RESUMEN
Radiotherapy (RT) is an integral component in the management of head and neck cancer. Despite progress in several respects, a noteworthy proportion of the treated patients do not achieve complete response after RT. Regardless of novel dose delivery technologies, RT for head and neck cancer is still associated with acute as well as late toxicity. These challenges could potentially be addressed by means of personalized treatment. In this paper, we discuss the possibilities for dose escalation, dose de-escalation and allocation to systemic concomitant treatment based on prognostic and predictive markers for tumor control as well as predictive markers for normal tissue radiosensitivity.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de Cabeza y Cuello/terapia , Medicina de Precisión/métodos , Traumatismos por Radiación/prevención & control , Radioterapia de Intensidad Modulada/métodos , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Aberraciones Cromosómicas , Relación Dosis-Respuesta en la Radiación , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Medicina de Precisión/efectos adversos , Pronóstico , Traumatismos por Radiación/etiología , Tolerancia a Radiación/genética , Tolerancia a Radiación/efectos de la radiación , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: In two previously published studies, associations with risk of radiation-induced subcutaneous fibrosis were found for single nucleotide polymorphisms (SNP) in TGFB1 (transforming growth factor beta 1 gene), XRCC1 (X-ray repair cross-complementing 1 gene), XRCC3 (X-ray repair cross-complementing 3 gene), SOD2 (manganese superoxide dismutase gene) and ATM (gene of ataxia telangiectasia mutated). The present study was conducted to seek a confirmation of these findings. MATERIALS AND METHODS: Like the 41 patients previously investigated, the 120 subjects included in the present study were accrued from a historical cohort of 319 post-mastectomy radiotherapy patients. All patients received hypo-fractionated radiotherapy. The TGFB1 position--509, codons 10 and 25, XRCC1 codons 194, 280 and 399, XRCC3 codon 241, SOD2 codon 16, ATM codon 1853 and APEX (apurinic/apyrimidinic exonuclease gene) codon 148 polymorphisms were assessed based on archival histological material. Differences in fibrosis risk were quantified from dose-response assessments. RESULTS: For none of the investigated polymorphisms, significant associations with risk of subcutaneous fibrosis were observed. A detailed analysis did not reveal any obvious explanation for the discrepancy between the previous and the present study. CONCLUSION: The previously observed associations with risk of radiation-induced subcutaneous fibrosis could not be replicated in the present study. Further studies are needed to elucidate the influence of genetic variation upon normal tissue radiosensitivity.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Traumatismos por Radiación/genética , Radioterapia/efectos adversos , Tejido Subcutáneo/patología , Tejido Subcutáneo/efectos de la radiación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Estudios de Cohortes , ADN/genética , ADN/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Fibrosis/genética , Humanos , Persona de Mediana Edad , Adhesión en Parafina , Polimorfismo de Nucleótido Simple/genética , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: An increasing amount of evidence indicates that single nucleotide polymorphisms (SNPs) may affect a variety of oncology related phenotypes. Occasionally, it is convenient to base studies addressing genotype-phenotype relationships on historical patient cohorts, from which only archival specimens are available. This study was conducted to validate protocols optimised for assessment of SNPs based on paraffin embedded, formalin fixed tissue samples. PATIENTS AND METHODS: In 137 breast cancer patients, three TGFB1 SNPs were assessed based on archival histological specimens. In 37 of these patients, the SNPs were also assessed using cultured fibroblasts and the assays were validated by direct comparison of the results. From the remaining 100 patients, only archival material was available. In these patients, the existence of a genetic linkage pattern between the assessed TGFB1 SNPs was used to provide an indirect validation of the genotyping results. Furthermore, two different methods for DNA extraction were compared (semi-automatic DNA extraction using the ABI Prism 6100 Nucleic Acid PrepStation versus Proteinase K digestion for 5 days followed by boiling and DNA precipitation). RESULTS: Assessment of SNPs based on archival histological material is encumbered by a number of obstacles and pitfalls. However, these can be widely overcome by careful optimisation of the methods used for sample selection, DNA extraction and PCR. Within 130 samples that fulfil the criteria for analysis a highly reliable SNP assessment was observed. The study demonstrated that different 'down-stream applications' ('single nucleotide primer extension' or 'TaqMan-based' real-time PCR) could be used as genotyping procedure. CONCLUSIONS: Reliable assessment of SNPs in formalin-fixed paraffin-embedded specimens is possible but a number of precautions should be carefully taken.