Publications by authors named "Noelia Tarazona"

28 Publications

  • Page 1 of 1

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of in Colorectal Cancer.

Cancers (Basel) 2021 Mar 21;13(6). Epub 2021 Mar 21.

Institute of Health Research, INCLIVA, 46010 Valencia, Spain.

The gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is -dependent in , and ; the level of H3K27me3 changes in accordance. G9A also binds and in a -dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.
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http://dx.doi.org/10.3390/cancers13061433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004037PMC
March 2021

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.

Cancer Cell 2021 May 1;39(5):708-724.e11. Epub 2021 Apr 1.

IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, Milan 20089, Italy.

Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.
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http://dx.doi.org/10.1016/j.ccell.2021.03.004DOI Listing
May 2021

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas's poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.
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http://dx.doi.org/10.3390/cancers13050994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956845PMC
February 2021

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010 Valencia, Spain.

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers.
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http://dx.doi.org/10.3390/cancers12123611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761666PMC
December 2020

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

ESMO Open 2020 11;5(6):e000929

CIBERONC, Instituto de Salud Carlos III, Madrid, Comunidad de Madrid, Spain; Department of Medical Oncology, University of Valencia, Valencia, Spain. Electronic address:

Introduction: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting.

Methods: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive data about patient's characteristics, neoadjuvant treatments, toxicities, curative resections, postoperative complications, pathology reports and adjuvant treatment were collected. Overall survival (OS) and progression-free survival was calculated with Kaplan-Meier method and log-rank test.

Results: Between August 2011 and July 2019, 49 patients fulfilled the inclusion criteria, and all of them received neoadjuvant ChT. Fluorouracil+folinic acid, irinotecan and oxaliplatin was the most frequently used scheme (77%). The most prevalent grade 3 or 4 toxicities were neutropenia (26.5%), neurotoxicity (12.2%), diarrhoea (8.2%) and nausea (8.2%). 18 patients (36.7%) received ChRT thereafter. In total, 22 patients (44,9%) became potentially resectable and 19 of them had an R0 or R1 pancreatic resection. One was found to be unresectable at surgery and two refused surgery. A vascular resection was required in 7 (35%). No postoperative deaths were observed. Postoperative ChT was given to 12 (66.7%) of resected patients. Median OS of the whole cohort was 24,9 months (95% CI 14.1 to 35.7), with 30.6 months for resected and 13.1 months for non-resected patients, respectively (p<0.001).

Conclusion: A neoadjuvant approach in BRPC and LAUPC was well tolerated and allowed a curative resection in 38.8% of them with a potential improvement on OS.
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http://dx.doi.org/10.1136/esmoopen-2020-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684818PMC
November 2020

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress.

J Clin Med 2020 Sep 22;9(9). Epub 2020 Sep 22.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Blasco Ibañez 17, 46010 Valencia, Spain.

Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. In this review, we sought to describe the novel pathways implicated in GEA progression and the results of the molecular matched therapies.
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http://dx.doi.org/10.3390/jcm9093049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564841PMC
September 2020

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer.

ESMO Open 2020 09;5(5):e000847

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain. Electronic address:

Background: Colon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.

Methods: One hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was analysed by immunostaining. Plasma levels of cytokines potentially involved in disease progression were measured using ELISAs. A 96 custom gene panel for nCounter assay was used to classify CC into colorectal cancer assigner and CMS.

Results: Most patients were classified into CMS4 (37%) and CMS2 (28%), followed by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary tumour location, stage, vascular and perineural invasion together with high interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 +CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; p=0.001) were found to be independent prognostic factors for disease-free survival in the multivariable model.

Conclusions: ctDNA detection after surgery and lack of CDX2 expression identified patients at very high risk of recurrence in localised CC.
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http://dx.doi.org/10.1136/esmoopen-2020-000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513635PMC
September 2020

In the literature: August 2020.

ESMO Open 2020 08;5(4)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-000909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437707PMC
August 2020

Personalized Medicine: Recent Progress in Cancer Therapy.

