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.
Keywords: colon cancer, BRAF mutation, molecular targets, targeted therapy
Colorectal cancer (CRC) is the third most common cancer worldwide1 and the fourth most common cancer in the USA.2 Globally, there are ~774,000 deaths each year from CRC.3 BRAF mutations are present in ~10% of CRC cases. Although malignant melanoma is a disease more commonly associated with BRAFV600E mutation, CRC is a much more prevalent disease and deaths from BRAF-mutant CRC are predicted to exceed those from BRAF-mutant melanoma.1
Moreover, the clinical significance, prognosis, and therapeutic targets of a detected BRAF mutation in metastatic CRC provide a stark contrast to melanoma; the alteration at codon 600 is present in ~50% of melanoma cases4 and is associated with response rates of up to 80% for treatment with single-agent BRAF inhibitors, including vemurafenib,5 dabrafenib,6 and encorafenib.7 While responses to single-agent BRAF inhibitors in metastatic melanoma are not necessarily durable, there is clear biologic activity. By comparison, single-agent vemurafenib was found to have a response rate of <5% in metastatic BRAF-mutant CRC.8 In recent years, BRAF-mutant CRC has emerged as a distinct biologic entity, refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis. Here, we summarize the current landscape and emerging data on the molecular, clinical, and therapeutic aspects of BRAF-mutant CRC.
THE MOLECULAR LANDSCAPE
BRAF is a serine/threonine kinase immediately downstream of KRAS in the MAPK signaling pathway; thus, mutations in this gene are detected almost exclusively in KRAS-wild-type CRC. BRAF-mutant CRC typically harbors a valine (V) to glutamic acid (E) change at codon 600 (c.1799T>A or p.V600E). This alteration in the BRAF kinase domain results in a constitutively active protein.
In addition to CRC and melanoma, the Cancer Genome Atlas identified BRAFV600E mutations in non-small-cell lung cancer, thyroid cancer, cholangiocarcinoma, and gliomas in addition to some hematologic malignancies.9 In a population-based study of CRC, BRAFV600E mutations strongly associated with hypermutated tumors, frequently exhibiting a CpG island methylator phenotype (CIMP) and sporadic microsatellite instability (MSI).10 The Cancer Genome Atlas similarly identified BRAFV600Emutations in 3% of nonhypermutated and 47% of hypermutated colon cancers (n=165 and 30, respectively);11 however, these numbers may reflect selection bias and likely overestimate the proportion of BRAF mutations in hypermutated CRC. A study of 218 CRC tumor specimens with BRAFV600E identified two distinct subgroups independent of MSI status, PI3K mutation, gender, and sidedness.12 One subset of tumors was characterized by high KRAS/mTOR/AKT/4EBP1/EMT activation, while the other was characterized by cell cycle dysregulation. Identification of these two unique subgroups of BRAFV600E mutations may explain the nonuniform responses seen to drug therapies including BRAF and MEK inhibitors.
Although there are other non-V600E BRAF mutations in CRC with a different phenotype, none have been identified as strongly prognostic.13 A study performing next-generation sequencing of CRC from ~10,000 patients identified non-V600E BRAF mutations in 2.2% of cases, accounting for 22% of the total BRAF mutations identified.14 In this study, non-V600E BRAF mutations in CRC were associated with younger age, male gender, lower-grade tumor, and less right-sided primaries. Additionally, these mutations were associated with improved overall survival (OS) compared to patients with either wild-type BRAF or BRAFV600E-mutant CRC. A study of 10 patients with BRAF mutations at codons 594 and 596 also found these unique mutations to be conversely associated with improved prognosis.15