Sandra Ruland

Successful Treatment of a Progressive BRAF V600E–Mutated Anaplastic Pleomorphic Xanthoastrocytoma With Vemurafenib Monotherapy

Introduction Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that most commonly affects children and young adults. PXA undergoes anaplastic transformation in 15% to 20% of patients. Although the prognosis is relatively favorable for patients with a WHO grade 2 PXA, data suggest that the prognosis for anaplastic PXA is significantly worse. Maximal resection is generally recommended, but the role of radiation or chemotherapy in the management of these tumors remains unclear. Alterations in the BRAF gene have been described in several pediatric low-grade gliomas. Approximately 70% of pilocytic astrocytomas contain BRAF fusions, resulting from a tandem duplication and rearrangement on 7q34 between BRAF and a gene centromeric to BRAF. This is in contrast with PXA, in which the described BRAF alteration is instead a BRAF mutation that results from an amino acid substitution replacing valine (V) with glutamic acid (E) at position 600. This BRAF V600E mutation is found in approximately 60% to 65% of WHO grade 2 and 3 PXAs, and is the same mutation that is found in approximately 50% of melanomas. Vemurafenib is a BRAF inhibitor that is approved for the treatment of BRAF-mutated metastatic melanoma in the United States and the European Union. There are several case reports of CNS melanoma metastases that were responsive to vemurafenib, and preliminary results from an open-label pilot study of vemurafenib for patients with melanoma and brain metastases suggest some activity. This evidence indicates that vemurafenib may penetrate CNS tumors. In addition, BRAF inhibition represses the growth of intracranial BRAF V600E pediatric malignant astrocytoma xenografts in mouse models. Hence, vemurafenib may have a role in the treatment of intracranial neoplasms with BRAF mutations. In support of this, we now present a case of a progressive BRAF V600E–mutated anaplastic PXA that was successfully treated with vemurafenib monotherapy.

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma

BACKGROUND Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. METHODS We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. RESULTS OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. CONCLUSIONS Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.

Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab

BACKGROUND Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen. METHODS In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment. RESULTS Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen. CONCLUSION The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort.