RESUMO
BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.
Assuntos
Anticorpos , Antineoplásicos , Imunoconjugados , Neoplasias , Adolescente , Adulto , Anticorpos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Teorema de Bayes , Moléculas de Adesão Celular , Relação Dose-Resposta a Droga , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The development of immune checkpoint blockade (ICB) has changed the way we treat various cancers. While ICB produces durable survival benefits in a number of malignancies, a large proportion of treated patients do not derive clinical benefit. Recent clinical profiling studies have shed light on molecular features and mechanisms that modulate response to ICB. Nevertheless, none of these identified molecular features were investigated in large enough cohorts to be of clinical value. MATERIALS AND METHODS: Literature review was carried out to identify relevant studies including clinical dataset of patients treated with ICB [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the combination] and available sequencing data. Tumor mutational burden (TMB) and 37 previously reported gene expression (GE) signatures were computed with respect to the original publication. Biomarker association with ICB response (IR) and survival (progression-free survival/overall survival) was investigated separately within each study and combined together for meta-analysis. RESULTS: We carried out a comparative meta-analysis of genomic and transcriptomic biomarkers of IRs in over 3600 patients across 12 tumor types and implemented an open-source web application (predictIO.ca) for exploration. TMB and 21/37 gene signatures were predictive of IRs across tumor types. We next developed a de novo GE signature (PredictIO) from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes, F2RL1 (encoding protease-activated receptor-2) and RBFOX2 (encoding RNA-binding motif protein 9), were concurrently associated with worse ICB clinical outcomes, T-cell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models. CONCLUSION: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy.
Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Camundongos , Animais , Antígeno CTLA-4/genética , Inibidores de Checkpoint Imunológico , Big Data , Antígeno B7-H1 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Biomarcadores Tumorais/genética , Fatores de Processamento de RNA/uso terapêutico , Proteínas RepressorasRESUMO
Better knowledge of the tumor genomic landscapes has helped to develop more effective targeted drugs. However, there is no tool to interpret targetability of genomic alterations assessed by next-generation sequencing in the context of clinical practice. Our aim is to rank the level of evidence of individual recurrent genomic alterations observed in breast cancer based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in order to help the clinicians to prioritize treatment. Analyses of databases suggested that there are around 40 recurrent driver alterations in breast cancer. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations were classified tier of evidence IA based on large randomized trials showing antitumor activity of targeted therapies in patients presenting the alterations. NTRK fusions and microsatellite instability (MSI) were ranked IC. ESR1 mutations and PTEN loss were ranked tier IIA, and ERBB2 mutations and AKT1 mutations tier IIB. Somatic BRCA 1/2 mutations, MDM2 amplifications and ERBB 3 mutations were ranked tier III. Seventeen genes were ranked tier IV based on preclinical evidence. Finally, FGFR1 and CCND1 were ranked tier X alterations because previous studies have shown lack of actionability.
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Neoplasias da Mama/genética , Instabilidade Genômica/genética , Terapia de Alvo Molecular , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Genoma Humano/genética , Humanos , Mutação/genética , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Receptor ErbB-2/genéticaRESUMO
OBJECTIVES: Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. METHODS: Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. RESULTS: From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. CONCLUSIONS: Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Técnicas de Genotipagem/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Feminino , Neoplasias dos Genitais Femininos/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Estudos Prospectivos , Doenças Raras/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto JovemRESUMO
Background: In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data. Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership. Results: This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability. Conclusions: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.
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Biomarcadores Tumorais/genética , Genômica/normas , Oncologia/normas , Neoplasias/genética , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/agonistas , Biomarcadores Tumorais/antagonistas & inibidores , Biologia Computacional/normas , Consenso , Bases de Dados Genéticas/normas , Europa (Continente) , Genômica/métodos , Humanos , Oncologia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Seleção de Pacientes , Projetos de Pesquisa/normas , Sociedades Médicas/normasRESUMO
Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov , 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials.
