BRAF MUTATION IN ADVANCED COLORECTAL CANCER

Background: Around 10% of advanced colorectal cancer (BRAF-mCRC) harbor BRAF V600E mutation, considered an unique entity with poor prognosis but heterogeneity has been described. BRAF mutation has been also detected in colorectal rhabdoid carcinomas (CRbCs), rare and aggressive subtypes. Methods: 59 BRAF mCRCs were selected analyzing clinical data, MSI status, immunohistochemical features, inflammatory profile and neuroendocrine markers. We reviewed the literature on CRbCs and compared 7 CRbCS with 4 poorly differentiated medullary carcinomas (PDMCs) analyzing the clinic and molecular profiles. Results: The 22 MSI BRAF mCRCs showed right sided, expansive grown pattern, PDL-1 expression, high CD8 T-cell content and lymph node metastases. The 37 MSS BRAF mCRCs were associated with stromal component, pulmonary metastases, p53 and synaptophysin expression, high rate of neuroendocrine differentiation. MSI, high CD8 T-cell content and their combination were associated with reduction in risk of death: 34%, 33% and 63% respectively. CRbCs showed loss of INI-1 expression, intense vimentin expression, rich neutrophilic infiltration, CIMP negative, MSI in 2 cases only. PDMCs were MSI and CIMP positive; they were positive for pancytokeratin but negative for vimentin, showed high INI-1 expression and moderate CD8+ T-cells. Both groups had coexistence of BRAF and TP53 mutations and poor prognosis. Conclusions: MSI, CD8 T-cell content and neuroendocrine markers may identify BRAF-mCRC subsets with different prognosis and potential eligibility for specific treatments. CRbCs may be better recognized by loss of INI-1 expression, intense vimentin immunostaining, dense neutrophilic infiltration, low frequency of CIMP and MSS status.