br Research in context br Evidence before this study
Research in context
Evidence before this study
Genetic mutations in key biomarkers are known to predict out-comes and response to treatment in metastatic colorectal cancer. Concordance in these biomarkers between the primary and meta-static sites is an important factor to consider with both diagnostic and therapeutic implications. We systematically reviewed all pub-lished comparative studies reporting on biomarker concordance between primary and metastatic sites. These studies were identi-fied using PubMed, MEDLINE, Ovid, Embase, Cochrane, and Goo-gle Scholar databases. Biomarkers that were studied included KRAS, BRAF, NRAS, PIK3CA and PTEN, among others.
Added value of this study
This study provides a comprehensive review of the concordance rates of genetic biomarker mutations between primary and meta-static sites in colorectal cancer. This allows us to quantify the pre-dictive value of a metastatic site biopsy in determining the biomarker mutation status of the primary colorectal cancer. It also presents what is currently known about biomarker concor-dance by metastatic site.
Implications of all the available evidence
This study demonstrates a high genetic concordance rate be-tween primary colorectal cancers and their liver/lung metastases. Despite peritoneal metastases being the third most common site, little remains known about their concordance with the primary co-lorectal cancer. There is currently no evidence that multiple meta-static site biopsies will provide benefit, with single sites sufficient for diagnosis and biomarker profiling provided adequate samples can be taken. This has important implications for reducing the time to diagnosis, commencement of treatment, and cost.
involved in the malignant transformation of CRC, with mutation in TP53 resulting in a non-functional p53 protein and reduced OS [27–30]. Un-like APC and TP53, which usually occur in early colorectal tumorigene-sis, inactivation of SMAD4 is associated with late-stage or metastatic disease . SMAD4, also known as DPC4, encodes a tumour suppressor that regulates transcriptional activity downstream of TGF-beta receptor signalling. Expression of SMAD4 is an important prognostic factor in CRC, with patients who retain higher levels of SMAD4 within their tu-mours having higher OS than those with low or absent PER977 [32,33].
This study aims to systematically review the literature and under-take meta-analysis where appropriate in order to determine the concor-dance between primary CRC and its metastatic site, with regards to the above-mentioned biomarkers and their combinations. It also aims to determine the variation in concordance by metastatic site, and the ‘absolute concordance’ in multiple biomarkers for mCRC. This is impor-tant for two reasons: First, it has implications for the understanding of how tumours evolve and differ between the primary and metastatic site. Studies demonstrating the dynamic changes in circulating DNA of mCRC patients with the clonal evolution and resistance to anti-EGFR treatments with time have suggested that the CRC genome adapts to drug schedules, providing a molecular explanation for changes in efficacy with re-challenge anti-EGFR therapies . Second it also has implications for personalized treatment strategies used for patients based on single site biopsies [35,36]. This study tries to shed light in respect to the heterogeneity (studied as mutational discordance)
between the primary and metastatic sites in light of evidence that sig-nificant intra-tumour heterogeneity exists between different points on the same primary CRC specimen . There are cases where the primary tumour cannot be accessed, in which case knowledge on con-cordance between the metastatic sites (liver, lung, lymph node or peri-toneum) is important.
This systematic review was undertaken in accordance with the PRISMA guidelines . A literature search was undertaken by two in-dependent reviewers (DB and OA) of all published studies using PubMed, MEDLINE, Ovid, Embase, Cochrane, and Google Scholar data-bases using the following MeSH terms: “colorectal neoplasm”, “perito-neal neoplasm” and “mutation”, plus additional search terms including: “primary colorectal cancer”, “metastasis”, “biomarker”, and “concordance”. Further references were identified manually using the bibliographies of relevant papers and review articles. Equal consider-ation was given to fully published studies and those available in only ab-stract form.
2.1. Study selection
Studies were included provided that patients had a confirmed diag-nosis of metastatic colorectal adenocarcinoma, and mutational biomarker analysis on biopsies both from the colorectal primary and at least one site of metastasis. Studies were excluded if the primary and metastatic tumour samples were unmatched, concordance was reported in relation to peripheral blood samples instead of solid tumour, or there was insufficient data available to provide a value for concor-dance. The method and extent of mutational analysis was not a criterion for exclusion. In this study the biomarker concordance between primary tumour and metastasis was defined in terms of both mutant and wild-type pairs, and not limited to the mutant-only population.