Value of KRAS and BRAF Mutations in Forecasting Survival

For stage II and III colon cancer, a tumor mutation in the KRAS gene does not impact either relapse-free survival or overall survival.

BRAF mutations, which are less common, don’t help with prognosis for relapse-free survival, but do provide information about overall survival in some tumors.   Patients with BRAF mutations and microsatellite-low or stable tumors had poorer overall survival than those without mutations.

As colon cancer develops, changes in genes accumulate that affect cell division and cell death.  When cells no longer divide or die normally, tumors get larger and some cells may break off and move to new and dangerous sites.

In earlier studies, changes in the KRAS and BRAF genes have been able to predict whether or not advanced colorectal cancer would respond to drugs that target epidermal growth factor receptors (EGFR).  Patients with tumors that have mutated KRAS or BRAF don’t benefit from either Erbitux® (cetuximab) or Vectibix™ (panitumumab).

But it has been unclear whether mutations in these two genes can provide information about whether early stage II or III colon cancer would recur or what the mutations meant for eventual survival.

Using over 1,400 tumor specimens collected during a large, randomized trial of chemotherapy for stage II and III colon cancer, researchers were able to analyze KRAS and BRAF mutations and their impact on both relapse-free and overall survival.  The scientists also looked at microsatellite instability (MSI) and coordinated it with the KRAS and BRAF results.  They had good long-term information about patient relapse and survival.

About 1 in 3 tumors (37 percent) had a KRAS mutation, similar to the percentages found in other studies in metastatic colorectal cancer.  7.9 percent had a BRAF mutation, and the two mutations were mutually exclusive.  Neither KRAS nor BRAF mutations differed between stages II or III.

KRAS mutations

• Were significantly more frequent in l0w-grade tumors and right-sided tumors.
• Were borderline more common in microsatellite-low and microsatellite-stable tumors.
• Did not predict relapse-free survival or overall survival.

BRAF mutations

• Were more frequent in right-sided tumors, high-grade tumors, and tumors that were MSI-high.
• Were more frequent in patients over 60 and in women.
• Did not predict relapse-free survival.
• Did predict poorer overall survival, particularly in patients with MSI-low or MSI-stable tumors.

Arnaud D. Roth, MD and his colleagues concluded,

In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

SOURCE:  Roth et al., Journal of Clinical Oncology, Early Release, December 14, 2009.