), it is subject to inter and intra-observer variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts.

Experimental Design: Using the QuPath open source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts and "other" cells on hematoxylin-eosin (H&E) stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets.

Results: We found that all five machine TIL variables had significant prognostic association with outcomes (p{less than or equal to}0.01 for all comparisons) but showed cell specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathological factors including stage, age and histological grade (p{less than or equal to}0.003 for all analyses).

Conclusions: Neural net driven cell classifier defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0325DOI Listing
June 2021

Quantitative Assessment of CD200 and CD200R Expression in Lung Cancer.

Cancers (Basel) 2021 Mar 1;13(5). Epub 2021 Mar 1.

Department of Pathology, BML 116, Yale University School of Medicine, 310 Cedar St. P.O. Box 208023, New Haven, CT 06520-8023, USA.

CD200/CD200R is an immune checkpoint with broad expression patterns and a potential target for immune therapy. In this study, we assess both CD200 and CD200R expression in solid tumors, with a focus on lung cancer, and evaluate their association with clinicopathologic characteristics, mutation status, outcome, and programmed death-ligand 1 (PD-L1) expression. We used multiplexed quantitative immunofluorescence (QIF) to measure the expression of CD200 and CD200R in a total of 455 patients from three lung cancer cohorts. Using carefully validated antibodies, we performed target measurement with tyramide-based QIF panels and analyzed the data using the PM2000 microscope and AQUA software. CD200 tumor positivity was found in 29.7% of non-small cell lung cancer (NSCLC) patients and 33.3% of lung large cell neuroendocrine carcinoma (LCNEC) patients. CD200 demonstrated notable intratumoral heterogeneity. CD200R was expressed in immune cells in 25% of NSCLC and 41.3% of LCNEC patients. While CD200R is predominantly expressed in immune cells, rare tumor cell staining was seen in a highly heterogeneous pattern. CD200R expression in the stromal compartment was significantly higher in patients with squamous differentiation ( < 0.0001). Neither CD200 nor CD200R were associated with other clinicopathologic characteristics or mutation status. Both biomarkers were not prognostic for disease-free or overall survival in NSCLC. CD200 showed moderate correlation with PD-L1. CD200/CD200R pathway is frequently expressed in lung cancer patients. Differential expression patterns of CD200 and CD200R with PD-L1 suggest a potential role for targeting this pathway alone in patients with NSCLC.
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http://dx.doi.org/10.3390/cancers13051024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957629PMC
March 2021

Quantitative analysis of CMTM6 expression in tumor microenvironment in metastatic melanoma and association with outcome on immunotherapy.

Oncoimmunology 2020 12 29;10(1):1864909. Epub 2020 Dec 29.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.

Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) modulates degradation of a number of proteins, including programmed death ligand-1 (PD-L1) by protecting it from ubiquitin-mediated degradation. In this role, it could modulate the effectiveness of immunotherapy. Here, for the first time, we characterize CMTM6 expression in melanoma and evaluate its association with response to immune checkpoint inhibitors (ICI). We evaluated the expression of CMTM6, PD-L1 and other immune-related proteins in 60 pretreatment biopsies from metastatic melanoma patients who received immunotherapy, in a tissue microarray (TMA) using quantitative immunofluorescence (QIF). Expression of mRNA from control patients obtained from The Cancer Genome Atlas (TCGA) database was also compared. CMTM6 expression was positively correlated with PD-L1, CD3, CD20, and CD68 markers, at protein (Pearson's r = 0.53-0.81, all < .0001) and mRNA (Spearman's r = 0.15-0.44, all < .002, except for CD68 where = .26) levels. CMTM6 protein was associated with longer survival after immunotherapy when measured in the stromal ( = .007) and all the immune compartments tested (T cells, B cells, and macrophages). Multivariable analyses also revealed significant CMTM6 survival associations when measured in stromal (Hazard Ratio (HR) = 0.12, = .001) and CD68-positive (HR = 0.30, = .043) compartments. Additionally, PD-L1 but not CMTM6 showed prognostic value in control patients. Finally, high CMTM6 and PD-L1 co-expression in the stromal compartment was significantly associated with longer survival in treated patients ( = .028). Consequently, CMTM6 expression shows potential as a predictive factor for ICI treatments.
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http://dx.doi.org/10.1080/2162402X.2020.1864909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781756PMC
December 2020

High risk of thrombosis in patients with advanced lung cancer harboring rearrangements in ROS1.

