Colorectal cancer screening

Usually, routine colorectal cancer (CRC) screening starts at 45 years and older with occult blood testing followed by colonoscopy. The U.S. Preventive Services Task Force recommends that adults aged from 45 to 75 years should be screened for colorectal cancer. Have you reached 45 years or more (1)? Did you receive a fecal occult blood test (FOBT)? A study found that after 10 years of CRC screening, the cumulative probability of a true-positive colorectal cancer result was 0.6% with annual FOBT screening and 0.4% with biennial screening and the true-positive rate of FOBT was only 1.9 per 1000 tests for people aged 65 years who undergone FOBT followed by sigmoidoscopy. Thus, FOBT was ensured to reduce colorectal cancer mortality whereas it also couldn’t replace nor reduce the rate of colonoscopy nor sigmoidoscopy (2).

What is the most challenging part you face when performing colonoscopy? Most people fear pain, bleeding, bloating and diarrhea post sigmoidoscopy or colonoscopy. Unfortunately, many people don’t show compliance when subjected to sigmoidoscopy.

What's the future? What do people need to do to overcome this dilemma? Blood based tests with reduced cost and time effectiveness in addition with significant true results are needed to decrease the need for sigmoidoscopy and colonoscopy, also to overcome the low true positive FOBT results. (2) Our team of researchers studied a panel of blood based biomarkers namely eotaxin-1 which was found to be present in high serum levels in colorectal cancer (3), macrophage inflammatory protein-1 beta (MIP-1 beta) an inflammatory cytokine found to be highly expressed in CRC tissues (4), granulocyte colony-stimulating factor (G-CSF) which is also highly expressed in CRC tissues and promote cancer migration (5) and finally vascular endothelial growth factor (VEGF-A) which was found to be an independent prognostic factor in patients with non-metastatic colorectal cancer (6). When we studied the serum levels of these four biomarkers in early stage of colorectal cancer patients and compared their overall combined performance with FOBT we found that the ROC curve generated cut-off value for serum eotaxin-1 was (113.31 pg/mL), serum MIP-1β (96.07 pg/mL), serum G-CSF (23.35 pg/mL) and serum VEGF (195.94 pg/mL). It can be noted that MIP-1β has the highest sensitivity (91.43%) and NPV (92.5%). While VEGF has the highest specificity (92.31%) and PPV (85.2%). Stool occult blood was false positive for CRC diagnosis in 33 subjects out of 52 non-malignant subjects i.e. (63.5%). Thus, the studied serum markers were more sensitive and specific in detecting CRC patients, in addition the area under the ROC curve for the combined panel of the studied markers (eotaxin-1, MIP-1β, G-CSF and VEGF-A) was 0.863 which was better than area under the ROC curve 0.597 for routinely used occult blood in the stool. Additionally, on combining the ROC curve of the studied panel together with occult blood, the area under the curve was increased to 0.875 thus if combined with the occult blood test they may increase the performance of FOBT in the diagnosis of colorectal cancer. Furthermore, the used multiplex bead assay is a promising technique in measuring multiple biomarkers at the same time while being cost efficient and highly sensitive (7). Previous studies were done in the USA (8), Malaysia (9), Poland (10) and Japan (11) on various combinations of serum biomarker in colorectal cancer patients that augment our results. We hope more work can be done to implement these biomarkers in routine colorectal cancer screening practice.

References

1. Knudsen AB, Rutter CM, Peterse EF, et al. Colorectal Cancer Screening: A Decision Analysis for the US Preventive Services Task Force. Agency for Healthcare Research and Quality; 2021. AHRQ publication 20-05271-EF-2
2. Hubbard RA, Johnson E, Hsia R, Rutter CM. The cumulative risk of false-positive fecal occult blood test after 10 years of colorectal cancer screening. Cancer Epidemiol Biomarkers Prev. 2013 Sep;22(9):1612-9. doi: 10.1158/1055-9965.EPI-13-0254. Epub 2013 Jul 18. PMID: 23868091; PMCID: PMC3770276.
3. Zajkowska M, Mroczko B. Eotaxins and Their Receptor in Colorectal Cancer-A Literature Review. Cancers (Basel). 2020 May 28;12(6):1383. doi: 10.3390/cancers12061383. PMID: 32481530; PMCID: PMC7352276
4. Erreni M, Mantovani A, Allavena P. Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenviron. 2011 Aug;4(2):141-54. doi: 10.1007/s12307-010-0052-5. Epub 2010 Sep 17. PMID: 21909876; PMCID: PMC3170420
5. Morris, K. T., Khan, H., Ahmad, A., Weston, L. L., Nofchissey, R. A., Pinchuk, I. V., & Beswick, E. J. (2014). G-CSF and G-CSFR are highly expressed in human gastric and colon cancers and promote carcinoma cell proliferation and migration. British journal of cancer, 110(5), 1211-1220
6. Pascual, M., Alonso, S., Salvans, S., Mayol, X., Mojal, S., Gil, M. J. & Pera, M. (2018). Postoperative serum Vascular Endothelial Growth Factor is an independent prognostic factor of disease free survival and overall survival in patients with non metastatic colon cancer. American journal of surgery, 216(2), 255-259.
7. Nicole C. Japp, Joshua J. Souchek, Aaron R. Sasson, Michael A. Hollingsworth, Surinder K. Batra, Wade M. Junker, "Tumor Biomarker In-Solution Quantification, Standard Production, and Multiplex Detection", Journal of Immunology Research, vol. 2021, Article ID 9942605, 12 pages, 2021. https://doi.org/10.1155/2021/9942605
8. Henry, C. J., Sedjo, R. L., Rozhok, A., Salstrom, J., Ahnen, D., Levin, T. R. & Byers, T. (2015). Lack of significant association between serum inflammatory cytokine profiles and the presence of colorectal adenoma. BMC cancer, 15, 123
9. Johdi, N. A., Mazlan, L., Sagap, I., & Jamal, R. (2017). Profiling of cytokines, chemokines and other soluble proteins as a potential biomarker in colorectal cancer and polyps. Cytokine, 99, 35-42.
10. Krzystek-Korpacka, M., Zawadzki, M., Kapturkiewicz, B., Lewandowska, P., Bednarz-Misa, I., Gorska, S. & Gamian, A. (2018). Subsite heterogeneity in the profiles of circulating cytokines in colorectal cancer. Cytokine, 110, 435-441.
11. Yamaguchi, M., Okamura, S., Yamaji, T., Iwasaki, M., Tsugane, S., Shetty, V., & Koizumi, T. (2019). Plasma cytokine levels and the presence of colorectal cancer. PloS one, 14(3), e0213602.