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  • br This study was also able to determine biomarker concordan

    2020-08-18


    This study was also able to determine biomarker concordance by metastatic site, with hepatic metastases most commonly studied and displaying a remarkably concordant relationship with the primary tu-mour [63,69]. The liver is a site that can be relatively easily biopsied with sufficient sample sizes (core biopsies). In contrast, pulmonary me-tastases are more challenging to sample and therefore not surprisingly were sampled less frequently than the liver. Much of the variation in concordance with lung metastases may be explained by this. It is how-ever a valid site for biopsy and determination of RAS status. Peritoneal samples were extremely infrequently sampled and would also be
    Table 5
    Absolute concordance in all biomarkers (n = 15).
    Study Year N Sequencing Biomarkers included Sites of metastases Absolute (%) concordance
    Abbreviations: Abw, abdominal wall; Adr, adrenal gland; AS-PCR; allele-specific polymerase chain reaction; Br, brain; DNA, deoxyribonucleic acid; Li, liver; LN, lymph node; Lu, lung; Mes, mesocolon; NGS, next generation sequencing; OTM, omentum; Ov, ovary; PCR, polymerase chain reaction; PTM, peritoneum; Pyro, pyrosequencing; Sanger, sanger sequencing; SI, small intestine; ST, soft tissue; Ut, uterus; Va, vagina. (…) = additional CRC-related Chlorpromazine but not listed.
    Fig. 2. Forest plot for proportion of discordance of KRAS. 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.
    potentially more difficult to obtain sufficient tissue from due to their lo-cation and size. It is therefore difficult to comment on their relationship with the primary. Only two studies reported on biomarker concordance specifically comparing peritoneal metastases to the primary tumour [45,53]. This suggests the need to investigate this area, particularly as peritoneal metastases have a significantly worse median OS (16.3 months) compared to liver (19.1 months) and lung (24.6 months) metastases [107].
    It is not surprising that we found that absolute concordance in more than one biomarker fell as the number of biomarkers was increased. For example limiting analysis to KRAS and BRAF demonstrated a 92–95% concordance [45,80,83], falling to 87% with extended RAS mutation analysis (including KRAS, NRAS and HRAS) [93]. Cohorts tested for KRAS and BRAF as well as additional alterations in PIK3CA/PTEN/TP53/ APC demonstrate a more variable absolute concordance ranging from 57 to 84% [44,51,54]. Finally studies comparing 12, 230 and 1321 gene sequencing have demonstrated how absolute concordance falls as 
    more genes 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>