In a recent blog, I noted that the CEO of ImClone said KRAS testing has grown substantially since the announcements earlier this summer linking mutations in KRAS with resistance to Erbitux and Vectibix therapies. We may now have to add mutations in BRAF as well, in order to get a more comprehensive view of whether a patient will benefit from these therapies.
A study presented this week at the annual EORTC meeting in Geneva showed that patients with a mutation in the BRAF gene also do not benefit Erbitux or Vectibix. So far, these clinical observations fit perfectly with what we know about the biology of the EGFR pathway. Because KRAS lies downstream of the EGFR, activating mutations in KRAS would be expected to override any inhibition of the EGFR that occurs upstream. Similarly, BRAF lies downstream of KRAS, so activating mutations in BRAF would also be expected to override any inhibition of the EGFR that occurs upstream as well. The study (of 113 patients) found that KRAS and BRAF mutations were mutually exclusive, suggesting that a BRAF mutation is as sufficient as a KRAS mutation in mediating resistance to these therapies, although larger studies would be needed to truly determine this. If these observations fit so well with the biology of EGFR – KRAS – BRAF signaling, you might wonder why it took so long to figure it out (given that we’ve understood these pathways for a quite a long time). To be sure, hindsight is always 20/20, but studies on patient specimens are immensely more challenging than pre-clinical studies, and only in the last several years have more sensitive methods of sequencing and mutation detection come about that can really pinpoint mutations in clinical specimens, where the DNA is generally of poor quality and also may be limiting if only small amounts of tumor are present in a specimen.
So it looks like we may need to test colon cancer patients for both KRAS and BRAF together. While the exact frequency of BRAF mutations in colorectal cancer is not yet known, it is probably at least 10% and perhaps as high as 25%. So even being conservative, we can probably say that almost half (and possibly more) of colon cancer patients will have either a KRAS or BRAF mutation. This is another step forward for personalized medicine since more patients can be put on therapies sooner that will have a real chance of helping them.
At TMD, we’ve been ahead of the curve, by providing the KRAS Mutation test since earlier this year, and also validating the BRAF Mutation test, as we expected that it was only a matter of time before BRAF was found to be important as well. The BRAF Mutation test we use employs the same highly sensitive technology as the KRAS Mutation test. Please contact us to find out how we can provide both KRAS and BRAF testing.