Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer.

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E ) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E . Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAFV600E /BRAFnon-V600E , KRAS/NRAS exons 2-4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAFV600E /BRAFnon-V600E , KRAS (including exons 2-4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAFV600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAFnon-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAFnon-V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine.

Clinicopathological features and clinical outcomes associated with TP53 and BRAFNon-V600 mutations in cutaneous melanoma patients.

BACKGROUND: BRAFV600 , NRAS, TP53, and BRAFNon-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAFV600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAFNon-V600 mutations. METHODS: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926). RESULTS: The prevalence of BRAFV600 , NRAS, TP53, and BRAFNon-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAFNon-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAFNon-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAFNon-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy. CONCLUSIONS: These results add to the understanding of the clinical features associated with TP53 and BRAFNon-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society.