RESUMEN
BACKGROUND: In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001. PATIENTS AND METHODS: ROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily. RESULTS: Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment. CONCLUSIONS: These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT00585195.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. Patients and methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.
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Quinasa de Linfoma Anaplásico/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Crizotinib/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Hibridación Fluorescente in Situ , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
BACKGROUND: SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression. PATIENTS AND METHODS: Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m(2) i.v., days 1 and 8) and cisplatin (75 mg/m(2) i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors. RESULTS: A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine-cisplatin group than in the gemcitabine-cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%). CONCLUSIONS: In line with SQUIRE ITT, addition of necitumumab to gemcitabine-cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors. CLINICAL TRIAL: NCT00981058.
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Anticuerpos Monoclonales/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , GemcitabinaRESUMEN
The limitations of cancer cell lines have led to the development of direct patient-derived xenograft models. However, the interplay between the implanted human cancer cells and recruited mouse stromal and immune cells alters the tumor microenvironment and limits the value of these models. To overcome these constraints, we have developed a technique to expand human hematopoietic stem and progenitor cells (HSPCs) and use them to reconstitute the radiation-depleted bone marrow of a NOD/SCID/IL2rg(-/-) (NSG) mouse on which a patient's tumor is then transplanted (XactMice). The human HSPCs produce immune cells that home into the tumor and help replicate its natural microenvironment. Despite previous passage on nude mice, the expression of epithelial, stromal and immune genes in XactMice tumors aligns more closely to that of the patient tumor than to those grown in non-humanized mice-an effect partially facilitated by human cytokines expressed by both the HSPC progeny and the tumor cells. The human immune and stromal cells produced in the XactMice can help recapitulate the microenvironment of an implanted xenograft, reverse the initial genetic drift seen after passage on non-humanized mice and provide a more accurate tumor model to guide patient treatment.
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Neoplasias de Cabeza y Cuello/genética , Células Madre Hematopoyéticas/patología , Microambiente Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Médula Ósea/patología , Línea Celular Tumoral , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/patología , Humanos , RatonesRESUMEN
The family of fibroblast growth factor (FGFs) and their receptors (FGFRs) regulates vital roles in many biological processes affecting cell proliferation, migration, differentiation and survival. Deregulation of the FGF/FGFR signaling pathway in cancers has been better understood and the main molecular mechanisms responsible for the activation of this pathway are gene mutations, gene fusions and gene amplification. DNA and RNA-based technologies have been used to detect these abnormalities, especially in FGFR1, FGFR2 and FGFR3 and tests have been developed for their detection, but no assay has been proved ideal for molecular diagnosis. Interestingly, the increase in the molecular biology knowledge has supported and assisted the development of therapeutic drugs targeting the most important components of this pathway. Multi- and selective tyrosine kinase inhibitors (TKIs) as well as monoclonal antibodies anti-FGFR are under investigation in preclinical and clinical trials. In this article, we reviewed those aspects with special emphasis on the pathway genomic alterations related to solid tumors, and the molecular diagnostic assays potentially able to stratify patients for the treatment with FGFR TKIs.
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Antineoplásicos/uso terapéutico , Carcinogénesis/genética , Factores de Crecimiento de Fibroblastos/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal/genética , Carcinogénesis/efectos de los fármacos , Humanos , Mutación/efectos de los fármacos , Mutación/genética , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: PA is a grade I glial tumor that mostly occurs in children. However, although apparently similar to paediatric PA, adult PA presents a different clinical follow-up that could arise from specific molecular alterations. A variety of genetic alterations have been identified as diagnostic or prognostic glioma molecular markers. MATERIAL AND METHODS: We describe a right infratentorial tumor that occurred in a 58-year-old man. Neuroimaging and neuropathological examination suggested PA as an initial diagnosis. The tumor was completely resected. Unexpectedly, two years later, a rapidly growing tumor on the operative site was observed with a second location in the pineal region. Immunohistochemical reactions (IHC), Multiplex ligation probe amplification (MLPA) and fluorescence in situ hybridization (FISH) was performed in both primary and relapse tumor. RESULTS: Neuroimaging and neuropathological examinations suggested an unusual diagnosis for adult patients: a recurrent PA. Both MLPA and FISH analysis contribute to diagnostic confirmation by KIAA1549: BRAF fusion detection. Additional genetic results revealed interesting findings that justified the tumor aggressivity. CONCLUSION: Molecular analysis of adult PA cases should be routinely combined with histopathological and neuroimaging examination to further refine prognostic diagnoses.
