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1.
Int J Cancer ; 154(3): 488-503, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37724848

RESUMEN

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.


Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/patología , Mutación
2.
Br J Cancer ; 130(12): 1921-1928, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38664577

RESUMEN

BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Nivolumab , Oxaliplatino , Humanos , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Inestabilidad de Microsatélites , Supervivencia sin Progresión , Adulto , Metástasis de la Neoplasia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética
3.
Br J Cancer ; 131(4): 676-684, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38909137

RESUMEN

BACKGROUND: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited. METHODS: Digestive HG-NEN patients (n = 229) were prospectively included 2013-2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival. RESULTS: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS. CONCLUSION: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.


Asunto(s)
Mutación , Tumores Neuroendocrinos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/tratamiento farmacológico , Adulto , Resultado del Tratamiento , Pronóstico , Anciano de 80 o más Años , Etopósido/administración & dosificación , Variaciones en el Número de Copia de ADN , Estudios Prospectivos , Clasificación del Tumor , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/tratamiento farmacológico , Carboplatino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto Joven , Proteína p53 Supresora de Tumor/genética
4.
Acta Oncol ; 63: 248-258, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38698698

RESUMEN

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.


Asunto(s)
Capecitabina , Cardiotoxicidad , Neoplasias Colorrectales , Combinación de Medicamentos , Fluorouracilo , Ácido Oxónico , Tegafur , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Tegafur/efectos adversos , Tegafur/administración & dosificación , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Ácido Oxónico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Cardiotoxicidad/etiología , Capecitabina/efectos adversos , Capecitabina/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Adulto , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
5.
Br J Cancer ; 129(12): 1930-1939, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37872405

RESUMEN

BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).


Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Everolimus/efectos adversos , Temozolomida , Calidad de Vida , Estudios Prospectivos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología
6.
Acta Oncol ; 62(5): 431-437, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37194281

RESUMEN

Lung neuroendocrine neoplasms (NEN) are a heterogeneous population of neoplasms with different pathology, clinical behavior, and prognosis compared to the more common lung cancers. The diagnostic work-up and treatment of patients with lung- NEN has undergone major recent advances and new methods are currently being introduced into the clinic. These Nordic guidelines summarize and update the Nordic Neuroendocrine Tumor Group's current view on how to diagnose and treat lung NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients. This review reflects our view of the current state of the art of diagnosis and treatment of patients with lung-NEN. Small cell lung carcinoma (SCLC) is not included in these guidelines.


Asunto(s)
Carcinoma Neuroendocrino , Neoplasias Pulmonares , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Pronóstico , Pulmón/patología , Neoplasias Pancreáticas/patología
7.
Curr Oncol Rep ; 25(10): 1127-1139, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37606874

RESUMEN

PURPOSE OF REVIEW: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space. RECENT FINDINGS: After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.

8.
Tidsskr Nor Laegeforen ; 143(18)2023 12 12.
Artículo en Inglés, Noruego | MEDLINE | ID: mdl-38088292

RESUMEN

BACKGROUND: Fluoropyrimidines have been linked to cardiovascular toxicity. CASE PRESENTATION: A woman in her forties with locally advanced rectal cancer received curative-intent treatment according to the RAPIDO protocol. Shortly after starting the first 5-fluorouracil infusion she developed chest/epigastric pain, nausea and vomiting. Electrocardiogram showed mild ST elevation in multiple contiguous leads. Troponin I was elevated. Transthoracic echocardiogram (TTE) displayed signs suggestive of myocardial infarction. Coronary angiogram indicated no obstructive coronary artery disease. Ventriculography demonstrated apical hypokinesia and basal hyperkinesia. MRI revealed no signs of myocardial infarction or myocarditis. The patient was diagnosed with Takotsubo syndrome, possibly induced by 5-fluorouracil. Follow-up TTE three weeks later was normal. Subsequently, she received treatment with tegafur/gimeracil/oteracil (Teysuno®) in place of 5-fluorouracil, combined with oxaliplatin. No further cardiotoxicity was observed during three cycles. INTERPRETATION: The patient was diagnosed with Takotsubo syndrome following 5-fluorouracil infusion, likely to represent 5-fluorouracil-induced cardiotoxicity. Following replacement of 5-fluorouracil with Teysuno®, she experienced no signs of cardiotoxicity.


Asunto(s)
Infarto del Miocardio , Cardiomiopatía de Takotsubo , Femenino , Humanos , Cardiotoxicidad/etiología , Electrocardiografía , Fluorouracilo/efectos adversos , Infarto del Miocardio/diagnóstico , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/diagnóstico por imagen , Adulto , Persona de Mediana Edad
9.
Br J Cancer ; 126(1): 48-56, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34671130

RESUMEN

BACKGROUND: Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established. METHODS: A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated. RESULTS: Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration. CONCLUSIONS: In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours-potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.


Asunto(s)
Factor de Transcripción CDX2/genética , Neoplasias Colorrectales/patología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Inestabilidad de Microsatélites , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Tasa de Supervivencia , Adulto Joven
10.
Br J Cancer ; 127(12): 2227-2233, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36229579

RESUMEN

BACKGROUND: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. METHODS: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. RESULTS: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3-19.7) and 3.9 months (95% CI, 2.3-5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9-14.7) for control arm patients (N = 31). CONCLUSIONS: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).


Asunto(s)
Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Humanos , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN
11.
Oncologist ; 27(4): 299-306, 2022 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-35380711

RESUMEN

BACKGROUND: Although the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear. METHODS: Data from the National Cancer Database between 2004 and 2016 were used for this study. RESULTS: Of 2314 GEP NEC cases (stages I-III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I-II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients. CONCLUSIONS: Treatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I-II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.


Asunto(s)
Carcinoma Neuroendocrino , Neoplasias Esofágicas , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Carcinoma Neuroendocrino/patología , Bases de Datos Factuales , Humanos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Pronóstico
12.
Gut ; 70(9): 1768-1781, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33692095

RESUMEN

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.


Asunto(s)
Neoplasias Intestinales/terapia , Tumores Neuroendocrinos/terapia , Neoplasias Pancreáticas/terapia , Medicina de Precisión/métodos , Neoplasias Gástricas/terapia , Biomarcadores de Tumor , Epigénesis Genética , Humanos , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/genética , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética
13.
Int J Cancer ; 149(6): 1385-1397, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-33961700

RESUMEN

Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.


Asunto(s)
Neoplasias Colorrectales/genética , GTP Fosfohidrolasas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Proteínas de la Membrana/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Femenino , Frecuencia de los Genes , Humanos , Modelos Logísticos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Pronóstico , Análisis de Supervivencia
14.
Neuroendocrinology ; 111(9): 883-894, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33002892

RESUMEN

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival.


Asunto(s)
Consenso , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/mortalidad , Neoplasias Intestinales/patología , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Sistema de Registros , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Supervivencia sin Progresión
15.
Neuroendocrinology ; 111(9): 840-849, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32721955

RESUMEN

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.


Asunto(s)
Neoplasias Duodenales/sangre , Neoplasias del Íleon/sangre , Neoplasias del Yeyuno/sangre , Tumores Neuroendocrinos/sangre , Biomarcadores/sangre , Neoplasias Duodenales/diagnóstico , Humanos , Neoplasias del Íleon/diagnóstico , Neoplasias del Yeyuno/diagnóstico , Aprendizaje Automático , Tumores Neuroendocrinos/diagnóstico
16.
Acta Oncol ; 60(7): 931-941, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33999752

RESUMEN

BACKGROUND: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. AIM: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.


Asunto(s)
Neoplasias Gastrointestinales , Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Neoplasias Intestinales/diagnóstico , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia
17.
Neuroendocrinology ; 110(3-4): 217-224, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31578011

RESUMEN

BACKGROUND: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. METHODS: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. RESULTS: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. CONCLUSIONS: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.


Asunto(s)
Biomarcadores de Tumor/sangre , Cromogranina A/sangre , Progresión de la Enfermedad , Neoplasias Intestinales/diagnóstico , Neoplasias Primarias Desconocidas/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Neoplasias Intestinales/sangre , Neoplasias Intestinales/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/sangre , Neoplasias Primarias Desconocidas/patología , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Estudios Prospectivos
18.
Acta Oncol ; 59(3): 284-290, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31769323

RESUMEN

Background: Survival and response to therapy in patients with metastatic colorectal cancer (mCRC) are very heterogeneous. There is an unmet need for better markers of prognosis and treatment benefit for mCRC patients. The homeobox 2 gene SATB2 has a highly specific expression in colorectal tissue and is associated with better prognosis in non-metastatic CRC.Material and methods: A population-based cohort of 798 mCRC patients was analysed. From primary tumour material, protein expression was assessed by immunohistochemistry. BRAF and KRAS mutation status was also determined. Associations with clinicopathological data, overall and progression-free survival and response to first-line chemotherapy were analysed.Results: Tumour tissue and clinical data were available from 467 patients. SATB2 was strongly expressed in 58% of cases, significantly more in left-sided, low-grade and wild-type BRAF tumours. Patients with high SATB2 tumours had longer overall survival compared with low SATB2 tumours (median 13 vs 8 months respectively, p < .001). Chemotherapy was given to 282 patients (63%). Patients with high SATB2 tumours had longer OS (median 22 vs 15 months respectively, p = .001) and more often responded to chemotherapy than those with low SATB2 (objective response 43% vs 29%, p = .02; clinical response 83% vs 67%, p = .004). Progression-free survival on first-line irinotecan chemotherapy was longer in high SATB2 cases (median 8 vs 4 months respectively, p = .019). Patients with both low SATB2 expression and mutated BRAF (n = 69) had particularly poor survival compared to the rest (median 8 and 12 months respectively, p = .001). In multivariable analysis, the SATB2 findings were independent of known clinicopathological prognostic markers, including BRAF mutation status.Conclusion: Patients with mCRC expressing high level of SATB2 have better prognosis and response to chemotherapy than those with low SATB2 expression. Patients with both low SATB2 expression and mutated BRAF had particularly poor prognosis and could thus benefit from more aggressive therapies.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/análisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción/análisis , Quinasas raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunoquímica , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Pronóstico , Países Escandinavos y Nórdicos
19.
Acta Oncol ; 59(4): 417-426, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31924107

RESUMEN

Background: We have reported that BRAF V600E mutations and microsatellite instability-high (MSI-H) are more prevalent in a population-based cohort of metastatic colorectal cancer (mCRC) patients than has been reported from clinical trials or hospital-based patient groups. The aim was to explore if other mutations in mCRC differ in prevalence between these cohorts in relation to mismatch repair status and primary tumor location and if presence of bone or brain metastases is associated with any mutations.Material and methods: A population-based cohort of 798 mCRC patients from three regions in Scandinavia was used. Forty-four cancer related genes were investigated in a custom designed Ampliseq hotspot panel. Differences in survival were analyzed using the Kaplan-Meier estimator and the Cox regression analysis.Results: Determination of mutations was possible in 449/501 patients for 40/44 genes. Besides BRAF V600E, seen in 19% of the tumors, none of the other mutations appeared more prevalent than in trial cohorts. BRAF V600E and MSI-H, seen in 8%, were associated with poor prognosis as was right-sided primary tumor location (39%) when compared to left-sided and rectum together; however, in a multivariable regression, only the BRAF mutation retained its statistical significance. No other mutations were associated with poor prognosis. ERBB2 alterations were more common if bone metastases were present at diagnosis (17% vs. 4%, p = .011). No association was found for brain metastases. Fifty-two percent had an alteration that is treatable with an FDA-approved targeted therapy, chiefly by EGFR-inhibitor for RAS wild-type and a check-point inhibitor for MSI-H tumors.Conclusions: Right-sided tumor location, BRAF V600E mutations, but no other investigated mutation, and MSI-H are more commonly seen in an unselected cohort than is reported from clinical patient cohorts, likely because they indicate poor prognosis. Half of the patients have a tumor that is treatable with an already FDA-approved targeted drug for mCRC.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/secundario , Neoplasias Encefálicas/secundario , Neoplasias Colorrectales/patología , Genes Relacionados con las Neoplasias , Inestabilidad de Microsatélites , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/genética , Neoplasias Encefálicas/genética , Estudios de Cohortes , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Países Escandinavos y Nórdicos , Tasa de Supervivencia , Adulto Joven
20.
Health Qual Life Outcomes ; 18(1): 188, 2020 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-32546236

RESUMEN

BACKGROUND: Patients with metastatic small-intestinal neuroendocrine tumours (NET) have been shown to have a reduced quality of life compared to the general population and many have disabling symptoms during somatostatin analogue (SSA) treatment. The aim of this prospective study was to document the patient-reported symptoms, coping and quality of life during SSA treatment and to measure patients' fat-soluble vitamin levels. METHODS: Patients with metastatic small-intestinal NET on treatment with long-acting SSA were included. Data on patient characteristics, blood samples, questionnaires (EORTC-QLQ-C30 and GI.NET-21) and structured patient interviews were collected at inclusion and after 1 year. RESULTS: Eighty-eight patients were included, 77 (88%) attended 1 year follow-up. Approximately 50% of patients reported symptoms, the most common symptoms at baseline and after 1 year follow-up were diarrhoea, flatulence, fatigue, abdominal discomfort and sore injection lumps. Diarrhoea and fatigue were reported as their main complaint, 23% had > 5 daily episodes of diarrhoea and 59% reported fatigue. However, patients reported a high perceived quality of life, high daily activity, coped with their symptoms and managed their daily life well. Deficiency of vitamin D (27%) and A (13%) were observed. CONCLUSIONS: Patients with metastatic small-intestinal NET on SSA treatment reported a high frequency of symptoms. Minor improvements were seen after 1-year of follow-up, illustrating that many symptoms might be difficult to improve, or may not be recognised by the health service. Patients, however, generally reported a high quality of life. Care for NET patients on SSA treatment should include a regular systematic symptom registration and vitamin measurements.


Asunto(s)
Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Calidad de Vida , Somatostatina/efectos adversos , Adaptación Psicológica , Adulto , Anciano , Femenino , Humanos , Neoplasias Intestinales/psicología , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/psicología , Estudios Prospectivos , Somatostatina/análogos & derivados , Encuestas y Cuestionarios
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