Clinical application of BRAF V600 mutation frequency and its inhibitors in glioma patients

Lily J.
Andrews et al.
of MRC Epidemiology Headquarters at University Hospital Bristol, UK, conducted a comprehensive and systematic literature review
of BRAF V600 mutation frequency and clinical application of its inhibitors in glioma patients.

The review was published in the April 2022 issue of the journal
Neuro-Oncology.

- Excerpted from the article chapter

【Ref: Andrews LJ, et al.
Neuro Oncol.
2022 Apr 1; 24(4):528-540.
doi: 10.
1093/neuonc/noab247.
】

Research background

The BRAF gene encodes serine/threonine protein kinase (B-Raf protein), which plays a key role
in the mitogen-activating protein kinase-extracellular signal-regulatory kinase (MAPK/ERK) signaling pathway.

BRAF mutations are widely present in a variety of solid tumors, and 90% of BRAF mutations occur in exon 15 at position 1799 nucleotide T mutation-A (p.
T1799A), resulting in the 600th glutamate encoding protein being overactivated by valine (V600E) and the MAPK signaling cascade pathway, and cell division is out of control, resulting in tumors
.

BRAF inhibitors (BRAFi) selectively bind to V600E mutated B-Raf protein and prevent MEK activation, thereby inhibiting the MAPK/ERK signaling cascade and preventing abnormal cell signaling
.

Lily J.
Andrews et al.
of the MRC Epidemiology Headquarters (IEU) of University Hospital Bristol, UK, conducted a comprehensive and systematic literature review
of BRAF V600 mutation frequency and clinical application of its inhibitors in glioma patients.

The review was published in the April 2022 issue of the journal
Neuro-Oncology.

Research methods

The authors searched MEDLINE and Embase databases up to October 2020 using "glioma" and "BRAF V600" as keywords
.

The clinical use of BRAFi was also analysed
using keywords such as "glioma", "verafenib" and "dabrafenib".

When analyzing the frequency of BRAF V600 mutations, the sample size is preferred to the detection method according to the hierarchical system.
Secondly, Sanger sequencing is superior to pyrosequencing and immunohistochemical analysis
.

To minimize the number of repeat patient reports, the study was grouped by institute/hospital and single cohorts
were selected from the same location over the same time period.

When BRAFi is analyzed, each patient is assigned a patient identification number (ID) and the patient's characteristics
are recorded.

If individual patient data cannot be obtained, aggregate data such as median age, duration of treatment, overall survival (OS), and progression-free survival (PFS)
are collected.

Collect primary tumor data, including tumor type, WHO tumor grade, glioma stage, tumor spread and location
.

If there is no WHO grade, but there is a clear type, it is classified according to the 2016 WHO classification of central nervous system tumors
.

Risk assessment
of bias was performed using the Hoy tool for BRAF V600 mutation frequency studies.

Study results

The search results showed that in the databases of MEDLINE and Embase, there were 5188 articles on BRAF V600 mutation frequency studies and 2220 articles on BRAFi studies
.

After removing duplicates, 820 BRAF V600 mutation frequency studies were reviewed in full text, and finally 182 research papers
were selected.

In the BRAFi study, 93 of the 222 full-text papers were screened
.

The 182 studies on the frequency of BRAF V600 mutations included 13,682 glioma patients
.

Patients are aged 0-90 years
.

Among them≤ 2324 children aged 18 years and 2109 patients > 18-year-old adult patients; The existing adult and pediatric studies included a total of 6983 patients and an unknown age of 2266 patients
.

Thirty-four (18.
7%) studies included > 100 patients with glioma, and 61 (33.
5%) studies included patients with glioma ≤ 20 patients
.

Among the included research projects, the detection methods of BRAF V600 mutation varied, and most (29.
7%) used multiple methods
.

NGS, PCR and next-generation sequencing, IHC and Sanger sequencing alone accounted for 12.
6%, 12.
1%, 9.
9% and 9.
9%,
respectively.

Seventy-three studies (40.
1%) were at low risk of bias, 81 (44.
5%) were at moderate risk of bias, and 28 (15.
4%) were at high risk
of bias.

In 182 studies, the BRAF V600 mutation frequency averaged 7% (95% CI, 5%-8%); The I2 value was 83%, indicating high heterogeneity
between the studies.

BRAF V600 mutations are more frequent in pediatric patients than in adults
.

The overall mutation rate of BRAF V600 in children was 7% (95% CI, 4% to 10%); The mean mutation frequency in adults was 4% (95% CI, 1% to 8%)
.

These estimates varied in both children and adults, with I2 values of 63% and 75%, respectively, reflecting a high degree of heterogeneity
.

