Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy

Abstract

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.

Figure 1.

Targeted inhibition of BRAF/MEK pathway in a patient with a multiply recurrent papillary craniopharyngioma. A) Demonstration of the patient represented to our hospital with obtundation three times within a span of eight weeks with CT imaging revealing re-accumulation of a suprasellar cyst. B) The MRI on initial presentation to our institution seven months following his initial resection at an outside institution. C) The specimen obtained at time of the second neurosurgical decompression at our institution, which revealed diffuse positivity for BRAF V600E by IHC (VE1 antibody). We have validated the specificity of the antibody in prior work (4,16). D) The brain MRI following five craniotomies when the patient was re-admitted 10 months following the initial resection at the outside hospital for bitemporal vision loss. The brain MRI showed recurrence of solid enhancing tumor. E) The MRI scan after the patient received dabrafenib alone for 17 days with 52% reduction in enhancing tumor volume. F) The MRI scan after an additional 14 days of dabrafenib and trametinib treatment; the final volumetric reduction in the enhancing mass was 85%. G) The tumor volume for both the enhancing (red) and cyst (blue) components. Note logarithmic axes.

Figure 2.

Characterization of dabrafenib/trametinib effects in a craniopharyngioma using pre- and on-treatment samples. A) Hematoxylin and eosin (H&E)–stained section (left) of the resected residual papillary craniopharyngioma tissue post-treatment that shows that some of the fibrovascular cores are engorged with foamy macrophages, while others are densely sclerotic. A) The immunohistochemistry (IHC) for BRAF V600E (VE1 antibody) on the post-treatment resection specimen. B) IHC for immune markers on pre- and post-treatment samples, including CD3 (T cells), CD4 (green)/CD8 (red), CD68 (macrophages). B) IHC for Ki-67 (Mib1) (right panels) to monitor proliferative index pre- and post-treatment. C) Detection of circulating BRAF V600E RNA in the blood of a patient with papillary craniopharyngioma using a polymerase chain reaction–based assay. Samples: blood samples were available starting from the 10^th day after dabrafenib treatment was started and were taken weekly thereafter. Trametinib was initiated on Day 20. Mean values and standard deviation error bars are plotted. Surgery was performed on Day 38; Normal 1–5 are controls from individuals with no history of papillary craniopharyngioma or other BRAF V600E mutant tumor. D) The cancer cell fraction (CCF) distribution plot of single nucleotide variations and small insertions/deletions (Indels) from whole exome sequencing data from the pre- and post-treatment resection samples. Indicated in red is BRAF V600E, which has a cancer cell fraction of 1 indicating clonal status. All other events are in black. The red line indicates the mean CCF. SNV = single nucleotide variation.