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PURPOSE: Radiochemotherapy (RCT) is an effective standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Nonetheless, toxicity is common, with patients often requiring dose modifications. METHODS: To investigate associations of RCT toxicities according to CTCAE version 5.0 and subsequent therapy modifications with short- and long-term treatment outcomes, we studied all 193 patients with HNSCC who received RCT (70 Gy + platinum agent) at an academic center between 03/2010 and 04/2018. RESULTS: During RCT, 77 (41%, 95% CI 34-49) patients developed at least one ≥ grade 3 toxicity, including seven grade 4 and 3 fatal grade 5 toxicities. The most frequent any-grade toxicities were xerostomia (n = 187), stomatitis (n = 181), dermatitis (n = 174), and leucopenia (n = 98). Eleven patients (6%) had their radiotherapy schedule modified (mean radiotherapy dose reduction = 12 Gy), and 120 patients (64%) had chemotherapy modifications (permanent discontinuation: n = 67, pause: n = 34, dose reduction: n = 7, change to other chemotherapy: n = 10). Objective response rates to RCT were 55% and 88% in patients with and without radiotherapy modifications (p = 0.003), and 84% and 88% in patients with and without chemotherapy modifications (p = 0.468), respectively. Five-year progression-free survival estimates were 20% and 50% in patients with and without radiotherapy modifications (p = < 0.001), and 53% and 40% in patients with and without chemotherapy modifications (p = 0.88), respectively. CONCLUSIONS: Reductions of radiotherapy dose were associated with impaired long-term outcomes, whereas reductions in chemotherapy intensity were not. This suggests that toxicities during RCT should be primarily managed by modifying chemotherapy rather than radiotherapy.
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Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Quimiorradioterapia/métodos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Dermatite/etiologia , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Indução/estatística & dados numéricos , Leucopenia/etiologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/uso terapêutico , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estomatite Aftosa/etiologia , Resultado do Tratamento , Xerostomia/etiologiaRESUMO
PURPOSE: The role of mean platelet volume (MPV) as a predictor of outcomes in various cancer entities including colorectal cancer (CRC) has already been analyzed. However, data on the prognostic and predictive value of MPV in CRC over multiple lines of systemic therapy are missing. METHODS: In this retrospective single-center cohort study, 690 patients with UICC stage II, III or IV CRC receiving adjuvant and/or palliative chemotherapy were included. Primary endpoints in the adjuvant, palliative and best supportive care (BSC) setting were 3-year recurrence-free survival (RFS), 6-months progression-free survival (PFS), and 6-months overall survival (OS), respectively. Kaplan-Meier estimators, log-rank tests, and uni- and multivariable Cox models were used to analyze RFS, PFS and OS. A cut-off defining patients with low MPV was chosen empirically at the 25th percentile of the MPV distribution in the respective treatment setting. RESULTS: Three-year RFS was 76%. Median 6-month PFS estimates in 1st, 2nd and 3rd line therapy were 59, 37 and 27%, respectively. Median 6-month OS in BSC was 31%. Small platelets as indicated by low MPV did not predict for shorter RFS. In the first 3 palliative treatment lines a consistent association between low MPV and decreased 6-month PFS was not observed. In the BSC setting, patients with low MPV had numerically but not significantly shorter OS. Higher MPV levels did not consistently predict for ORR or DCR across the first 3 palliative treatment lines. CONCLUSION: Small platelets are not predicting CRC outcomes, and thus are hardly useful for influencing clinical decision making.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Plaquetas/patologia , Neoplasias Colorretais/sangue , Volume Plaquetário Médio/estatística & dados numéricos , Recidiva Local de Neoplasia/sangue , Idoso , Biomarcadores Tumorais , Plaquetas/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE: The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. METHODS: This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. RESULTS: During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). CONCLUSION: We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation.
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Carboplatina/efeitos adversos , Doenças Cardiovasculares/etiologia , Terapia Combinada/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Seminoma/complicações , Neoplasias Testiculares/complicações , Adulto , Doenças Cardiovasculares/diagnóstico , Quimioterapia Adjuvante , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Seminoma/patologia , Seminoma/terapia , Taxa de Sobrevida , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapiaRESUMO
Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.
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Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , DNA de Neoplasias/sangue , Recidiva Local de Neoplasia/sangue , Biópsia , Neoplasias Colorretais/patologia , Humanos , Recidiva Local de Neoplasia/patologia , Células Neoplásicas Circulantes/patologia , Prognóstico , Transdução de SinaisRESUMO
Results of several clinically relevant studies were presented at the 2016 Annual Meeting of the European Society of Medical Oncology (ESMO). This article summerizes the personal highlights of three medical oncologists in their respective areas of expertise.
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Sclerostin has been proposed as a potent inhibitor of bone formation. Sclerostin antibodies are under clinical development to treat osteoporosis and metastatic bone disease. Serum sclerostin level is elevated in multiple myeloma, an osteolytic malignancy, where it might serve as predictive marker for the use of sclerostin-directed antibodies. As renal cell carcinoma (RCC) patients often present with osteolytic metastases, we aimed to investigate serum sclerostin levels in RCC patients. Our study included 53 RCC patients (19 with bone metastases, 25 with visceral metastases and 9 with localized disease) and 53 age- and gender-matched non-osteoporotic controls. Frozen serum samples were subjected to sclerostin quantitative sandwich ELISA. The mean serum sclerostin levels of RCC patients and controls were 45.8 pmol/l and 45.1 pmol/l, respectively (p = 0.86). Analysis of variance showed no difference between the subgroups of RCC patients with regard to visceral or bone metastases or localized disease (p = 0.22). There was no significant association between eGFR (estimated glomerular filtration rate) and serum sclerostin levels in RCC patients (r = 0.05; p = 0.74) and controls (r = 0.06; p = 0.68). Our results indicate that serum sclerostin levels appear not to be a valuable biomarker to assess the occurrence of bone metastases in RCC patients.
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BACKGROUND: Patients with soft tissue sarcoma (STS) being treated following the standardized guidelines can still not be guaranteed to remain free from local recurrence (LR). A complete tumour resection has been accepted as a major prognostic factor for LR. This retrospective study was designed to analyse the influence of two different classifications of resection margins (R-classification and UICC-classification) on LR in STS patients. MATERIALS AND METHODS: Of 411 patients treated at our institution for STS, 265 were eligible for statistical analysis. Kaplan-Meier curves and Cox regression models were used to assess the impact of an R0 resection according to the R-classification (resection margin clear but allowing <1 mm) and according to the UICC-classification (minimal resection margin ≥1 mm) on LR. RESULTS: Survival curves showed a lower LR rate for R0 resections in the UICC-classification, namely 1.3%, 12% and 12% as compared to 2.1%, 9.5% and 16.5% for the R-classification. In multivariate analysis calculated separately for each classification, R1 resection as defined by the R-classification (HR: 11.214; 95%CI: 2.394-52.517; p = 0.002) as well as by UICC-classification (HR: 15.634; 95%CI: 2.493-98.029; p = 0.003) remained significant. CONCLUSION: In our study, margin status according to both classifications represents an independent prognostic factor for LR in patients with STS following curative surgery. Local control rates were superior after a minimal resection margin of 1 mm (R0 by UICC-classification) compared to R0 resections after the R-classification.
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Margens de Excisão , Recidiva Local de Neoplasia/diagnóstico , Sarcoma/patologia , Sarcoma/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Radioterapia Adjuvante , Fatores de Risco , Sarcoma/terapiaRESUMO
We recently found variants in cancer stem cell genes (CD44, ALCAM and LGR5) significantly associated with increased time to recurrence (TTR) in patients with stage III and high-risk stage II colon cancer treated with 5-fluorouracil (5-FU)-based chemotherapy. In this study, we validated these genetic biomarkers in a large and independent patient cohort (n=599). Patients who received 5-FU-based adjuvant chemotherapy (n=391) carrying at least one C allele in LGR5 rs17109924 had a significantly increased TTR compared with patients carrying the homozygous T/T variant (HR 0.38, 95%CI 0.19-0.79; P=0.006). In patients treated with surgery alone (n=208), no association between LGR rs17109924 and TTR was found (P=0.728). In the multivariate Cox-analysis, LGR5 rs17109924 remained statistically significant (HR 0.38, 95%CI 0.18-0.78; P=0.008) for patients who received adjuvant chemotherapy. We confirmed in a large and independent study cohort that LGR5 rs17109924 is a predictive genetic biomarker for TTR in patients with colon cancer treated with 5-FU-based adjuvant chemotherapy.
