Discordancy in BRAF mutations among primary and metastatic melanoma lesions: clinical implications for targeted therapy.

Systemic targeted molecular therapy, in the form of a selective BRAF inhibitor with or without a MEK inhibitor, is a standard treatment for patients with BRAF V600 mutation-positive melanoma with unresectable stage III and IV disease. Patients with BRAF mutation-negative primary tumors may manifest BRAF mutation-positive metastatic disease. It is unclear whether all metastatic lesions carry the same BRAF mutation status found in the primary tumor and if discordancy exists, in what frequency it occurs. Primary and matched metastatic lesions in 25 melanoma patients were tested for the BRAF V600E/Ec, V600K, V600D, and V600R mutations using a BRAF RGQ PCR kit (Qiagen). Four patients (16%) had discrepancies between their primary and metastatic melanoma BRAF status. Of these patients, 2 (8%) had BRAF mutation-positive primary melanomas with BRAF mutation-negative metastatic lesions and 2 (8%) patient had BRAF mutation-negative melanoma with a BRAF mutation-positive metastatic lesion. In summary, discordancy of BRAF mutation status is not an infrequent finding between primary and metastatic melanoma. It may be prudent in previously negative patients to determine BRAF mutation status of new metastatic tumors for proper allocation of BRAF inhibitor therapy. Discordant BRAF status may have a role in the varying patterns of response and inevitable resistance seen with BRAF inhibitor therapies.

KRAS mutation is present in a small subset of primary urinary bladder adenocarcinomas.

AIMS: To determine whether KRAS mutations occur in primary bladder adenocarcinoma. METHODS AND RESULTS: Twenty-six cases of primary urinary bladder adenocarcinoma were analysed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and amplified with shifted termination assay technology, which recognizes wild-type or mutant target sequences and selectively extends detection primers with labelled nucleotides. A mutation in KRAS was found in three (11.5%) of 26 primary bladder adenocarcinomas. Two of these three cases exhibited a G13D mutation, whereas the remaining case contained a mutation in G12V. None of the ten cases of urothelial carcinoma with glandular differentiation displayed KRAS mutation. Colonic adenocarcinoma contained a KRAS mutation in 18 (33%) of 55 cases. There was no distinct difference with regard to grade, stage or outcome according to the limited clinicopathological data available. However, the two youngest patients, aged 32 and 39 years, in our study group, with a mean population age of 61 years, were found to have mutations in KRAS. CONCLUSIONS: KRAS mutations are present in a small subset of primary urinary bladder adenocarcinomas. Future clinical trials for treatment of bladder adenocarcinoma, employing targeted therapies similar to those used for treatment of colon cancer, may also benefit from the predictive implications of KRAS mutational testing.