Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression.

BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression. METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator. RESULTS: SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b - cT4 (OR = 2.21 (confidence interval (CI) 95% 1.47 - 3.31), p < 0.001) and Gleason scores ≥ 7 (OR = 2.22 (CI 95% 1.38 - 3.57), p < 0.001), respectively. Moreover, those patients wild homozygous for both SNPs had the greatest risk of presenting D'Amico high-risk tumors (OR = 2.57 (CI 95% 1.28 - 5.16)). CONCLUSIONS: Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer.

The single nucleotide variant rs2868371 associates with the risk of mortality in non-small cell lung cancer patients: A multicenter prospective validation.

BACKGROUND AND PURPOSE: Definitive radiation therapy (RT) with or without chemotherapy has become the standard treatment for non-metastatic unresectable non-small cell lung cancer (NSCLC). However, treatment outcomes can differ substantially and patients' genetic background could play a crucial role. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta-1 (HSPB1) and survival have been reported in prior single-institution retrospective reports. MATERIALS AND METHODS: The current assay aims to validate such connection in a prospective multicenter study in a European cohort including 181 NSCLC patients. Median follow-up time for all patients was 13 months (range, 3-57 months). RESULTS: The results obtained show an association between the rs2868371 GG genotype and better overall survival (HR: 0.35; 95%CI: 0.13-0.96; p = 0.042) in multivariate analysis. Two-year overall survival rate was 72% for patients carrying the rs2868371 GG genotype versus 36% for those patients harboring the rs2868371 CC/CG genotypes (p = 0.013). Additionally, the rs2868371 GG genotype was found to be associated with better disease-free survival in the multivariate analysis (HR: 0.36; 95%CI: 0.13-0.99; p = 0.048). In silico analysis of the potential functional SNP suggested significant difference in the affinity of the Glucocorticoid Receptor binding site between alternative allelic variants, confirmed by chromatin immunoprecipitation analysis displaying stronger affinity for the risk allele (C). Furthermore, our findings indicate that the rs2868371 influences (mRNA) HSPB1 expression, offering insight into the regulation of HSPB1 transcription. CONCLUSION: The functional HSPB1 rs2868371 promoter variant may affect lung cancer survival by regulation of HSPB1 expression levels through glucocorticoid receptor interaction.

Association of single nucleotide polymorphisms at HSPB1 rs7459185 and TGFB1 rs11466353 with radiation esophagitis in lung cancer.

BACKGROUND AND PURPOSE: Radiochemotherapy (RCT) success in lung cancer (LC) can be limited due to the onset of adverse effects in the adjacent normal tissue such as radiation-induced esophageal toxicity (RIET). Therefore, specific biomarkers to customize the RCT dose administration and esophageal toxicity prediction are necessary to improve treatment effectiveness. MATERIALS AND METHODS: 247 LC patients prospectively recruited between 2012 and 2016 from 3 institutions were genotyped for 7 SNPs along TGFB1 and HSPB1 genes seeking an association with RIET risk development. Kaplan-Meier cumulative probability and Cox proportional hazards analyses were used to evaluate the effect of TGFB1 and HSPB1 genotypes on such risk. RESULTS: Multivariate analyses showed that patients carrying the HSPB1 rs7459185 CC genotype were associated with a significantly higher risk of acute grade 3 RIET than those carrying the GG/GC genotypes (HR = 17.73; 95% CI = 2.896-108.49; p = 0.002). LC patients who received higher (>median) volume of esophagus exposed to 30 Gy and harboring the rs7459185 GG/GC genotypes showed a significantly lower RIET incidence (p < 0.001). Additionally, LC patients carrying the TGFB1 rs11466353 GG genotype were found to be associated with a lower risk of late grade 2 RIET compared with those with the TT/TG genotypes (HR = 0.29; 95% CI = 0.103-0.830; p = 0.021). Patients receiving a high (>60 Gy) radiation dose who presented the rs11466353 GG genotype had a significantly lower RIET incidence (p = 0.025). CONCLUSION: The presence of different rs7459185/rs11466353 genotypes in LC patients associated with RIET risk and may be useful biomarkers along with other risk factors for guiding therapy intensity in an individualized therapy.

Prevention of oral mucositis secondary to antineoplastic treatments in head and neck cancer by supplementation with oral glutamine.

OBJECTIVES: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. MATERIAL AND METHODS: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy ± concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. RESULTS: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). CONCLUSION: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube.

Genetic variations in genes involved in testosterone metabolism are associated with prostate cancer progression: A Spanish multicenter study.

