Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study.
BACKGROUND
This study investigated the potential clinical utility of circulating free DNA (cfDNA) as a source of BRAF mutation detection in patients enrolled into a phase II study of AZD6244, a specific MEK1/2 inhibitor, in patients with advanced melanoma.


METHODS
BRAF mutations were detected using Amplification Refractory Mutation System allele-specific PCR. BRAF mutation status was assessed in serum-derived cfDNA from 126 patients enrolled into the study and from 94 matched tumour samples.


RESULTS
Of 94 tumour samples, 45 (47.9%) were found to be BRAF mutation positive (BRAF+). Serum-derived cfDNA was BRAF+ in 33 of 126 (26.2%) samples, including in five samples for which tumour data were unavailable. Of BRAF+ tumours, 25 of 45 (55.6%) were BRAF+ in cfDNA. In three cases in which the tumour was negative, cfDNA was BRAF+. Progression-free survival (PFS) of patients with BRAF+ tumour and cfDNA was not significantly different compared with tumour BRAF+ but cfDNA BRAF-negative patients, indicating that cfDNA BRAF detection is not associated with poorer prognosis on PFS in stage III/IV advanced melanoma.


CONCLUSIONS
These data demonstrate the feasibility of BRAF mutation detection in cfDNA of patients with advanced melanoma. Future studies should aim to incorporate BRAF mutation testing in cfDNA to further validate this biomarker for patient selection.
AstraZeneca Pharmaceuticals, Alderley Park, Cheshire SK10 4TG, UK.
R E
RE
Board
G
G
Ellison
M C M
MC
Orr
K R
KR
Kemsley
G
G
McWalter
L Y
LY
Blockley
S P
SP
Dearden
C
C
Morris
M
M
Ranson
M V
MV
Cantarini
C
C
Dive
A
A
Hughes
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D018572:Disease-Free Survival; D019073:HT29 Cells; D006801:Humans; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf