Publications by authors named "Alfredo Carrato"

197 Publications

Correction: Earl et al. Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals KRAS Negativity and a Longer Overall Survival. 2021, , 1612.

Cancers (Basel) 2021 Jul 22;13(15). Epub 2021 Jul 22.

Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain.

The authors wish to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/cancers13153687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345141PMC
July 2021

Cancer-associated fibroblast-derived gene signatures determine prognosis in colon cancer patients.

Mol Cancer 2021 04 29;20(1):73. Epub 2021 Apr 29.

Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), Salamanca, Spain.

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http://dx.doi.org/10.1186/s12943-021-01367-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082938PMC
April 2021

Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study.

Cancers (Basel) 2021 Apr 4;13(7). Epub 2021 Apr 4.

Molecular Epidemiology and Predictive Tumor Markers Group, Alcalá University, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain.

First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.
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http://dx.doi.org/10.3390/cancers13071710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038427PMC
April 2021

Somatic Mutation Profiling in the Liquid Biopsy and Clinical Analysis of Hereditary and Familial Pancreatic Cancer Cases Reveals Negativity and a Longer Overall Survival.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain.

Pancreatic ductal adenocarcinoma (PDAC) presents many challenges in the clinic and there are many areas for improvement in diagnostics and patient management. The five-year survival rate is around 7.2% as the majority of patients present with advanced disease at diagnosis that is treatment resistant. Approximately 10-15% of PDAC cases have a hereditary basis or Familial Pancreatic Cancer (FPC). Here we demonstrate the use of circulating free DNA (cfDNA) in plasma as a prognostic biomarker in PDAC. The levels of cfDNA correlated with disease status, disease stage, and overall survival. Furthermore, we show for the first time via BEAMing that the majority of hereditary or familial PDAC cases (around 84%) are negative for a somatic mutation. In addition, mutation negative cases harbor somatic mutations in potentially druggable genes such as and that could be exploited in the clinic. Finally, familial or hereditary cases have a longer overall survival compared to sporadic cases (10.2 vs. 21.7 months, respectively). Currently, all patients are treated the same in the clinic with cytotoxic agents, although here we demonstrate that there are different subtypes of tumors at the genetic level that could pave the way to personalized treatment.
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http://dx.doi.org/10.3390/cancers13071612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038004PMC
March 2021

Chart review of diagnostic methods, baseline characteristics and symptoms for European patients with pancreatic cancer.

Future Oncol 2021 May 5;17(15):1843-1854. Epub 2021 Mar 5.

Vall d'Hebron University Hospital (HUVH) & Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

To survey European physicians managing patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and understand differences in baseline characteristics, diagnostic methods, symptoms and co-morbidities. Patient record inclusion criteria were: ≥18 years old, metastatic PDAC diagnosis and completion of first-line treatment between July 2014 and January 2016. Records were grouped by patient age, gender and primary tumor location. Records (n = 2565) were collected from nine countries. Baseline characteristics varied between subgroups. Computed tomography was the most frequently used diagnostic technique. Symptoms at diagnosis included abdominal and/or mid-back pain (72% of patients) and weight loss (61.5%). Co-morbidities varied with patient age. Greater awareness of symptoms, diagnostic methods and co-morbidities present at PDAC diagnosis may support better patient management decisions.
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http://dx.doi.org/10.2217/fon-2020-0749DOI Listing
May 2021

Implementation of the Quality Oncology Practice Initiative Program in Spain: First Results and Implications.

JCO Oncol Pract 2021 Aug 23;17(8):e1162-e1169. Epub 2021 Feb 23.

Fundación ECO (Excelencia y Calidad en Oncología), Madrid, Spain.

Purpose: Measuring and tracking quality of care is highly relevant in today's health care. The Quality Oncology Practice Initiative (QOPI) program is a referral for evaluating oncology practices worldwide. Excellence and Quality in Oncology Foundation, a collaboration of oncology experts from major Spanish hospitals involved in cancer treatment, reached an agreement with QOPI to include Spanish hospitals in this program.

Methods: We analyzed the results of the QOPI Core module measures from 19 Spanish hospitals over nine rounds (from fall 2015 to fall 2019).

Results: Of the 19 hospitals, 15 completed more than one round; none participated in all nine (two hospitals participated in eight rounds). The highest scores were for pathology report confirming malignancy, documenting a plan of care for moderate or severe pain and chemotherapy dose, and chemotherapy administered to patients with metastatic solid tumor with performance status undocumented. Measures regarding a summary of chemotherapy treatment, tobacco use cessation counseling, and assessment of patient emotional well-being were among the lowest scored measures. Six of the 15 practices that participated repeatedly achieved a better score in their last round compared with their first. Overall, scores of Spanish hospitals improved from 67.79% in fall 2015 to 68.91% in fall 2019.

Conclusion: To our knowledge, this is the first study to evaluate QOPI scores in Spain. There was high variability in scores, with quality of care improving with repeated participation in some hospitals, but worsening in others. Excellence and Quality in Oncology Foundation will support practices to increase their participation to improve oncology care and implement strategies that address the areas for improvement.
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http://dx.doi.org/10.1200/OP.20.00683DOI Listing
August 2021

First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis.

Drugs Aging 2021 Mar 22;38(3):219-231. Epub 2021 Feb 22.

IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain.

Background: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited.

Objective: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy.

Methods: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety.

Results: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%).

Conclusions: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.
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http://dx.doi.org/10.1007/s40266-021-00834-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914239PMC
March 2021

Onset of ulcerative colitis and complete response during the treatment of a metastatic colon cancer: case report and literature review.

Anticancer Drugs 2021 08;32(7):763-766

Medical Oncology Department, Ramón y Cajal Hospital, IRYCIS, CIBERONC.

Colorectal cancer is a common cancer worldwide. Several risk factors have been described, such as age, lifestyle and family history. Inflammatory bowel diseases (IBD) are a well-recognized risk factor for the development of colorectal cancer. However, the onset of an IBD de novo in the context of the treatment of a colorectal neoplasia has not been reported before, except in the context of the treatment with immunocheckpoint inhibitors. Fifty-nine-years old man diagnosed with a metastatic colorectal cancer who received conventional treatment with chemotherapy and an antiangiogenic inhibitor. The patient had a complete response with the therapy after few cycles. Nevertheless, during the treatment, the patient presented with rectal bleeding, and was diagnosed with ulcerative colitis. Although the treatment was discontinued, tumoral complete remission is maintained. The relevance of this case lies in the concurrence of the onset of an autoimmune disease and a complete response of the malignancy. The concurrence of these events has been described previously only with immunotherapy. There are not cases reported involving chemotherapy and antiangiogenic drugs. Other causes of colitis were ruled out due to the unusual presentation of the case.
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http://dx.doi.org/10.1097/CAD.0000000000000922DOI Listing
August 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Novel Tyrosine Kinase Targets in Urothelial Carcinoma.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain.

Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.
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http://dx.doi.org/10.3390/ijms22020747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828553PMC
January 2021

Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma.

Int J Cancer 2021 04 15;148(8):2048-2058. Epub 2021 Jan 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.
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http://dx.doi.org/10.1002/ijc.33464DOI Listing
April 2021

Tyrosine Kinase Receptors in Oncology.

Int J Mol Sci 2020 Nov 12;21(22). Epub 2020 Nov 12.

Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, Alcalá University, University Hospital Ramon y Cajal, 28034 Madrid, Spain.

Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
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http://dx.doi.org/10.3390/ijms21228529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696731PMC
November 2020

Bratislava Statement: consensus recommendations for improving pancreatic cancer care.

ESMO Open 2020 11;5(6):e001051

Catalonian Cancer Strategy, Department of Health, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain.

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required.
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http://dx.doi.org/10.1136/esmoopen-2020-001051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668355PMC
November 2020

A European survey on the insights of patients living with metastatic colorectal cancer: the patient journey before, during and after diagnosis - an Eastern European perspective.

ESMO Open 2020 09;5(5):e000850

Dom Zdravlja Vozdovac, Belgrade, Serbia.

Background: Despite being highly preventable and treatable if diagnosed early, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Europe. Limited information is available from the patient perspective on the persisting unmet needs of the journey of the patient with CRC.

Objective: To capture European metastatic CRC (mCRC) patients' insights during the patient journey (prediagnosis; diagnosis; postdiagnosis) through a patient survey.

Methods: In total, 883 patients from 15 European countries participated. Participants were divided into four groups from Hungary, Poland, Serbia and 'other European countries' (n=103, 163, 170 and 447 patients, respectively).

Results: General awareness of CRC and its symptoms prediagnosis varied among groups, with patients from Poland recording the lowest levels. Screening practices and attitudes also varied; while more patients from Serbia had been invited to CRC screening (~15%) compared with the other groups, the ones not invited claimed mostly (~20%) that would not have attended if they had been invited. Whereas most patients were diagnosed within a month after the first consultation/positive screening, the percentages varied substantially being lowest among patients in Poland (~30%) and Serbia (~25%). Although CRC-related information provision varied, with most informed patients from Hungary (~90%) and least from Serbia (~50%), all groups requested an easier-to-understand language by the healthcare team. Approximately 50% of patients from Eastern Europe had to wait longer than a month to receive treatment, in contrast to ~30% from other European countries. All groups emphasised the unmet need for support from psychologists and other patients.

Conclusions: Our survey reveals the key aspects of the journey of the patient with mCRC and highlights the areas of similarities and differences between patients with mCRC from Eastern Europe versus those from other European countries as well as among patients from different Eastern European countries, calling for improvement particularly around awareness, screening, treatment availability, communication and support networks.
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http://dx.doi.org/10.1136/esmoopen-2020-000850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528429PMC
September 2020

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results.

Eur J Cancer 2020 11 22;139:51-58. Epub 2020 Sep 22.

CIBERONC, Madrid. Spain; IMIBIC, Córdoba. Spain; Reina Sofia University Hospital, Córdoba. Spain; University of Córdoba, Córdoba. Spain.

Background: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Materials And Methods: Treatment consisted of nab-paclitaxel (125/100 mg/m) plus GEM (1000/800 mg/m) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m], 5-FU bolus [400/300/200 mg/m], 5-FU infusion [2400/2000/1600 mg/m]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan.

Results: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m, GEM 1000 mg/m, oxaliplatin 85 mg/m, 5-FU bolus 400 mg/m and 5-FU infusion 2400 mg/m. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%.

Conclusions: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.
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http://dx.doi.org/10.1016/j.ejca.2020.07.035DOI Listing
November 2020

Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy.

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.

Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.
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http://dx.doi.org/10.3390/ijms21144951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403957PMC
July 2020

Hyperprogression to a dual immune blockade followed by subsequent response with cabozantinib in metastatic poor-risk clear cell renal cell carcinoma with NOTCH mutation.

Oncotarget 2020 Jun 2;11(22):2137-2140. Epub 2020 Jun 2.

MD Anderson Cancer Center, Madrid, Spain.

Currently, more and more patients receive first-line treatment with immunotherapy combinations and not all patients respond in metastatic renal cell carcinoma. After IO-IO progression, we don't have a standard of treatment because it is not available prospective data on this setting. We present the case of a patient with metastatic renal cell carcinoma who suffered hyperprogression with IO-IO combination in first line. Second line with cabozantinib results in a deep response of the disease. We performed a Foundation One testing to the patient which showed a mutation in NOTCH. The molecular mechanism to explain patient's response, it's the probably crosstalk between MET and NOTCH pathway. Nowadays, there is not clear the subsequent treatment in those patients who progress to IO-IO first line. More efforts in biomarkers development should be made to better selection of patients treatment along the disease.
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http://dx.doi.org/10.18632/oncotarget.27598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275785PMC
June 2020

BRAF Mutated Colorectal Cancer: New Treatment Approaches.

