<b>Objective:</b> The COMBI-AD trial demonstrated the efficacy and safety of dabrafenib and trametinib in combination vs placebo as adjuvant treatment of patients with BRAFV600E/K mutation-positive resected Stage IIIA (lymph node metastasis >1 mm), IIIB, or IIIC melanoma.
The association between central lymph node metastasis (LNM) and risk factors, including the presence of the BRAF mutation, BRAF<sup>V600E</sup>, in patients with papillary thyroid cancer (PTC) requires further investigation.
In the pediatric PTCs, BRAF <sup>V600E</sup> was positively associated with older age, classical histology, and the lymph node metastasis but independent from other clinicopathological factors.
BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03).
Statistical analysis demonstrated that the BRAF mutation rate was not associated with any of the following clinicopathological features: Sex, age, smoking history, clinical stages, distant metastasis, differentiation degree, tumor size and regional lymph node metastasis (P≥0.05).
For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAFV600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]).
Kruskal-Wallis test was used for the univariate correlation analyses and comparison of mutation rate and expression rate, and Chi-square test was used for the association of central lymph node metastasis with BRAF gene and TSHR.
Additionally, there were significant associations (P<0.05) between BRAF(V600E) and a higher tumor-node-metastasis staging (III/IV), and between miR-21* over-expression and lymph node metastasis.
In PTC, BRAF mutation is closely associated with extrathyroidal extension, lymph node metastasis, advanced tumor stages, disease recurrence, and even patient mortality.
Our results showed that BRAF mutation was associated with a larger tumor size, higher frequency of lymph node metastasis, and lower TIMP3 protein levels.
Direct bidirectional sequencing of EGFR gene exons 18 to 21, KRAS gene codons 12/13 and 61 to 68, and BRAF exon 15 was done on 96 paired samples of primary lung adenocarcinomas and corresponding locoregional lymph node metastases.
BRAF mutation examined in FNAB specimens, compared with the wild-type allele, strongly predicted perithyroidal invasion (48 vs. 29%; P = 0.017), extracapsular spread (65 vs. 45%; P = 0.017), occult central lymph node metastasis (35 vs. 15%; P = 0.004), and advanced TNM stage (44 vs. 28%; P = 0.035).
There was no statistically significant correlation in age, gender, multifocality, extrathyroidal extension, presence of Hashimoto thyroiditis, and lymph node metastasis between the BRAF(V600E) mutant group and wild group.
Genetic heterogeneity of BRAF was studied by comparing the mutation status in different samples of tumor as follows: (a) 2 separate areas (each >1.5 cm in diameter) within the primary tumor, (b) a more than 1.5 cm area of primary carcinoma and a second 5 mm area simulating a fine needle aspiration sample from a different portion of the primary tumor, (c) primary carcinoma and its lymph node metastasis at thyroidectomy, (d) primary carcinoma and the recurrent metastasis, and (e) differentiated and anaplastic areas in the primary carcinoma.
The patients with BRAFp.Val600Glu mutation of primary tumour had only non-significantly higher risk of cervical lymph node metastases [OR=2.39 (95%) CI 1.00-5.75, p=0.052].
We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery.