Another mutated gene has been discovered that appears to cause resistance to treatment with the EGFR inhibitors Erbitux® (cetuximab) and Vectibix™ (panitumumab).
Only a fraction of patients who receive Erbitux or Vectibix respond to it. There is now convincing evidence that the 30 to 40 percent of colorectal cancer patients whose tumors have mutated KRAS genes don’t benefit, but what about others who have normal or wild-type KRAS and don’t respond either?
Scientists in Italy have found that about 12 percent of wild-type patients have a mutation in their tumor’s BRAF gene, and these patients showed no response to Erbitux or Vectibix.
Testing 113 colorectal cancer tumors from patients who had been treated with either Erbitux or Vectibix, they found 30 percent had a KRAS mutation. Going further, they tested the remaining 79 tumors for a mutation in BRAF. Patients with mutated BRAF showed no response to the EGFR inhibiting drugs. None had tumors shrink, and they had a shorter time until their cancer got worse and shorter survival.
All of the patients who did respond to Erbitux or Vectibix had normal or wild-type BRAF.
Dr Federica Di Nicolantonio, from the University of Turin School of Medicine said,
None of the patients with tumours containing BRAF mutations had responded to the treatment, and in cases where the treatment did work, none of those patients had BRAF mutations. This shows that for anti-EGFR therapy to work, the BRAF gene must be the wild type and suggests that BRAF status could be a useful biomarker for selecting patients suitable for anti-EGFR treatment.
In a laboratory experiment, cells that contained mutated BRAF had a dramatically reduced response to cetuximab and panitumumab, but when they were also treated with the BRAF inhibitor sorafenib (Nexavar®), the cells died.
Dr. Di Nicolantonio said,
These findings suggest that combination therapy that simultaneously blocks EGFR and BRAF in patients with BRAF-mutated tumours may be a useful approach to increase the number of patients who could benefit from anti- EGFR therapy, but that remains to be assessed in a clinical trial.
Despite finding another gene that stops response to EGFR inhibiting drugs, the picture isn’t yet complete. More than half of patients who had no response to Erbitux or Vectibix didn’t have mutations in either KRAS or BRAF.
Dr. Di Nicolantonio adds,
This research does not complete the picture of resistance to EGFR inhibitors. In spite of the predictive value of both KRAS and BRAF mutations, in our cohort 52 per cent of non-responsive patients did not have mutations in either gene. This means further molecular markers are needed to better define patients who are unlikely to benefit from EGFR-targeted treatment.
SOURCES: The research was reported by Federica Di Nicolantonio and her colleagues on October 23, 2008 at the Molecular Targets and Cancer Therapeutics Symposium, jointly sponsored by EORTC, NCI, and AACR in Geneva.
Di Nicolantonio et al., Journal of Clinical Oncology, Online ahead of print, November 10, 2008.