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Biomarcadores Tumorais/genética , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Adulto , Quimioterapia Adjuvante , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.
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Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Receptor alfa de Estrogênio/genética , Polimorfismo Genético/genética , Proteínas Quinases/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Doença , Éxons/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Linfonodos/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Receptor ErbB-2/genética , Transdução de Sinais/genética , Tamoxifeno/uso terapêuticoRESUMO
Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.
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Neoplasias do Colo/genética , Integrinas/genética , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Feminino , Fluoruracila/uso terapêutico , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Adulto JovemRESUMO
BACKGROUND: The lymphocyte-to-monocyte ratio (LMR) is easily determined from the white blood cell count. Lymphocytes were previously investigated as a part of the neutrophil-to-lymphocyte ratio (NLR) in patients with atherosclerotic disease and an elevated NLR was negatively associated with cardiovascular endpoints. As monocytes play a leading role in the progression of atherosclerosis, especially in peripheral arterial occlusive disease (PAOD), we investigated LMR and its association with critical limb ischemia and other vascular endpoints in PAOD patients. METHODS AND FINDINGS: We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. LMR was calculated and the cohort was divided into tertiles according to the LMR. An optimal cut-off value for the continuous LMR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI decreased significantly with an increase in LMR. An LMR of 3.1 was identified as an optimal cut-off. Two groups were categorized, one with 1021 patients (LMR < 3.1) and a second one with 1100 patients (LMR ≥ 3.1). CLI was more frequent in LMR < 3.1 patients [426 (41.7%)] than in LMR ≥ 3.1 patients [254 (23.1%)] (p < 0.001), as was also the case with prior myocardial infarction [60 (9.5%) vs. 35 (3.2%), p = 0.003] and congestive heart failure [136 (13.3%) vs. 66 (6.0%), p < 0.001). As to inflammatory parameters, C-reactive protein [median 9.0 mg/l (4.0-30.0) vs. median 4.0 mg/l (2.0-8.0)] and fibrinogen (median 438 mg/dl (350-563) vs. 372 mg/dl (316-459.5)] also differed significantly in the two patient groups (both p < 0.001). A LMR < 3.1 was associated with an odds ratio (OR) of 2.0 (95% CI 1.8-2.2, p < 0.001) for CLI, even after adjustment for other vascular risk factors. CONCLUSIONS: A decreased LMR is significantly associated with a high risk for CLI and other vascular endpoints. The LMR is an easily determinable, broadly available and inexpensive marker that could be used to identify patients at high risk for vascular endpoints.
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Arteriopatias Oclusivas/diagnóstico , Isquemia/diagnóstico , Doença Arterial Periférica/diagnóstico , Idoso , Índice Tornozelo-Braço/normas , Índice Tornozelo-Braço/estatística & dados numéricos , Biomarcadores/sangue , Estudos de Coortes , Extremidades/irrigação sanguínea , Feminino , Humanos , Linfócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Monócitos/microbiologia , Estudos Retrospectivos , Medição de Risco/métodosRESUMO
BACKGROUND: The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients. METHODS: Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points. RESULTS: Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57-4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03-4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43-4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01-3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18-3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043-6.177, P=0.040). CONCLUSIONS: In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.
