This week at the EORTC-NCI-AACR meeting, it was reported that metastatic colorectal cancer patients with a mutated BRAF gene do not respond to anti-EGFR monoclonal antibody therapy with cetuximab (Erbitux) or panitumumab (Vectibix). This means that screening patients for the mutation may determine who would benefit most from receiving the treatment.
Colorectal cancer (CRC) is one of the most common cancers globally. Once the disease has spread, five year survival rate is less that 10%. At present, EGFR therapies are used after several prior treatments have failed and are only effective in 10-20% of cases. It has previously been shown that KRAS mutations account for 30-40% of non-responsive cases. The new research suggests that BRAF mutations may acount for an additional 12% of resistant cases.
The study found that none of the tumours containing BRAF mutations responded to treatment and where it did work, none of the tumours expressed the mutation, suggesting that EGFR targets the wild-type BRAF gene.
Interestingly, when a BRAF inhibitor, sorafenib (Nexavar) was added to the treatment regimen of patients with mutated BRAF, the sensitivity of the cells to EGFR therapy was restored, resulting in cell death (apoptosis) with the combination therapy. This approach has yet to be validated in a broader clinical trial, but offers a promising approach in patients with mutated BRAF in colorectal cancer, if validated.
It should be noted though, that while the KRAS and BRAF mutations offer some predictive value for treatment, 52% of non-responsive patients in the study did not have mutations in either gene, so the search continues for other molecular markers.
This data, while preliminary, raises all sorts of questions. Currently, patients are treated by diagnosis and line of therapy.
Thus, first line treatment of metastatic colorectal cancer is usually standard chemotherapy (FOLFOX or FOLFIRI) plus or minus bevacizumab (Avastin). Second line might typically comprise irinotecan with or without cetuximab or panitumumab and third line irinotecan with panitumumab or cetuximab.
What happens with a newly diagnosed advanced CRC patient who presents with wild type KRAS or BRAF? Or mutated BRAF? Should they now be treated with an EGFR inhibitor and EGFR inhibitor plus sorafenib respectively? With or without chemotherapy? This complicates physician decision making enormously, especially as neither EGFR inhibitor is approved for front-line use in CRC and sorafenib use would be off-label since it is approved for renal cell and hepatocellular carcinoma.
The next few years will be very interesting in this disease as key opinion leaders wrestle with the problem and decide optimal sequencing for different patient types. What is clear though, is that a new era of personalised medicine based on particular biomarker profiles is gradually being ushered in.