ORCID Profile
0000-0001-7623-1583
Current Organisations
Ludwig-Maximilians-Universität München
,
Boston University
,
The Graduate Center, CUNY
,
Western Sydney University
,
Università degli Studi di Padova
,
Freie Universität Berlin
,
Vall d'Hebron University Hospital/ Vall d'Hebron Institute of Oncology
,
International Breast Cancer Center, IBCC
,
IOB- Institute of Oncology Baselga, Quiron
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Publications
Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
DOI: 10.1038/NCOMMS9839
Abstract: Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.
The AURORA pilot study for molecular screening of patients with advanced breast cancer–a study of the breast international group
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/S41523-017-0026-6
Abstract: Several studies have demonstrated the feasibility of molecular screening of tumour s les for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data.
Data from Lucitanib for the Treatment of HR<sup>+</sup>/HER2<sup>−</sup> Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6528728.V1
Abstract: AbstractPurpose: The i FGFR1 /i gene is lified in 14% of patients with HR b sup + /sup /b /HER2 b sup − /sup /b breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed. Patients and Methods: Patients with HR b sup + /sup /b /HER2 b sup − /sup /b metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) i FGFR1 /i lified, (ii) i FGFR1 /i non lified, 11q13 lified, and (iii) i FGFR1 /i and 11q13 non lified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. i FGFR1 /i copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. Results: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high i FGFR1 /i lification (≥4 CNV) than those without high lification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. Conclusions: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR b sup + /sup /b /HER2 b sup − /sup /b MBC. Although based on small s le sizes, exploratory biomarker analyses suggested that patients with high i FGFR1 /i lification or expression might derive greater benefit. /
Critique and Speculation: Reconsidering Hegel's Early Dialectical Logic
Publisher: Cambridge University Press (CUP)
Date: 19-12-2023
DOI: 10.1017/HGL.2022.41
Abstract: The aim of this article is to clarify the critical role of Hegel's early logic, through an assessment of the dialectical process of sublation [ Aufhebung ] of the determinations of finite thinking at stake within its exposition. I want to show that the dialectical-critical work of logic has a speculative meaning for Hegel, thereby displaying the inward correspondence between critical and speculative aspects of philosophical activity. By pointing out the evidence from fragmentary texts on logic relating to Hegel's teaching activity in 1801–1802, I will first put into question the idea of an introductory role of logic. In so doing I challenge a widespread reading which argues for the presence of a sharp separation between critical logic and speculative metaphysics. I will then focus on the texts on logic in the 1804–1805 Reinschrift , reading them as the worksite wherein the dawning form of a full-fledged dialectical logic is first prepared and elaborated. More generally, if this paves the way for establishing a continuity between Hegel's early and mature logic and his concept of dialectic, it is also paramount for understanding how the activity of systematic philosophy in the mature version of the system essentially constitutes an ongoing work on the forms of the finite.
Data from Lucitanib for the Treatment of HR<sup>+</sup>/HER2<sup>−</sup> Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6528728
Abstract: AbstractPurpose: The i FGFR1 /i gene is lified in 14% of patients with HR b sup + /sup /b /HER2 b sup − /sup /b breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed. Patients and Methods: Patients with HR b sup + /sup /b /HER2 b sup − /sup /b metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) i FGFR1 /i lified, (ii) i FGFR1 /i non lified, 11q13 lified, and (iii) i FGFR1 /i and 11q13 non lified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. i FGFR1 /i copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. Results: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high i FGFR1 /i lification (≥4 CNV) than those without high lification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. Conclusions: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR b sup + /sup /b /HER2 b sup − /sup /b MBC. Although based on small s le sizes, exploratory biomarker analyses suggested that patients with high i FGFR1 /i lification or expression might derive greater benefit. /
Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: The role of massively parallel sequencing
Publisher: Wiley
Date: 31-10-2013
The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
DOI: 10.1038/S41523-021-00282-0
Abstract: The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data ( N = 88 s les) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression ( N = 96 s les) and stromal TILs ( N = 105 s les). Tumour mutation burden varied across patients at baseline but not across the s ling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated ( R 2 = 0.94, p = .001) neoantigen load was weakly correlated with stromal TILs ( R 2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders . VEGF was downregulated over time in the good responder group and FABP5 , an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred ( p 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
Research needs in breast cancer
Publisher: Elsevier BV
Date: 02-2017
Abstract: New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes (ii) explore optimal adjuvant treatment durations (iii) develop better tools and strategies to identify patients with genetic predisposition (iv) improve care in young patients with breast cancer (v) develop tools to speed up drug development in biomarker-defined populations (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies (vii) evaluate the efficacy of local-regional treatments for metastatic disease (viii) better define the optimal sequence of treatments in the metastatic setting (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity) (x) better understand the biology and identify new targets in triple-negative breast cancer (xi) better understand immune surveillance in breast cancer and further develop immunotherapies and (xii) increase survivorship research efforts including supportive care and quality of life.
Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2 + breast cancer patients
Publisher: Proceedings of the National Academy of Sciences
Date: 14-02-2011
Abstract: Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 lified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 lified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal lification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2 + patients treated with trastuzumab-based therapy, we found that cyclin E lification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E- lified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E co lification/overexpression.
Table S1, Table S2; Figure S1, Figure S2, Figure S3, Figure S4, Figure S5 from Lucitanib for the Treatment of HR<sup>+</sup>/HER2<sup>−</sup> Metastatic Breast Cancer: Results
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474223.V1
Abstract: Supplementary Table S1. Treatment dose, duration, interruption and reduction. Supplementary Table S2A. Performance of the FGF23 ELISA, Kainos Laboratories Inc., cat# CY4000. Supplementary Table S2B. Concentration range of FGF23 in serum and plasma s les. Supplementary Table S2C. ddPCR assays used for determination of FGFR1 CNV. Supplementary Figure S1. A) FINESSE study design. B) Supplementary Figure S1B. FINESSE CONSORT diagram. Supplementary Figure S2. FISH screening results for FGFR1, CCND1/11q and FGF3,4,19. All s les were screened for both FGFR1 and CCND1/11q. Only s les positive for CCND1/11q lification were assessed for FGF3,4,19 lification. Of these, 1 patient was not assessed for FGF3,4,19 at the request of the site. 3 patients assessed as FGF3,4,19 lified by additional evalution criteria to those described in the Methods section, with % of tumour cells showing {greater than or equal to}5 gene signals/nucleus. Supplementary Figure S3. Progression-free survival by A) FGFR1 lification status by FISH and B) FGFR1 expression by IHC. Supplementary Figure S4. Expression of endothelial FGF2 and Ki67 presented by trial cohort. Supplementary Figure S5. Progression free survival by A) endothelial FGF2 and B) endothelial Ki67 expression.
Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2020
DOI: 10.1158/1078-0432.CCR-19-1164
Abstract: The FGFR1 gene is lified in 14% of patients with HR+/HER2− breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed. Patients with HR+/HER2− metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 lified, (ii) FGFR1 non lified, 11q13 lified, and (iii) FGFR1 and 11q13 non lified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 lification (≥4 CNV) than those without high lification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR+/HER2− MBC. Although based on small s le sizes, exploratory biomarker analyses suggested that patients with high FGFR1 lification or expression might derive greater benefit.
