The overall objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of Kirsten rat sarcoma viral oncogene (KRAS) mutation tests (commercial or in-house) for the differentiation of adults with metastatic colorectal cancer (mCRC) whose metastases are confined to the liver and are unresectable and who may benefit from first-line treatment with cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone, as recommended in the National Institute for Health and Care Excellence (NICE) technology appraisal TA176.¹ To address clinical effectiveness, data on the clinical validity of the different KRAS mutation tests (sensitivity/specificity for detection of mutations known to be linked to insensitivity to cetuximab) are required. Because methods of testing KRAS mutation status differ in terms of both the mutations targeted and the limit of detection (the lowest proportion of tumour cells with a mutation that can be detected), the definitions of KRAS mutant and KRAS wild type vary according to which test is used. All testing methods are essentially reference standard methods for classifying mutation status, as defined by the specific test characteristics, and it is therefore not useful to select any particular test as the reference standard. In addition, the relationship between insensitivity to cetuximab and the presence of specific mutations or combinations of mutations, as well as the relationship between insensitivity to cetuximab and the level of mutation present, are uncertain. Therefore, the following research questions were formulated to address the review objectives:

1. What is the technical performance of the different KRAS mutation tests {e.g. proportion of tumour cells needed, limit of detection [minimum percentage mutation detectable against a background of wild-type deoxyribonucleic acid (DNA)], failures, costs, turnaround time}?
2. What is the accuracy (clinical validity) of KRAS mutation testing, using any test, for predicting response to treatment with cetuximab in combination with standard chemotherapy?
3. How do clinical outcomes from treatment with cetuximab in combination with standard chemotherapy and, when reported, from treatment with standard chemotherapy alone vary according to which test is used to select patients for treatment?
4. What is the cost-effectiveness of the use of the different KRAS mutation tests to decide between standard chemotherapy or cetuximab in combination with standard chemotherapy?

First-line chemotherapy of unresectable colorectal liver metastases seeks to achieve a tumour response such that the tumour is judged to be resectable. For this reason, resection rate is considered the ideal reference standard for question 2 and the optimal outcome measure for question 3.