Implications for service provision
There was no strong evidence that any one method of KRAS mutation testing had greater accuracy than any other for predicting tumour response or potentially curative resection following treatment with cetuximab plus standard chemotherapy in patients with mCRC whose metastases were limited to the liver and were unresectable before chemotherapy. The clinical effectiveness of cetuximab plus standard chemotherapy in patients whose tumours are KRAS wild type did not appear to vary according to which method was used to determine tumour KRAS mutation status. However, it should be noted that the available data were not adequate to fully address either the comparative accuracy of different KRAS mutation testing methods for predicting tumour response or the comparative clinical effectiveness of cetuximab plus standard chemotherapy in patients whose tumours are KRAS wild type, as defined by different testing methods.
The results of the linked evidence analysis indicated that the Therascreen KRAS RGQ PCR Kit was more costly and more effective than pyrosequencing, with an ICER of £17,019 per QALY gained. Sensitivity analyses did not show substantial differences compared with the base case. The key driver behind the outcome was the difference in resection rate between treatment with and treatment without cetuximab and the proportions of patients with KRAS wild-type, KRAS mutant and unknown tumour status, which is determined by test accuracy and therefore, for the most part, is dependent on ORR (for Therascreen KRAS RGQ PCR Kit) or resection rate (for pyrosequencing). It should be noted that some problematic and substantial assumptions were necessary to arrive at the economic results, in particular the assumption that the differences in resection rates observed between the different studies are solely the result of the different tests used. This ignores all other factors that can explain variations in outcomes between the studies. Therefore, these outcomes of the assessment of cost-effectiveness should be interpreted with extreme caution.
The results of the assumption of equal prognostic value analysis (including all tests for which information on technical performance was available from the online survey of NHS laboratories in England and Wales) showed that the cobas KRAS Mutation Test is the least expensive and least effective strategy and that Sanger sequencing and HRM analysis are equally the most costly and most effective, with an ICER of £69,815 per QALY gained compared with the cobas KRAS Mutation Test. The other two strategies included in this analysis, that is, the Therascreen KRAS RGQ PCR Kit and pyrosequencing, are ruled out by extended dominance.
There are no data on the clinical effectiveness or cost-effectiveness of next-generation sequencing of codons 12, 13 and 61; the KRAS StripAssay; MALDI-TOF mass spectrometry of codons 12, 13 and 61 used alone; and HRM analysis of codons 12, 13 and 61 used alone. No published studies were identified for any of these methods and none of these methods are currently in routine clinical use in any of the NHS laboratories in England and Wales that responded to our survey.
Suggested research priorities
The available data have limitations in respect of their ability to address the overall aim of this assessment, that is, to compare the clinical effectiveness of different methods of KRAS mutation testing to determine which patients may benefit from the addition of cetuximab to treatment with standard chemotherapy and which should receive standard chemotherapy alone. Because each different testing method potentially selects a subtly different population, based on the targeting of a different range of mutations and different limits of detection, the most informative studies are those that provide full information on the comparative treatment effect (cetuximab plus standard chemotherapy vs. standard chemotherapy alone) for both patients with KRAS wild-type tumours and patients with KRAS mutant tumours. No published studies of this type were identified. Additional data supplied by the COIN trial investigators meant that these data could be derived for a combination of pyrosequencing and MALDI-TOF mass spectrometry (both methods used for all samples) (D FIsher, personal communication). The very high concordance (> 99%) between the two KRAS mutation testing methods used in the COIN trial means that data from this trial may be assumed to also be representative of the expected values when pyrosequencing or MALDI-TOF are used as single tests to define tumour KRAS mutation status. However, further similar trials are unlikely as randomisation of patients to cetuximab plus standard chemotherapy or standard chemotherapy alone, regardless of tumour KRAS mutation status, would be against current clinical guidance and would be likely to be considered unethical. One possible solution to this problem would be to retest stored samples from previous studies in which patient outcomes are already known, using those KRAS mutation testing methods for which adequate data are currently unavailable. This approach could provide a ‘black box’ answer whereby the relative effectiveness of cetuximab plus standard chemotherapy and standard chemotherapy alone in patients with KRAS wild-type and KRAS mutant tumours could be determined for each testing method. However, it would not provide any information on the underlying reason(s) for any observed differences between tests. As they are likely to represent the most practical approach to obtaining informative data, retrospective comparative accuracy studies, using stored samples for which the patient outcome is already known, should be given priority. The application of this approach to the evaluation of next-generation sequencing might be considered a particular priority, given the likely adoption of next-generation sequencing techniques by laboratories in the near future.
Some methods of KRAS mutation testing, for example the Therascreen KRAS Pyro Kit, can provide quantitative results. Should quantitative testing become part of routine practice, longitudinal follow-up studies relating the level of mutation and/or the presence of rarer mutations to patient outcomes would become possible. Studies of this type could help to assess which features of KRAS mutation tests are likely to be important in determining their clinical effectiveness and should be considered going forward.
Building on information gained from the two study types described above, preliminary research to develop a multifactorial prediction model should be considered. Initially, research of this type is likely to be exploratory in nature; however, models developed could form the basis of tools that will eventually help determine more accurately which patients are most likely to benefit from the addition of cetuximab to treatment with standard chemotherapy.
As the uncertainties associated with clinical effectiveness forced the major assumptions in the economic evaluation, this type of research would also facilitate economic analyses of KRAS mutation testing.