Cancers (Basel) 2020 Apr 19;12(4). Epub 2020 Apr 19.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.
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http://dx.doi.org/10.3390/cancers12041009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226371PMC
April 2020

In the literature: April 2020.

ESMO Open 2020 Apr;5(2)

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

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http://dx.doi.org/10.1136/esmoopen-2020-000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204796PMC
April 2020

In the literature: October 2019.

ESMO Open 2019 13;4(6):e000613. Epub 2019 Nov 13.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

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http://dx.doi.org/10.1136/esmoopen-2019-000613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863657PMC
November 2019

ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer.

Sci Rep 2019 06 27;9(1):9339. Epub 2019 Jun 27.

Institute of Health Research, INCLIVA, Valencia, Spain.

Most of colorectal cancer CRC-related death is due to metastasis and the finding of markers for prognosis of invasiveness, constitutes an appealing challenge. Here, after analysing cDNA array containing 43 tumour and 5 normal mucosa samples, we report that the expression of the ZNF518B gene as a whole and that of its two major splicing isoforms are significantly increased in tumours. The canonical isoform was also up-regulated in a patients' cohort containing 70 tumour and 69 adjacent tissue samples. The effects of silencing ZNF518B on the phenotype of CRC cell lines were then studied. The gene does not affect cell proliferation, but plays a significant role in cell migration and invasiveness and induces changes in the epithelial-to-mesenchymal transition markers, suggesting that ZNF518B favours tumour cell dissemination. To study the regulation of the gene, transcription-related changes in nucleosomal organisation and epigenetic marks around the transcriptional start site were analysed. The positioning of a nucleosome over the transcription start site and the differential presence of the epigenetic marks H3K9ac, H3K27ac, H3K4me3 and H3K9me3 correlate with gene expression. Inhibition of histone deacetylases increases the transcription of ZNF518B, which may be a candidate for invasiveness prognosis in CRC and a target for epigenetic drugs.
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http://dx.doi.org/10.1038/s41598-019-45411-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597559PMC
June 2019

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications.

ESMO Open 2019 27;4(3):e000470. Epub 2019 May 27.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain.

Background: The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors.

Material And Methods: We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation.

Results: Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04).

Conclusions: The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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http://dx.doi.org/10.1136/esmoopen-2018-000470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555614PMC
May 2019

Analytical Validation of Multiplex Biomarker Assay to Stratify Colorectal Cancer into Molecular Subtypes.

Sci Rep 2019 05 21;9(1):7665. Epub 2019 May 21.

Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.

Previously, we classified colorectal cancers (CRCs) into five CRCAssigner (CRCA) subtypes with different prognoses and potential treatment responses, later consolidated into four consensus molecular subtypes (CMS). Here we demonstrate the analytical development and validation of a custom NanoString nCounter platform-based biomarker assay (NanoCRCA) to stratify CRCs into subtypes. To reduce costs, we switched from the standard nCounter protocol to a custom modified protocol. The assay included a reduced 38-gene panel that was selected using an in-house machine-learning pipeline. We applied NanoCRCA to 413 samples from 355 CRC patients. From the fresh frozen samples (n = 237), a subset had matched microarray/RNAseq profiles (n = 47) or formalin-fixed paraffin-embedded (FFPE) samples (n = 58). We also analyzed a further 118 FFPE samples. We compared the assay results with the CMS classifier, different platforms (microarrays/RNAseq) and gene-set classifiers (38 and the original 786 genes). The standard and modified protocols showed high correlation (> 0.88) for gene expression. Technical replicates were highly correlated (> 0.96). NanoCRCA classified fresh frozen and FFPE samples into all five CRCA subtypes with consistent classification of selected matched fresh frozen/FFPE samples. We demonstrate high and significant subtype concordance across protocols (100%), gene sets (95%), platforms (87%) and with CMS subtypes (75%) when evaluated across multiple datasets. Overall, our NanoCRCA assay with further validation may facilitate prospective validation of CRC subtypes in clinical trials and beyond.
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http://dx.doi.org/10.1038/s41598-019-43492-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529539PMC
May 2019

Improving tumour budding evaluation in colon cancer by extending the assessment area in colectomy specimens.

