Emerging treatment options for <em>BRAF</em>-mutant colorectal cancer

Abstract

The personalization of cancer care is rooted in the premise that there are subsets of patients with tumors harboring clinically relevant targets for patient-specific treatments. Colorectal cancer (CRC) is a disease that has historically been notable for its dearth of biomarkers that are predictive of response to targeted therapies. In recent years, BRAFV600E-mutated CRC has emerged as a distinct biologic entity, typically refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis. Multiple clinical trials sought to replicate the successes of targeted therapies seen in BRAFV600E-mutated melanoma without success; metastatic BRAFV600E-mutated CRC is clearly a distinct biologic entity. We review a number of recent studies demonstrating the evidence of modest responses to combinations of BRAF, EGFR, and/or MEK inhibition in patients with metastatic BRAFV600E-mutated CRC; however, despite advances, overall survival remains far inferior for these patients compared to their BRAF-wild-type counterparts. Development of combination therapies to impede signaling through the MAPK pathway through alternate targets remains an area of active investigation. Reflecting the rapid evolution of efforts for this small subset of CRC patients, the first-ever Phase III study is now underway evaluating the combination of BRAF, EGFR, and MEK inhibition. Immunotherapies are also an area of active research, particularly for the subset of patients with tumors that are also microsatellite instability (MSI) high. Here, we summarize the current landscape and emerging data on the molecular, clinical, and therapeutic aspects of BRAF-mutant CRC.

GLI1 Inhibitor SRI-38832 Attenuates Chemotherapeutic Resistance by Downregulating NBS1 Transcription in BRAFV600E Colorectal Cancer

“…Length and width were measured for each tumor. Tumor volume was determined using the formula for an ellipsoid sphere: (Length × Width 2 )/2 = Volume (mm 3 ). This formula was also used to calculate tumor weight, assuming unit density (1 nm 3 = 1 mg).…”

“…A predominant driver of this mortality rate is inherent or acquired resistance to the standard-of-care combination regimens with the anti-metabolite 5-Flurouracil (5-FU) as the base therapy (i.e., FOLFOX and FOLFIRI). Genetic analysis of biopsied tissue from CRC patients indicates that a significant subset, ∼10%, expressed oncogenic BRAF (2,3). Within this subset, patients bearing a missense mutation within BRAF at position V600E faced significantly shorter overall survival and an 80% mortality rate (4).…”

Current Update of Laboratory Molecular Diagnostics Advancement in Management of Colorectal Cancer (CRC)

“…BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation occurs in 10% of CRC cases, with most of the mutations being presented in Codon 600 [61]. Recent evidences suggest that BRAF mutation is a better predictor for the determination of anti-EGFR therapy responses than RAS status.…”

Stratification and prediction of drug synergy based on target functional similarity

“…Such mutation can lead to a 500-fold increased activation, stimulating the constitutive activation of MEK/ERK pathway in tumor cells (21). Thus, there is a need for novel combination therapies (22)(23)(24) with BRAF inhibitors in colorectal cancer.…”