Researchers today presented promising results from two new blood tests that can aid in the early identification of patients with gastrointestinal (GI) cancers. The results were presented at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the comined 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin (Germany). The new blood tests will make GI cancer detection simpler, cost-effective, and more acceptable to patients than current methods, the researchers say.
The first study, presented by Joost Louwagie, PhD, Vice President at OncoMethylome Sciences (Liège, Belgium), showed data in which tumor markers for colorectal cancer were selected, the analytical performance of the test and the first results from a multi-centre feasibility study. “This test has potential to provide a better balance of performance, cost-effectiveness and patient compliance than other options currently available for colorectal cancer screening,” Louagie said.
The scientists collected blood before surgery from 193 patients known to have colorectal cancer, as well as from 688 controls undergoing colonoscopy for cancer screening. DNA was extracted from the blood plasma and tested for the presence of DNA methylation of specific genes. DNA methylation is involved in the regulation of protein expression, and methylation or silencing of key genes has been linked to the initiation and progression of tumors.
Based on studies conducted in colorectal tissues, methylated genes that were capable of discriminating accurately between cancerous and normal tissues were chosen. The scientists then evaluated the best-performing methylated genes in blood samples, with the ultimate goal of providing a sensitive, specific and patient-friendly option for colorectal cancer screening.
SYNE1 and FOXE1
Says Louwagie: “We optimized the methods of DNA extraction and methylation detection so that we could detect low levels of methylated genes in people with colorectal cancer. We were able to find a high frequency of two newly reported methylation genes, SYNE1 and FOXE1, in colorectal cancer patients. The same methylation genes occurred infrequently in non-cancerous individuals.”
When testing a first set of 444 controls and 124 colorectal cancer patients, with plasma volumes ranging between 0.8 and 4.3 ml, the sensitivity and specificity for the combination of SYNE1 and FOXE1 was 58% and 90% respectively. Testing this marker combination in a second, independent group of 242 controls and 69 cases, the sensitivity (proportion of positives correctly identified) and specificity (proportion of negatives correctly identified) were 56% and 91% respectively (77% and 91% in the samples with at least 3.3 ml of plasma). The sensitivity for stage I and II disease was 41% and 80% respectively.
Colorectal cancer occurs in approximately one in every 17 people during their lifetime and is the second leading cause of cancer death in the United States and Europe; in these places a combined total of about 560,000 people develop the disease each year, and 250,000 die from it. Deaths can be reduced if the cancer is diagnosed at an early stage, when it is most treatable. Although there are already two effective screening methods, they both have drawbacks.Colonoscopy, where the interior of the colon and rectum is examined using a tiny camera mounted on a flexible tube, is the most sensitive test currently available and has the benefit of allowing removal of pre-cancerous polyps. Colonoscopy, however, is invasive, expensive, requires bowel preparation and skilled practitioners, making it inaccessible or unacceptable for many patients.
Faecal occult blood testing (FOBT), where patients give stool samples to be analyzed, is less invasive, inexpensive and is used in national screening programs in some European countries. However, due to patients’ reluctance to handle stool samples, compliance for even the best-organized national screening programs is often less than 50%.
“Once validated in a prospective colorectal screening trial, the new methylation test could be used as a non-invasive screening option for patients who decline or do not have access to colonoscopy or do not wish to undertake the faecal occult blood test,” said Louwagie. “The blood sample can be taken by nurses or primary care doctors without the need for special equipment or training, leading to higher rates of patient compliance and the identification of patients needing the more expensive and diagnostic colonoscopy procedure. Giving such a blood sample could become part of the regular physical examination undertaken as part of a health insurance package in many countries.”
The scientists are currently enrolling people into a prospective colorectal screening study in several German colonoscopy centers. “We plan to complete enrollment of 7000 people by the end of 2009,” noted Louwagie “and are currently talking to several partners about distribution rights. This new test will not replace colonoscopy, but provide a way of screening a larger part of the population in a more patient-friendly and non-invasive manner so that more cancers are detected and treated successfully.”
Another test: S100A4 mRNA
In a different study, researchers from Germany said that they have developed another blood test that helps diagnose tumors in patients with colon, rectal, or gastric cancers. Professor Ulrike Stein, PhD, at ECRC Charité University of Medicine, and the Max-Delbrueck-Centre for Molecular Medicine, both based in Berlin (Germany), says that the test can also predict the likelihood of metastatic disease in patients after diagnosis of these cancers.
Stein and her team looked for the existence of an S100A4 transcript, by isolating RNA from blood plasma samples from patient with GI tumors. Genetic transcription takes place when the information carried in DNA is copied into an RNA molecule, and is the first stage in the expression of a protein. They collected daily blood samples from hospitalized and outpatients; 185 samples for colon cancer, 190 for rectal, and 91 for gastric cancer patients. They also analyzed the blood of 51 age-matched, tumor-free volunteers.
“We found that S100A4 mRNA was present at significantly higher levels in the group of cancer patients, no matter whether they had colorectal or gastric cancer, than in the tumor-free control group,” Stein explained. “And there were yet higher levels in the patients with metastases than in those where the disease had not yet metastasized. More importantly, prospective analysis of the data showed that follow-up patients who later developed metastases showed higher S100A4 levels at initial blood analysis than those whose disease did not metastasize. This means that in future we might be able to identify those patients who are likely to develop metastases.”
Because the new test could be useful in identifying tumors in patients showing no signs of disease, it could be an effective tool in population screening for GI cancers. This needs to be tested in a large prospective trial, the researchers say. The S100A4 transcript was already known to promote the increased metastatic capability of cancer cells, but the problem to date has been that tests to establish its existence in a tumor have been expensive and complicated.
The scientists now intend to look at the correlation of S100A4 transcript levels in blood and the survival of individual patients after a minimum of three years follow-up. “We are hoping that, by enabling the identification of those patients whose disease is likely to progress more quickly, we will be able to treat them in the future accordingly by tailoring therapy to their individual needs,” Stein said.
For more information:
- Gastrointestinal malignancies, colorectal cancer 1, Monday 12.45 and 13.00 hrs CEST (Hall 2) Abstract #12LBA (Louwagie) and 13LBA (Stein).
Also read these PubMed Abstracts:
- Mokarram P, Kumar K, Brim H, Naghibalhossaini F, Saberi-firoozi M, et al. Distinct high-profile methylated genes in colorectal cancer. PLoS One. 2009 Sep 11;4(9):e7012.
- Ikenaga N, Ohuchida K, Mizumoto K, Yu J, et al. S100A4 mRNA is a Diagnostic and Prognostic Marker in Pancreatic Carcinoma. J Gastrointest Surg. 2009 Aug 4. [Epub ahead of print]
- Ohuchida K, Mizumoto K, Miyasaka Y, Yu J, Cui L et al. Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis. J Pathol. 2007 Nov;213(3):275-82
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