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  • br more genes are included within the analysis to only

    2022-07-25

    
    more 4-Aminophenyl Phosphate are included within the analysis to only 5% [59,63,108]. This suggests that the metastases are distinctly different in their genetic composition to the primary tumour [64]. In any case poor absolute con-cordance may provide some explanation as to the complexities of colo-rectal tumours and their resistance to cytotoxic and biological therapies [109]. Furthermore, as metastases generally possess greater mutational load than primary tumours as well as less intra-tumour heterogeneity, basing clinical decision-making on the profile of metastases in prefer-ence to generalising the data obtained from primary tumours may be beneficial [64,67].
    It is important to note a number of limitations of this study. First it should be noted that the studies included were retrospective and varied in their sample size. This was reflected in the meta-analysis showing a clear publication bias for the KRAS and BRAF papers. Second, there was heterogeneity in sample collection and processing techniques as well as sequencing techniques used which have evolved over time, making absolute comparisons difficult. This would for example explain
    Fig. 3. Forest plot for proportion of discordance of BRAF. The estimate proportion and 95% CI interval at the level of the total number of cases reflects the calculation under a fixed effect model. The estimate proportion and 95% CI interval at the level of the Pooled Discordance Proportion are the random effects pooled estimates to take into account heterogeneity.
    Fig. 4. Forest plot for proportion of discordance of PIK3CA. The estimate proportion and 95% CI interval at the level of the total number of cases reflects the calculation under a fixed effect model. The estimate proportion and 95% CI interval at the level of the Pooled Discordance Proportion are the random effects pooled estimates to take into account heterogeneity. r> the higher concordance for newer biomarkers such as NRAS. Third, the patients varied in the systemic treatments they received, and the impact of this on the metastasis (tumour regression after chemo- or radiother-apy) may have affected the sequencing result through adequacy of the sample. Fourth, it is important to note that any change in concordance may represent the evolution of the tumour as it metastasises and there-fore the time between the primary tumour and metastasis sampling is an important factor to consider which could not be accounted for. Fi-nally inter-tumour heterogeneity means that sufficient samples may not have been possible to obtain in many of 4-Aminophenyl Phosphate the studies to determine biomarker status especially at the metastatic sites.
    Despite the above limitations, we feel that this study has demon-strated high biomarker concordance rate between primary tumours and the metastases with challenges in getting adequate sample size from metastatic sites likely to account for most discordance. This has important practical implications as it suggests there is little evidence 
    for separate biopsy of the primary and metastatic sites. Whether the evolving use of liquid biopsy through circulating tumour DNA (ctDNA) analysis adds anything further to a patient's treatment options remains to be seen. We also feel that little information is currently available on peritoneal metastases and this is an area for further research.
    5. Conclusion
    mCRC demonstrates remarkably high concordance across a number of individual biomarkers, suggesting that molecular testing of either the primary or liver and lung metastasis is adequate for determining bio-marker status to personalize treatment. More research is required to de-termine concordance in colorectal cancer peritoneal metastases which may explain why these tumours have a significantly worse prognosis compared to other sites. Clonal selection and tumour evolution add