Histopathology 2019 Oct 7;75(4):517-525. Epub 2019 Aug 7.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain.

Aims: It is recommended that tumour budding in colon cancer be counted on haematoxylin and eosin-stained sections in a hotspot area of 0.785 mm with a ×20 microscope objective. However, tumour buds may be difficult to visualise on haematoxylin and eosin-stained sections, and counting in such a limited area may result in overestimation in cases with focal budding. The aim of this study was to assess the contributions of various factors to improving tumour budding risk stratification: increasing the number of fields counted, using cytokeratin immunostaining, and recording proliferation, the apoptotic index and the emperipoletic index in tumour buds.

Methods And Results: We created an exploratory series composed of 172 cases of colon cancer in all stages, and we analysed the survival probability in a second cohort of 158 stage I-II patients. According to our results, counting of budding in 10 fields was the only factor that was significantly correlated with disease-free survival probability in stage I-II patients [hazard ratio (HR) for high versus low grade of 7.64, 95% confidence interval (CI) 5.54-27.92, P = 0.01; HR for intermediate versus low grade of 3.02, 95% CI 1.54-26.72, P = 0.04). Emperipolesis was frequently observed in tumour buds, whereas the mitotic index and the apoptotic index were extremely low. Although cytokeratin immunostaining increased interobserver concordance, it did not improve the accuracy of tumour budding grading.

Conclusions: According to our results, counting in 10 fields significantly enhanced the budding grade risk stratification in colon cancer patients, and cytokeratin immunostaining could be reserved as a complementary technique for challenging cases with an inflammatory infiltrate and/or striking fibrosis.
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http://dx.doi.org/10.1111/his.13900DOI Listing
October 2019

NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in -Amplified Gastric Cancer.

Clin Cancer Res 2019 03 30;25(5):1639-1649. Epub 2018 Nov 30.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.

Purpose: Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in -amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed.

Experimental Design: We generated lapatinib- and trastuzumab-resistant clones deriving from two different -amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies were corroborated . The translational relevance of our findings was verified in a patient cohort.

Results: We found RPS6 activation and NRF2 to be related to anti-HER2 drug resistance. RPS6 or NRF2 inhibition with siRNA reduced viability and resistance to anti-HER2 drugs. In knockdown cells for RPS6, a decrease of NRF2 expression was demonstrated, suggesting a potential link between these two proteins. The use of a PI3K/TORC1/TORC2 inhibitor, tested and , inhibited pRPS6 and NRF2 expression and caused cell and tumor growth reduction, in anti-HER2-resistant models. In a cohort of -amplified patients treated with trastuzumab and chemotherapy, a high level of NRF2 at baseline corresponds with worse progression-free survival.

Conclusions: NRF2 through the PI3K/AKT/mTOR/RPS6 pathway could be a potential effector of resistance to anti-HER2 drugs in our models. RPS6 inhibition decreases NRF2 expression and restores sensitivity in -amplified gastric cancer and . High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2421DOI Listing
March 2019

Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression.

Mod Pathol 2019 02 11;32(2):306-313. Epub 2018 Sep 11.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CiberOnc, University of Valencia, Valencia, Spain.

At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-β) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center. We found significant ZEB overexpression and a reduction in miR200 in budding areas, a profile compatible with epithelial-to-mesenchymal transition. In multivariate analysis of the cases with localized disease, low miR200c expression in budding areas, but not at the tumor center, was an adverse tumor-specific survival factor (hazard ratio: 0.12; 95% confidence interval: 0.03-0.81; p = 0.02) independent of the clinical stage of the disease. PD-L1 was significantly overexpressed in the budding areas and its levels correlated with a mesenchymal transition profile. These results highlight the importance of including budding areas among the samples used for biomarker evaluation and provides relevant data on the influence of mesenchymal transition in the immune resistance mediated by PD-L1 overexpression.
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http://dx.doi.org/10.1038/s41379-018-0124-5DOI Listing
February 2019

The role of chemotherapy in localized and locally advanced rectal cancer: A systematic revision.