Cancers (Basel) 2020 Jun 14;12(6). Epub 2020 Jun 14.

Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.

Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
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http://dx.doi.org/10.3390/cancers12061571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353017PMC
June 2020

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

Int J Mol Sci 2020 Jun 8;21(11). Epub 2020 Jun 8.

Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dúbravská cesta 9, 845 05 Bratislava, Slovakia.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial-mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.
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http://dx.doi.org/10.3390/ijms21114091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311973PMC
June 2020

Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion.

Clin Colorectal Cancer 2020 09 20;19(3):165-177. Epub 2020 Apr 20.

Medical Oncology, Hospital Reina Sofía, University of Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), CIBERONC, Córdoba, Spain.

Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.
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http://dx.doi.org/10.1016/j.clcc.2020.04.003DOI Listing
September 2020

ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity.

Nat Commun 2020 05 29;11(1):2682. Epub 2020 May 29.

Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid, Spain.

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.
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http://dx.doi.org/10.1038/s41467-020-16395-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260233PMC
May 2020

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

Gut 2021 02 14;70(2):319-329. Epub 2020 May 14.

National Cancer Registry Ireland, Cork, Ireland.

Objectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).

Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.

Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (OR=1.08, 95% CI: 0.86 to 1.29, OR=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).

Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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http://dx.doi.org/10.1136/gutjnl-2019-319990DOI Listing
February 2021

The Oncology Data Network (ODN): Methodology, Challenges, and Achievements.

Oncologist 2020 10 21;25(10):e1428-e1432. Epub 2020 May 21.

John Radcliffe Hospital, Nuffield Division of Clinical Laboratory Sciences, Oxford, United Kingdom.

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http://dx.doi.org/10.1634/theoncologist.2019-0855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543245PMC
October 2020

A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.

EBioMedicine 2020 Mar 27;53:102675. Epub 2020 Feb 27.

Molecular Epidemiology and Predictive Tumor Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; Biomedical Research Network in Cancer (CIBERONC), C/Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain. Electronic address:

Background: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes.

Methods: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome.

Findings: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC.

Interpretation: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development.

Funding: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).
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http://dx.doi.org/10.1016/j.ebiom.2020.102675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100610PMC
March 2020

Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships.

Cancer Epidemiol Biomarkers Prev 2020 05 12;29(5):1009-1018. Epub 2020 Feb 12.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, Sweden.

Background: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study.

Methods: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape.

Results: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely.

Conclusions: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations.

Impact: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1027DOI Listing
May 2020

Ramucirumab treatment in hepatocellular carcinoma.

Chin Clin Oncol 2020 Dec 8;9(6):83. Epub 2020 Jan 8.

Medical Oncology Department, Ramón y Cajal University Hospital, IRYCIS, CIBERONC, Alcalá University, Madrid, Spain.

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http://dx.doi.org/10.21037/cco.2019.12.18DOI Listing
December 2020

First-line and second-line treatment of patients with metastatic pancreatic adenocarcinoma in routine clinical practice across Europe: a retrospective, observational chart review study.

ESMO Open 2020 01;5(1)

Vall d'Hebron University Hospital (HUVH), Barcelona, Spain.

Background: Treatment of metastatic pancreatic adenocarcinoma (mPAC) relies on chemotherapeutic regimens. We investigated patterns of first-line and second-line treatment choices, their geographical variation between European countries, and alignment with current European recommendations.

