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1.
Ann Oncol ; 31(11): 1561-1568, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32739409

RESUMO

BACKGROUND: By understanding prognostic biomarkers, we gain insights into disease biology and may improve design, conduct, and data analysis of clinical trials and real-world data. In this context, we used the Flatiron Health Electronic Health Record-derived deidentified database that provides treatment outcome and biomarker data from >280 oncology centers in the USA, organized into 17 cohorts defined by cancer type. PATIENTS AND METHODS: In 122 694 patients, we analyzed demographic, clinical, routine hematology, and blood chemistry parameters within a Cox proportional hazard framework to derive a multivariable prognostic risk model for overall survival (OS), the 'Real wOrld PROgnostic score (ROPRO)'. We validated ROPRO in two independent phase I and III clinical studies. RESULTS: A total of 27 variables contributed independently and homogeneously across cancer indications to OS. In the largest cohort (advanced non-small-cell lung cancer), for example, patients with elevated ROPRO scores (upper 10%) had a 7.91-fold (95% confidence interval 7.45-8.39) increased death hazard compared with patients with low scores (lower 10%). Median survival was 23.9 months (23.3-24.5) in the lowest ROPRO quartile Q1, 14.8 months (14.4-15.2) in Q2, 9.4 months (9.1-9.7) in Q3, and 4.7 months (4.6-4.8) in Q4. The ROPRO model performance indicators [C-index = 0.747 (standard error 0.001), 3-month area under the curve (AUC) = 0.822 (0.819-0.825)] strongly outperformed those of the Royal Marsden Hospital Score [C-index = 0.54 (standard error 0.0005), 3-month AUC = 0.579 (0.577-0.581)]. We confirmed the high prognostic relevance of ROPRO in clinical Phase 1 and III trials. CONCLUSIONS: The ROPRO provides improved prognostic power for OS. In oncology clinical development, it has great potential for applications in patient stratification, patient enrichment strategies, data interpretation, and early decision-making in clinical studies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Estudos de Coortes , Humanos , Prognóstico , Estudos Retrospectivos
2.
Ann Oncol ; 30(8): 1381-1392, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31114846

RESUMO

BACKGROUND: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. RESULTS: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. CONCLUSIONS: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Macrófagos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Paclitaxel/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/sangue , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/patologia , Paclitaxel/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Pele/citologia , Pele/imunologia , Resultado do Tratamento , Adulto Jovem
3.
Oncogene ; 32(19): 2463-74, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-22751112

RESUMO

Truncated-ERBB2 isoforms (t-ERBB2s), resulting from receptor proteolysis or alternative translation of the ERBB2 mRNA, exist in a subset of human breast tumors. t-ERBB2s lack the receptor extracellular domain targeted by therapeutic anti-ERBB2 antibodies and antibody-drug conjugates, including trastuzumab, trastuzumab-DM1 and pertuzumab. In clinical studies, expression of t-ERBB2 in breast tumors correlates with metastasis as well as trastuzumab resistance. By using a novel immuno-microarray method, we detect a significant t-ERBB2 fraction in 18 of 31 (58%) of immunohistochemistry (IHC)3+ ERBB2+ human tumor specimens, and further show that t-ERBB2 isoforms are phosphorylated in a subset of IHC3+ samples (10 of 31, 32%). We investigated t-ERBB2 biological activity via engineered expression of full-length and truncated ERBB2 isoforms in human mammary epithelial cells (HMECs), including HMEC and MCF10A cells. Expression of p110 t-ERBB2, but not p95m (m=membrane, also 648CTF) or intracellular ERBB2s, significantly enhanced cell migration and invasion in multiple cell types. In addition, only expression of the p110 isoform led to human breast epithelial cell (HMLE) xenograft formation in vivo. Expression of t-ERBB2s did not result in hyperactivation of the phosphoinositide kinase-3/AKT or mitogen-activated protein kinase signaling pathways in these cells; rather, phosphoproteomic array profiling revealed attenuation of phosphorylated signal transducer and activator of transcription 5 (STAT5) in p110-t-ERBB2-expressing cells compared to controls. Short hairpin-mediated silencing of STAT5 phenocopied p110-t-ERBB2-driven cell migration and invasion, while expression of constitutively active STAT5 reversed these effects. Thus, we provide novel evidence that (1) expression of p110 t-ERBB2 is sufficient for full transformation of HMEC, yielding in vivo xenograft formation, and (2) truncated p110 t-ERBB2 expression is associated with decreased phosphorylation of STAT5.


Assuntos
Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Receptor ErbB-2/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Fragmentos de Peptídeos/metabolismo , Fosforilação , Fator de Transcrição STAT5/genética , Transdução de Sinais , Transplante Heterólogo
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