Among the 48 glioma entities, BRAF V600 mutation was most common in epithelioid glioblastoma (e-GBM), with an average mutation rate of 69%; followed by pleomorphic xanthoastrocytoma (PXA), with an average of 56%; anaplastic pleomorphic xanthoastrocytoma (aPXA), average 38%; ganglioglioma (GG), average 40%; Anaplastic ganglioglioma (aGG), an average of 46%.


Among other glioma entities, BRAF V600 mutation frequency is greater than 1%, and astrocytes are 24%; desmoplastic infantile astrocytoma (DIA), 16%; LGG unspecified, 11%; subependymal giant cell astrocytoma (SEGA), 8%; glial neuronal tumors, 6%; dysembryoplastic neuroepithelial tumor (DNET), 3%; diffuse astrocytoma (DA), 3%; pilocytic astrocytoma (PA), 3%; glioma, 2%; Infantile fibroproliferative ganglioglioma/desmoplastic infantile ganglioglioma (DIA/DIG), 77%; neuroepithelial tumors, 13%; anaplastic glioma (AG), 27%; ganglioma, 46%; Polymorphous low-grade neuroepithelial tumor of the young (PLNTY), 50%, and fibrillary astrocytoma (FA), 9%.

In 93 studies on BRAFi, data were collected on 394 patients, including 241 children, 144 adults, and 9 NR.


The median age of 160 children was 9.
0 years (0.
1-17.
0 years), and 69 (48.
6%)
were women among the 142 children.

The median age of 143 cases in the adult group was 34.
0 years (18.
0-62.
0 years) and 60 cases (50.
8%)
were female.

Among the 241 pediatric patients, 158 (65.
5%) had V600E mutations, 3 (1.
2%) had V600D mutations, and 80 (33.
2%)
had V600 unspecified patients.

In the adult group, there were 120 cases (83.
3%) with V600E mutation and 24 cases (16.
7%)
with V600 NOS.

Among the 91 cases of LGG in the children's group, 66 cases were WHO grade I and 25 cases were WHO grade II.
Among the 27 cases of HGG, 18 cases were WHO grade III and 9 cases were WHO class IV
.

There were 17 cases (7.
1%) of gliomas without grade and 106 cases (44.
0%)
of gliomas without grading or classification.

Among the 41 adult group of LGG, 19 cases were WHO grade I and 22 cases were WHO grade II.
Among the 100 adult group HGGs, 46 were WHO grade III and 54 were WHO IV grade; There were 3 cases (2.
1%)
of glioma who were not graded.

Among pediatric patients, there were 42 cases of glioma stage, including 9 cases of recurrent glioma and 33 cases of primary disease
.

60 patients (24.
9%) underwent surgery, 68 (28.
2%) received radiotherapy, 93 (38.
6%) received chemotherapy, and 135 did not receive any treatment
.

Sixty-one (25.
3%) children were treated with vemurafenib monotherapy, 66 (27.
4%) with dabrafenib monotherapy, and 47 (19.
5%) with dabrafenib combined with trametinib (MEKi).


In 67 patients (27.
8%), the use of BRAFi was unclear
.

The median duration of treatment for 152 children was 13.
8 months (IQR 17.
2 months; 0.
1-63 months).

Among adult patients, 81 glioma stages included 56 recurrent gliomas and 25 initial cases
.

There were 109 patients (75.
7%), 131 patients (91.
0%) of radiotherapy, and 121 cases (84.
0%)
of chemotherapy.

Two adults did not receive any treatment
.

Forty-three (29.
9%) adult patients were treated with vemurafenib monotherapy, 3 (2.
1%) with trametinib, and 4 (2.
8%) with
carbitinib.

Dabrafenib was treated with monotherapy in 13 cases (9.
0%) and in combination with trametinib in 81 cases (56.
3%)
.

The average duration of treatment for 140 adults was 8 months (IQR 12.
4 months; 0.
1-54.
6 months).


Nine patients with HGG (including 1 child and 8 adults) had an adverse reaction or a lack of response to treatment to adjust BRAFi during treatment
.

Among the 6 patients, 5 patients were treated with vemurafenib, 1 case was changed to dalafenib in PLX8394 treatment, and 3 patients were changed to vemurafenib
in 3 cases.

Data analysis reported by 35 children (14.
5%) showed a median PFS of 9 months (IQR 10.
7 months; 0.
5-38 months).


Data analysis reported by 90 adult patients (62.
5%) showed a median PFS of 3.
8 months (IQR 7.
2 months; 0.
1-40 months).


The median OS in the children's group was 4.
5 months (IQR 8.
2; 0.
5-22 months); 10 (90.
9%) died
.

