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Utility of the Methylated SEPT9 Test for the Early Detection of Colorectal Cancer: a Systematic Review and Meta-­Analysis of Diagnostic Test Accuracy

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Utility of the Methylated SEPT9 Test for the Early Detection of Colorectal Cancer: a Systematic Review and Meta-­Analysis of Diagnostic Test Accuracy BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000355 on 18 February 2020. Downloaded from Colorectal cancer Utility of the methylated SEPT9 test for the early detection of colorectal cancer: a systematic review and meta- analysis of diagnostic test accuracy Rohit Hariharan, Mark Jenkins To cite: Hariharan R, Jenkins M. ABSTRACT Summary box Utility of the methylated SEPT9 Background Circulating tumour DNA from colorectal test for the early detection cancer (CRC) is a biomarker for early detection of the What is already known about this subject? of colorectal cancer: a disease and therefore potentially useful for screening. One systematic review and meta- The methylation of the SEPT9 (mSEPT9) test has such biomarker is the methylated SEPT9 (mSEPT9) gene, analysis of diagnostic test shown promise as a screening test for early detec- which occurs during CRC tumourigenesis. This systematic accuracy. BMJ Open Gastro tion of colorectal cancers. review and meta-analysis aims to establish the sensitivity, 2020;7:e000355. doi:10.1136/ What are the new findings? specificity and accuracy of mSEPT9 tests for the early bmjgast-2019-000355 This updated meta- analysis estimates the sensitiv- diagnosis of CRC. ity to be 69% and specificity of 92% and adds to ► Additional material is Methods A systematic search of the relevant literature current evidence by including new studies, evaluat- published online only. To view, was conducted using Medline and Embase databases. ing the covariate effects and how these interact with please visit the journal online Data were extracted from the eligible studies and analysed (http:// dx. doi. org/ 10. 1136/ pooled estimates of diagnostic performance. to estimate pooled sensitivity, specificity and diagnostic bmjgast- 2019- 000355). While diagnostic performance seems promising copyright. test accuracy. for colorectal cancers, the mSEPT9 test has poor- Results Based on 19 studies, the pooled estimates (and er performance for detecting precancerous lesions Received 19 November 2019 95% CIs) for mSEPT9 to detect CRC were: sensitivity 69% (advanced adenomas and polyps) and is more Revised 23 January 2020 (62–75); specificity 92% (89–95); positive likelihood ratio Accepted 30 January 2020 expensive. 9.1 (6.1–13.8); negative likelihood ratio 0.34 (0.27–0.42); diagnostic OR 27 (15–48) and area under the curve 0.89 How might it impact on clinical practice in the (0.86–0.91). The test has a positive predictive value forseeable future? of 2.6% and negative predictive value of 99.9% in an The clinically relevant findings of this study posits average risk population (0.3% CRC prevalence), and 9.5% the potential use of an alternative screening method (positive predictive value) and 99.6% (negative predictive http://bmjopengastro.bmj.com/ for those that decline the faecal immunochemical value) in a high- risk population (1.2% CRC prevalence). test (FIT) to provide cover to individuals who would Conclusion The mSEPT9 test has high specificity and otherwise miss out on the benefits offered by col- moderate sensitivity for CRC and is therefore a potential orectal cancer screening. alternative screening method for those declining faecal Further studies are needed to test whether mSEPT9 immunochemical test for occult blood (FIT) or other is acceptable for those that decline the FIT and screening modalities. However, it is limited by its poor whether this strategy would be cost-effective. diagnostic performance for precancerous lesions (advanced adenomas and polyps) and its relatively high costs, and little is known about its acceptability to those declining to use the FIT. tumour DNA (ctDNA), which can be present 2 in the earliest stages of tumourigenesis. on October 2, 2021 by guest. Protected © Author(s) (or their ctDNA is released into the bloodstream from employer(s)) 2020. Re- use INTRODUCTION malignant cells during apoptosis. These frag- permitted under CC BY- NC. No Colorectal cancer (CRC) survival is highly ments of DNA are representative of cancer commercial re- use. See rights and permissions. Published dependent on stage and therefore methods cells of the tumour. Commonly, the DNA by BMJ. for early detection are critical to reduce of tumour cells and therefore the ctDNA is Centre for Epidemiology and mortality. In the USA, only 40% of CRC cases methylated at the 5’-Cytosine- phosphate- 2 Biostatistics, The University of are diagnosed at an early stage; the 5-year Guanine-3’ sites. Therefore, detection of Melbourne, Melbourne, Victoria, relative survival for stage 1 is 89.9%, stage 2 is methylated ctDNA is used as a biomarker Australia 71.1%, stage 3–4 is 14.2%.1 for the detection of asymptomatic cancer Correspondence to Liquid biopsy screening tests are blood- including CRC. Dr Mark Jenkins; based tests for early detection of cancer. They For the early detection of CRC, methyla- m. jenkins@ unimelb. edu. au examine peripheral blood for circulating tion of the SEPT9 (mSEPT9) gene located on Hariharan R, Jenkins M. BMJ Open Gastro 2020;7:e000355. doi:10.1136/bmjgast-2019-000355 1 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000355 on 18 February 2020. Downloaded from Open access chromosome 17 at q25.33 has shown promise as a ctDNA removed. A detailed search strategy is provided in online biomarker as CRC tumours have an increased likelihood supplementary file 1. of exhibiting methylation of the promoter region of the SEPT9 gene.3 For this test, a purified DNA sample Eligibility criteria obtained from peripheral blood is evaluated using duplex The inclusion criteria for the papers were: full-text avail- real- time PCR to identify methylation in the v2 region of able, English language, human studies, case-control the SEPT9 gene,3 which is suggestive of CRC. study design, CRC diagnosis either prior or following A previous meta- analysis of diagnostic performance of mSEPT9 test, report of sufficient data to enable construc- mSEPT94 reported estimates of the sensitivity of mSEPT9 tion of 2×2 tables of mSEPT9 result and CRC status, and for CRC ranging from 37% up to 88%. However, most the use of a mSEPT9 single gene assay for both cases and of the studies within this meta-analysis have not assessed controls. Exclusion criteria were: articles that were meta- the effect of covariates on sensitivity and specificity analysis, conference and meeting abstracts, studies that (such as the study sample size, region of recruitment of used a multigene ctDNA panel; and studies with <20 CRC participants, total number of CRC cases and the distri- case participants. bution of stage). Additionally, four studies included in Study selection this meta- analysis were assessed as having a high prob- Endnote X9 was used to manage citations. Each article ability of patient selection bias and could not include 5 6 was assigned to one or more of the following reference research reported since 2017. Two other meta-analyses categories: ‘articles with SEPT9 information’, ‘potential did not conduct a comprehensive analysis of diagnostic 5 candidates for meta-analysis’, ‘irrelevant to this study’ accuracy of mSEPT9 tests: the first study considered and ‘selected studies’ by the following method. Arti- covariates to assess sources of heterogeneity but provided cles that matched the inclusion criteria, identified by limited evidence of the effect of those covariates on the 6 the three search phases were assigned to ‘article with diagnostic efficacy of mSEPT9. The second study only SEPT9 information’. The abstracts of these papers were provided estimates on sensitivity and specificity. Finally, scanned for validity. Those meeting all inclusion criteria few studies have estimated the accuracy of the newer and were assigned to ‘potential candidates for meta-analysis’. commonly used mSEPT9 test, Epi- ProColon V.2.0 to the The full-text of these articles were evaluated, and the commonly used screening method for CRC, the faecal applicable studies for the meta-analysis were assigned copyright. immunochemical tests (FIT), thereby limiting under- to ‘selected studies’. Articles such as meeting abstracts, standing of its clinical applicability. Only one previous 4 conference notes, meta-analysis and those studies which meta- analysis assessed the impact of the threshold level matched one exclusion criteria were assigned to ‘irrele- for the number of PCR results that constitute a posi- vant for this study’. tive test, which is a major issue affecting the accuracy of mSEPT9 test for CRC.7 Quality assessment of individual studies The aim of this systematic review was to conduct an The two authors (RH and MJ) independently carried updated meta- analysis stratified by the region of recruit- out quality assessment of each study to assess risk of bias ment, sample size and stage, and to evaluate the accuracy and applicability concerns using the Quality Assessment http://bmjopengastro.bmj.com/ of a range of positivity thresholds for the mSEPT9 test. of Diagnostic Accuracy Studies V.2.0 tool.9 Risk of bias and applicability concerns of the study methodology was assessed under four domains: ‘patient selection’, METHODS ‘index test (mSEPT9)’, ‘reference standard (histopa- This systematic review and meta-analysis was conducted thology or colonoscopy to define CRC)’. The ‘flow and as per Guidelines of the Preferred Reporting Items for timing’ domain was omitted when assessing ‘applica- 8 bility concerns’ as instructed by the tool. Each domain Systematic Reviews and Meta-Analysis. comprised two or three signalling questions, for which each reviewer answered ‘yes’, ‘no’ or ‘unclear’. Based Search strategy on this, each study was graded ‘high’, ‘low’ or ‘unclear’ on October 2, 2021 by guest. Protected Medline and Embase databases were searched for rele- in each of the four domains, and the assessment results vant literature. The search was divided into three phases. were then graphed (see online supplementary table 1, All articles included in these databases from January 1946 online supplementary figure 1). Inter-rater reliability/ to May 2018 were considered.
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