BackgroundIn an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health... Show moreBackgroundIn an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health Organization grade 2 or 3 gliomas with a first and contrast-enhancing recurrence after initial radiotherapy, and overall survival at 12 months was not significantly different (61% in the TMZ arm and 55% in the TMZ + BEV arm).ObjectivesHealth-related quality of life (HRQoL) was a key secondary end-point in this trial, and the main objective of this study was to determine the impact of the addition of BEV to TMZ on HRQoL.MethodsHRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until disease progression. The pre-selected primary HRQoL end-point was the QLQ-C30 global health scale, with self-perceived cognitive functioning and pain selected as secondary HRQoL issues. Analysis was undertaken using linear mixed modelling and complemented with sensitivity analyses using summary statistics. A difference was considered clinically relevant with ≥10 points difference on a 100-point scale.ResultsBaseline compliance was high at 94% and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statistically significant or clinically significant differences between the primary HRQoL end-point in both treatment arms (p = 0.2642). The sensitivity analyses confirmed this finding. The overall test for post-baseline differences between the two treatment arms also showed no statistically or clinically significant differences regarding the selected secondary end-point scales. Show less
Bos, M.K.; Lam, S.W.; Motta, G.; Helmijr, J.C.A.; Beaufort, C.M.; Jonge, E. de; ... ; Sleijfer, S. 2023
BackgroundESR1 mutations have been identified as mechanism for endocrine resistance and are also associated with a decreased overall survival. We assessed ESR1 mutations in circulating tumor DNA ... Show moreBackgroundESR1 mutations have been identified as mechanism for endocrine resistance and are also associated with a decreased overall survival. We assessed ESR1 mutations in circulating tumor DNA (ctDNA) for impact on outcome to taxane-based chemotherapy in advanced breast cancer patients.MethodsESR1 mutations were determined in archived plasma samples from patients treated with paclitaxel and bevacizumab (AT arm, N = 91) in the randomized phase II ATX study. Samples collected at baseline (n = 51) and at cycle 2 (n = 13, C2) were analyzed using a breast cancer next-generation sequencing panel. This study was powered to detect a benefit in progression-free survival (PFS) at six months for patients treated with paclitaxel/bevacizumab compared to historical trials with fulvestrant. PFS, overall survival (OS), and ctDNA dynamics were exploratory analyses.ResultsPFS at six months was 86% (18/21) in patients with an ESR1 mutation detected and 85% (23/27) in wildtype ESR1 patients. In our exploratory analysis, median progression-free survival (PFS) was 8.2 months [95% CI, 7.6-8.8] for ESR1 mutant patients versus 8.7 months [95% confidence interval (CI), 8.3-9.2] for ESR1 wildtype patients [p = 0.47]. The median overall survival (OS) was 20.7 months [95% CI, 6.6-33.7] for ESR1 mutant patients versus 28.1 months [95% confidence interval (CI), 19.3-36.9] for ESR1 wildtype patients [p = 0.27]. Patients with >= two ESR1 mutations had a significantly worse OS, but not PFS, compared to those who did not [p = 0.003]. Change in ctDNA level at C2 was not different between ESR1 and other mutations.ConclusionsPresence of ESR1 mutations in baseline ctDNA might not be associated with inferior PFS and OS in advanced breast cancer patients treated with paclitaxel/bevacizumab. Show less
Background: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival ... Show moreBackground: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated. Methods: The Triple-B study is a multicenter, randomized phase IIb trial that aims to prospectively validate predictive biomarkers, including baseline plasma vascular endothelial growth factor receptor-2 (pVEGFR-2), for bevacizumab benefit. mTNBC patients were randomized between CC and paclitaxel (P) without or with bevacizumab (CC +/- B or P +/- B). Here we report on a preplanned safety and preliminary efficacy analysis after the first 12 patients had been treated with CC+B and on the predictive value of pVEGFR-2. Results: In 58 patients, the median follow-up was 22.1 months. Toxicity was manageable and consistent with what was known for each agent separately. There was a trend toward a prolonged PFS with bevacizumab compared to chemotherapy only (7.0 vs. 5.2 months; adjusted HR = 0.60; 95% CI 0.33-1.08; p = 0.09), but there was no effect on OS. In this small study, pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Both the intention-to-treat analysis and the per-protocol analysis did not yield a significant treatment-by-biomarker test for interaction (p(interaction) = 0.69). Conclusions:CC and CC+B are safe first-line regimens for mTNBC and the side effects are consistent with those known for each individual agent. pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Show less
Uveal melanoma (UM) is a disease with many faces: ophthalmologists treat the primary tumor, but the patient faces the problem of developing metastases, which are often deadly after a short period.... Show moreUveal melanoma (UM) is a disease with many faces: ophthalmologists treat the primary tumor, but the patient faces the problem of developing metastases, which are often deadly after a short period. Recent insight, indicates the need for knowledge-based treatment of UM. The __pseudohypoxic__ and tumor promoting effects of bevacizumab as described in this thesis is especially relevant. Bevacizumab is frequently used off-label to treat macular edema in UM patients suffering of radiation retinopathy, without the knowledge of possible effect on still viable UM cells. We further observed that specific peptides, such as UMAP1, which can successfully be internalized by targeted UM cells, have demonstrated potential for UM-targeted treatment. These peptides have to be investigated in vivo, to ascertain whether they are a viable clinical tool. Labeling the peptides with radionuclides, and demonstrating specificity for UM cells are some of the challenges which have to be overcome. Another aspect in the patient-specific treatment of UM is the in vitro analysis of primary UM samples to predict treatment responses. In case of Dasatinib, we describe treatment responses associated with monosomy 3 and __kinase__ activity in different primary UM samples. Show less
