Extended RAS Testing in Metastatic CRC

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The collection of evidence from multiple clinical trials has suggested that extending RAS testing beyond KRAS exon 2 enhances patient selection in metastatic colorectal cancer (mCRC). The extended testing, which includes KRAS and NRAS, optimizes the use of the EGFR inhibitors cetuximab and panitumumab and prevents potential harm for patients with mCRC, notes Tanios S. Bekaii-Saab, MD.

Given the level of added benefit seen across several phase III studies, extended RAS testing should become mandatory, believes Axel Grothey, MD, and Al B. Benson III, MD. Despite this need, some community oncologists still do not have the capacity to run the extended testing, particularly since insurers and payers do not require it as part of the prescreening process, notes Bekaii-Saab.

Traditionally, in the United States physicians have been unlikely to select cetuximab as a frontline therapy due to the associated skin toxicity, Venook says. Moreover, in terms of the chemotherapy backbone used, data from the 80405 trial suggests that FOLFOX was administered for 73% of patients compared with FOLFIRI. In the United States, bevacizumab is most commonly combined with FOLFOX, notes Venook, suggesting a predisposition toward frontline bevacizumab.

The magnitude of benefit seen with these drugs warrants accurate and effective patient selection, Benson states. As a result, the NCCN guidelines now recommend that all patients with mCRC should have tumor tissue genotyped for KRAS and NRAS mutations. Patients with any KRAS or NRAS mutation should not be treated with cetuximab or panitumumab.

To help accelerate extended RAS testing, studies are exploring plasma-based circulating tumor cell tests, Venook notes. The number of patients excluded from treatment with EGFR inhibitors when using the extended RAS testing is substantial. On average, 60% of patients will be ineligible for EGFR inhibitors compared with 40% using traditional KRAS testing, Venook notes. This adds to the treatment puzzle, since a standard option is being taken away for many patients.