Cancer Treat Rev 2018 Feb 11;63:156-171. Epub 2018 Jan 11.

CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain. Electronic address:

Curative treatment of rectal cancer depends on an optimal surgical resection, with the addition of neoadjuvant radiotherapy (RT) with or without concomitant chemotherapy (ChT) in more advanced tumors. The role of adjuvant ChT is controversial and a more intensified neoadjuvant approach with the addition of ChT before or after RT, or even as single modality, is currently being explored in trials. A systematic review selecting randomised phase II and III trials on the role of ChT in localized rectal cancer was performed. Data show that neoadjuvant ChRT improves locoregional control in resected rectal cancer. Short-course RT (SCRT) could give similar outcomes to ChRT. The addition of oxaliplatin to neoadjuvant ChRT marginally increases the pathological complete remission rate without improving survival and increasing toxicity. A more intensified approach remains investigational as trials to date have not shown significant advantages. Adjuvant ChT trials after preoperative ChRT are contentious, although the addition of oxaliplatin in high risk patients may benefit outcomes. Despite a wide heterogeneity in the target population, different staging procedures and diverse treatment approaches among different trials, this systematic review confirms the role of ChT in combination with neoadjuvant long-course RT. Adjuvant ChT could be of value in selected patients with high-risk features, mainly if they do not respond to neoadjuvant RT. Further investigation is warranted on more intensified neoadjuvant regimens including ChT for MRI-defined high-risk patients.
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http://dx.doi.org/10.1016/j.ctrv.2018.01.001DOI Listing
February 2018

KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer.

Sci Rep 2018 01 23;8(1):1445. Epub 2018 Jan 23.

The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.
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http://dx.doi.org/10.1038/s41598-018-19212-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780472PMC
January 2018

Personalised Treatment in Gastric Cancer: Myth or Reality?

Curr Oncol Rep 2016 07;18(7):41

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

Despite recent diagnostic and therapeutic advances, the survival of patients with gastric cancer is still poor. The majority of patients are diagnosed with advanced disease and chemotherapy represents the only possible therapeutic approach. However, chemotherapy seems to have reached an efficacy plateau in this setting. Gastric cancer is a complex and heterogeneous disease because it emerges from multiple interactions of genetic, environmental and host factors. A better understanding of its molecular characteristics may lead to an improvement of outcomes. The recent molecular classification by The Cancer Genome Atlas project divides gastric cancer into four subtypes that could be taken into consideration in future clinical trials with targeted agents. So far trastuzumab, a monoclonal antibody addressing the HER2 receptor, is the only targeted agent approved in the first-line setting, but only in patients overexpressing HER2. Negative data have been obtained in first-line therapy when antiangiogenics, anti-EGFR or anti-MET monoclonal antibodies have been studied in randomised controlled trials. Ramucirumab, a monoclonal antibody binding to VEGFR2, is the only antiangiogenic agent currently recommended in patients progressing after first-line treatment. In this review, we discuss whether personalised therapy may have a role in gastric cancer.
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http://dx.doi.org/10.1007/s11912-016-0525-xDOI Listing
July 2016

High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.

Cancer Discov 2016 08 13;6(8):838-851. Epub 2016 May 13.

The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

Unlabelled: FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.

Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
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http://dx.doi.org/10.1158/2159-8290.CD-15-1246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338732PMC
August 2016

Efficacy and toxicity of salvage weekly paclitaxel chemotherapy in non-Asian patients with advanced oesophagogastric adenocarcinoma.

Ther Adv Med Oncol 2016 Mar;8(2):104-12

Department of Gastrointestinal Oncology, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK.

Objectives: Survival for oesophagogastric adenocarcinoma (OGA) patients varies globally and clinical trial results are seldom replicated in clinical practice. We sought to examine the efficacy and toxicity of salvage paclitaxel chemotherapy for patients with advanced OGA at our institution.