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Ensaios Clínicos Fase I como Assunto , Bases de Dados Factuais/normas , Oncologia/normas , Revisão da Pesquisa por Pares/normas , Projetos de Pesquisa/normas , HumanosRESUMO
BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
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Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário , Feminino , GTP Fosfo-Hidrolases/genética , Genes ras , Genótipo , Humanos , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Many classes of anticancer therapy, including chemotherapeutic agents, hormonal and molecular targeted treatments, can produce ocular toxicity. Novel agents that target different cellular pathways have been related to a wide spectrum of ophthalmologic toxicities that can range from mild to severe, and include conjunctivitis, blurred vision, keratitis and optic neuritis, among others. Special attention has been drawn to the inhibitors of the MEK signaling pathway, due to their sine qua non ocular toxicity, defined as MEK retinopathy and described as symmetrical bilateral disease that develops in a time-dependent and dose-dependent manner. In this review, we discuss ophthalmologic toxicities associated with molecular targeted therapies, with particular focus on MEK retinopathy, including its nomenclature, incidence, symptoms and management.
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Antineoplásicos/efeitos adversos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Doenças Retinianas/fisiopatologia , Antineoplásicos/uso terapêutico , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/classificação , Doenças Retinianas/epidemiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.
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Biomarcadores Tumorais/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas , Piridonas/farmacocinética , Pirimidinonas/farmacocinética , Quinolinas/farmacocinética , Sulfonamidas/farmacocinética , Taxa de Sobrevida , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND: Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). METHODS: Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. CONCLUSIONS: Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.
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Antineoplásicos/administração & dosagem , Proteínas de Choque Térmico Pequenas/administração & dosagem , Neoplasias/tratamento farmacológico , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico Pequenas/efeitos adversos , Proteínas de Choque Térmico Pequenas/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: There are limited data about the quality of immune-related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications. METHODS: A systematic search of citations from Medline, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003 to 2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with quality reporting. RESULTS: After a review of 2628 articles, 50 trial reports were included, with ICIs as either monotherapy (54%) or part of a combination regimen (46%). The mean QS was 11.21 points (range 3.50-17.50 points). The median grade 3/4 AE rate reported was 21% (range 0%-66%) and 29/50 (58%) trials concluded that irAEs were tolerable. Multivariate regression analysis revealed that year of publication (within last 5 years, P = 0.01) and journal impact factor >15 (P = 0.004) were associated with higher QS. Complete reporting of specific characteristics of irAEs including onset, management and reversibility were reported by 14%, 8% and 6% of studies, respectively. The incidence of grade 3/4 adverse events was higher for inhibitors against CTLA-4 compared with other immune checkpoints (P < 0.001). CONCLUSIONS: The reporting of irAEs is suboptimal. A standardized reporting method of irAEs that accounts for tolerability, management and reversibility is needed and would enable a more precise evaluation of the therapeutic risk benefit ratio of ICIs.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Ensaios Clínicos como Assunto/métodos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Humanos , Controle de QualidadeRESUMO
BACKGROUND: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. METHODS: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. RESULTS: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzazepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Sarcoma do Estroma Endometrial/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: overexpression of HER-2 is observed in 15-25% of breast cancers, and is associated with increased risk of recurrence. Current guidelines recommend trastuzumab and chemotherapy for most HER-2-positive patients. However, the majority of patients does not recur and might thus be overtreated with adjuvant systemic therapy. We investigated whether the 70-gene MammaPrint signature identifies HER-2-positive patients with favourable outcome. METHODS: in all, 168 T1-3, N0-1, HER-2-positive patients were identified from a pooled database, classified by the 70-gene signature as good or poor prognosis, and correlated with long-term outcome. A total of 89 of these patients did not receive adjuvant chemotherapy. RESULTS: in the group of 89 chemotherapy-naive patients, after a median follow-up of 7.4 years, 35 (39%) distant recurrences and 29 (33%) breast cancer-specific deaths occurred. The 70-gene signature classified 20 (22%) patients as good prognosis, with 10-year distant disease-free survival (DDFS) of 84%, compared with 69 (78%) poor prognosis patients with 10-year DDFS of 55%. The estimated hazard ratios (HRs) were 4.5 (95% confidence interval (CI) 1.1-18.7, P=0.04) and 3.8 (95% CI 0.9-15.8, P=0.07) for DDFS and breast cancer-specific survival (BCSS), respectively. In multivariate analysis adjusted for known prognostic factors and hormonal therapy, HRs were 5.8 (95% CI 1.3-26.7, P=0.03) and 4.7 (95% CI 1.0-21.7, P=0.05) for DDFS and BCSS, respectively. INTERPRETATION: the 70-gene prognosis signature is an independent prognostic indicator that identifies a subgroup of HER-2-positive early breast cancer with a favourable long-term outcome.