BACKGROUND: Prostate cancer (PCa) is an androgen-dependent disease. Nonetheless, the role of single nucleotide polymorphisms (SNPs) in genes encoding androgen metabolism remains an unexplored area. PURPOSE: To investigate the role of germline variations in cytochrome P450 17A1 (CYP17A1) and steroid-5α-reductase, α-polypeptides 1 and 2 (SRD5A1 and SRD5A2) genes in PCa. PATIENTS AND METHODS: In total, 494 consecutive Spanish patients diagnosed with nonmetastatic localized PCa were included in this multicenter study and were genotyped for 32 SNPs in SRD5A1, SRD5A2, and CYP17A1 genes using a Biotrove OpenArray NT Cycler. Clinical data were available. Genotypic and allelic frequencies, as well as haplotype analyses, were determined using the web-based environment SNPator. All additional statistical analyses comparing clinical data and SNPs were performed using PASW Statistics 15. RESULTS: The call rate obtained (determined as the percentage of successful determinations) was 97.3% of detection. A total of 2 SNPs in SRD5A1-rs3822430 and rs1691053-were associated with prostate-specific antigen level at diagnosis. Moreover, G carriers for both SNPs were at higher risk of presenting initial prostate-specific antigen levels>20ng/ml (Exp(B) = 2.812, 95% CI: 1.397-5.657, P = 0.004) than those who are AA-AA carriers. Haplotype analyses showed that patients with PCa nonhomozygous for the haplotype GCTTGTAGTA were at an elevated risk of presenting bigger clinical tumor size (Exp(B) = 3.823, 95% CI: 1.280-11.416, P = 0.016), and higher Gleason score (Exp(B) = 2.808, 95% CI: 1.134-6.953, P = 0.026). CONCLUSIONS: SNPs in SRD5A1 seem to affect the clinical characteristics of Spanish patients with PCa.

Prevention of oral mucositis secondary to antineoplastic treatments in head and neck cancer by supplementation with oral glutamine / Prevención de la mucositis oral secundaria a los tratamientos antineoplásicos en el cáncer de cabeza y cuello mediante suplemento con glutamina oral

Objectives: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. Material and methods: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy ± concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. Results: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus 6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). Conclusion: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube

Objetivos: evaluar la eficacia de la glutamina en la prevención de la incidencia de mucositis secundaria a las terapias oncológicas en pacientes con carcinoma de cabeza y cuello. Los objetivos secundarios fueron conocer la incidencia de odinofagia e interrupciones de los tratamientos y los requerimientos de analgesia y sonda nasogástrica. Material y métodos: estudio prospectivo de cohortes de pacientes con carcinoma epidermoide de cabeza y cuello tratados con radioterapia ± quimioterapia concomitante. Se compararon 131 pacientes que recibieron glutamina oral a una dosis de 10 g/8 horas con 131 pacientes que no la recibieron. Resultados: los pacientes que no tomaron glutamina tuvieron una hazard ratio 1,78 veces mayor de mucositis (IC 95% [1,01-3,16], p = 0,047). Respecto a la odinofagia, los pacientes que no tomaron glutamina tuvieron una hazard ratio 2,87 veces mayor (IC 95% [1,62-5,18], p = 0,0003]. El 19,8% de los pacientes que no tomaron glutamina interrumpieron el tratamiento versus 6,9% de los pacientes que la tomaron (p = 0,002). En cuanto a los tratamientos de soporte, el 87,8% de los pacientes sin glutamina requirieron analgesia versus 77,9% de los pacientes con glutamina (p = 0,03) y la sonda nasogástrica fue indicada en un 9,9% y 3,1% respectivamente (p = 0,02). Conclusión: la glutamina oral en pacientes que reciben tratamiento por carcinoma de cabeza y cuello, previene la incidencia de mucositis oral y odinofagia y disminuye las interrupciones de tratamientos y el uso de analgesia y sonda nasogástrica

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies.

BACKGROUND: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. OBJECTIVE: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. DESIGN SETTING AND PARTICIPANTS: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. RESULTS AND LIMITATIONS: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. CONCLUSION: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Costes de los servicios sanitarios asociados al tratamiento del cáncer de mama precoz con radioterapia adyuvante / Healthcare costs associated with adjuvant radiation therapy for early breast cancer

Objetivo. Valorar el coste sanitario asociado a 6 técnicas de radioterapia (RT) adyuvante para el tratamiento del cáncer de mama precoz. Métodos. Estudio descriptivo del coste sanitario asociado al tratamiento con RT en el cáncer de mama mediante la previa identificación, por un grupo de oncólogos expertos formado por 6 facultativos especialistas en oncología radioterápica y un economista de la salud, del consumo de servicios sanitarios asociados a 6 técnicas de RT: RT tridimensional conformada (3DCRT) según fraccionamiento convencional (2 Gy/sesión) e hipofraccionamiento (2,6 Gy/sesión), irradiación parcial de la mama (IPM) mediante 3DCRT, braquiterapia de baja y alta tasa y RT intraoperatoria (RIO). Los servicios sanitarios que se incluyeron en el análisis fueron: estancia hospitalaria, consultas médicas y de enfermería, simulación, delimitación de volúmenes, aceptación y verificación del tratamiento, pruebas radiológicas (radiografías, tomografías y ecografías) y cálculos dosimétricos. Los costes se obtuvieron de los precios públicos vigentes en el Sistema Sanitario Público de Andalucía, actualizados a precios de 2013. Resultados. Se estimó un coste de 6.786,75 y 4.998,17 Euros para el tratamiento con 3DCRT según fraccionamiento convencional e hipofraccionamiento, respectivamente. Para las técnicas de IPM se obtuvo un coste de 4.066,10, 4.797,35, 4.376,97 y 7.715,43 Euros mediante 3DCRT, braquiterapia de baja y alta tasa, y RIO, respectivamente. Conclusiones. Se aprecia una variabilidad en el coste sanitario asociado a las distintas técnicas de RT adyuvante para el tratamiento del cáncer de mama precoz, siendo la IPM mediante 3DCRT la técnica de RT más económica. Es necesaria una actualización de los registros oficiales que además incluya las nuevas tecnologías incorporadas en los últimos años (AU)

