There has been a recent flurry of papers and reports from ASCO-GI 2013 pushing more molecular testing in colorectal cancer (CRC) and its clinical significance with regard to prognostic and predictive factors, especially with MMR/MSI.
One area that caught my interest was BRAF mutations in colorectal cancer. Given the justifiable excitement around BRAF-mutated malignant melanoma responses with vemurafenib, I was curious about BRAF mutation in CRC. Here's my notes--
- 5% to 10% of CRCs have the BRAF mutation and the predominant mutation is similar to that seen in a large minority of melanomas, viz, the V600E mutation.
- Activating mutations in BRAF lead to constitutive activation of downstream signaling through the MAPK/MEK/ERK pathway.
- Recognition of this led to reflexive testing for BRAF if a CRC tumor was found to be KRAS-wildtype, since BRAF-mutant tumors would also be resistant to therapy with cetuximab similar to KRAS-mutant tumors.
- BRAF mutation appears to occur early in CRC progression and is associated with CpG island methylation.
- It leads to serrated adenoma-type polyps that have defective mismatch repair leading to a tumor that displays microsatellite instability.
- Important clinicopathologic associations: female gender, older age, right-sided location, high histologic grade, MSI-high--but not HNPCC.
- Advanced stage BRAF-mutated tumors have a poor prognosis: in a study of 524 patients with metastatic CRC (mCRC) by Tran et al. in Cancer (2011), OS for patients with BRAF-mutant tumors was 10.4 months versus 34.7 months in patients with BRAF-wild type tumors.
- Unlike the 81% response rate with vemurafinib in BRAF-mutated melanomas, the response rate in patients with mCRC is only about 5%.
- ?more heterogenous distribution of BRAF mutation in CRC
- similar mutations do not equal similar tumor biology (and thus) response to same targeted therapy
- In CRC (and in general?), mutations need to be viewed in context of other signaling pathways--
- Data from CRC cell lines and clinical tissue specimens show that BRAF mutation alone is insufficient for vemurafinib sensitivity: CRC can escape through activation of the PTEN/PI3K/AKT pathway and feedback activation of EGFR or other RTKs. This suggests multiple pathway inhibition as a possible therapeutic strategy in BRAF-mutant CRC.