Publications by authors named "J Cortes"

2,390 Publications

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Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy: ER activity in pre-menopausal HR+ breast cancer during CT.

EBioMedicine 2021 Jun 20;69:103451. Epub 2021 Jun 20.

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clinic of Barcelona, Spain; SOLTI cooperative group, Barcelona, Spain; Institute of Oncology (IOB)-Hospital Quirónsalud, Barcelona, Spain; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA; Department of Medicine, University of Barcelona, Barcelona, Spain. Electronic address:

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation.

Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels.

Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy.

Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods.

Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).
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http://dx.doi.org/10.1016/j.ebiom.2021.103451DOI Listing
June 2021

Review of New-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

Curr Oncol Rep 2021 Jun 14;23(8):91. Epub 2021 Jun 14.

Georgia Cancer Center, Augusta University, 1410 Laney Walker Rd., CN2222, Augusta, GA, 30912, USA.

Purpose Of Review: In this review, we analyzed the available data from clinical trials with new tyrosine kinase inhibitors (TKIs) under development and how to consider chronic myeloid leukemia (CML) patients who had either resistance or intolerance to current TKIs for treatment with such agents.

Recent Findings: Nearly 50% of CML patients treated with TKIs frontline have required a change of therapy by 10 years. Second-line therapy is effective (by achievement of complete cytogenetic response) in only approximately 50% of patients, and available third-generation TKI has been marred by concerns of arterio-occlusive events. These facts highlight the need for additional treatment options. New TKIs have shown promising efficacy and tolerance in CML patients with resistance or intolerance to multiple available TKIs. Additional studies will determine their role in the management of CML.
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http://dx.doi.org/10.1007/s11912-021-01087-xDOI Listing
June 2021

Biomarker Analyses in the Phase 3 ASCENT Study of Sacituzumab Govitecan Versus Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer.

Ann Oncol 2021 Jun 8. Epub 2021 Jun 8.

Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address:

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-Trop-2 antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy of physician's choice (TPC) in previously-treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.

Patients And Methods: Patients with mTNBC refractory to or progressing after ≥2 prior chemotherapies, with ≥1 in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (either capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.

Results: Of 468 evaluable patients, 290 had Trop-2 expression data (64% [n=151 SG] versus 60% [n=139 TPC] and 292 had known BRCA1/2 mutation status (63% [n=149 SG] versus 61% [n=143 TPC]). Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38% and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.

Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.
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http://dx.doi.org/10.1016/j.annonc.2021.06.002DOI Listing
June 2021

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers.

NPJ Breast Cancer 2021 Jun 7;7(1):73. Epub 2021 Jun 7.

Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK.

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 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling 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 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R = 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.
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http://dx.doi.org/10.1038/s41523-021-00282-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185105PMC
June 2021

83JAK-STAT inhibition mediates romidepsin and mechlorethamine synergism in Cutaneous T-cell Lymphoma.

J Invest Dermatol 2021 Jun 2. Epub 2021 Jun 2.

Institute for Cancer Genetics, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. Electronic address:

Sézary Syndrome (SS) is an aggressive and disseminated form of Cutaneous T-cell lymphoma (CTCL) associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin, has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. Here, we show synergistic anti-lymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in CTCL cell lines and primary samples with strong antitumor effects in an in vivo model of SS. Mechanistically, gene expression profiling points to abrogation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling as important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary SS samples, but not in romidepsin-resistant tumors. Moreover, and in further support of JAK/STAT signaling as a modulator of romidepsin activity in CTCL, treatment with romidepsin in combination with JAK inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of CTCL and uncover a previously unrecognized role for JAK-STAT signaling in the response to romidepsin and romidepsin-based combination therapies in SS.
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http://dx.doi.org/10.1016/j.jid.2021.04.023DOI Listing
June 2021