RESUMO
Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%-15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.
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Esclerose Tuberosa , Proteínas Supressoras de Tumor , Humanos , Proteínas Supressoras de Tumor/genética , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Mutação , Proteína 1 do Complexo Esclerose Tuberosa/genética , FenótipoRESUMO
The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progressed, and had pre-treatment and post-treatment tumor samples available for analysis. We performed deep whole exome sequencing on the paired tumor samples and a blood sample. Sequence data was analyzed using Mutect, CapSeg, Absolute, and Phylogic to identify mutations, copy number changes, and their changes over time. We also performed in vitro functional assays on PBRM1 in RCC cell lines. Five patients had clear cell and one had chromophobe RCC. 434 somatic mutations in 416 genes were identified in the 12 tumor samples. 201 (46%) of mutations were clonal in both samples while 129 (30%) were acquired in the post-treatment samples. Tumor heterogeneity or sampling issues are likely to account for some mutations that were acquired in the post-treatment samples. Three samples had mutations in TSC1; one in PTEN; and none in MTOR. PBRM1 was the only gene in which mutations were acquired in more than one post-treatment sample. We examined the effect of PBRM1 loss in multiple RCC cell lines, and could not identify any effect on rapalog sensitivity in in vitro culture assays. We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC. Furthermore, mechanisms of resistance to rapalogs in RCC remain unclear and our results suggest that PBRM1 loss may contribute to sensitivity through complex transcriptional effects.
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Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Renais/tratamento farmacológico , Proteínas Nucleares/genética , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA , Progressão da Doença , Epigênese Genética , Everolimo/farmacologia , Everolimo/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Heterogeneidade Genética/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Sequenciamento do ExomaRESUMO
PURPOSE: Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype. METHODS: cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier. RESULTS: cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy. CONCLUSION: cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.
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Carcinoma de Células Renais , Ácidos Nucleicos Livres , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Ácidos Nucleicos Livres/genética , DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , PlasmaRESUMO
PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
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Esclerose Tuberosa , Pré-Escolar , Humanos , Lactente , Mosaicismo , Mutação , Fenótipo , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
PURPOSE: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk. METHODS: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples. RESULTS: TSC mosaic patients (MVAF: 0-10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically. CONCLUSION: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.
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Esclerose Tuberosa/epidemiologia , Esclerose Tuberosa/genética , Adulto , Transmissão de Doença Infecciosa/estatística & dados numéricos , Feminino , Genótipo , Humanos , Masculino , Mosaicismo , Mutação , Fenótipo , Prevalência , Fatores de Risco , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Estados UnidosRESUMO
PURPOSE: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. METHODS: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. RESULTS: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24 years, n = 7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10 years, n = 12), and germline TSC patients (10 findings, 4 years, n = 29). Cutaneous and internal organ involvement positively correlated in mosaic (R = 0.62, p = 0.005), but not germline (R = -0.24, p = 0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R = 0.55, p = 0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. CONCLUSION: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.
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Esclerose Tuberosa/classificação , Esclerose Tuberosa/genética , Adulto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação/genética , Fenótipo , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
CONTEXT: Data regarding health-related quality of life in breast cancer patients in the Middle East are limited with fatigue and sleep disturbance being the most distressing symptoms reported by patients treated for early breast cancer. AIMS: The aim of this study was to examine the prevalence and incidence of insomnia among patients with early-stage breast cancer patients treated with chemotherapy. SUBJECTS AND METHODS: This was a prospective cohort study. We enrolled patients with stage I-III breast cancer patients treated with chemotherapy at the American University of Beirut Medical Center. At three different time points (prior to, during, and following chemotherapy), we assessed the severity of sleep disturbances using the Pittsburgh Sleep Quality Index and the Insomnia Severity Index. The Institution Review Board approved the study. RESULTS: Fifty-two patients were recruited. There was a significant increase in sleep disturbances during chemotherapy which improved to below baseline levels on completion of therapy. Prior to chemotherapy, 36% of patients reported poor sleep versus 58% during chemotherapy. The percentage of patients reporting clinical insomnia rose from 11% pretreatment to 36% during chemotherapy reflecting a significant symptomatic burden that is poorly documented and managed in routine clinical practice. CONCLUSIONS: Patients with nonmetastatic breast cancer experience an increase in sleep disturbances during the treatment phase. Physicians should be aware of the need to routinely screen for sleep disturbance in breast cancer patients undergoing chemotherapy.