Immune analysis of lymph nodes in relation to the presence or absence of tumor infiltrating lymphocytes in triple-negative breast cancer
Publisher: Elsevier BV
Date: 05-2021
Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2023
DOI: 10.1200/PO.22.00317
Abstract: In the two-cohort phase II KEYNOTE-086 study (ClinicalTrials.gov identifier: NCT02447003 ), first-line and second-line or later pembrolizumab monotherapy demonstrated antitumor activity in metastatic triple-negative breast cancer (mTNBC N = 254). This exploratory analysis evaluates the association between prespecified molecular biomarkers and clinical outcomes. Cohort A enrolled patients with disease progression after one or more systemic therapies for metastatic disease irrespective of PD-L1 status Cohort B enrolled patients with previously untreated PD-L1–positive (combined positive score [CPS] ≥ 1) metastatic disease. The association between the following biomarkers as continuous variables and clinical outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) was evaluated: PD-L1 CPS (immunohistochemistry), cluster of differentiation 8 (CD8 immunohistochemistry), stromal tumor-infiltrating lymphocyte (sTIL hematoxylin and eosin staining), tumor mutational burden (TMB whole-exome sequencing [WES]), homologous recombination deficiency-loss of heterozygosity, mutational signature 3 (WES), mutational signature 2 (apolipoprotein B mRNA editing catalytic polypeptide–like WES), T-cell–inflamed gene expression profile (Tcell inf GEP RNA sequencing), and 10 non-Tcell inf GEP signatures (RNA sequencing) Wald test P values were calculated, and significance was prespecified at α = 0.05. In the combined cohorts (A and B), PD-L1 ( P = .040), CD8 ( P .001), sTILs ( P = .012), TMB ( P = .007), and Tcell inf GEP ( P = .011) were significantly associated with ORR CD8 ( P .001), TMB ( P = .034), Signature 3 ( P = .009), and Tcell inf GEP ( P = .002) with PFS and CD8 ( P .001), sTILs ( P = .004), TMB ( P = .025), and Tcell inf GEP ( P = .001) with OS. None of the non-Tcell inf GEP signatures were associated with outcomes of pembrolizumab after adjusting for the Tcell inf GEP. In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and Tcell inf GEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy.
Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement
Publisher: Elsevier BV
Date: 12-2012
Abstract: The 2012 IMPAKT task force investigated the medical usefulness of current methods for the classification of breast cancer into the 'intrinsic' molecular subtypes (luminal A, luminal B, basal-like and HER2). A panel of breast cancer and/or gene expression profiling experts evaluated the analytical validity, clinical validity and clinical utility of two approaches for molecular subtyping of breast cancer: the prediction analysis of microarray (PAM)50 assay and an immuno-histochemical (IHC) surrogate panel including oestrogen receptor (ER), HER2 and Ki67. The panel found the currently available evidence on the analytical validity and clinical utility of Ki67 based on a 14% cut-off and PAM50 to be inadequate. The majority of the working group members found the available evidence on the analytical validity, clinical validity and clinical utility of ER/HER2 to be convincing. The panel concluded that breast cancer classification into molecular subtypes based on the IHC assessment of ER, HER2 and Ki67 with a 14% cut-off and on the PAM50 test does not provide sufficiently robust information to modify systemic treatment decisions, and recommended the use IHC for ER and HER2 for the identification of clinically relevant subtypes of breast cancers. Methods for breast cancer classification into molecular subtypes should, however, be incorporated into clinical trial design.
Table S1, Table S2; Figure S1, Figure S2, Figure S3, Figure S4, Figure S5 from Lucitanib for the Treatment of HR<sup>+</sup>/HER2<sup>−</sup> Metastatic Breast Cancer: Results
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474223
Abstract: Supplementary Table S1. Treatment dose, duration, interruption and reduction. Supplementary Table S2A. Performance of the FGF23 ELISA, Kainos Laboratories Inc., cat# CY4000. Supplementary Table S2B. Concentration range of FGF23 in serum and plasma s les. Supplementary Table S2C. ddPCR assays used for determination of FGFR1 CNV. Supplementary Figure S1. A) FINESSE study design. B) Supplementary Figure S1B. FINESSE CONSORT diagram. Supplementary Figure S2. FISH screening results for FGFR1, CCND1/11q and FGF3,4,19. All s les were screened for both FGFR1 and CCND1/11q. Only s les positive for CCND1/11q lification were assessed for FGF3,4,19 lification. Of these, 1 patient was not assessed for FGF3,4,19 at the request of the site. 3 patients assessed as FGF3,4,19 lified by additional evalution criteria to those described in the Methods section, with % of tumour cells showing {greater than or equal to}5 gene signals/nucleus. Supplementary Figure S3. Progression-free survival by A) FGFR1 lification status by FISH and B) FGFR1 expression by IHC. Supplementary Figure S4. Expression of endothelial FGF2 and Ki67 presented by trial cohort. Supplementary Figure S5. Progression free survival by A) endothelial FGF2 and B) endothelial Ki67 expression.
Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle
Publisher: Elsevier BV
Date: 09-2014
Related Organisations
Vall D'Hebron University Hospital/ Vall D'Hebron Institute Of Oncology
Location: Spain
Related Funding Activities
No related grants have been discovered for Javier Cortes.