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Neoplasias da Mama/sangue , Contagem de Linfócitos , Contagem de Plaquetas , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Tamanho da AmostraRESUMO
BACKGROUND: MicroRNAs (miRNAs) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled miRNAs associated with E-cadherin expression in CRC cells in an attempt to identify miRNAs that are associated with aggressive clinical course in CRC patients. METHODS: Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for differences in abundance for more than 1000 human miRNAs using microarray technology. One of the most differentially expressed miRNAs, miR-200a was evaluated for its prognostic role in a cohort of 111 patients and independently validated in 217 patients of the Cancer Genome Atlas data set. To further characterise the biological role of miR-200a expression in CRC, in vitro miR-200a inhibition and overexpression were performed and the effects on cellular growth, apoptosis and epithelial-mesenchymal transition (EMT)-related gene expression were explored. RESULTS: In situ hybridisation specifically localised miR-200a in CRC cells. In both cohorts, a low miR-200a expression was associated with poor survival (P<0.05). Multivariate Cox regression analysis identified low levels of miR-200a expression as an independent prognostic factor with respect to cancer-specific survival (HR=2.04, CI=1.28-3.25, P<0.002). Gain and loss of function assays for miR-200a in vitro led to a significantly differential and converse expression of EMT-related genes (P<0.001.) A low expression of miR-200a was also observed in cancer stem cell-enriched spheroid growth conditions (P<0.05). CONCLUSIONS: In conclusion, our data suggest that low miR-200a expression is associated with poor prognosis in CRC patients. MiR-200a has a regulatory effect on EMT and is associated with cancer stem cell properties in CRC.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , Idoso , Apoptose/genética , Células CACO-2 , Processos de Crescimento Celular/genética , Feminino , Expressão Gênica , Humanos , Hibridização In Situ , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Retrospectivos , TransfecçãoRESUMO
BACKGROUND AND PURPOSE: Vascular endothelial growth factor-A (VEGF-A), a key regulator of tumor-induced angiogenesis, is critical for tumor growth and metastasization. The goal of the present study was to evaluate the prognostic value of VEGF single nucleotide polymorphisms (SNPs) and haplotypes for clinical recurrence after definitive radiotherapy for prostate cancer. PATIENTS AND METHODS: The association of seven VEGF-A polymorphisms and their haplotypes with clinical recurrence (defined as the occurrence of local recurrence and/or distant metastases) in 496 prostate cancer patients treated with definitive radiotherapy were investigated. Genotypes were determined by 5'-nuclease (TaqMan) assays; haplotypes were analyzed using the Haploview program. RESULTS: Within a median follow-up time of 80 months, 44 patients (9 %) developed clinical recurrences. Haplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms (- 2578C > A, - 2489C > T, - 1498C > T, - 634G > C, - 7C > T) upstream of the coding sequence (CCCCC, ATTGC, CCCGC, ATTGT) and two polymorphisms (936C > T, 1612G > A) downstream of the coding sequence (CA, CG, TG). Carriers of at least 1 copy of the ATTGC haplotype were at higher risk of recurrence (hazard ratio [HR] 3.83; 95 %CI 1.48-9.90, p = 0.006); for carriers of 2 copies, the HR was 4.85 (95 %CI 1.72-13.6; p = 0.003). In multivariate analysis, patients harboring at least one copy of the ATTGC haplotype remained at increased risk of recurrence (HR 3.63, 95 %CI 1.38-9.55, p = 0.009); in patients carrying 2 copies, the HR was 4.72 (95 %CI 1.64-13.6, p = 0.004). CONCLUSION: Our findings indicate that the VEGF-A ATTGC haplotype may predict clinical recurrence in prostate cancer patients treated with radiotherapy.
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Predisposição Genética para Doença/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/radioterapia , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Fator A de Crescimento do Endotélio Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Intervalo Livre de Doença , Estudos de Associação Genética , Predisposição Genética para Doença/epidemiologia , Variação Genética/genética , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Prevalência , Neoplasias da Próstata/mortalidade , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND AND PURPOSE: Fas ligand (FASL) triggers apoptotic cell death by cross-linking with its receptor FAS, and after irradiation, expression of FAS and FASL is increased. In the present study, we investigated the association between common polymorphisms in the genes for FAS and FASL and the risk of late side effects after radiotherapy for prostate cancer. PATIENTS AND METHODS: The role of FAS (- 1377G > A, rs2234767 and - 670A > G, rs1800682) and FASL (- 844C > T, rs763110) gene polymorphisms in the development of high-grade late rectal and/or urinary toxicity (defined as late toxicity EORTC/RTOG grade ≥ 2) was analyzed in 607 prostate cancer patients treated with radiotherapy. DNA was isolated and the selected polymorphisms were determined by 5'-nuclease (TaqMan) assays. RESULTS: After a median follow-up time of 82 months, high-grade late rectal and/or urinary toxicity was observed in 175 patients (29.7 %). Univariate analysis revealed a significantly decreased risk of high-grade late toxicity in carriers of the FASL - 844T allele. After adjusting for covariates, patients harboring at least one - 844T allele (CT or TT genotype) remained at decreased risk of high-grade late toxicity compared with patients harboring the CC genotype [hazard ratio (HR) 0.585, 95 %CI 0.39-0.878; p = 0.010]. For patients with the - 844TT genotype, the HR was 0.404 (95 %CI 0.171-0.956; p = 0.039) in multivariate analysis. No significant associations were found for the remaining polymorphisms analyzed. CONCLUSIONS: These results provide the first evidence that the presence of the FASL - 844T variant allele may have a protective effect against the development of high-grade late rectal and/or urinary side effects after prostate cancer radiotherapy.