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Angiomiolipoma/genética , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Linfangioleiomiomatose/genética , Mosaicismo , Neoplasias Primárias Múltiplas/genética , Neoplasias Retroperitoneais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adulto , Idoso , Ácidos Nucleicos Livres/genética , Feminino , Humanos , Linfangioleiomiomatose/sangue , Pessoa de Meia-Idade , Pneumotórax , Fator D de Crescimento do Endotélio Vascular/sangue , Adulto JovemRESUMO
BACKGROUND: Patients with primary refractory metastatic renal cell carcinoma (mRCC) have a dismal prognosis and poor response to subsequent treatments. While there are several approved second-line therapies, it remains critical to choose the most effective treatment regimen. PATIENTS AND METHODS: We identified 7 patients with clear cell mRCC who had primary resistance to vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) combination therapy. The patients were treated with lenvatinib (a multitargeted TKI) plus everolimus (a mammalian target of rapamycin inhibitor). Among these 7 patients, 2 had prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. We collected the patients' clinical characteristics, molecular profiles, treatment durations, and toxicity outcomes. RESULTS: The median time to progression on prior therapies was 1.5 months. Lenvatinib plus everolimus was used either as a second-line (n = 4) or third-line (n = 3) therapy. As best responses, 3 patients had partial responses and 3 achieved stable disease. Patients were followed for ≥17 months; progression-free survival ranged from 3 to 15 months, and overall survival ranged from 4 to 17 months. CONCLUSION: These 7 cases provide real-world data for the use of lenvatinib plus everolimus in patients with mRCC with primary resistance to first-line VEGF-targeted TKIs or ICI combination therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Adulto , Carcinoma de Células Renais/secundário , Everolimo/administração & dosagem , Feminino , Seguimentos , Humanos , Imunoterapia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Quinolinas/administração & dosagem , Sirolimo/administração & dosagem , Taxa de SobrevidaRESUMO
We previously showed that alterations in mTOR pathway genes were correlated with response to rapalog therapy in metastatic renal cell carcinoma (mRCC), when the analysis focused on extremes of response. Herein, we expand on the prior cohort and examine genetic correlations with rapalog response in a dataset not selected for extremes of response. Tumors from 58 patients from the phase III trial of temsirolimus and 51 local patients with mRCC treated with rapalogs were studied. Somatic mutations were investigated using a targeted sequencing platform covering 27 genes. Clinical benefit (CB) was defined as patients with complete remission, partial response, or stable disease lasting at least 22 weeks. Mutational analyses focused on 5 mTOR pathway genes (TSC1, TSC2, MTOR, PTEN, PIK3CA) and 6 genes commonly mutated in RCC (BAP1, KDM5C, PBRM1 SETD2, TP53, and VHL). Among the 109 patients, 93 (85%) patients had clear cell histology, and 31 (28%) showed CB. Nine of 30 (30%) patients harboring mTOR pathway mutations in their tumor achieved CB versus 22 of 79 (28%) in the wild-type group. There was no distinct association between any individual or combination of mTOR pathway gene mutations and CB. Three of 7 patients with TSC1 mutations showed CB. In addition, none of the 6 genes commonly mutated in RCC showed a mutation pattern that correlated with CB. Overall, in this large and diverse population of patients with mRCC, there is no suggestion of a correlation between response to rapalog therapy and mutation status for mTOR pathway genes.
