RESUMO
We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.
Assuntos
Benzamidas , Neoplasias da Mama , Piperazinas , Pirazóis , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Piperazinas/efeitos adversos , Pirazóis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use. PATIENTS AND METHODS: We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient. RESULTS: ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively). CONCLUSIONS: ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , DNA Tumoral Circulante/genética , Progressão da Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/patologia , Estudos ProspectivosRESUMO
Molecular profiling has changed the treatment landscape in advanced non-small-cell lung cancer. Accurately identifying the tumours that harbour sensitizing EGFR mutations, the most common targetable molecular alteration, as well as those with acquired resistance mutations (e.g. T790M) on treatment is a high clinical priority. The current clinical gold standard is genotyping of tumour specimens. However, the practical utility of this approach is limited by the lack of available tissue and the potential complications associated with biopsies. With the advent of newer sequencing assays, it has become feasible to assess tumour genomics via a blood sample, termed a 'liquid biopsy'. In this review, we summarize the available techniques for liquid biopsies and their applicability for detecting sensitizing and resistance EGFR mutations and how these results may be used for making treatment decisions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Técnicas de Genotipagem/métodos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Tomada de Decisão Clínica , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Estudos de Viabilidade , Humanos , Biópsia Líquida/métodos , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Valor Preditivo dos Testes , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Medição de Risco/métodos , Resultado do TratamentoRESUMO
Background: Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Patients and methods: Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI. Results: Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival. Conclusions: Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.
Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , DNA Tumoral Circulante/sangue , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.
Assuntos
DNA de Neoplasias/sangue , DNA de Neoplasias/urina , Mutação , Neoplasias da Bexiga Urinária/genética , Idoso , Feminino , Seguimentos , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/genética , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapiaRESUMO
Background: Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. Material and methods: ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. Results: The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. Conclusion(s): ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Análise Mutacional de DNA/métodos , DNA de Neoplasias/sangue , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , DNA de Neoplasias/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.
Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteômica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/patologia , Medicina de PrecisãoAssuntos
Procedimentos Cirúrgicos Ambulatórios , Arquitetura Hospitalar , Ambulatório Hospitalar/organização & administração , Arquitetura , Eficiência Organizacional , Hospitais Especializados/organização & administração , Modelos Estruturais , Cidade de Nova Iorque , Oftalmologia , Otolaringologia , Ambulatório Hospitalar/estatística & dados numéricos , Cuidados Pós-Operatórios , Cuidados Pré-OperatóriosRESUMO
A case of chondroma of the soft tissues of the right middle finger is presented. The possible origins and treatment are discussed.
Assuntos
Condroma/diagnóstico , Dedos , Neoplasias de Tecidos Moles/diagnóstico , Condroma/cirurgia , Dedos/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/cirurgiaRESUMO
The use of articular branch of the dorsal sensory ulnar nerve as a nerve graft is discussed. A case of traumatic neuroma of the dorsal ulnar nerve which was treated by this method is presented.