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Editorial |

Fecal Blood Testing or Colonoscopy What Is the Best Method for Colorectal Cancer Screening?

Rita F. Redberg, MD, MSc1,2
[+] Author Affiliations
1University of California, San Francisco
2Editor, JAMA Internal Medicine
JAMA Intern Med. 2016;176(8):1071-1073. doi:10.1001/jamainternmed.2016.3892.
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Extract

This editorial discusses the US Preventive Services Task Force Recommendation on Colorectal Cancer Screening.

The US Preventive Services Task Force (USPSTF) has updated its evidence review and continues to recommend colorectal cancer (CRC) screening for persons between the ages of 50 and 75 to reduce CRC mortality.1 The USPSTF declined, however, to express a preference in screening methods, stating “Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit.”1 Nonetheless, the USPSTF evidence review offers an opportunity to compare the benefits and risks of different screening methods, which is the focus of this editorial.

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Plasma methylated septin 9: may be an early colorectal cancer screening marker but not a first option
Posted on June 22, 2016
Professor (Dr.) Pranab Kumar Bhattacharya ; Miss Upasana Bhattacharya Dr Sumana Mukherjee Assoc Prof Pathology STM kolkata Mr Rupak BhattacharyaBsc( Calcutta Univ) Ritwick Bhattacharya B.Com (calcutta Univ)
Professor Pathology at Murshidabad Medical College, Behrampore Court; District -Murshidabad, West Benga,l India also Professor Pathology ( detailment ) Calcutta Schhol of Tropical Medicine 108,
Conflict of Interest: None Declared




Colorectal cancer (CRC) is the 3rd leading cause of new cancer cases in the United States in 2014[1]. The prevention of CRC should aim at early most detection. However, 60%-70% of patients are found at middle or late stage CRC when they are first-time diagnosed, leading to the high mortality in CRC [2]. The low detection rate of early stage CRC is mainly due to late onset of clinical symptoms and lack of effective early detection methods. Therefore, regular screening with effective early detection methods is needed to prolong patients’ lives and reduce mortality.
Four types of test are currently available for CRC detection or screening, including faecal-based occult blood test (FOBT or FIT),tumour marker blood test, combined faecal DNA and FIT test, and imaging test (colonoscopy). The specificity or sensitivity for FOBT or FIT is not sufficient, and compliance is low due to the inconvenience in sampling and the interference of the test results by many factors . The serum-based non-invasive tumour markers used in clinical laboratories, including carcino -embryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), are not appropriate for screening due to their low sensitivity and the lack of CRC specificity, especially for early stage CRC [3-5 ]. More recently, the FDA-approved faecal DNA test (Cologuard, Exact Sciences, Madison, WI, USA) exhibited high sensitivity in detecting CRC (87 %) and adenomas ≥ 1 cm (82%) [6]. The test includes mutation detection, methylation detection and FIT. However, the price of the test is much higher than that of the SEPT9 or FIT test, due to the combination of multiple indicators. Colonoscopy is still now regarded as the gold standard for CRC diagnosis when combined with pathological examinations. However, its compliance is low due to its high costs, inconvenient preparation process, invasive procedure, and multiple complications. Septin-9 is a protein that in humans is encoded by the SEPT9 gene. SEPT9 has been shown to interact with SEPT2 [7] and SEPT7[7 ]Along with AHNAK, eIF4E and S100A11, SEPT9 was shown to be essential for pseudopod protrusion, tumour cell migration and invasion. The v2 region of the SEPT9 promoter had been shown to be methylated in colorectal cancer tissue compared with normal colonic mucosa Using highly sensitive real time PCR assays, methylated SEPT9 can be detected in the blood of colorectal cancer patients. This alternate methylation pattern in cancer samples is suggestive of an aberrant activation or repression of the gene compared to normal tissue samples
The SEPT9 gene methylation assay, a blood-based test used specifically for CRC detection and screening, was developed and used clinically for the above purposes. Septins are a group of scaffolding proteins that provide structural support during cell division Individual septins exist in stable six-to eight-subunit core heteromers, and the octamer contains two molecules of each of SEPT2, SEPT6, SEPT7, and SEPT9 subunits [7]. It was suggested that SEPT9 occupies a terminal position in the complex and plays a key role in subunit polymerization and the whole octamer stabilization [7]. It is also critical for the final separation of daughter cells during cytokinesis . Therefore, cytokinesis may be seriously affected if abnormal SEPT9 or no SEPT9 is expressed, and this could be a key factor in CRC carcinogenesis when the promoter region of the SEPT9 gene is hypermethylated and the transcription is compromised The SEPT9 gene methylation assay aim at detecting the aberrant methylation at the promoter region of the SEPT9 gene DNA released from CRC cells into the peripheral blood. In brief, the promoter region of the SEPT9 gene is hyper methylated and DNA of the gene is released into the peripheral circulating blood from necrotic and apoptotic cancer cells during CRC carcinogenesis, therefore, the risk of CRC can be determined by detecting the degree of DNA methylation of the specific promoter region of the SEPT9 gene in the peripheral blood. It was shown recently that major changes in the methylation pattern of SEPT9_V2 transcriptin colon adenoma and cancer tissues is confined to only one of the CpG islands, the CGI3. Due to the presence of trace amount of methylated SEPT9 DNA in the peripheral blood, the detection of DNA methylation must be sensitive enough to distinguish tiny amount of methylated DNA from much higher concentration of background un-methylated genome DNA. This requires accurate design of methylation probes and optimization of the whole PCR reaction system. Since the amount of methylated SEPT9 DNA from 10 ml whole blood sample is always as low as several genome copies, multiple PCR reactions has to be performed to enhance the detection sensitivity. The current commercialized SEPT9 assay (e.g., Epi proColon2.0) performs three PCR reactions and can detect as low as 2genome copies of methylated SEPT9 per milliliter of plasma in the background of 100 ng/ml unmethylated genome DNA
In spite of big variation in sensitivity of SEP9 from 48.2% to 95.6% observed among the assays with different algorithm, the specificity (80%-100%) remained high regardless of the variation in sensitivity In CRC .
Testing to detect methylated SEPT9 is not how ever indicated as a first option for colorectal cancer screening or colorectal adenoma .[8 ] It is similar in specificity and sensitivity to the stool guaiac test or faecal immune tests, and those tests should be used in preference.[8 ] In cases when the physician aggressively has recommended a colonoscopy and the patient has declined that and these other tests, then this test has advantages over patients having no screening at all
References
1] Cancer Facts & Figures (2013) Atlanta, GA: American Cancer Society.
2] Colorectal Cancer Facts & Figures 2011-2013. Atlanta, GA American Cancer Society.
3] Wild N1, Andres H, Rollinger W, Krause F, Dilba P, et al. (2010) A combination of serum markers for the early detection of colorectal cancer. Clin Cancer Res 16: 6111-6121.

