A significant response to sunitinib in a patient with anaplastic thyroid carcinoma

Anaplastic thyroid cancer (ATC) is a rare disease with an incidence of less than three cases per million of habitants in western countries. ATC accounts for 1-10% of all tumors derived from the thyroid gland. Classic chemotherapy approach based on platinum and anthracyclines regimens have been considered standard for the last decades. Novel multitarget agents have shown promising responses; however, no positive randomized clinical trials are available up to now. To our knowledge, the case we are presenting here is the first reported case showing clinical and visual activity using sunitinib as a salvage treatment in an ATC patient who was not fit to receive systemic chemotherapy treatment

SEOM-GEMCAD-TTD clinical guidelines for localized rectal cancer (2021)

The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional therapies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined

Sorafenib for the treatment of metastatic thyroid cancer patients

Segons resultats de fases II amb inhibidors tirosina quinasa i el coneixement de les alteracions moleculars de la carcinogènesis tiroïdal, es va dissenyar un estudi retrospectiu de pacients amb càncer de tiroide metastàtic tractats amb sorafenib. S'analitzaren la taxa de respostes, toxicitat, supervivència i la correlació amb els marcadors tumorals de 34 pacients. Segons subtipus histològic, la taxa de respostes va ser 47% en medul·lars, 19% en diferenciats i 33% en anaplàsics. La mitjana de supervivència-lliure-de-progressió va ser 13.5, 10.5 i 4.4 mesos, respectivament. Es va observar correlació significativa entre la reducció dels nivells de marcador tumoral i la resposta. El perfil de toxicitat va ser favorable.Based on recent results of several phase II studies with tyrosine kinase inhibitors and the better knowledge of molecular aberrations that characterize thyroid carcinogenesis a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib was designed. 34 patients were analyzed for response rate, toxicity, survival and tumor marker correlation. Regarding histological subtype, response rates observed were 47% for medullary, 19% for differentiated and 33% for anaplastic. Median progression-free-survival was 13.5, 10.5 and 4.4 months for differentiated, medullary and anaplastic, respectively. Significant correlation was observed between tumor marker levels reduction and response. The toxicity profile was favorable

Economics of gastroenteropancreatic neuroendocrine tumors : a systematic review

Despite current interest, enthusiasm and progress in the development of therapies for gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), there are substantial gaps in the published literature regarding cost-of-illness analyses, economic evaluation and budget impact analyses. Compounding the issue is that data on resource utilization and cost-effectiveness of different diagnostic and therapeutic modalities for GEP-NETs are scarce. A systematic review on the economic impact of GEP-NETs was carried out using four databases: EMBASE, PubMed, the National Health Service Economic Evaluation Database and Cochrane review. Fully published articles from January 2000 to May 2017, in English and Spanish, were included. All articles that satisfied the inclusion criteria were included in the systematic review; summary descriptive statistics were used to describe the methodological characteristics. The 14 studies selected included cost-of-illness analyses (n = 4), economic evaluations (n = 7) and budget impact analyses (n = 3). Almost all studies were performed in the United States. Healthcare costs for patients with NETs included medication, outpatient visits, hospitalizations, and check-ups/tests. Reducing adverse events is an area where cost savings could be achieved; however, there was not enough evidence on the cost impact of adverse events. There is a lack of data related to resource utilization in the field of GEP-NETs. Therefore, cost-effectiveness and budget impact studies of existing and emerging treatments are urgently needed to help the decision-making process for patients with NETs

Genomic profiling of NETs : A comprehensive analysis of the RADIANT trials

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies

Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib

Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib

Evaluating radiological response in pancreatic neuroendocrine tumours treated with sunitinib : comparison of Choi versus RECIST criteria (CRIPNET_ GETNE1504 study)

The purpose of our study was to analyse the usefulness of Choi criteria versus RECIST in patients with pancreatic neuroendocrine tumours (PanNETs) treated with sunitinib. A multicentre, prospective study was conducted in 10 Spanish centres. Computed tomographies, at least every 6 months, were centrally evaluated until tumour progression. One hundred and seven patients were included. Median progression-free survival (PFS) by RECIST and Choi were 11.42 (95% confidence interval [CI], 9.7-15.9) and 15.8 months (95% CI, 13.9-25.7). PFS by Choi (Kendall's τ = 0.72) exhibited greater correlation with overall survival (OS) than PFS by RECIST (Kendall's τ = 0.43). RECIST incorrectly estimated prognosis in 49.6%. Partial response rate increased from 12.8% to 47.4% with Choi criteria. Twenty-four percent of patients with progressive disease according to Choi had stable disease as per RECIST, overestimating treatment effect. Choi criteria predicted PFS/OS. Changes in attenuation occurred early and accounted for 21% of the variations in tumour volume. Attenuation and tumour growth rate (TGR) were associated with improved survival. Choi criteria were able to capture sunitinib's activity in a clinically significant manner better than RECIST; their implementation in standard clinical practice shall be strongly considered in PanNET patients treated with this drug

Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (s, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of s of driver alterations in unpaired primary and metastatic colorectal cancer () at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 samples, 622 had detailed annotation on overall survival in the metastatic setting (met) and 89 received targeted agents matched to ( inhibitors), ( inhibitors), or 3 mutations (3K pathway inhibitors). s of each variant were normalized for tumor purity in the sample (adjs). We found lower adjs for 600E and 3 than for , , and non-V600 variants. 53 and 600E adjs were higher in metastases as compared to primary tumors, and high adjs were found in metastases of patients with wild-type primary tumors previously exposed to antibodies. Patients with - or 600E -mutated tumors, irrespective of adjs, had worse met. There was no significant association between adjs and time to progression on targeted therapies matched to , , or 3 mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower 600E and 3 adjs in subsets of primary tumors indicate subclonality of these driver genes. Differences in adjs between metastases and primary tumors suggest that approved therapies may result in selection of 600E - and -resistant clones and an increase in genomic heterogeneity with acquired 53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting

Sorafenib for the treatment of metastatic thyroid cancer patients.

Segons resultats de fases II amb inhibidors tirosina quinasa i el coneixement de les alteracions moleculars de la carcinogènesis tiroïdal, es va dissenyar un estudi retrospectiu de pacients amb càncer de tiroide metastàtic tractats amb sorafenib. S’analitzaren la taxa de respostes, toxicitat, supervivència i la correlació amb els marcadors tumorals de 34 pacients. Segons subtipus histològic, la taxa de respostes va ser 47% en medul•lars, 19% en diferenciats i 33% en anaplàsics. La mitjana de supervivència-lliure-de-progressió va ser 13.5, 10.5 i 4.4 mesos, respectivament. Es va observar correlació significativa entre la reducció dels nivells de marcador tumoral i la resposta. El perfil de toxicitat va ser favorable.Based on recent results of several phase II studies with tyrosine kinase inhibitors and the better knowledge of molecular aberrations that characterize thyroid carcinogenesis a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib was designed. 34 patients were analyzed for response rate, toxicity, survival and tumor marker correlation. Regarding histological subtype, response rates observed were 47% for medullary, 19% for differentiated and 33% for anaplastic. Median progression-free-survival was 13.5, 10.5 and 4.4 months for differentiated, medullary and anaplastic, respectively. Significant correlation was observed between tumor marker levels reduction and response. The toxicity profile was favorable

Tipificació molecular de tumors neuroendocrins gastroenteropancreàtics. Desenvolupament de noves teràpies i búsqueda de nous biomarcadors

El coneixement de la biologia molecular responsable de la carcinogènesi de les neoplàsies neuroendocrines segueix essent limitada avui en dia. Aquest fet, ha limitat la identificació de biomarcadors pronòstics i predictius i el desenvolupament de teràpies dirigies en aquesta població de pacients. L’objectiu de la present tesi doctoral ha estat identificar les alteracions genòmiques i epigenòmiques de neoplàsies neuroendocrines digestives i valorar la possibilitat de crear models murins derivats de pacients com a pas previ al disseny d’estudis clínics en pacients segons les alteracions moleculars observades. El treball s’ha centrat en carcinomes neuroendocrins de primari colònic, un tipus tumoral poc freqüent, d’elevada agressivitat i orfe de tractament. Inicialment, a través del grup nacional de tumors endocrins (GETNE) s’han identificat mostres tumorals parafinades de pacients amb carcinomes neuroendocrins de primari colònic, s’ha confirmat el diagnòstic anatomopatològic i s’han realitzat estudis genòmics i epigenòmics per a la correcta tipificació molecular de les alteracions presents en aquest tipus de tumor. Paral·lelament, s’ha aconseguit crear un model murí derivat de pacient amb carcinoma neuroendocrí portador de mutació en el gen BRAF per a poder realitzar experiments in vitro amb teràpies dirigides contra aquesta mutació. En resum, els resultats han permès identificar les mutacions més prevalents en carcinomes neuroendocrins de còlon, destacant l’elevat percentatge de mutacions V600E en el gen BRAF comparat amb l’adenocarcinoma de còlon. Així mateix, el perfil de metil·lació de l’ADN dels carcinoma neuroendocrins de còlon és significativament diferent a l’observat en adenocarcinomes de còlon, que juntament amb el perfil genòmic i l’inestabilitat cromosòmica observada en el neuroendocrí confirmen les diferències tant en l’origen de les dues neoplàsies, com en la biologia molecular i la probabilitat de resposta a teràpies dirigides confirmada en els models PDX. Els resultats del present treball de tesi doctoral permetran continuar amb l’estudi de les característiques moleculars d’aquesta població de pacients, la búsqueda de nous biomarcadors i el disseny d’estudis dirigits per a una població de pacients actualment orfe de tractament efectiu.The knowledge of the molecular biology of the neuroendocrine tumors carcinogenesis is still limited today. This fact has limited predictive and prognostic biomarker identification and the development of therapies aimed at this population of patients. The aim of this work was to identify genomic and epigenomic changes of neuroendocrine tumors of gastrointestinal tract and assess the possibility of creating mouse models derived from patients as a prelude to the design of clinical studies in patients based on the molecular alterations observed. The work has focused on primary colonic neuroendocrine carcinomas, a rare, treatment orphan and highly aggressive tumor. Initially, through the national group of endocrine tumors (GETNE) paraffin-embedded tumor samples were identified of patients with neuroendocrine carcinoma of primary colonic. After centrally pathological confirmation genomic and epigenomic studies have been conducted to characterize the molecular alterations of this tumor type. Meanwhile, it has managed to create an animal model derived from patients with neuroendocrine carcinoma carrier of the gene mutation in BRAF to carry out experiments in vitro with targeted therapies against this mutation. In summary, the results have enabled us to identify the most prevalent mutations in neuroendocrine carcinomas of the colon, highlighting the high percentage of mutations V600E in the gene BRAF compared with the adenocarcinoma of the colon. Also, the DNA methylation profile of neuroendocrine carcinoma of the colon is significantly different from that observed in adenocarcinomas of the colon, which together with the genomic profile and chromosomal instability observed in neuroendocrine carcinomas confirm the differences in the origin of the two cancers, the molecular biology of both cancer types and the likelihood of response to targeted therapies confirmed in the PDX models. The results of this doctoral thesis will continue with the study of the molecular characteristics of this patient population, the search for new biomarkers and the design of clinical trials aimed for an orphan patient population currently lacking of effective treatment