Eur J Cancer 2020 12 7;141:193-198. Epub 2020 Nov 7.

Portuguese Institute of Oncology of Porto, Portugal.

Introduction: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal.

Methods: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival.

Results: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period.

Conclusions: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs.
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http://dx.doi.org/10.1016/j.ejca.2020.10.002DOI Listing
December 2020

Antibody validation for protein expression on tissue slides: a protocol for immunohistochemistry.

Biotechniques 2020 12 27;69(6):460-468. Epub 2020 Aug 27.

Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.

Antibodies play a crucial role in basic research and clinical decision-making. However, there are no standardized algorithms or guidelines to ensure their accuracy and validity. There have been efforts to generate consensus, but, with the exception of clinical labs, antibody validation remains variable in the literature and sometimes in clinical practice. Here we focus on immunohistochemistry, an example of a scientific and clinical tool where validation of antibodies is critical. We describe a protocol that we use to validate antibodies specifically for immunohistochemistry, including some of the pillars of antibody validation from Uhlen 2016, as an example of a rigorous approach to build antibody-based tests for both basic and translational science labs and for the clinic.
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http://dx.doi.org/10.2144/btn-2020-0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807291PMC
December 2020

Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non-Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling.

Clin Cancer Res 2020 08 6;26(16):4360-4368. Epub 2020 Apr 6.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Only a minority of patients with advanced non-small cell lung cancer (NSCLC) truly benefits from single-agent PD-1 checkpoint blockade, and more robust predictive biomarkers are needed.

Experimental Design: We assessed tumor samples from 67 immunotherapy-treated NSCLC cases represented in a tissue microarray, 53 of whom had pretreatment samples and received monotherapy. Using GeoMx Digital Spatial Profiling System (NanoString Technologies), we quantified 39 immune parameters simultaneously in four tissue compartments defined by fluorescence colocalization [tumor (panCK), leucocytes (CD45), macrophages (CD68), and nonimmune stroma].

Results: A total of 156 protein variables were generated per case. In the univariate unadjusted analysis, we found 18 markers associated with outcome in spatial context, five of which remained significant after multiplicity adjustment. In the multivariate analysis, high levels of CD56 and CD4 measured in the CD45 compartment were the only markers that were predictive for all clinical outcomes, including progression-free survival (PFS, HR: 0.24, = 0.006; and HR: 0.31, = 0.011, respectively), and overall survival (OS, HR: 0.26, = 0.014; and HR: 0.23, = 0.007, respectively). Then, using an orthogonal method based on multiplex immunofluorescence and cell counting (inForm), we validated that high CD56 immune cell counts in the stroma were associated with PFS and OS in the same cohort.

Conclusions: This pilot scale discovery study shows the potential of the digital spatial profiling technology in the identification of spatially informed biomarkers of response to PD-1 checkpoint blockade in NSCLC. We identified a number of relevant candidate immune predictors in spatial context that deserve validation in larger independent cohorts.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442721PMC
August 2020

Digital quantitative assessment of PD-L1 using digital spatial profiling.

Lab Invest 2020 10 6;100(10):1311-1317. Epub 2020 Apr 6.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

The assessment of programmed death 1 ligand 1 (PD-L1) expression by Immunohistochemistry (IHC) is the US Food and Drug Administration (FDA)-approved predictive marker to select responders to checkpoint blockade anti-PD-1/PD-L1 axis immunotherapies. Different PD-L1 immunohistochemistry (IHC) assays use different antibodies and different scoring methods in tumor cells and immune cells. Multiple studies have compared the performance of these assays with variable results. Here, we investigate an alternative method for assessment of PD-L1 using a new technology known as digital spatial profiling. We use a previously described standardization tissue microarray (TMA) to assess the accuracy of the method and compare digital spatial profiler (DSP) to each FDA-approved PD-L1 assays, one LDT assay and three quantitative fluorescence assays. The standardized cell line Index tissue microarray contains 10 isogenic cells lines in triplicates expressing various ranges of PD-L1. The dynamic range of PD-L1 digital counts was measured in the ten cell lines on the Index TMA using the GeoMx DSP assay and read on the nCounter platform. The digital method shows very high correlation with immunohistochemistry scored with quantitative software and with quantitative fluorescence. High correlation of PD-L1 digital DSP counts were seen between rows on the same Index TMA. Finally, experiments from two Index TMAs showed reproducibility of DSP counts were independent of variable slide storage time over a three-week period after antibody labeling but before collection of cleaved tags. In summary, DSP appears to have quantitative potential comparable to quantitative immunohistochemistry. It is possible that this technology could be used as a PD-L1 protein measurement system for companion diagnostic testing for immune therapy.
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http://dx.doi.org/10.1038/s41374-020-0424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502436PMC
October 2020

FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy.

