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  • br The proportion of changes discordance proportion with

    2020-08-18


    The proportion of changes (discordance proportion) with exact 95% confidence intervals (CIs) was calculated for each study. The Freeman– Tukey double arcsine transformation was the chosen approach for the calculation of pooled estimates and corresponding 95% CIs [39,40]. If a study had a sample size below 10, the arcsine transformation was pre-ferred. Random effects pooled estimates were calculated in order to take into account heterogeneity between estimates [41]. Statistical heterogeneity among studies was evaluated using the chi-square test statistic and was measured using the I2 statistic, which is the proportion of total variation contributed by between-study variance tau-squared (τ2) [42]. Publication bias was evaluated using funnel plots and the asymmetry test developed by Egger et al. [43]
    All analyses were carried out with R software (http://cran.r-project. org/) with packages ‘meta’ and ‘metafor’. All the reported P values were two sided.
    3. Results
    Literature search identified 1498 studies reporting on concordance in mCRC between 1991 and 2018. Of these, 61 articles including 3565 patients matched the selection criteria and were deemed suitable for qualitative synthesis as outlined in Fig. 1.
    3.1. Concordance between primary CRC and its metastatic site
    Fig. 1. PRISMA flow diagram of the literature search.
    3.2. Concordance depending on metastatic site
    The liver was the most commonly included metastatic site within studies (n = 53 studies including 2276 patients), followed by the: lung (n = 37 studies including 438 patients), ST2825 nodes (n = 30 studies including 1123 patients), and peritoneum (n = 17 studies, in-cluding 132 patients). 27 studies analysed biomarker concordance sep-arately within these metastatic sites as displayed in Table 4, thus allowing comparison between metastatic location and the possible 
    3.3. Absolute concordance
    3.4. Meta-analysis of the discordance
    The discordance rate was assessed in 3066 patients for KRAS, 1312 patients for BRAF, 727 patients for PIK3CA and 626 patients with overall molecular profiles. There was no evidence for publication bias for PIK3CA and the overall molecular profiles (labelled as “ALL” in the Supplementary Fig. 1 (Egger's test: p = .76 and p = .08 respectively). However, publication bias was found in KRAS and BRAF studies (Egger's test: p = .01 and p = .01 respectively).
    Table 1
    Study Year N Analysis Codons Sites of Concordance
    metastasis (%)
    N = no. of patients with matched samples
    L = local metastasis e.g. loco-regional lymph nodes
    D = distant metastasis e.g. liver, lung, peritoneum, omentum, mesentery, brain, bone, ovary, uterus, vagina, small intestine, adrenal gland, pancreas
    Li = Liver only
    Lu = Lung only
    BM = Bone marrow only
    Abbreviations: ARMS, amplification-refractory mutation system analysis; ASO, allele-specific oligonucleotide hybridisation; AS-PCR; allele-specific polymerase chain reaction; NGS, next generation sequencing; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; Pyro, pyrosequencing; qPCR; quantitative PCR; qRT, quantitative reverse tran-scription; Sanger, sanger ST2825 sequencing; Seq, sequencing; SSCP, single-stranded conformation polymorphism; −, information unavailable/unspecified.
    (i) KRAS - Fig. 2 shows the discordance proportions reported for
    (ii) BRAF - Fig. 3 shows the discordance proportions reported for
    (iii) PIK3CA - Fig. 4 shows the discordance proportions reported for 
    (iv) Overall molecular profiles – Fig. 5 shows the discordance propor-tions reported considering the overall molecular profiles. PIK3CA in for all studies included in the analysis. The heterogeneity be-tween proportions ranged from 5% to 95% (I2 = 93%, τ2 = 0.1, p b .0001). The meta-analytic pooled discordance proportion was 28% (95% CI: 14–44%).
    Study Year N Analysis Codons Sites of Concordance
    metastasis (%)
    N = no. of patients with matched samples
    L = local metastasis e.g. loco-regional lymph nodes
    D = distant metastasis e.g. liver, lung, peritoneum, omentum, mesentery, brain, bone, ovary, uterus, vagina, small intestine, adrenal gland, pancreas
    Li = Liver only
    Lu = Lung only
    BM = Bone marrow only
    Abbreviations: ARMS, amplification-refractory mutation system analysis; AS-PCR; allele-specific polymerase chain reaction; NGS, next generation sequencing; PCR, polymerase chain reaction; Pyro, pyrosequencing; Sanger, sanger sequencing; Seq, sequencing; SSCP, single-stranded conformation polymorphism; −, information unavailable/unspecified.
    4. Discussion