Experts Describe Challenges of Targeting BRAF Mutations in CRC

Tanios Bekaii-Saab, MD

Tanios Bekaii-Saab, MD, FACP, and Rona D. Yaeger, MD, are involved in research at the cutting edge of colorectal cancer (CRC) treatment, including clinical trials of novel therapeutic strategies for BRAF-mutant disease.

Bekaii-Saab is co-leader of the gastrointestinal cancer program and senior associate consultant in the Division of Hematology and Oncology at Mayo Clinic in Phoenix, Arizona. Yaeger is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

How do CRC tumors with the most common type of BRAF mutations, V600, differ from those without?

In separate interviews with OncologyLive^®, the doctors discussed the current treatment landscape and other key issues relating to this distinct subset of CRC.Bekaii-Saab: These tumors tend to be more aggressive with a high propensity for diffuse metastasis including a high proportion of peritoneal involvement. They tend to respond poorly to doublet chemotherapy with or without bevacizumab.

They also do not seem to be sensitive to EGFR inhibitors. The median survival for these patients tends to be poor, with an average of slightly more than 1 year.

Yaeger: The presence of the most common BRAF mutation [V600E] in metastatic colorectal tumors is associated with more aggressive disease and shorter patient survival. These tumors are less responsive to standard therapy, especially in the second-line setting after progression through a standard chemotherapy regimen. BRAF V600E metastatic CRCs commonly exhibit a distinct pattern of metastases from other metastatic CRCs and frequently metastasize to the abdominal lining (peritoneum), cause fluid accumulation (ascites), and involve the abdominal wall and distant lymph nodes, including less typical sites like axillary lymph nodes.

Importantly now, the BRAF V600E mutation is associated with tumor microsatellite instability from hypermethylation and silencing of MLH1. About 30% of metastatic BRAF V600E CRCs are microsatellite unstable. This opens a potential treatment opportunity with immune checkpoint inhibitors.

What about other types of BRAF mutations? How might these transform clinical practice?

Microsatellite instability in BRAF V600E CRCs is associated with advanced age, female gender, proximal primary tumor site, and poor tumor differentiation.Bekaii-Saab: Interestingly, compared with the V600E mutations, the BRAF non-V600E mutations are associated with a very good prognosis and a much better outcome overall. A recent study published in the Journal of Clinical Oncology confirmed these findings.¹

Why has the success of BRAF and MEK inhibitors in melanoma not translated to CRC?

Yaeger: About a quarter to one-third of alterations in BRAF in metastatic CRC do not involve the V600 site. Some of these alterations activate BRAF (eg, K601E) and thus result in clinical resistance to EGFR inhibitors and may respond to newer ERK pathway inhibitors now in clinical development. Others have low activating potential, but serve to amplify signaling from upstream receptors or RAS, and these alterations (eg, at D594 or G466) have been associated with better prognosis and clinical responses to EGFR inhibitors.Bekaii-Saab: In the first-line treatment of patients with V600E mutations, FOLFIRINOX [leucovorin, fluorouracil, irinotecan, oxaliplatin] with or without bevacizumab would be the preferred standard-of-care option. Unlike melanoma, multiple loop feedback mechanisms and epigenetic influences affect single-agent inhibition strategies in CRC. Interestingly, when combining BRAF inhibitors with EGFR inhibitors, the response rate jumps from 5% for single agent to 20% for the doublet, indicating synergism between the 2.

What are the most significant challenges or limitations to the development of effective therapies for BRAF-mutant CRC?

Yaeger: The activity of BRAF and MEK inhibitors in CRC has likely been limited by reactivation of receptors, with ERK pathway inhibition and rapid adaptive resistance to the drug. This effect is believed to be more pronounced in CRC than melanoma because of abundant receptors, particularly EGFR, in the colon. Receptor tyrosine kinase signaling is modulated, in part, by a negative feedback loop from activated ERK. ERK inhibition with BRAF and MEK inhibitors removes this negative feedback loop and leads to reactivation of receptors. Current trial strategies for BRAF V600E CRC are combining BRAF and MEK inhibitors with EGFR inhibitors to more profoundly block ERK signaling.Bekaii-Saab: The lack of universal and reflexive testing. The low likelihood of finding this mutation makes it less likely to be on the radar for therapeutic considerations in practice. Most studies have focused on refractory patients. Unfortunately, most patients with BRAF V600E mutations do not survive long enough to make it to secondline therapy, thus making the pool of eligible patients smaller.

Yaeger: Current targeted therapies for BRAF V600E CRCs have been limited by short duration of response. Our group and others have studied samples from patients who originally respond to targeted therapies and then develop resistance to identify the underlying causes of acquired resistance and develop more effective treatment strategies.

Jones JC, Renfro LA, Al-Shamsi HO, et al. Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017;35(23):2624-2630. doi: 10.1200/JCO.2016.71.4394.