Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS). PATIENTS AND METHODS: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. RESULTS: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. CONCLUSIONS: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment.

Prevention and Management of Radiation-induced Late Gastrointestinal Toxicity.

In the UK, about 90,000 cancer survivors will suffer from pelvic radiation disease (PRD) due to their curative treatment including radiotherapy. The National Cancer Survivorship Initiative aims to improve the understanding and management of PRD by the oncology community. This overview covers the prevention, investigation and treatment for late radiation-induced gastrointestinal symptoms in PRD. Multiple pharmacological and nutritional interventions have been studied, as prophylaxis for acute gastrointestinal toxicity (aiming to prevent late consequential effects), although predominantly only small randomised controlled trials have been conducted. These have produced mixed results, although promising signals for some agents have been observed. Evidence for the pharmacological prevention of late gastrointestinal toxicity is scarce. Even fewer randomised controlled trials have investigated the late gastrointestinal toxicity profile of advanced radiotherapy technologies. There are nationally agreed algorithms for the investigation and management of PRD, but a lack of awareness means patients still do not get referred appropriately. This overview outlines the management of radiation proctopathy and diarrhoea, and signposts other accessible resources. Finally, we provide recommendations for the management of late gastrointestinal symptoms in PRD and research in this field, especially the need for high-quality clinical trials.

Long-term swallow function after chemoradiotherapy for oropharyngeal cancer: the influence of a prophylactic gastrostomy or reactive nasogastric tube.

AIMS: Two contrasting approaches of a prophylactic gastrostomy or a nasogastric tube as needed are widely used to support patients receiving chemoradiotherapy for head and neck cancer. The influence of the type and timing of enteral feeding tube support upon long-term swallowing is uncertain. This study analysed the patients' perspective on long-term swallowing, comparing two groups of patients who received chemoradiotherapy for oropharyngeal cancer managed with the two approaches. MATERIALS AND METHODS: The MD Anderson Dysphagia Inventory (MDADI) was posted to 63 consecutive patients with oropharyngeal squamous cell cancer treated with concurrent chemoradiotherapy between January 2007 and June 2009, who had not required therapeutic enteral feeding before treatment and who were disease free on follow-up at least 2 years after treatment. RESULTS: In total, 56/63 patients completed questionnaires; 43 had been managed with a prophylactic gastrostomy and 13 with a policy of nasogastric tube as needed. There were no significant differences in all global, emotional, physical or functional domains of the MDADI according to enteral feeding strategy. Diet at 6 months after treatment was significantly correlated with better MDADI scores. CONCLUSIONS: In this study, the choice of a prophylactic gastrostomy or nasogastric tube as needed did not seem to influence long-term swallowing function.