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Neoplasias da Mama/mortalidade , Perfilação da Expressão Gênica , Receptor ErbB-2/análise , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
AIMS: Venous thromboembolism (VTE) is a potential complication among germ cell tumour patients. We evaluated the incidence rate, timing and factors associated with VTE among patients with germ cell cancer in routine practice. MATERIALS AND METHODS: The Ontario Cancer Registry was linked to electronic records of treatment to identify all cases of testicular cancer treated in Ontario during 2000-2010. Administrative databases were used to identify VTE in the 3 months before and 5 years after orchiectomy. We explored patient-, disease- and treatment-related factors associated with VTE among all patients as well as those with detailed chemotherapy records available. RESULTS: During 2000-2010, 2650 patients underwent orchiectomy for testicular cancer; among this cohort, 920 (33%) received chemotherapy. The VTE rate was 8% (69/920) among patients treated with chemotherapy and 0.6% (11/1730) among those without chemotherapy. Among the patients treated with chemotherapy who had VTE, 13% (9/69) occurred in the month before starting chemotherapy, 62% (42/69) in the first 3 months after starting and 25% thereafter. For patients who received three and four cycles, VTE rates were 8% (21/258) and 16% (19/121), respectively. In adjusted analyses, the only factor independently associated with VTE was increasing number of cycles (odds ratio 3.91 for four cycles, odds ratio 1.63 for three cycles (P = 0.022) compared with one to two cycles). CONCLUSION: This population-based study confirms findings from institutional case series regarding the high rate of VTE among patients with germ cell tumours treated with chemotherapy. Future studies should evaluate the extent to which VTE prophylactic strategies might mitigate this risk.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bases de Dados Factuais , Neoplasias Testiculares/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Adolescente , Adulto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/patologia , Adulto JovemRESUMO
Background: Bleomycin is commonly used to treat advanced testicular cancer and can be associated with severe pulmonary toxicity. The primary objective of the present study was to describe the use of pulmonary function tests (pfts) and chest imaging before, during, and after treatment with bleomycin. Methods: To identify all incident cases of testicular cancer treated with bleomycin-based chemotherapy in the Canadian province of Ontario during 2005-2010, the Ontario Cancer Registry was linked with chemotherapy treatment records. Health administrative databases were used to describe use of pfts, chest imaging, and physician visits for respiratory complaints. Results: Of 394 patients treated with orchiectomy and chemotherapy who received at least 1 dose of bleomycin, 93% had complete chemotherapy records available. In the 4 weeks before, during, and within 2 years after finishing bleomycin-based chemotherapy, pfts were performed in 17%, 17%, and 29% of patients respectively. Chest imaging was performed in 68%, 62%, and 98% of patients in the same time periods. In the 2 years after bleomycin-based chemotherapy, 23% of treated patients had a physician visit for respiratory symptoms. That rate was substantially higher for men with greater exposure to bleomycin: 40% (24 of 60) for 10-12 doses bleomycin compared with 21% (53 of 250) for 7-9 doses and with 14% (8 of 58) for 1-6 doses (p = 0.002). Conclusions: Quality improvement initiatives are needed to increase baseline rates of chest imaging within 4 weeks of starting chemotherapy for testicular cancer; to understand why such a high proportion of men have chest imaging during bleomycin-based chemotherapy; and to mitigate the excess pulmonary toxicity seen with increasing exposure to bleomycin.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Bleomicina/efeitos adversos , Cisplatino , Humanos , Masculino , Ontário , Neoplasias Testiculares/tratamento farmacológicoRESUMO
AIMS: Neurotoxicity may affect the quality of life of survivors of testicular cancer. Understanding the burden of neurotoxicity is important to guide survivorship care. A population-based study was undertaken to describe the proportion of patients in the 'real world' with neurotoxicity. MATERIALS AND METHODS: A population-based, retrospective, cohort study of patients with advanced testicular cancer treated in the province of Ontario. The Ontario Cancer Registry was linked to electronic treatment records to identify all incident cases of testicular cancer during 2000-2010. Administrative databases were used to describe health system visits for symptoms potentially related to neurotoxicity. Health system visit rates were explored by number of chemotherapy cycles among patients treated during 2005-2010 for whom complete chemotherapy details were available. RESULTS: During 2000-2010, 2650 patients