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Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Análise de SobrevidaRESUMO
Background: Despite pain awareness and the development of treatment guidelines, cancer-related pain assessment and management remain suboptimal. Our objectives were to estimate the prevalence and severity of pain and its interference with daily activities, and evaluate adequacy of treatment in cancer patients in Lebanon. Methods: A total of 400 cancer patients aged 18 and above were interviewed at the American University of Beirut Medical Center surgical and medical oncology floors, outpatient clinics and chemotherapy units from March 2016-February 2017. The subjects covered were socio-demographics, clinical data, and presence of pain in the past month with use of the Brief Pain Inventory questionnaire. Descriptive statistics were conducted using t-test, chi-square and Fischer's exact tests. Pearson's correlation coefficients were used to examine relationships between pain severity and pain interference. Logistic regression was employed to determine risk factors for pain. Results: The majority of participants were Lebanese (76.0%), females (62.7%), married (80.2%), of Muslim faith (64.2%), of urban residence (85.8%), and with insurance plans (81.3%). Most had breast cancer (38.8%), were stage 4 (52.7%) and underwent a combination of surgery and systemic therapy (55.1%). The prevalence of pain in the past month was 29.8%. Among patients with pain, the highest proportion had moderate pain (37.8%) and around 46% received inadequate treatment. Conclusion: More awareness about cancer-related pain is needed to improve pain management and encourage referral to palliative care and pain specialists early-on in diagnosis of disease.
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Dor do Câncer/epidemiologia , Dor do Câncer/terapia , Neoplasias/complicações , Manejo da Dor/métodos , Índice de Gravidade de Doença , Centros de Atenção Terciária , Dor do Câncer/patologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Líbano/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/cirurgia , Prevalência , Prognóstico , Qualidade de Vida , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients (n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% (n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. ©2018 AACR.
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Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Poor-risk patients with metastatic renal-cell carcinoma remain poorly characterized in prospective clinical trials. Therefore, we sought to provide a comprehensive analysis of this patient population, defined by 3 widely used prognostic models, treated with targeted therapy. PATIENTS AND METHODS: We conducted a pooled retrospective analysis of 4736 metastatic renal-cell carcinoma patients treated on phase 2 and 3 clinical trials. Poor-risk patients were defined according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), and Hudes risk models. Baseline characteristics, overall survival, progression-free survival, objective response rate, and adverse events were reported in poor-risk patients defined by each of the 3 models. The concordance (C)-index was used to assess the prognostic performance of the models. A subset of poor-risk patients who continued to receive treatment for > 12 months was characterized. RESULTS: Overall, we identified 1145 (24%), 904 (19%), and 1901 (40%) poor-risk patients by the IMDC, MSKCC, and Hudes models, respectively. Median overall survival was 8.5 months, 7.5 months, and 10.6 months; and median progression-free survival was 3.7 months, 3.5 months, and 4.2 months in the IMDC, MSKCC, and Hudes models, respectively. The objective response rate ranged between 10% and 14%. Additionally, 9% to 14% of poor-risk patients continued to receive treatment for > 12 months. Most importantly, the C-index was 0.826, 0.830, and 0.825 in the IMDC, MSKCC, and Hudes risk models, respectively. CONCLUSION: We demonstrate that poor-risk patients continue to have dismal outcomes and warrant alternative treatment strategies to help improve outcomes. A subset of patients experienced prolonged clinical benefit and should be further explored.
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INTRODUCTION: Observational studies have suggested that metformin use is associated with favorable outcomes in several cancers. For renal cell carcinoma (RCC), data have been limited. Therefore, we investigated the effect of metformin on survival in metastatic RCC (mRCC) using a large clinical trial database. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with mRCC in phase II and III clinical trials. The overall survival (OS) in metformin users was compared with that of users of other antidiabetic agents and those not using antidiabetic agents. Progression-free survival, objective response rate, and adverse events were secondary endpoints. Subgroup analyses were conducted after stratifying by class of therapy, type of vascular endothelial growth factor tyrosine kinase inhibitors, and International Metastatic RCC Database Consortium (IMDC) risk groups. RESULTS: We identified 4736 patients with mRCC, including 486 with diabetes, of whom 218 (4.6%) were taking metformin. Metformin use did not affect OS when compared with users of other antidiabetic agents or those without diabetes. Furthermore, metformin use did not confer an OS advantage when stratified by class of therapy and IMDC risk group. However, in diabetic patients receiving sunitinib (n = 128), metformin use was associated with an improvement in OS compared with users of other antidiabetic agents (29.3 vs. 20.9 months, respectively; hazard ratio, 0.051; 95% confidence interval, 0.009-0.292; P = .0008). CONCLUSION: In the present study, we found a survival benefit for metformin use in mRCC patients treated with sunitinib. Clinical and preclinical studies are warranted to validate our results and guide the use of metformin in the clinic.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Metformina/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Metástase Neoplásica , Estudos Retrospectivos , Sunitinibe , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen. CASE PRESENTATION: Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab. CONCLUSION: The exact cause of our patient's sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response.