Methods: This retrospective, observational chart review study was conducted between July 2014 and January 2016. Physicians were recruited from nine European countries. Patient data were collected in electronic patient record forms (PRFs) by physicians managing patients with mPAC. Patients with a current mPAC diagnosis aged ≥18 years old who had completed first-line therapy during the study period were included.

Results: Participating physicians (n=225) completed 2565 PRFs. The vast majority of PRFs were from France, Germany, Italy, Spain and the UK. Most patients (86.6%) had stage IV disease at diagnosis. The most common first-line treatments were FOLFIRINOX (5-fluorouracil, leucovorin/folinic acid, irinotecan and oxaliplatin) (35.6%), gemcitabine+nab-paclitaxel (25.7%) and gemcitabine monotherapy (20.5%). Physicians in France and the UK prescribed FOLFIRINOX more frequently than gemcitabine+nab-paclitaxel. Gemcitabine-based therapies were more widely used at second-line, although 5-fluorouracil-based therapies were preferred in Italy and Spain, where gemcitabine-based treatments were more frequently selected for first-line. For patients receiving first-line modified FOLFIRINOX, second-line gemcitabine monotherapy was preferred in the overall population (45.9%).

Conclusion: Although treatment choices for patients with mPAC varied between countries, they align with current European guidelines. Factors including drug availability, reimbursement, patient characteristics, physician preference and prior first-line therapy affect treatment choices. Approved, recommended therapies for patients who progress following first-line treatment are lacking. These findings may influence the development of effective treatment plans, potentially improving future patient outcomes.
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http://dx.doi.org/10.1136/esmoopen-2019-000587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003396PMC
January 2020

Fibroblast-Derived 3D Matrix System Applicable to Endothelial Tube Formation Assay.

J Vis Exp 2019 12 26(154). Epub 2019 Dec 26.

Medical Oncology Department, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBERONC;

The extracellular matrix (ECM) is a three-dimensional scaffold that acts as the main support for cells in tissues. Besides its structural function, the ECM also participates in cell migration, proliferation, and differentiation. Fibroblasts are the main type of cells modifying ECM fiber arrangement and production. In cancer, CAFs (cancer associated fibroblasts) are in permanent activation status, participating in ECM remodeling, facilitating tumor cell migration, and stimulating tumor-associated angiogenesis, among other pro-tumorigenic roles. The objective of this method is to create a three-dimensional matrix with a fiber composition that is similar to in vivo matrices, using immortalized fibroblasts or human primary CAFs. Fibroblasts are cultured in pre-treated cell culture plates and grown under ascorbic acid stimulation. Then, fibroblasts are removed and matrices are blocked for further cell seeding. In this ECM model, fibroblasts can be activated or modified to generate different kinds of matrix, whose effects can be studied in cell culture. 3D matrices are also shaped by cell signals, like degradation or cross-linking enzymes that might modify fiber distribution. In this context, angiogenesis can be studied, along with other cell types such as epithelial tumor cells.
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http://dx.doi.org/10.3791/60304DOI Listing
December 2019

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

Environ Int 2020 02 18;135:105346. Epub 2019 Dec 18.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Electronic address:

Background: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence).

Objective: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes.

Methods: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors.

Results: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 μg/m-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 μg/m-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019).

Conclusions: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.
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http://dx.doi.org/10.1016/j.envint.2019.105346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237313PMC
February 2020

Tumour location and efficacy of first-line EGFR inhibitors in wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials.

ESMO Open 2019 1;4(6):e000599. Epub 2019 Dec 1.

Medical Oncology Service, Hospital General Universitario Gregorio Maranon, Madrid, Spain.

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis.

Methods: Patients with /-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: Patients with -wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with -wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the -wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours.

Conclusion: We observed significantly improved efficacy outcomes in patients with /-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours.

Trial Registration Numbers: NCT01161316 and NCT00885885.
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http://dx.doi.org/10.1136/esmoopen-2019-000599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890384PMC
June 2020
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