Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study.

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.

BACKGROUND: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like(CGH) classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. PATIENTS AND METHODS: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). RESULTS: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like(CGH) tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04-0.43] compared with patients with non-BRCA1-like(CGH) tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50-1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like(CGH) tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). CONCLUSION: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.