2023 GEIS Guidelines for gastrointestinal stromal tumors

Avapritinib; Gastrointestinal stromal tumor; SurgeryAvapritinib; Tumor estromal gastrointestinal; CirurgiaAvapritinib; Tumor estromal gastrointestinal; CirugíaGastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients’ advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.This work was supported in part by AECC (CLSEN20004SERR) and the Fero Foundation, both to CS

Differences in the Impact of COVID-19 on Pathology Laboratories and Cancer Diagnosis in Girona

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer; Diagnòstic; PatologiaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cancer; Diagnóstico; PatologiaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cancer; Diagnosis; PathologyIntroduction: The recent COVID-19 pandemic has compromised socio-health care, with consequences for the diagnosis and follow-up of other pathologies. The aim of this study was to evaluate the impact of COVID-19 on cancer diagnosis in Girona, Spain. Methodology: Observational study of samples received in two pathology laboratories during 2019-2020 (tertiary hospital in Girona and county hospital in Figueres). Date, sample type, and location and morphology were available. Samples were recoded to determine malignancy and grouped by location. Comparisons were made by calendar year and period of exposure to COVID-19. Results: 102,360 samples were included: 80,517 from Girona and 21,843 from Figueres. The reduction in activity in the pathology laboratories in 2020 compared to the previous year was 25.4% in Girona and 27.5% in Figueres. The reduction in cancer diagnoses in 2020 compared to 2019 was 6.8% in Girona and 21% in Figueres. In both laboratories, a decrease was observed in the diagnoses of neoplasms of the lip, oral cavity and pharynx, larynx, colon, rectum and anus, kidney and urinary system, melanoma, and central nervous system. A statistically significant higher probability of a sample received in the pathology laboratory displaying malignancy during COVID-19 was found (Girona: OR = 1.28, 95% CI: 1.23-1.34; Figueres: OR = 1.10, 95% CI: 1.01-1.20) with respect to the COVID-19-free period. Conclusions: The COVID-19 pandemic has resulted in a reduction in cancer diagnoses by pathology departments that varies according to tumor location and type of hospital. Despite this, the optimization of care resources and the recovery effort have partially reduced the impact of the pandemic in certain neoplasms.This work was partially funded by the Josep Carreras Leukaemia Research Institute (grant number: FIJC1100) and the Agency for Management of University and Research Grants, Government of Catalonia (grant number: 2017SGR00733

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients’ samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)—the main effector of muscular atrophy in cachexia—resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.This project was funded by the 2014 SARC International Career Development Award (SARC Sarcoma Spore 1U54CA168512–01), Fundación Mari Paz Jiménez Casado, FERO Foundation, Spanish Society of Medical Oncology (SEOM), PERIS SLT006/17/221, ISCIII PI16/01371 and PI19/01271, all to C.S. ISCIII FI20/00275 (to DG-P), and a Ph.D. fellowship from the National Secretary for Higher Education, Science, Technology and Innovation of Ecuador (SENESCYT) (to DFP-J). AE-C is funded by ISCIII PT17/0009/0019 and co-funded by FEDER

ICO-ICS Praxis para el tratamiento médico y con irradiación del cáncer de orofaringe, hipofaringe, laringe y nasofaringe

Tractament mèdic; Tractament amb irradiació; Càncer de cap i coll; Carcinoma de nasofaringeTratamiento médico; Tratamiento con irradiación; Cáncer de cabeza y cuello; Carcinoma de nasofaringeMedical treatment; Irradiation treatment; Head and neck cancer; Nasopharyngeal carcinomaL’anomenat càncer de cap i coll engloba un grup de tumors malignes localitzats en diverses zones de les vies aerodigestives superiors: sins paranasals, nasofaringe, orofaringe (amígdala, paladar tou, base de la llengua), hipofaringe, laringe, cavitat oral (mucosa oral, geniva, paladar dur, llengua i terra de la boca) i glàndules salivals. L'objectiu d'aquest document és - Desenvolupar, difondre, implementar i avaluar resultats de la ICO-ICSPraxi per al tractament del càncer d’orofaringe, hipofaringe, laringe i nasofaringe. - Disminuir la variabilitat terapèutica entre els pacients tractats en els diversos centres d’aquesta institució. - Implementar els resultats de la terapèutica en els pacients amb càncer de càvum, orofaringe, hipofaringe o laringe tractats d’acord amb les recomanacions d’aquesta guia

Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p<0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p<0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours

Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients

Introduction: there are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions: we identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155)

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck

ObjectivesThe aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy.Materials and methodsThis retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness.ResultsA total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4–6.6). With a median follow-up of 8.7 months (95% CI: 7.7–10.2), median PFS and OS were 4.5 months (95% CI: 3.9–5.0) and 8.9 months (95% CI: 7.8–10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia.ConclusionThis study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias

Epidemiologia descriptiva i molecular dels tumors estromals gastrointestinals a Tarragona i Girona.