underwent an orchiectomy for testicular cancer; 920 (33%) also received chemotherapy. The proportion of patients with health system visits for neurotoxicity in the 2 years before surgery compared with the 2 years after surgery remained stable among patients treated with orchiectomy alone (18% [303/1730] versus 18% [316/1730], P = 0.523); however, there was a substantial increase among patients treated with chemotherapy (16% [151/920] versus 25% [231/920], P < 0.001). Among patients treated with chemotherapy in 2005-2010 for whom complete details were available regarding number of treatment cycles there was a dose-response effect. The increase in health system visits for neurotoxicity from 2 years before compared with 2 years after orchiectomy was greater among patients treated with four cycles of chemotherapy (17% [21/121] versus 37% [45/121]) and three cycles of chemotherapy (17% [45/258] versus 28% [72/258]) compared with those treated with one to two cycles of chemotherapy (<13% [<6/45] versus 20% [9/45], P = 0.013). CONCLUSIONS: This population-based study suggests that symptoms of neurotoxicity are common among survivors of testicular cancer and that this seems to be driven by increasing exposure to chemotherapy. Clinicians should carefully evaluate patients for neurotoxicity during the survivorship phase of treatment.
Assuntos
Síndromes Neurotóxicas/fisiopatologia , Neoplasias Testiculares/complicações , Adolescente , Adulto , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sobreviventes , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
Background: A pilot inter-laboratory proficiency scheme for 5 Ontario clinical laboratories testing tumour samples for the Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) study was undertaken to assess proficiency in the identification and reporting of next-generation sequencing (ngs) test results in solid tumour testing from archival formalin-fixed, paraffin-embedded (ffpe) tissue. Methods: One laboratory served as the reference centre and provided samples to 4 participating laboratories. An analyte-based approach was applied: each participating laboratory received 10 ffpe tissue specimens profiled at the reference centre, with tumour site and histology provided. Laboratories performed testing per their standard ngs tumour test protocols. Items returned for assessment included genes and variants that would be typically reported in routine clinical testing and variant call format (vcf) files to allow for assessment of ngs technical quality. Results: Two main aspects were assessed:â Technical quality and accuracy of identification of exonic variantsâ Site-specific reporting practicesTechnical assessment included evaluation of exonic variant identification, quality assessment of the vcf files to evaluate base calling, variant allele frequency, and depth of coverage for all exonic variants. Concordance at 100% was observed from all sites in the technical identification of 98 exonic variants across the 10 cases. Variability between laboratories in the choice of variants considered clinically reportable was significant. Of the 38 variants reported as clinically relevant by at least 1 site, only 3 variants were concordantly reported by all participating centres as clinically relevant. Conclusions: Although excellent technical concordance for ngs tumour profiling was observed across participating institutions, differences in the reporting of clinically relevant variants were observed, highlighting reporting as a gap where consensus on the part of Ontario laboratories is needed.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Ensaio de Proficiência Laboratorial , Neoplasias/genética , Humanos , Ontário , Projetos Piloto , Reprodutibilidade dos Testes , Projetos de PesquisaRESUMO
BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.
Assuntos
Neoplasias/genética , Ensaios Clínicos como Assunto , Tomada de Decisões , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Disseminação de Informação , Cooperação Internacional , Biópsia Líquida , Neoplasias/diagnóstico , Ontário , Medicina de PrecisãoRESUMO
Breast cancer remains the most common malignancy in women. Since the late 1980s, significant advances have been made in the treatment of this cancer. Those advances, particularly the ones in the adjuvant setting, have led to declines in the mortality associated with breast cancer. But another result has been treatments that are more complex and that potentially carry more toxicity. One key toxicity related to the adjuvant therapy of breast cancer is cardiac toxicity. Some of the agents commonly used for the treatment of breast cancer, including anthracyclines, trastuzumab, and possibly even aromatase inhibitors, have been associated with cardiac toxicity. The present article reviews the current understanding of cardiac toxicity risk and strategies to minimize cardiac morbidity associated with cytotoxic chemotherapy, trastuzumab therapy, and hormonal therapy with aromatase inhibitors for early-stage breast cancer.