EBioMedicine 2020 Mar 27;53:102683. Epub 2020 Feb 27.

H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Medical Oncology Department, Hospital Universitario Doce de Octubre. Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain.

Background: Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success.

Methods: In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study.

Findings: We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression.

Interpretation: Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.
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http://dx.doi.org/10.1016/j.ebiom.2020.102683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047190PMC
March 2020

Blood mRNA expression of REV3L and TYMS as potential predictive biomarkers from platinum-based chemotherapy plus pemetrexed in non-small cell lung cancer patients.

Cancer Chemother Pharmacol 2020 03 12;85(3):525-535. Epub 2019 Dec 12.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.

Purpose: Therapeutic options for cancer patients have increased in the last years, although drugs resistance problem remains unresolved. Genetic background in individual susceptibility to cancer treatment could influence the therapy responses. The aim of this study was to explore the feasibility of using blood 4 genes (AEG-1, BRCA-1, REV3L and TYMS) expression levels as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer.

Methods: Sixteen patients from the Medical Oncology Department at "12 de Octubre" Hospital, were included in the study. Total mRNA was isolated from blood samples, and gene expression was analyzed by RT-qPCR. A panel of lung tumor cell lines were used in cell proliferation tests and siRNA-mediated silencing assays.

Results: Similarity between blood gene expression levels and protein expression in matched tumor tissue was observed in 54.54% (REV3L) and 81.81% (TYMS) of cases. Gene expression of REV3L and TYMS in blood correlated directly and inversely, respectively, with progression-free survival and overall survival in the patients from our cohort. In tumor cell lines, the knockdown of REV3L conferred resistance to pemetrexed treatment, and the TYMS silencing increased the pemetrexed sensitivity of tumor cells.

Conclusions: The use of peripheral blood samples for expression quantification of interest genes is an affordable method with promising results in the evaluation of response to pemetrexed treatment. Therefore, expression levels of REV3L and TYMS genes might be used as predictive biomarkers in advanced NSCLC patients.
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http://dx.doi.org/10.1007/s00280-019-04008-9DOI Listing
March 2020

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort.

J Thorac Oncol 2020 03 17;15(3):426-435. Epub 2019 Oct 17.

Sarah Cannon Research Institute/Tennessee Oncology Nashville, Nashville, Tennessee.

Introduction: Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.

Methods: Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.

Results: Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06-4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8-7.6) versus 4.7 months (3.1-8.3). Twenty-four-month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.

Conclusions: Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.
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http://dx.doi.org/10.1016/j.jtho.2019.10.004DOI Listing
March 2020

Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy.

Clin Cancer Res 2020 02 15;26(4):970-977. Epub 2019 Oct 15.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: Programmed death ligand 1 (PD-L1) is expressed in tumor cells and immune cells, and both have been associated with response to anti-PD-1 axis immunotherapy. Here, we examine the expression of PD-L1 to determine which cell type carries the predictive value of the test.

Experimental Design: We measured the expression of PD-L1 in multiple immune cells with two platforms and confocal microscopy on three retrospective Yale NSCLC cohorts (425 nonimmunotherapy-treated cases and 62 pembrolizumab/nivolumab/atezolizumab-treated cases). The PD-L1 level was selectively measured in different immune cell subsets using two multiplexed quantitative immunofluorescence panels, including CD56 for natural killer cells, CD68 for macrophages, and CD8 for cytotoxic T cells.

Results: PD-L1 was significantly higher in macrophages in both tumor and stromal compartment compared with other immune cells. Elevated PD-L1 in macrophages was correlated with high PD-L1 level in tumor as well as CD8 and CD68 level ( < 0.0001). High PD-L1 expression in macrophages was correlated with better overall survival (OS; = 0.036 by cell count/ = 0.019 by molecular colocalization), while high PD-L1 expression in tumor cells was not.

Conclusions: In nearly 500 non-small cell lung cancer (NSCLC) cases, the predominant immune cell type that expresses PD-L1 is CD68 macrophages. The level of PD-L1 in macrophages is significantly associated with the level of PD-L1 in tumor cells and infiltration by CD8 T cells, suggesting a connection between high PD-L1 and "hot" tumors. In anti-PD-1 axis therapy-treated patients, high levels of PD-L1 expression in macrophages are associated with longer OS and may be responsible for the predictive effect of the marker.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024671PMC
February 2020

Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non-Small Cell Lung Cancer.

J Thorac Oncol 2019 12 9;14(12):2084-2096. Epub 2019 Oct 9.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine (Oncology), Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Introduction: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been described as a programmed death ligand 1 (PD-L1) regulator at the protein level by modulating stability through ubiquitination. In this study, we describe the patterns of CMTM6 expression and assess its association with response to programmed cell death 1 pathway blockade in NSCLC.

Methods: We used multiplexed quantitative immunofluorescence to determine the expression of CMTM6 and PD-L1 in 438 NSCLCs represented in tissue microarrays, including in two independent retrospective cohorts of immunotherapy-treated (n = 69) and non-immunotherapy-treated (n = 258) patients and a third collection of EGFR- and KRAS-genotyped tumors (n = 111).

Results: Tumor and stromal CMTM6 expression was detected in approximately 70% of NSCLCs. CMTM6 expression was not associated with clinical features or EGFR/KRAS mutational status and showed a modest correlation with T-cell infiltration (R < 0.40). We found a significant correlation between CMTM6 and PD-L1, which was higher in the stroma (R = 0.51) than in tumor cells (R = 0.35). In our retrospective NSCLC cohort, neither CMTM6 nor PD-L1 expression alone significantly predicted immunotherapy outcomes. However, high CMTM6 and PD-L1 coexpression in the stromal and CD68 compartments (adjusted hazard ratio = 0.38, p = 0.03), but not in tumor cells (p = 0.15), was significantly associated with longer overall survival in treated patients but was not observed in the absence of immunotherapy.

Conclusion: This study supports the mechanistic role for CMTM6 in stabilization of PD-L1 in patient tumors and suggests that high coexpression of CMTM6 and PD-L1, particularly in stromal immune cells (macrophages), might identify the greatest benefit from programmed cell death 1 axis blockade in NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2019.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951804PMC
December 2019

Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance.

Lung Cancer 2019 08 30;134:72-78. Epub 2019 May 30.

CIBERONC, Spain; Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Universidad Alcalá, Madrid, Spain. Electronic address:

Objectives: Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance.

Materials And Methods: We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay).

Results: We included 53 patients separated in 3 cohorts: 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib.

Conclusion: NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting.
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http://dx.doi.org/10.1016/j.lungcan.2019.05.032DOI Listing
August 2019

Immune Checkpoint Inhibitor-Associated Pericarditis.

J Thorac Oncol 2019 06 7;14(6):1102-1108. Epub 2019 Mar 7.

Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.

Side effects of immune checkpoint inhibitors, termed immune-related adverse events, are relatively common, but immune checkpoint inhibitor-mediated cardiotoxicities are rare; however, they can be serious and potentially fatal. Pericarditis is an infrequent cardiac toxicity of immunotherapy and predisposing factors remain unknown. Here we report three patients with NSCLC who developed pericarditis during therapy with programmed death 1/programmed death ligand 1+/- CTLA-4 inhibitors. We review the clinical presentation of these three cases and histopathologic findings from autopsies from the first two patients and a pericardial sampling that has been obtained from a pericardial window procedure in the third patient who recovered from the pericarditis episode. We also discuss the potential mechanisms, as well as what is known about pericarditis secondary to immune-related adverse events.
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http://dx.doi.org/10.1016/j.jtho.2019.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617516PMC
June 2019

KRAS-Mutant non-small cell lung cancer: From biology to therapy.

Lung Cancer 2018 10 19;124:53-64. Epub 2018 Jul 19.

Lilly Deutschland GmbH, Werner-Reimers-Strasse 2-4, D-61352 Bad Homburg, Germany; Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation.
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http://dx.doi.org/10.1016/j.lungcan.2018.07.013DOI Listing
October 2018

Targeting EGFR in Lung Cancer: Current Standards and Developments.

Drugs 2018 Jun;78(9):893-911

Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.

Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.
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http://dx.doi.org/10.1007/s40265-018-0916-4DOI Listing
June 2018

Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials.

Oncotarget 2018 Feb 20;9(9):8706-8715. Epub 2018 Jan 20.

Medical Oncology Service, University Hospital 12 de Octubre, Madrid, Spain.

Background: Anti-PD1/PD-L1 monoclonal antibodies (mAbs) increase overall survival compared to standard of care (SOC) in different tumors. However, a proportion of patients (pts) will have progressive disease (PD) as best response. We conducted a meta-analysis to study the rates of response comparing these antibodies with SOC.

Methods: A search of published trials in MEDLINE and EMBASE analyzing anti-PD1/PD-L1mAbs monotherapy compared to SOC. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Subgroup analyses for location of primary tumor, number of previous treatment lines, selected population by PD-L1 expression and type of radiological assessment were made.

Results: Twelve studies accounting for 6,700 pts were included (anti-PD1/PD-L1 mAbs: 3,451 pts; SOC: 3,249 pts [2,823 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N, %): Complete Response (CR) (69/3153, 2.19%), Partial Response (PR) (596/3153, 18.90%), Stable Disease (SD) (632/2463, 25.66%) and PD (1027/2463, 41.70%); and CR (16/2955, 0.54%), PR (263/2955, 8.90%), SD (835/2269, 36.80%) and PD (834/2269, 36.76%) with anti-PD1/PD-L1 mAbs and SOC, respectively. Anti-PD1/PD-L1 mAbs improved CR rate (RR 3.48) and PR rate (RR 2.27). There were no differences in the PD rate between groups (RR 1.10). Subgroup analyses showed an improvement in clinical benefit with anti-PD1/PD-L1 mAbs for melanoma (RR 1.59; 1.37-1.84 95% CI) and those treated in the first line setting (RR 1.57; 1.27-1.95 95% CI).

Conclusions: Anti-PD1/PD-L1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti-PD1/PD-L1 mAbs.

Findings: In this systematic meta-analysis, anti-PD1/PD-L1 mAbs were associated with a greater overall response rate. Patients with melanoma and those managed in the first line setting seem to have an additional benefit with anti-PD1/PD-L1 mAbs.
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http://dx.doi.org/10.18632/oncotarget.24283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823578PMC
February 2018

Prospective Clinical Integration of an Amplicon-Based Next-Generation Sequencing Method to Select Advanced Non-Small-Cell Lung Cancer Patients for Genotype-Tailored Treatments.

Clin Lung Cancer 2018 01 23;19(1):65-73.e7. Epub 2017 Jun 23.

Medical Oncology Department, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain; Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

Introduction: A substantial fraction of non-small-cell lung cancers (NSCLCs) harbor targetable genetic alterations. In this study, we analyzed the feasibility and clinical utility of integrating a next-generation sequencing (NGS) panel into our routine lung cancer molecular subtyping algorithm.

Patients And Methods: After routine pathologic and molecular subtyping, we implemented an amplicon-based gene panel for DNA analysis covering mutational hot spots in 22 cancer genes in consecutive advanced-stage NSCLCs.

Results: We analyzed 109 tumors using NGS between December 2014 and January 2016. Fifty-six patients (51%) were treatment-naive and 82 (75%) had lung adenocarcinomas. In 89 cases (82%), we used samples derived from lung cancer diagnostic procedures. We obtained successful sequencing results in 95 cases (87%). As part of our routine lung cancer molecular subtyping protocol, single-gene testing for EGFR, ALK, and ROS1 was attempted in nonsquamous and 3 squamous-cell cancers (n = 92). Sixty-nine of 92 samples (75%) had sufficient tissue to complete ALK and ROS1 immunohistochemistry (IHC) and NGS. With the integration of the gene panel, 40 NSCLCs (37%) in the entire cohort and 30 NSCLCs (40%) fully tested for ALK and ROS1 IHC and NGS had actionable mutations. KRAS (24%) and EGFR (10%) were the most frequently mutated actionable genes. Ten patients (9%) received matched targeted therapies, 6 (5%) in clinical trials.

Conclusion: The combination of IHC tests for ALK and ROS1 and amplicon-based NGS is applicable in routine clinical practice, enabling patient selection for genotype-tailored treatments.
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http://dx.doi.org/10.1016/j.cllc.2017.06.008DOI Listing
January 2018

Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib.

Front Med (Lausanne) 2017 5;4:36. Epub 2017 Apr 5.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain.

Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping efficacy data in chemotherapy-pretreated wild-type (WT) patients in the ARCHER 1009 trial. Similarly, it failed to demonstrate any survival benefits as compared to placebo in WT subsets progressing on chemotherapy and at least one previous first-generation TKI (erlotinib or gefitinib) in the BR.26 trial. In the case of -mutant NSCLCs, a pooled analysis of the ARCHER 1009 and ARCHER 1028 trials comparing the efficacy of dacomitinib vs. erlotinib in chemotherapy-pretreated, EGFR TKI-naïve patients showed a trend to a longer progression-free survival (PFS) and overall survival in favor of dacomitinib that did not reach statistical significance, with a higher rate of treatment related adverse events (mainly skin rash, paronychia, and gastrointestinal toxicities). On the other hand, the clinical activity in patients with -mutant NSCLCs with acquired TKI resistance that were included in phase II/III trials was equally poor (response rate <10%; PFS 3-4 months). Therefore, with the results of the ARCHER 1050 trial (NCT01774721) still pending, the current clinical development of dacomitinib is largely focused on -mutant, TKI-naïve patients. Here, we review the most relevant clinical data of dacomitinib in advanced NSCLC. We discuss the potential role of dacomitinib in pretreated WT and -mutant (TKI-naïve and TKI-resistant) patients. Finally, we briefly comment the available clinical data of dacomitinib in HER2-mutant NSCLC patients.
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http://dx.doi.org/10.3389/fmed.2017.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380728PMC
April 2017

Biological therapies in nonsmall cell lung cancer.

Eur Respir J 2017 03 2;49(3). Epub 2017 Mar 2.

Medical Oncology Dept, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain

Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer (NSCLC). Genotype-directed therapies have changed treatment paradigms of patients with -mutant and -rearranged lung adenocarcinomas, and the list of druggable targets with demonstrated clinical actionability ( and ) continues to expand. Furthermore, we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them, particularly at the immune checkpoint level. Drugs targeting the tumour immune-evasive PD-1 pathway have demonstrated remarkable treatment benefits in this disease, with a non-negligible fraction of patients potentially receiving long-term survival benefits. Herein, we briefly discuss the role of various medical disciplines in the management of advanced-stage NSCLC and review the most relevant biological therapies for this disease, with particular emphasis in genotype-directed therapies and immune checkpoint inhibitors.
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http://dx.doi.org/10.1183/13993003.01520-2016DOI Listing
March 2017

Osimertinib in EGFR-mutant NSCLC: how to select patients and when to treat.

Lancet Oncol 2016 12 14;17(12):1622-1623. Epub 2016 Oct 14.

Hospital Universitario Doce de Octubre & Instituto de Investigación i+12, 28041 Madrid, Spain; Unidad de Cáncer de Pulmón, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Universidad Complutense de Madrid, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(16)30506-XDOI Listing
December 2016

Current Challenges in Cancer Treatment.

Clin Ther 2016 Jul 2;38(7):1551-66. Epub 2016 May 2.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación I+12. Lung Cancer Clinical Research Unit CNIO, I+12, Madrid, Spain. Electronic address:

Purpose: In this review, we highlight the current concepts and discuss some of the current challenges and future prospects in cancer therapy. We frequently use the example of lung cancer.

Methods: We conducted a nonsystematic PubMed search, selecting the most comprehensive and relevant research articles, clinical trials, translational papers, and review articles on precision oncology and immuno-oncology. Papers were prioritized and selected based on their originality and potential clinical applicability.

Findings: Two major revolutions have changed cancer treatment paradigms in the past few years: targeting actionable alterations in oncogene-driven cancers and immuno-oncology. Important challenges are still ongoing in both fields of cancer therapy. On the one hand, druggable genomic alterations are diverse and represent only small subsets of patients in certain tumor types, which limits testing their clinical impact in biomarker-driven clinical trials. Next-generation sequencing technologies are increasingly being implemented for molecular prescreening in clinical research, but issues regarding clinical interpretation of large genomic data make their wide clinical use difficult. Further, dealing with tumor heterogeneity and acquired resistance is probably the main limitation for the success of precision oncology. On the other hand, long-term survival benefits with immune checkpoint inhibitors (anti-programmed death cell protein-1/programmed death cell ligand-1[PD-1/L1] and anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies) are restricted to a minority of patients, and no predictive markers are yet robustly validated that could help us recognize these subsets and optimize treatment delivery and selection. To achieve long-term survival benefits, drug combinations targeting several molecular alterations or cancer hallmarks might be needed. This will probably be one of the most challenging but promising precision cancer treatment strategies in the future.

