br The results for PIK
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%) . 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 . 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 . Mutation within these tu-mour suppressors, such as TP53, is at times more common in the metas-tasis than the primary . 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 Aprotinin [95,96].
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
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 genes 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 .
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) . 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