Objective. To assess the healthcare costs associated with six radiation therapy (RT) techniques for the adjuvant treatment of early breast cancer. Methods. A team of six radiation oncologists and a specialist in health economics performed a descriptive cost analysis among the following RT techniques: 3-dimensional conformal RT (3DCRT) using either conventional fractionation (2 Gy/fraction) or hypofractionation (2,6 Gy/fraction), partial-breast irradiation (PBI) delivered with the use of 3DCRT or brachytherapy (high and low dose rate), and intraoperative RT (IORT). Treatment costs included hospitalization, medical (simulation, contouring, and verification and approval of treatment plans) and nursing consults, radiological examinations, and dosimetry calculation. Costs were obtained from the last update of public prices in the Andalusian Public Health System, updated to 2013. Results. The treatment cost for conventional fractionation with 3DCRT was 6,786.75 Euros, whereas the cost of the hypofractionated regimen using the same technology was 4,998.17 Euros. PBI costs were 4,066.10 Euros, 4,797.35 Euros, 4,376.97 Euros and 7,715.43 Euros for 3DCRT, low-dose rate brachytherapy, high-dose rate brachytherapy, and IORT, respectively. Conclusions. There is wide cost variation among RT techniques for the adjuvant treatment of early breast cancer. The technique with the lowest healthcare cost is PBI through 3DCRT. Official government prices should be updated and should also include the new technologies incorporated in recent years (AU)

Estudio preliminar sobre extracción automática del tamaño tumoral para la estadificación del cáncer de mama a partir de texto libre de informes clínicos / Preliminary study of automatic extraction of breast cancer staging from free text clinical reports

Objetivo. El estadio del cáncer de mama constituye uno de los factores pronósticos más relevantes. Sin embargo, la compleja clasificación TNM, la existencia de diferentes versiones y la variabilidad de la fuente de la información hacen que la recogida de datos sobre texto libre sea compleja. El objetivo de este trabajo es desarrollar una herramienta que permita ayudar a la estadificación de manera automática. Pacientes y métodos. El trabajo incluyó el estudio de los informes de 100 pacientes con cáncer de mama no metastásico tratadas con cirugía y radioterapia en 2012. La recogida del tamaño tumoral posquirúrgico (séptima edición TNM) se realizó con la herramienta desarrollada y manualmente por un médico en formación especializada de tercer año de oncología radioterápica. Resultados. La aplicación fue capaz de detectar el 62% de los casos tras examinar los informes de anatomía patológica, y el 77% al añadir el examen de los informes de oncología radioterápica. Los casos no detectados se debieron a que la información estaba almacenada en otra sección de la estación clínica. Comparando los resultados entre la aplicación y la recogida manual, hubo una diferencia del 13% (10/77). Se observó que en el 50% de los casos (5/10) la aplicación era correcta, mientras que en el otro 50% lo fue la recogida manual. Conclusiones. Esta herramienta innovadora permite recoger automáticamente el tamaño tumoral en el cáncer de mama, ahorrando tiempo en la recogida de datos y evitando errores en la clasificación tumoral, por lo que puede contribuir de modo notable en la decisión terapéutica(AU)

Objective. Staging of breast cancer is one of the most important prognostic factors. However, collecting data for staging manually from unstructured free text is variable and imprecise because of the complexity of the TNM classification, the existence of different versions over time, and variability in the source used to obtain data. The aim of this study was to develop an artificial intelligence tool to allow data on tumoral staging to be mined automatically. Patients and methods. The study included the reports of the first 100 patients with nonmetastatic breast cancer treated with surgery and radiotherapy in 2012. Data on postoperative tumor size (TNM seventh edition) were collected with a specially designed software tool and manually by a third-year resident physician in radiation oncology. Results. The software application detected 62% of cases when pathology reports were included, and 77% when radiation oncology reports were added. Non-detection was due to the information being stored in another section of the clinical station. When we compared the results of the software application and manual collection, we found a difference of 13% (10/77). In these 10 cases, the application was correct in 50%, while manual collection was correct in the remaining 50%. Conclusions. This innovative system allows automatic staging of tumoral size in breast cancer. The use of this tool would save time in data collection and prevent errors in tumoral classification and could also improve therapeutic decisions(AU)