Implications: Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, this approach to cancer treatment is still reductionist, and many challenges need to be met to improve treatment outcomes with our patients.
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http://dx.doi.org/10.1016/j.clinthera.2016.03.026DOI Listing
July 2016

Necitumumab for first-line treatment of advanced, squamous, non-small-cell lung cancer: a relevant step forward?

Transl Lung Cancer Res 2016 Feb;5(1):95-7

Medical Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain.

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http://dx.doi.org/10.3978/j.issn.2218-6751.2015.08.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758970PMC
February 2016

Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).

PLoS One 2015 16;10(3):e0121071. Epub 2015 Mar 16.

Medical Oncology Service/Vall d´Hebron Institute Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: The increasing incidence and poor outcome associated with MPM requires finding effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM.

Methods: 119 MPM patients (p) from two institutions between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N). Cases showing more than 1% of tumor cells expression of PD-L1 were considered positive.

Results: PD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012).

Conclusions: We have shown PD-L1 is expressed in 20% of patients, associated with no epithelioid histology and poor prognostic in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361537PMC
October 2015

The new IASLC/ATS/ERS lung adenocarcinoma classification from a clinical perspective: current concepts and future prospects.

J Thorac Dis 2014 Oct;6(Suppl 5):S526-36

1 Medical Oncology Department, 2 Pathology Department, Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain.

The new the International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) pathologic classification of lung cancer has markedly changed the pathologic diagnosis of lung adenocarcinoma. This classification deals with many aspects that directly affect clinical practice, and opens new gateways for future research. By means of a multidisciplinary approach, it differs significantly from the former 2004 the World Health Organization (WHO) classification, which was mainly written by pathologist. The present review, in line with the consensus article, is divided in two components: the diagnosis and classification of lung adenocarcinoma in resection specimens and the diagnosis of lung cancer in small biopsies and cytology. Resection specimens are currently classified according to the predominant histologic pattern after comprehensive subtyping in 5% increments. This approach has led to the addition of new pathologic subtypes [adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and micropapillary predominant adenocarcinoma)] and to the discontinuation of some heterogeneous entities included in the former 2004 WHO classification (mixed subtype adenocarcinoma and bronchioloalveolar carcinoma). Overall, these changes have resulted in a better stratification of lung adenocarcinoma tumors in more homogeneous morphologic, clinical and biological subgroups. Pathologic subtyping has demonstrated prognostic utility in resected stage I-III patients, and recent data support their predictive role for the benefit of adjuvant chemotherapy. Moreover, comprehensive pathologic subtyping may potentially affect TNM staging and surgical management or early-stage tumors. On the other hand, for the first time, the novel pathologic classification provides standardized terminology and diagnostic criteria of small biopsies and cytology. Criteria are proposed not only for adenocarcinoma but also for other histologies, but special emphasis was put on the distinction between adenocarcinoma and squamous-cell carcinoma due to its major clinical implications. This review outlines the main issues of the new lung adenocarcinoma classification from a clinical perspective. We describe the different pathologic subtypes in resection specimens, with their most relevant clinical implications. Further on, we address the new terminology and diagnostic criteria for lung adenocarcinomas in small specimens, oriented to their importance for the management and treatment of metastatic lung cancer patients. Finally, we discuss some unanswered questions and relevant issues for the near future.
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http://dx.doi.org/10.3978/j.issn.2072-1439.2014.01.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209392PMC
October 2014

Limited family structure and triple-negative breast cancer (TNBC) subtype as predictors of BRCA mutations in a genetic counseling cohort of early-onset sporadic breast cancers.

Breast Cancer Res Treat 2014 Nov 24;148(2):415-21. Epub 2014 Oct 24.

Genetic Counseling Unit, Department of Clinical Oncology, Hospital Clínico San Carlos, Madrid, Spain.

Early-onset diagnosis is an eligibility criterion for BRCA1 and BRCA2 (BRCA) testing in sporadic breast cancer patients. Limited family structure has been proposed as a predictor of BRCA mutation status in this group of patients. An overwhelming amount of data supports a strong association between BRCA1 mutations and triple-negative breast cancer (TNBC). Here, we analyze the feasibility of using limited family structure and TNBC as predictors of BRCA mutation status in early-onset breast cancer patients attending genetic counseling units. We have conducted the study in a cohort of sporadic early-onset (≤35 years) breast cancer patients (N = 341) previously selected for BRCA genetic testing in Academic Hereditary Cancer Clinics from Spain. A retrospective review of medical records available at the time of risk assessment allowed us classifying patients according to family structure and TNBC. In addition, BRCAPRO score was calculated for all patients. Association between categorical variables was investigated using the Fisher's exact test. Binary Logistic Regression Analysis was used for multivariate analysis. Limited family structure (OR 3.61, p = 0.013) and TNBC (OR 3.14, p = 0.013) were independent predictors of BRCA mutation status. Mutation prevalence in the subgroup of patients with at least one positive predictor was 14%, whereas it dropped to 3% in non-TNBCs with adequate family history (OR 5.31, 95% CI 1.38-23.89, p = 0.006). BRCAPRO correctly discerned between limited and adequate family structures. Limited family structure and TNBC are feasible predictors of BRCA mutation status in sporadic early-onset (≤35 years) breast cancer patients attending genetic counseling units. The low prevalence of mutations observed in non-TNBCs with adequate family structure suggests that this subgroup of patients might be excluded from genetic testing.
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http://dx.doi.org/10.1007/s10549-014-3167-4DOI Listing
November 2014

Sorafenib for non-selected patient population with advanced hepatocellular carcinoma: efficacy and safety data according to liver function.

Clin Transl Oncol 2013 Feb 9;15(2):146-53. Epub 2012 Aug 9.

Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), c/Martin Lagos s/n, 28040, Madrid, Spain.

Objective: Sorafenib is the standard treatment of patients with advanced hepatocellular carcinoma, regardless of the liver functional reserve. We present a single institutional series of Child-Pugh A and Child-Pugh B patients treated with sorafenib with the aim to establish the efficacy and safety of sorafenib in patients of daily clinical conditions and to compare these results between Child-Pugh A and Child-Pugh B patients.

Materials And Methods: A total of 51 patients were treated with sorafenib 400 mg/12 h until disease progression or unacceptable toxicity.

Results: The median progression-free survival and overall survival for the overall population were 3.5 and 8.2 months, respectively, with a 1-year survival rate of 27 %. Overall survival was significantly longer for patients Child-Pugh A compared with those with Child-Pugh B liver function (8.7 vs. 4.7 months, respectively). The most common adverse events were fatigue (62.7 %), diarrhea (58 %), hypertension (31.3 %), and hand-foot syndrome (31.3 %), and in most cases grade 1 or 2 according to the NCI-CTC 3.0. Grade 4 liver-related events occurred mainly in Child-Pugh B patients with decompensated cirrhosis at the time of sorafenib initiation (54.5 % of that group).

Discussion: The benefit of sorafenib in Child-Pugh B patients, if exist, may be limited by frequent liver-related events, especially in decompensated patients, and then, toxicity and impact in quality of life should be carefully monitored.
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http://dx.doi.org/10.1007/s12094-012-0902-3DOI Listing
February 2013

Severe perirenal hematoma in a patient with a single kidney treated with sunitinib for metastatic pancreatic neuroendocrine tumor.

J Cancer Res Ther 2012 Apr-Jun;8(2):303-5

Department of Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain.

A better understanding of the angiogenic process has markedly expanded the use of antiangiogenic therapy in many solid tumors. It is known that there is a close relationship between cancer disease, vascular homeostasis, angiogenesis and coagulation cascade. In this setting, antiangiogenic therapy could interfere and potentially increase the risk of bleeding or thromboembolic events. Sunitinib is an orally available small molecule multikinase inhibitor recently approved for the treatment of unresectable or metastatic, well-differenciated pancreatic neuroendocrine tumors with disease progression in adults. Here we present the first case of a severe perirenal hematoma in a patient treated with sunitinib for metastatic pancreatic neuroendocrine tumor.
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http://dx.doi.org/10.4103/0973-1482.98997DOI Listing
December 2012