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  • ST-2825 br A total of studies reported absolute concordance

    2020-08-18


    A total of 9 studies reported absolute concordance in KRAS point mutations within codons 12 and 13, despite apparent differences in se-quencing methodologies, suggesting the stability in KRAS status be-tween the primary and metastatic sites [53,54,59,63,66,81,88,91,92].
    Table 3
    Of note, Tórtola et al. did identify some discordance when using single-stand conformational polymorphism (SSCP) analysis of bone micrometastases [89]. In this study, 17 mutations were found among the primary tumours compared to only 7 in corresponding metastases, and whereas the majority (88%) of mutated KRAS in primary CRC's were located in ST-2825 12, in the bone marrow these mutations were
    Study Year N Analysis Codons Site of metastases Concordance (%)
    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; −, information unavailable/unspecified
    Table 4
    Concordance studies by metastatic type (n = 27).
    Biomarker concordance according to metastatic site (%)
    Study Year Biomarker LN Liver Lung PTM Other
    Moorcraft et al. 2017 KRAS
    NRAS
    BRAF
    PIK3CA
    PTEN
    APC
    PIK3CA
    Kovaleva et al. 2016 KRAS
    NRAS
    PIK3CA
    APC
    SMAD4
    PIK3CA
    PTEN
    APC
    SMAD4
    NRAS
    BRAF
    PIK3CA
    PTEN
    APC
    BRAF
    APC
    SMAD4
    NRAS
    BRAF
    PIK3CA
    Watanabe et al. 2011 KRAS
    Etienne-Grimaldi et al. 2008 KRAS
    Biomarker concordance according to metastatic site (%)
    Study Year Biomarker LN Liver Lung PTM Other
    Abbreviations: LN, lymph nodes; PTM, peritoneum. ‘Other’ – includes bone, ovary, pancreas etc.
    mainly localised to codon 13 (71%) [89]. There are however studies that identified discordance rates in KRAS as high as 30% [86,87]. In the case of Baldus et al., the lower reported concordance was suggested to be at-tributable to intra-tumour heterogeneity; a phenomenon strongly evi-denced in colorectal tumours as well as numerous other solid malignancies [37,73,105,106]. In a comparable study by He et al., a com-bination of low sensitivity testing and unrepeated mutation analysis of the tissues could have led to false-negatives [50,73]. This is effectively il-lustrated in the study by Vakiani and colleagues where concordance rates increased by 5% when more sensitive analysis methods were used [68]. KRAS status can therefore be determined from the primary tumour or the metastatic site as long as the sample is sufficient and se-quencing technique adequate.
    Although significantly fewer studies have evaluated NRAS status compared to KRAS in matched tumours, the available data suggests con-cordance rates are also high (median of 100%, range 90–100%) regard-less of sequencing method [56,60,63]. BRAF notably demonstrated 100% mutation concordance in half of the identified studies, despite similar variances in the type of metastasis sampled and sequencing method [48,54,65,68]. Expanded analysis of BRAF mutations to include exons 11 and 15 did result in a slightly lower concordance (median of 99.4%, range 80–100%), with discordance limited to V600E region of exon 15 [76]. It is important to note that all of the studies reporting lower rates of BRAF concordance demonstrated a small sample size of paired specimens which may have impacted their results. This is aligned to the publication bias detected in this particular subset where usually smaller studies are published only with positive findings. Altogether 7 BRAF studies had sample sizes that were considered small, defined as less than or equal to 20 matched patient samples [49,71,76].
    The results for PIK3CA in some cases show a much more discordant relationship between the primary tumour and the metastasis, with a 
    median concordance of 93% (42–100%) [50]. While the aforementioned report is unhindered by its adequate sample size (N50 matched pairs), a combination of the low sensitivity method of sequencing within this study and the unusually high proportion of patients with detected PIK3CA mutation may somewhat explain its contradiction to the rest of the literature [50]. Thus, based on the consistent results of other stud-ies, the concordance rate for PIK3CA is relatively high overall within the average CRC population [60,63,73]. Importantly, this study identified that some of the tumour suppressor genes (PTEN, TP53, APC and SMAD4) can show a more variable and discordant relationship between the primary tumour and the metastasis [59]. Mutation within these tu-mour suppressors, such as TP53, is at times more common in the metas-tasis than the primary [68]. However, cumulative data indicate that the PTEN and APC genes are among those demonstrating the greatest vari-ation, revealing less consistency for higher rates of concordance [24,51,52,63,64,67,94]. We also found that although primary tumours and their metastases displayed a variable concordance with regards to MSI and EGFR, the number of studies reporting on these biomarkers was small making our findings difficult to interpret [24,45,95,97]. None-theless, EGFR does show notable evidence of a predisposition toward discordant expression [95,96].