4] J.S. Chen, K.T. Chen, W.C. Fan, Yu JS, Chang YS, et al. (2010) Combined analysis of survivin autoantibody and carcinoembryonic antigenbiomarkers for improved detection of colorectal cancer. Clin ChemLab Med 48: 719-725

5] Yu H, Son GM, Joh YG (2013) The clinical significance of pre operative serum levels of carbohydrate antigen 19-9 in colorectal cancer. J Korean Surg Soc 84: 231-237..

6] Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, et al. (2012)Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142: 248-256.
.
7] Osaka M, Rowley JD, Zeleznik-Le NJ (May 1999). \"MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25)\". Proceedings of the National Academy of Sciences of the United States of America 96 (11): 6428–33. doi:10.1073/pnas.96.11.6428. PMC 26898. PMID 10339604.
8]American Society for Clinical Pathology, \"Five Things Physicians and Patients Should Question\", Choosing Wisely: an initiative of the ABIM Foundation (American Society for Clinical Pathology), retrieved August 1, 2013, which cites
9] Potter NT1, Hurban P2, White MN3, Whitlock KD3, Lofton-Day CE4,et al. (2014) Validation of a real-time PCR-based qualitative assay forthe detection of methylated SEPT9 DNA in human plasma. Clin Chem60: 1183-1191.

Is FBOT \"FIT\" for use as a population screening test for CRC?‏
Posted on June 23, 2016
Shyan Goh
Sydney, Australia
Conflict of Interest: None Declared
It is often a curious thing that 2 persons can read the same document and yet reach different conclusions with respect to certain important aspects of the communication.

Dr Redberg had concluded in her editorial (Ref 1) that \"Although the USPSTF did not make a recommendation about what method to use for colon cancer screening, an evidence-based review of the literature they have assembled would favor either annual FOBT with colonoscopy in cases in which occult blood is detected or onetime flexible sigmoidoscopy.\" and made sure readers has understood the nomenclature used including the fecal occult blood test [FOBT] as distinct from fecal immunochemical test [FIT]

Having read the same USPSTF document (Ref 2), I cannot understand how this conclusion can be made, since at every level FIT testing appears to be superior to FOBT for the purpose of population screen for colorectal cancer.

The following extract from the section headed \"Effectiveness of Early Detection and Treatment\" in the document reflects some of the \"convincing evidence of benefit associated with colorectal cancer screening\" the USPSTF have on hand:

\"The CISNET models commissioned for this review estimated the number of life-years gained, colorectal cancer deaths averted, lifetime colonoscopies required (as a proxy measure for the burden of screening), and resulting complications (ie, gastrointestinal and cardiovascular events) for various screening strategies, varying the age at which to start and stop screening and the frequency of screening. With an age to begin screening of 50 years and an age to end screening of 75 years, assuming 100% adherence to screening over a lifetime, 4 screening strategies were estimated to provide an efficient balance of benefits and harms while also providing roughly comparable life-years gained: colonoscopy every 10 years, annual FIT, flexible sigmoidoscopy every 10 yearscombinedwith annual FIT, and CT colonography every 5 years. For CT colonography, the findings depend on the perspective taken: if lifetime number of colonoscopies is used as the proxy measure for the burden of screening, it is efficient; if cathartic bowel preparations are considered as the proxy measure, it is not efficient. The CISNET models estimated that these strategies would produce about 226 to 275 life years gained over a lifetime, or about 20 to 24 colorectal cancer deaths averted per 1000 adults aged 50 to 75 years screened.\"

Furthermore, in international perspective FIT as the first screening test has higher participation rates compared to flexible sigmoidoscopy or guaiac-based FBOT (Ref 3,4)

Perhaps Dr Redberg would like to explain her interpretation as to how she concluded using FBOT rather than FIT as a high-sensitivity fecal-based test to be used annually in conjunction with colonoscopy when the test is positive.

References

1. Redberg R. Fecal Blood Testing or Colonoscopy: What Is the Best Method for Colorectal Cancer Screening? [published online June 15, 2016]. JAMA: E1-3 doi:10.1001/jamainternmed.2016.3892.
2. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement [published online June 21, 2016].. JAMA. doi:10.1001/jama.2016.5989.
3. Hol L, van Leerdam ME, van Ballegooijen M, et al. Screening for colorectal cancer: randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy. Gut 2010; 59: 62-68.
4. Castigloine G. Screening for colorectal cancer: flexible sigmoidoscopy and faecal occult blood immunochemical testing. Which test is superior? Gut 2010; 59: 9-10.
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