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Astrocitoma/diagnóstico , Neoplasias Infratentoriales/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico MolecularRESUMEN
We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
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Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Fusión de Oncogenes , Receptor trkA/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Antígenos de Diferenciación de Linfocitos B/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidoresRESUMEN
BACKGROUND: Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC. MATERIALS AND METHODS: IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I-II-IIIA NSCLC patients. RESULTS: Fourty-six tumors (40.3%) were IGF1R FISH-positive (FISH+), and 76 (67.2%) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1%). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0%) and 69 (55.2%) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8%) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ(2) = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II-III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS. CONCLUSIONS: IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Receptor IGF Tipo 1/biosíntesis , Receptor IGF Tipo 1/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Hibridación in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores Sexuales , Fumar/efectos adversosRESUMEN
BACKGROUND: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). METHODS: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. RESULTS: MET FISH-positive cases (N=36, mean î¶3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN î¶3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately. CONCLUSION: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Dosificación de Gen , Factor de Crecimiento de Hepatocito/genética , Proteínas Proto-Oncogénicas c-met/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , TrastuzumabAsunto(s)
Antineoplásicos/uso terapéutico , Receptores ErbB/genética , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Gefitinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Metaanálisis como Asunto , Técnicas de Diagnóstico Molecular , Mutación , Quinazolinas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: to evaluate the efficacy and safety of first-line single-agent cetuximab in fit elderly patients with metastatic colorectal cancer, as well as potential molecular predictive factors for efficacy. PATIENTS AND METHODS: patients aged 70 or older with metastatic CRC without criteria for frailty and no prior treatment for advanced disease were treated with single-agent cetuximab 400mg/m(2) followed by weekly 250mg/m(2) until disease progression or unacceptable toxicity. RESULTS: forty-one patients were included. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6%. Fifteen patients (36.6%) remained stable. Median time to progression was 2.9 months and median overall survival 11.1 months despite two-third of patients received chemotherapy at progression. Forty-five percent of EGFR gene copy number positive patients by FISH were progression-free at 12 weeks, in contrast with 12% of FISH negative patients (p=0.04). Grade 3 skin toxicity was reported in 5 patients (12.2%). Hypersensitivity infusion reactions were not reported and there were no toxic deaths. CONCLUSION: cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic colorectal cancer, but the present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Cetuximab , Progresión de la Enfermedad , Receptores ErbB/sangre , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Masculino , Cumplimiento de la Medicación , Metástasis de la Neoplasia , EspañaRESUMEN