Methods: Advanced OGA patients treated with paclitaxel between June 2011 and February 2014 were identified from the electronic record at the Royal Marsden Hospital (RMH), London. Chart review was performed to obtain demographics, performance status (PS), laboratory parameters, radiological response and dates of progression, death and last follow up. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis examined the interaction between clinical and laboratory parameters and survival.

Results: Fifty-seven patients were identified; OS and PFS were 5.8 and 2.6 months respectively. From first-line chemotherapy, median OS was 14.3 months. Two-year and three-year survival rates from diagnosis were 26% and 13%. More than or equivalent to Grade 3 neutropenia occurred in 13% of patients. In multivariate analysis, PS more than or equal to 2, alkaline phosphatase (ALP) more than or equal to100 U/L, and previous rechallenge with platinum were independent prognostic factors for OS.

Conclusions: OGA cancer patients treated at RMH with salvage paclitaxel had an OS equivalent to patients in clinical trials with more (33%) PS = 2 patients treated and less haematological toxicity than Asian patients. Eastern Cooperative Oncology Group (ECOG) PS more than or equal to 2, ALP more than or equal to 100 U/L, and prior platinum rechallenge were associated with poor survival. However, the proportion of patients surviving more than or equal to two years from diagnosis demonstrates a clinically relevant improvement from historical controls.
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http://dx.doi.org/10.1177/1758834015621669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753352PMC
March 2016

Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer.

Expert Opin Drug Metab Toxicol 2016 10;12(4):449-56. Epub 2016 Mar 10.

a Department of Medical Oncology , Biomedical Research Institute INCLIVA, University of Valencia , Valencia , Spain.

Introduction: Colorectal cancer is the third most common cancer worldwide. The prognosis of colorectal cancer patients still remains dismal and half of them will develop metastatic disease. Angiogenesis plays an essential role in colorectal tumorigenesis, and the VEGF pathway is one of the targets that has been validated up to now. The use of antiangiogenics along with chemotherapy has become an accepted standard for colorectal cancer.

Areas Covered: This review discusses the efficacy and safety profile of ramucirumab, a fully human immunoglobulin G1 monoclonal antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2), for the treatment of second-line metastatic colorectal cancer upon progression to first-line chemotherapy including anti-angiogenics.

Expert Opinion: Ramucirumab in combination with chemotherapy represents a valid option in second-line treatment of advanced colorectal cancer patients, who progressed on previous bevacizumab-based combinations. This agent demonstrates a similar benefit in terms of overall survival to other angiogenesis inhibitors (bevacizumab and ziv-aflibercept) used in this setting.
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http://dx.doi.org/10.1517/17425255.2016.1156084DOI Listing
January 2017

Exclusion of Gastrointestinal Cancer Patients With Prior Cancer From Clinical Trials: Is This Justified?

Clin Colorectal Cancer 2016 06 27;15(2):e53-9. Epub 2015 Nov 27.

Department of Gastrointestinal Oncology, Royal Marsden Hospital, Sutton, UK. Electronic address:

Background: Strict eligibility criteria are necessary to maintain patient safety and scientific validity in clinical trials. However, this may lead to impaired generalizability of results. As survival in gastrointestinal (GI) cancer relates mainly to the GI malignancy, we hypothesized that previous cancers do not impact on survival and are not a rational exclusion criterion.

Materials And Methods: Patients treated with chemotherapy for a GI cancer in 2006 were identified from the electronic patient record at the Royal Marsden Hospital, London. Chart review was performed and patient age, gender, GI cancer stage, prior cancer stage, clinical trial availability/eligibility, and dates of cancer recurrence, death, and last follow-up were collated.

Results: A total of 697 patients were identified. Fifty-four patients (8%) had a prior cancer; commonly breast (26%), prostate (17%), or colon (9%); most were stage I (42%) or II (37%). Two hundred ninety-seven (65%) patients had GI cancer recurrence, 7 (12%) patients had relapse of a prior cancer. Five hundred four (72%) patients have died, 170 (24%) are alive with no cancer, and 23 (3%) patients are alive with cancer. A total of 476 (94%) died of GI cancer, 2 (0.3%) of their prior cancer. Of all patients, 489 (70%) had an available trial, but 30% of patients with a prior cancer were ineligible for this reason. Overall and GI-cancer-specific survival were comparable for patients with/without a prior cancer.