The median OS in the adult group was 8.
2 months (IQR 7.
5 months; 0.
1-40 months).


Thirty-four patients (100%) died
.

The authors performed a rank sum test (Mann-Whitney Wilcoxon, MWW) and found significant differences in PFS and OS in age groups (P=0.
001 and P=0.
17, respectively).


The P values of PFS and OS between children with LGG and HGG were P=0.
001 and P=0.
0002, respectively, while the P values of PFS and OS in adult patients with LGG and HGG were P=0.
02 and P=0.
03
, respectively.

Analysis of FPS and OS in combination therapy showed a median PFS of 12.
9 months (IQR 10.
7 months; 0.
5 to 38 months) in the single-agent group and a median FPS of 7.
3 months (IQR 8.
4 months; 1.
3 to 22.
1 months)
in the combination therapy group.

The median PFS for adults was 5.
5 months with monotherapy (IQR 7.
0 months; 0.
1 to 18 months) and 3.
0 months with combination therapy (IQR 5.
7 months; 0.
2 to 23.
9 months).


The P values of children and adults in MWW were P=0.
63 and P=0.
06
, respectively.

The median OS in the single-agent group was 3.
0 months (IQR 6 months; 0.
5-10 months) and 11.
0 months (IQR 9.
9 months; 2.
2-22 months)
in the combination group.

The median OS was 9.
6 months (IQR 8 months; 0.
1 to 40.
2 months) in the adult monotherapy group and 5.
0 months (IQR 5.
5 months; 2 to 9 months)
in combination therapy.

The P values for children and adults in MWW were P=0.
17 and P=0.
06
, respectively.

Of the 394 patients, 135 (34.
2%) received MEKi, including 62 patients with LGG, 70 patients with HGG, and 3 patients with NR, but only 65 (48.
1%) reported data on progression-free survival and 11 (8.
1%) reported data on overall survival
.

The median PFS was 8.
5 months (IQR 7.
9 months; 0.
2-23.
9 months) for 19 patients with LGG and 2.
9 months (IQR 3.
9; 0.
3-18.
6 months)
for 46 patients with HGG.

The median OS of combination therapy was 8.
5 months (IQR 3.
4 months; 2.
2-9.
0 months) in three patients with LGG and 4.
7 months (IQR 5.
5; 2-11 months)
in eight patients with HGG.

The P values of PFS and OS for MWW tests are P=0.
002 and P=0.
68
, respectively.

The Kaplan-Meier survival curves for OS and PFS were plotted for all patients and segmented
by age and grade.

154 children responded well
to BRAFi therapy.

Eight (5.
2%) were fully effective, 63 (40.
9%) were partially effective, 68 (44.
2%) were stable, and 15 (9.
7%) had disease progression
.

Among them, 125 patients with LGG were affected, of which 4 were fully effective, 53 were partially effective, 64 were stable, and 8 were progressive; There were 25 patients with HGG, of which 4 were fully effective, 10 were partially effective, 4 were stable, and 7 were progressive
.

137 adult patients responded well to BRAFi treatment
.

10 cases (7.
3%) were completely effective, 48 cases (35.
0%) were partially effective, 43 cases (31.
4%) were stable, and 36 cases (26.
3%) had progression.
There were 39 patients with LGG, of which 4 were fully effective, 17 were partially effective, 16 were stable, and 2 were progressive; There were 97 patients with HGG, of which 6 were fully effective, 31 were partially effective, 27 were stable, and 33 were progressive
.

In the pediatric patient group, 94 (39.
0%) survived and continued to receive BRAFi at
the end of the study.

Among the 241 cases, 38 (15.
8%) stopped drug treatment but survived, and 11 (4.
6%) died; The condition of the remaining 40.
7% of patients is unknown
.

Of the 144 adult patients, 54 (37.
5%) survived and continued to receive BRAFi at the end of the study; Eighteen (12.
5%) were alive despite drug therapy and 34 (23.
6%) died
.

Adverse events
related to BRAFi treatment occurred in 142 (58.
9%) pediatric patients and 109 (75.
7%) adult patients.

Adverse events
occurred in 1 pediatric patient and 49 adult patients.

Some patients did not report adverse events
in the literature.

Conclusion of the study

In summary, the BRAF V600 gene test can be applied to eGBM, PXA, APTA, GG and aGG, as well as astroblastoma, DIA, SEGA, DNET, DA and PA.


The authors believe that larger studies are needed to better characterize the frequency
of BRAF V600 mutations in the rare entity PLNTY.

Patients with recurrent gliomas with V600 mutations
respond to BRAFi in a variable manner.

Further clinical trials are being conducted to investigate the efficacy
of BRAFi alone or in combination with MEKi.