BACKGROUND: The purpose of this study is to investigate the prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected non-small-cell lung cancer (NSCLC). Patient characteristics and methods: This retrospective study was conducted in 369 stage I-II-IIIA, surgically resected, NSCLC patients. Patients exposed to anti-epidermal growth factor receptor (EGFR) agents were excluded. IGF1R expression was evaluated by immunohistochemistry in tissue microarray sections. RESULTS: A positive IGF1R expression (score > or = 100) was observed in 282 cases (76.4%) and was significantly associated with squamous cell histology (P = 0.04) and with grade III differentiation (P = 0.02). No difference in survival was observed between the positive and negative group when score 100 was used as cut-off for discriminating a positive versus a negative IGF1R result (52 versus 48 months, P = 0.99) or when median value of IGF1R expression was used (45 versus 55 months, P = 0.36). No difference in survival was observed between IGF1R-positive and -negative patients in a subgroup of stage I-II adenocarcinoma (n = 137) with known EGFR mutation and copy number status. CONCLUSIONS: IGF1R expression does not represent a prognostic factor in resected NSCLC patients. Patients with squamous cell carcinoma overexpress IGF1R more frequently than patients with nonsquamous histology, justifying the different sensitivity to anti-IGF1R agents observed in clinical trials.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Receptor IGF Tipo 1/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/mortalidad , Adenocarcinoma Bronquioloalveolar/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Estudios de Cohortes , Femenino , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Análisis de Matrices Tisulares , Resultado del TratamientoRESUMEN
There is a need for predictive biomarkers that identify non-small-cell lung cancer (NSCLC) patients most likely to respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There are numerous potential candidates, although none has been proven in prospective clinical trials. The EGFR gene copy number evaluated by fluorescence in situ hybridisation (FISH) has been highlighted as one of the most effective markers for sensitivity to EGFR TKIs in large phase III, randomised placebo-controlled trials and has been used in clinical settings to assist physicians in defining the therapeutic regimen. The EGFR FISH assay has technical challenges and it is critical that detailed guidelines are provided to help clinical laboratories in performing and interpreting the test. Excellent assay reproducibility and portability rates among laboratories are crucial to guarantee that accurate clinical decisions can be made for patients with NSCLC. This article discusses the consensus outcomes of a global workshop convened to discuss key technical issues and standardise reading strategies for the EGFR FISH assay of NSCLC tumour tissue.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/diagnóstico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto , Receptores ErbB/antagonistas & inhibidores , Humanos , Hibridación Fluorescente in Situ/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Guías de Práctica Clínica como Asunto , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib , Gefitinib , Dosificación de Gen , Expresión Génica , Humanos , Neoplasias Pulmonares/enzimología , Pronóstico , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are effective in a subset of patients with non-small-cell lung cancer (NSCLC). We previously showed that E-cadherin expression associates with gefitinib activity. Here, we correlated the expressions of ErbB-3 and E-cadherin in NSCLC tumors and cell lines, their effect on response to gefitinib, and induction of both by the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275. METHODS: Real-time RT-PCR was carried out on RNA isolated from 91 fresh-frozen NSCLC samples and from 21 NSCLC lines. Protein expression was evaluated with western blot and flow cytometry. Apoptosis was assessed using vibrant apoptosis assay. RESULTS: Expressions of E-cadherin and ErbB-3 correlated significantly in primary tumors (r = 0.38, P < 0.001) and in cell lines (r = 0.88, P < 0.001). Cotransfection of ErbB-3 and E-cadherin in a gefitinib-resistant cell line showed enhanced apoptotic response to gefitinib. vorinostat and SNDX-275 induced ErbB-3 and E-cadherin in gefitinib-resistant cell lines. When gefitinib-resistant lines were treated with vorinostat and gefitinib, synergistic effects were detected in four of the five lines tested. CONCLUSION: ErbB-3 and E-cadherin are coexpressed and induced by HDAC inhibitors. For tumors with low ErbB-3 and E-cadherin expressions, the combination of HDAC and EGFR-tyrosine kinase inhibitors increased expression of both genes and produced more than additive apoptotic effect.
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Antineoplásicos/uso terapéutico , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor ErbB-3/metabolismo , Secuencia de Bases , Western Blotting , Cadherinas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Estudios de Cohortes , Cartilla de ADN , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Femenino , Gefitinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas , Humanos , Inmunoprecipitación , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Receptor ErbB-3/genéticaRESUMEN
BACKGROUND: MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. PATIENTS AND METHODS: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. RESULTS: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. CONCLUSIONS: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Dosificación de Gen , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Línea Celular Tumoral , Ensayos Clínicos Fase II como Asunto , Estudios de Cohortes , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Gefitinib , Regulación Neoplásica de la Expresión Génica , Genes erbB-1/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-met , Análisis de SupervivenciaRESUMEN
Pulmonary arterial hypertension (PAH) is a fatal disease associated with severe remodeling of the large and small pulmonary arteries. Increased accumulation of inflammatory cells and apoptosis-resistant cells are contributing factors. Proliferative apoptosis-resistant cells expressing CD133 are increased in the circulation of PAH patients. Circulating cells can contribute to tissue repair via cell fusion and heterokaryon formation. We therefore hypothesized that in the presence of increased leukocytes and CD133-positive (CD133(pos)) cells in PAH lung tissue, cell fusion and resulting genomic instability could account for abnormal cell proliferation and the genesis of vascular lesions. We performed analyses of CD45/CD133 localization, cell fusion, and proliferation during late-stage PAH in human lung tissue from control subjects and subjects with idiopathic (IPAH) and familial (FPAH) PAH. Localization, proliferation, and quantitation of cell populations in individual patients were performed by immunolocalization. The occurrence of cellular fusion in vascular lesions was analyzed in lung tissue by fluorescence in situ hybridization. We found the accumulation of CD45(pos) leukocytic cells in the tissue parenchyma and perivascular regions in PAH patients and less frequently observed myeloid cells (CD45/CD11b). CD133(pos) cells were detected in occlusive lesions and perivascular areas in those with PAH and were more numerous in those with IPAH lesions than in FPAH lesions. Cells coexpressing CD133 and smooth muscle alpha-actin were occasionally observed in occlusive lesions and perivascular areas. Proliferating cells were more prominent in IPAH lesions and colocalized with CD45 or CD133. We found no evidence of increased ploidy to suggest cell fusion. Taken together, these data suggest that abnormal lesion formation in PAH occurs in the absence of cell fusion.
Asunto(s)
Apoptosis , Hipertensión Pulmonar/patología , Pulmón/patología , Células Mieloides/patología , Arteria Pulmonar/patología , Antígeno AC133 , Adulto , Antígenos CD/metabolismo , Fusión Celular , Proliferación Celular , Niño , Femenino , Células Gigantes/metabolismo , Células Gigantes/patología , Glicoproteínas/metabolismo , Humanos , Hipertensión Pulmonar/metabolismo , Antígenos Comunes de Leucocito/biosíntesis , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Células Mieloides/metabolismo , Péptidos/metabolismo , Arteria Pulmonar/metabolismoRESUMEN
Investigation of the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia patients is essential to predict prognosis and survival. In 20 patients treated at the Bone Marrow Transplantation Unit of São José do Rio Preto (São Paulo, Brazil), we used fluorescence in situ hybridization (FISH) to investigate the frequency of cells with BCR/ABL rearrangement at diagnosis and at distinct intervals after allo-HSCT until complete cytogenetic remission (CCR). We investigated the disease-free survival, overall survival in 3 years and transplant-related mortality rates, too. Bone marrow samples were collected at 1, 2, 3, 4, 6, 12, and 24 months after transplantation and additional intervals as necessary. Success rate of the FISH analyses was 100%. CCR was achieved in 75% of the patients, within on average of 3.9 months; 45% patients showed CCR within 60 days after HSCT. After 3 years of the allo-HSCT, overall survival rate was 60%, disease-free survival was 50% and the transplant-related mortality rate was 40%. The study demonstrated that the BCR-ABL FISH assay is useful for follow-up of chronic myeloid leukemia patients after HSCT and that the clinical outcome parameters in our patient cohort were similar to those described for other bone marrow transplantation units.
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Trasplante de Células Madre Hematopoyéticas/métodos , Hibridación Fluorescente in Situ/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Adolescente , Adulto , Trasplante de Médula Ósea , Brasil , Supervivencia sin Enfermedad , Departamentos de Hospitales , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Cetuximab , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-met , Proteínas Proto-Oncogénicas p21(ras) , Receptores de Factores de Crecimiento/genética , Receptores de Somatomedina/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. MATERIALS AND METHODS: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. RESULTS: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. CONCLUSIONS: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.