Conclusions: Survival for patients with a GI cancer requiring chemotherapy relates to the GI cancer and rarely a prior cancer. These patients should not be excluded from clinical trial participation.
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http://dx.doi.org/10.1016/j.clcc.2015.11.003DOI Listing
June 2016

Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.

Sci Transl Med 2015 Nov;7(313):313ra182

The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with advanced breast cancer. ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies and was accurately assessed in samples shipped at room temperature in preservative tubes. ESR1 mutations were found exclusively in estrogen receptor-positive breast cancer patients previously exposed to AI. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy [hazard ratio, 3.1; 95% confidence interval (CI), 1.9 to 23.1; P = 0.0041]. ESR1 mutation prevalence differed markedly between patients who were first exposed to AI during the adjuvant and metastatic settings [5.8% (3 of 52) versus 36.4% (16 of 44), respectively; P = 0.0002]. In an independent cohort, ESR1 mutations were identified in 0% (0 of 32; 95% CI, 0 to 10.9) tumor biopsies taken after progression on adjuvant AI. In a patient with serial sampling, ESR1 mutation was selected during metastatic AI therapy to become the dominant clone in the cancer. ESR1 mutations can be robustly identified with ctDNA analysis and predict for resistance to subsequent AI therapy. ESR1 mutations are rarely acquired during adjuvant AI but are commonly selected by therapy for metastatic disease, providing evidence that mechanisms of resistance to targeted therapy may be substantially different between the treatment of micrometastatic and overt metastatic cancer.
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http://dx.doi.org/10.1126/scitranslmed.aac7551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998737PMC
November 2015

Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer.

Oncotarget 2015 Sep;6(29):26935-45

Hematology and Medical Oncology Unit, Biomedical Research Institute INCLIVA, University of Valencia, 46010, Valencia, Spain.

Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.
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http://dx.doi.org/10.18632/oncotarget.4775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694964PMC
September 2015

Primary paraesophageal Ewing's sarcoma: an uncommon case report and literature review.

Onco Targets Ther 2015 14;8:1053-9. Epub 2015 May 14.

Department of Hematology and Medical Oncology, Biomedical Research Institute, INCLIVA, University of Valencia, Valencia, Spain.

Ewing's sarcoma is a rare and highly aggressive cancer most frequently arising in people under 20 years of age. We report an uncommon case of primary paraesophageal Ewing's sarcoma in a 25-year-old male harboring the infrequent EWSR1/ERG fusion transcript with multiple splice variants coexisting in the same tumor. The patient was totally refractory to chemotherapy and died 17 months after diagnosis. We underscore the need for better understanding of the molecular pathogenesis of the disease and improved systemic therapy options.
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http://dx.doi.org/10.2147/OTT.S80879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437600PMC
May 2015

Ramucirumab: targeting angiogenesis in the treatment of gastric cancer.

Immunotherapy 2014 ;6(11):1177-86

Department of Gastrointestinal Oncology, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.

Gastroesophageal cancer is responsible for over 1 million deaths annually worldwide; for patients with advanced disease treatment options are limited. Angiogenesis is an attractive therapeutic target that has been successfully exploited in other cancers. Ramucirumab, a fully humanized monoclonal antibody targeting VEGFR-2 has demonstrated efficacy as a single agent and in combination with paclitaxel in two large randomized trials (REGARD and RAINBOW) for the treatment of advanced previously treated gastroesophageal cancer. In combination with paclitaxel chemotherapy ramucirumab treated patients demonstrated increased rates of neutropenia, and ramucirumab is also associated with hypertension consistent with other antiangiogenic agents. Ramucirumab has been US FDA approved for patients with advanced gastroesophageal cancer who have progressed during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy.
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http://dx.doi.org/10.2217/imt.14.85DOI Listing
July 2015
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