Assuntos
Apoptose/genética , Proteína Ligante Fas/genética , Variação Genética/genética , Órgãos em Risco , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Reto/efeitos da radiação , Bexiga Urinária/efeitos da radiação , Receptor fas/genética , Idoso , Alelos , Terapia Combinada , Estudos Transversais , Fracionamento da Dose de Radiação , Seguimentos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo Genético/genética , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Planejamento da Radioterapia Assistida por Computador , Radioterapia Adjuvante , Fatores de RiscoRESUMO
Wnt/ß-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/ß-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/ß-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.
Assuntos
Neoplasias do Colo/genética , Recidiva Local de Neoplasia/genética , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Etnicidade/genética , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.
Assuntos
Neoplasias Colorretais/genética , Fluoruracila/efeitos adversos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Caracteres Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
Compelling evidence points to a key role for insulin-like growth factor 1 (IGF1) signaling in breast cancer development and progression. In addition, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling. Recent translational studies support a cross talk between IGF1R and ERα at different levels and data suggest enhanced IGF1R signaling as a causative mechanism of tamoxifen (TAM) resistance. We tested whether functional germline variations in the IGF pathway are associated with clinical outcome in ER-positive primary invasive breast cancer patients, who were treated with surgery and adjuvant TAM. Tissue samples of 222 patients with ER+ primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and six functional IGF1 pathway polymorphisms were analyzed using direct DNA sequencing and PCR-restriction fragment length polymorphism. In multivariable analysis, patients with primary invasive breast cancer carrying IGF1R_rs2016347 G allele had a significantly increased risk of early tumor progression (hazard ratio (HR) 2.01; adjusted P=0.004) and death (HR 1.84; adjusted P=0.023) compared with patients carrying G/T or T/T, independent of established clinicopathological determinants. This association remained significant after adjusting for multiple testing. In addition, we were able to demonstrate that IRS1_rs1801123 and IGFBP3_rs2854744 were significantly associated with lymph node involvement and tumor size, respectively. We provide the first evidence for IGF1R_rs2016347 as an independent prognostic marker for ER+ breast cancer patients treated with TAM and support a rational for combined treatment strategies.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Receptor IGF Tipo 1/genética , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Análise Multivariada , Invasividade Neoplásica , Receptores de Estrogênio/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagemRESUMO
Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.
Assuntos
Quimioterapia Adjuvante/efeitos adversos , Ciclina D1/genética , Fluoruracila/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: With growing evidence on the role of inflammation in cancer biology, the systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. Recently, the derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor in cancer patients. Nevertheless, its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients has never been explored. METHODS: Data from 290 consecutive DLBCL patients, diagnosed between 2004 and 2013 at a single Austrian centre, were evaluated retrospectively. The prognostic influence of the dNLR and other clinico-pathological factors including age, lactate dehydrogenase, cell of origin category and Ann Arbor stage on 5-year overall- (OS) and disease-free (DFS) survival was studied by Kaplan-Meier curves. To evaluate the independent prognostic relevance of dNLR, univariate and multivariate Cox regression models were applied. RESULTS: An independent significant association between high dNLR and poor clinical outcome in multivariate analysis for OS (HR=2.02, confidence interval (CI) 95%=1.17-3.50, P=0.011), as well as DFS (HR=2.15, CI 95%=1.04-4.47, P=0.038), was identified. CONCLUSION: In the present study, we showed that a high dNLR at diagnosis of DLBCL represents an independent poor prognostic factor for clinical outcome. Our data encourage the further validation of this easily available parameter in prospective studies and as a potential stratification tool in clinical trials.