Role of KRAS/BRAF in metastatic colorectal cancer still emerging

Results may help reveal up to 70% of patients who will not respond to EGFR-targeted therapies.

Two studies recently published in the Journal of Clinical Oncology continue to examine the role of KRAS and BRAF in the efficacy of treatment for colorectal cancer.

It is currently known that patients with KRAS mutations do not respond to treatment with anti-EGFR receptor antibodies; however, according to background information from the first study, only half of patients with wild-type KRAS respond to this type of treatment, revealing a need for additional biomarker studies.

In the study, Pierre Laurent-Puig, MD, professor at the Paris - Descartes University Medical School, France, and colleagues found that in patients with wild-type KRAS, BRAF mutations are associated with poor PFS and OS.

In addition, they determined that in those patients EGFR amplification predicted improved response to cetuximab (Erbitux, ImClone Systems). In an accompanying editorial, Monica M. Bertagnolli, MD, with Dana-Farber Cancer Institute, wrote that if those findings can be confirmed, it could result in better targeted therapy for patients with metastatic colorectal cancer.

“If these results are confirmed in additional studies, then as many as 70% of patients with metastatic colorectal cancer may reasonably be excluded from EGFR-directed therapies,” she wrote.

Wild-type KRAS tumors

In the study by Laurent-Puig and colleagues, researchers retrospectively reviewed tumor samples from 173 patients with metastatic colorectal cancer. Three patients had received cetuximab only, 141 had received a combination of irinotecan and cetuximab and 28 had received a combination of FOLFIRI and cetuximab. Outcome measures were response based on RECIST criteria, PFS and OS.

The researchers conducted a multivariate analysis of response and OS to determine the respective roles of EGFR, BRAF and PTEN in determining outcome for patients with KRAS wild-type tumors.

They determined that in patients with KRAS wild-type tumors (n=116), BRAF mutations were weakly associated with lack of response, resulted in a PFS of only 10 weeks vs. 30 weeks for patients without the KRAS mutation, and resulted in an OS of 8.4 weeks vs.14.4 weeks for patients without the mutation.

The researchers also found that EGFR FISH-positive phenotype was associated with a higher responses rate (71%) than in tumors with normal EGFR copy number (37%). The phenotype was also associated with a statistically insignificant trend towards longer OS and PFS.

“We found that EGFR and BRAF were significant predictors of response even after adjustment for all other covariates,” the researchers wrote. “This association was also significant for EGFR in the subset of patients who were wild-type for both KRAS and BRAF. Finally, we found that PTEN and BRAF were joint predictors of OS.”

Bertagnolli wrote, “Collectively, the clinical correlation of tumor EGFR pathway activation status and targeted agent response represents a major advance, sparing the majority of patients with advanced colorectal cancer therapies that are both costly and ineffective.”

Other cytotoxic agents

In the second article, Susan D. Richman, PhD, of the Leeds Institute of Molecular Medicine, U.K., and colleagues found that KRAS/BRAF mutation was associated with poor OS, but did not uncover any evidence that the presence of the mutation precluded patients from benefitting from irinotecan or oxiliplatin.

In the FOCUS trial, researchers conducted a biomarker analysis of 711 patients diagnosed with advanced colorectal cancer from 2000 to 2003. Patients were randomly assigned to first-line fluorouracil (FU) alone, FU/irinotecan, or FU/oxiliplatin. Overall, more than half of patients had KRAS (43.4%) or BRAF (7.9%) mutations.

The researchers found that having either mutation predicted poor OS (HR=1.40; 95% CI, 1.20-1.65), but not PFS (HR=1.16; 95% CI, 1.0-1.36).

When KRAS was assessed as a single marker, the researchers said there was no evidence of an effect on PFS in simple or multivariable analyses (HR=1.14; 95% CI, 0.98-1.33). However, there was evidence that patients with KRAS-mutations had poorer OS than patients with KRAS-wild-type (HR=1.24; 95% CI, 1.06-1.46).

Similarly, there was no evidence that BRAF-mutation alone was a prognostic factor for PFS (HR=1.14; 95% CI, 0.86-1.52), but the researchers did find evidence that BRAF-mutation was a negative prognostic marker for OS (HR=1.82; 95% CI, 1.36-2.43).

The researchers said the addition of either irinotecan (HR=0.77) or oxiliplatin (HR=0.75) to FU in first-line therapy had a major effect on first-line PFS, but did not have a similar effect on OS. There were no significant differences in the treatment HRs between patients with different KRAS or BRAF mutation status. The researchers concluded, “There is no evidence that KRAS or BRAF are predictive biomarkers for irinotecan or oxiliplatin: Patients benefit from these drugs regardless of KRAS/BRAF status.”

Bertagnolli said there no clear answer as to whether “constitutive activation of EGFR pathway is in itself a negative prognostic factor for colorectal cancer.” This study, she said, still has not answered that question.

“Unfortunately, despite the high quality of this study, anti-EGFR therapy was available for colorectal cancer clinical trials in Europe during the enrollment period of the MRC FOCUS trial, raising the possibility that second-line treatment could have biased this result,” she wrote.

However, in response, Richman said that in their paper, they wrote, “Trial treatment did not include anti-EGFR mAb therapy, and only 0.5% and 1.5% of patients in each arm received anti-EGFY mAb therapy during subsequent salvage therapy.” – Jason Harris