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Predictive Value of RAS Mutations in mCRC

Panelists: Tanios Bekaii-Saab, MD, OSUCCC; Fadi Braiteh, MD, CPI, CCC Nevada; Axel Grothey, MD, Mayo Clinic;John L. Marshall, MD, Georgetown; A
Published: Monday, Oct 21, 2013
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Two recent biomarker analyses that focused on the role of RAS mutations in metastatic colorectal cancer (mCRC) are beneficial but not immediately practice changing, suggests Tanios Bekaii-Saab, MD. The largest of these studies was the phase III PRIME study that explored panitumumab plus FOLFOX as a first-line treatment for patients with mCRC. This trial found a higher survival benefit in patients with wild-type RAS mutation treated with the EGFR inhibitor.

The second analysis was the phase II PEAK study, which examined KRAS and NRAS mutations. In this trial, FOLFOX6 plus panitumumab or bevacizumab was examined as a first-line treatment in patients with wild-type KRAS mutant CRC. These results were similar to the PRIME study, demonstrating an improvement in survival for patients with wild-type RAS mutant CRC treated with panitumumab.

These trials provide some insight into the role of certain RAS mutations in patients with CRC; however, their full impact is dulled by the administration of FOLFOX rather than FOLFIRI, believes Bekaii-Saab. Recent studies have demonstrated an apparent synergistic relationship between EGFR inhibitors and irinotecan. As a result of these findings, none of the panelists recommend the administration of oxaliplatin with an EGFR inhibitor in favor of irinotecan. Despite this, in the near future, Bekaii-Saab believes that an expanded definition of mutations will be utilized to select EGFR inhibitors in CRC, expanding the current definition to include KRAS, NRAS, and possibly HRAS mutations.

In current guidelines, all patients should be tested for KRAS upfront, even if an EGFR inhibitor is not the planned treatment, explains Fadi Braiteh, MD, CPI. Additionally, since KRAS mutations occur early in the process, a rebiopsy may not be needed. Furthermore, Braiteh notes, a reporting method that directly communicates mutational analysis results into an electronic health record is in development.


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Two recent biomarker analyses that focused on the role of RAS mutations in metastatic colorectal cancer (mCRC) are beneficial but not immediately practice changing, suggests Tanios Bekaii-Saab, MD. The largest of these studies was the phase III PRIME study that explored panitumumab plus FOLFOX as a first-line treatment for patients with mCRC. This trial found a higher survival benefit in patients with wild-type RAS mutation treated with the EGFR inhibitor.

The second analysis was the phase II PEAK study, which examined KRAS and NRAS mutations. In this trial, FOLFOX6 plus panitumumab or bevacizumab was examined as a first-line treatment in patients with wild-type KRAS mutant CRC. These results were similar to the PRIME study, demonstrating an improvement in survival for patients with wild-type RAS mutant CRC treated with panitumumab.

These trials provide some insight into the role of certain RAS mutations in patients with CRC; however, their full impact is dulled by the administration of FOLFOX rather than FOLFIRI, believes Bekaii-Saab. Recent studies have demonstrated an apparent synergistic relationship between EGFR inhibitors and irinotecan. As a result of these findings, none of the panelists recommend the administration of oxaliplatin with an EGFR inhibitor in favor of irinotecan. Despite this, in the near future, Bekaii-Saab believes that an expanded definition of mutations will be utilized to select EGFR inhibitors in CRC, expanding the current definition to include KRAS, NRAS, and possibly HRAS mutations.

In current guidelines, all patients should be tested for KRAS upfront, even if an EGFR inhibitor is not the planned treatment, explains Fadi Braiteh, MD, CPI. Additionally, since KRAS mutations occur early in the process, a rebiopsy may not be needed. Furthermore, Braiteh notes, a reporting method that directly communicates mutational analysis results into an electronic health record is in development.
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