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Antineoplásicos Imunológicos/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Humanos , Perna (Membro) , Masculino , Melanoma/cirurgia , Metástase Neoplásica , Cuidados Paliativos/métodos , Remissão Espontânea , Neoplasias Cutâneas/secundário , Neoplasias Cutâneas/cirurgiaRESUMO
Purpose: Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (PLOS One 2014). Gene expression profiles of tumors of treated patients were investigated for their association with immunotherapeutic benefit. Methods: Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks × 2 doses) before and after surgery. Tumor specimens were obtained at baseline and at definitive surgery (weeks 6-8). Gene expression profiling was performed on the tumor biopsies of 27 patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Significance analysis of microarrays was performed to test the association of each gene with outcome. Pathway analysis was performed using Ingenuity Pathway Analysis software. The Benjamini and Hochberg method was used to adjust for multiple testing in the pathway analysis. Results: Pathway analysis identified biologically relevant pathways enriched with genes that are significantly associated with clinical outcome at baseline in relation to relapse-free survival (RFS) and disease non-progression (as assessed preoperatively at week 6) as well as early on-treatment (RFS and overall survival). The molecules and pathways that achieved differential expression of highest statistical significance were notably immune related. Association of the gene signature with clinical outcome overlapped between baseline and on-treatment specimens and across clinical endpoints tested. Conclusion: Gene expression profiling identified a signature reflecting an immune active and proinflammatory tumor microenvironment that derived clinical benefit from neoadjuvant ipilimumab at baseline and early on-treatment. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics.
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BACKGROUND: Several retrospective studies have reported that younger age at presentation is associated with a worse prognosis for nonmetastatic breast cancer patients. In this study, we prospectively assessed the association between different baseline characteristics (age, tumor characteristics, mode of treatment, etc) and outcomes among newly diagnosed nonmetastatic Lebanese breast cancer patients. METHODS: We recruited a sample of 123 women newly diagnosed with nonmetastatic breast cancer presenting to American University of Beirut Medical Center. Immunohistochemical, molecular (vitamin D receptor, methylene tetrahydrofolate reductase polymorphisms), and genetic assays were performed. Patient characteristics were compared by age group (<40 and ≥40 years). A Cox regression analysis was performed to evaluate the variables affecting the disease-free survival (DFS). Outcome data were obtained, and DFS was estimated. RESULTS: Among the 123 patients, 47 were 40 years of age or younger, and 76 were older than 40 years. Median follow-up duration was 58 months. Nine out of 47 patients <40 years (19.1%) experienced disease relapse in contrast to four out of 76 patients >40 years (5.2%). A wide immunohistochemical panel included Ki-67, cyclin B1, p53, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor, and did not reveal any significant difference in these markers between the two age groups. Older patients had a larger percentage of Luminal A than younger patients. On multivariate analysis including age, stage, grade, and subtype, only age <40 and stage were significantly associated with shorter DFS with hazard ratios of 4 (p=0.03, 95% confidence interval [CI]: 1.1-13.5) and 3 (p=0.03, 95% CI: 0.8-14.9), respectively. The estimated 5-year DFS for patients >40 years was 90%, and for patients <40 years was 37%. CONCLUSION: Being <40 years old was an independent risk factor for recurrence in this cohort of patients.
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BACKGROUND: Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity. OBJECTIVE: To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs). DESIGN, SETTING, AND PARTICIPANTS: Germline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n=159) or mTOR inhibitors (n=62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were grade ≥3 AEs for all patients; grade ≥3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors. RESULTS AND LIMITATIONS: In total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08-0.88; p=0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with analyzed toxicities. CONCLUSIONS: We observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed. PATIENT SUMMARY: We found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma.
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PURPOSE: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. RESULTS: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. CONCLUSIONS: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.