Aquesta tesi és un estudi epidemiològic sobre els Tumors Estromals Gastrointestinals (GIST) basat en la publicació de tres articles. El descobriment al 1999 d’una mutació activadora en el gen anomenat c-KIT portà a determinar aquesta característica com identificativa d’aquest tipus de tumor que, per haver rebut diferents nomenclatures, no havia estat registrat prèviament com a entitat pròpia en els Registres Poblacionals de Càncer. L’objectiu principal ha estat analitzar l’epidemiologia d’aquesta neoplàsia en els Registres de Càncer de Tarragona i Girona. S’han reclassificat tots els tumors mesenquimàtics gastrointestinals usant immunohistoquímica i segons criteris diagnòstics avui consensuats i determinant en base poblacional les mutacions del gen c-KIT i del gen PDGFR-alpha. Les conclusions són: els GIST no eren registrats amb total exhaustivitat, atès que es perdien casos de potencial maligne incert a més de la utilització de nomenclatures diferents. La incidència (taxa bruta) del període 2001-2005 és de 1.18 casos per cada 100.000 habitants/any a Tarragona i 1.36 a Girona. La taxa ajustada és de 0.75 i 0.80 respectivament. La supervivència relativa a 5 anys (període 1994-2001) dels GIST varia del 21.4% al 97% entre els grups de baix o alt risc de comportament agressiu. L'anàlisi de les tendències no demostra un increment significatiu en la incidència. El perfil mutacional poblacional és similar al descrit en series no poblacionals, excepte en la mutació de l’exó 18 del gen PDGFR-alpha, més present en GIST gàstrics i de baix risc. Per últim, els pacients amb GIST tenen un risc augmentat de presentar una segona neoplàsia respecte a la població generalEsta tesis es un estudio epidemiológico sobre los Tumores Estromales Gastrointestinales (GIST) basado en la publicación de tres artículos. El descubrimiento en 1999 de una mutación activadora en el gen c-KIT llevó a definir esta característica como identificativa de este tipo de tumor, que por haber recibido diferentes nomenclaturas no había sido registrado como entidad propia en los Registros Poblacionales de Cáncer. El objetivo principal ha sido analizar la epidemiologia de esta neoplasia en los Registros de Cáncer de Tarragona y Girona. Se han reclasificado todos los tumores mesenquimales gastrointestinales usando inmuohistoquímica y según criterios diagnósticos hoy consensuados y determinando en base poblacional las mutaciones del gen c-KIT y del gen PDGFR-alpha. Las conclusiones son: los GIST no eran registrados con total exhaustividad, dado que se perdían casos de potencial maligno incierto y se utilizaban nomenclaturas diferentes. La incidencia ( tasa bruta) de los GIST en el período 2001-2005 es de 1.18 casos por cada 100.000 habitantes / año en Tarragona y 1.36 en Girona. La tasa ajustada es de 0.75 i 0.80 respectivamente. La supervivencia relativa a 5 años (período 1994-2001) de los GIST varía del 21.4% al 97% entre los grupos de bajo y alto riesgo de comportamiento agresivo. El análisis de tendencias no muestra incremento significativo en la incidencia. El perfil mutacional poblacional es similar al descrito en series no poblacionales, salvo en la mutación del exón 18 del gen PDGFR-alpha, más presente en GIST gástricos y de bajo riesgo. Por último, los pacientes con GIST tienen mayor riesgo de presentar una segunda neoplasia en relación a la población general.This thesis is an epidemiological study of Gastrointestinal Stromal Tumors (GIST) based on the publication of three research articles. The discovery in 1999 of an activating mutation in the c-KIT gene in GIST, led to finally define this type of tumour, which had received different nomenclatures in the past and had not been correctly recorded in Cancer Registries. The main objective was to define the epidemiology of this neoplasm in Tarragona’s and Girona Cancer Registries. All gastrointestinal mesenchymal tumours were reclassified using immunochemistry and modern diagnostic criteria and the population-based mutational profile about c-KIT and PDGFR-alpha genes were identified. The conclusions are: GIST were not registered with total completeness, given that cases of uncertain malignancy were lost and morphological terms changed. The crude incidence rate of GIST in the period 2001-2005 was 1.18 cases per 100,000 inhabitants / year in Tarragona and 1.36 in Girona. Adjusted rates were 0.75 and 0.80 respectively. The 5-year relative survival (period 1994-2001) of GIST of low and high risk of aggressive behaviour ranged from 21.4% to 97%. The temporal trends of incidence analysis did not show a significant increase. The population-based mutational profile was similar to that described in other non-population-based studies, except in those with mutation of exon 18 of the gene PDGFR-alpha, more frequent in gastric and low risk GIST. Finally, patients with GIST had an increased risk of being diagnosed with a second neoplasm compared to the general population

Population-Based Analysis of Trends in Incidence and Survival of Human Papilloma Virus-Related Oropharyngeal Cancer in a Low-Burden Region of Southern Europe

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona&rsquo;s population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997&ndash;1999, 2003&ndash;2005, 2009&ndash;2011, and 2016&ndash;2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016&ndash;2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC