Experts Describe Challenges of Targeting BRAF Mutations in CRC

Published: Tuesday, Dec 12, 2017
Tanios Bekaii-Saab, MD
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.

In separate interviews with OncologyLive®, the doctors discussed the current treatment landscape and other key issues relating to this distinct subset of CRC.

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

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.

Microsatellite instability in BRAF V600E CRCs is associated with advanced age, female gender, proximal primary tumor site, and poor tumor differentiation.

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

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

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.

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

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.

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