Early Detection of Colorectal Cancer Made Easy with a Blood Test

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1 INFORMATION FOR PHYSICIANS Early Detection of Colorectal Cancer Made Easy with a Blood Test Epi pro Colon 2.0 : 2 nd Generation Septin 9 Test

2 CRC SCREENING SAVES LIVES Colorectal cancer is a major health problem in the industrialized world. More than 148,000 people in Europe and about 50,000 in the U. S. die of the disease every year, making colorectal cancer the second most common cause of cancer-related deaths (Figure 1). 1, 2 Death from colorectal cancer vs. traffic accidents 27,000 deaths from colorectal cancer < 4,000 deaths by traffic accidents Figure 1: Deaths from colorectal cancer and deaths by car accidents in Germany. Source: Felix Burda Foundation, 2009 Colorectal cancer is curable if diagnosed early Early detection can save the lives of people suffering from colorectal cancer. Most cases of colorectal cancer (CRC) are curable if diagnosed early enough. However, the chances of survival decrease, when the disease is diagnosed in more progressed stages (Figure 2) Survival Rate [%] Stage I Stage II Stage III Stage IV Figure 2: Survival rate for colorectal cancer by stage. Source: National Cancer Institute, PDQ, Treatment, Health Professionals Years

3 Colorectal cancer screening There is a variety of alternative procedures for CRC screening that may be divided into invasive and non-invasive methods. Established invasive methods comprise colonoscopic and sigmoidoscopic examination, while conventional methods include fecal occult blood testing (FOBT) by either guaiac-based (gfobt) or immunochemical-based stool tests (fecal immunochemical test, FIT) detection. All CRC screening methods have been proven to be effective in the battle against colorectal cancer. However, the majority of patients avoid such examinations, thus depriving themselves of the chance of early detection and a potential cure. Compliance to CRC screening a blood test makes the difference Despite numerous educational and informational campaigns, colorectal cancer screening is still not well-accepted: less than half of all eligible individuals participate in colorectal cancer screening today. A nationwide telephone survey in the United States with 1,304 participants aged 50 + conducted for Colorectal Cancer Alliance demonstrated that 75 % of the participants would get regular screening if a blood-based CRC screening assay was available. 3 In France 86 % of patients would agree to do regular screening with the blood test. 4 For these people the Septin 9 blood test is a viable alternative. THE SEPTIN 9 BLOOD TESTS: Early detection of colorectal cancer in the blood With Septin 9 blood tests, such as Epi pro Colon 2.0 CE, you can offer your patients a simple and safe alternative for early detection of colorectal cancer. The test detects the epigenetic biomarker Septin 9 in blood plasma. This biomarker methylated DNA of the Septin 9 gene correlates strongly with the presence of colorectal cancer. As the Septin 9 blood tests can be performed at any time and without discomfort to the patient, it offers considerable potential for increased patient acceptance and a real opportunity to lower the mortality rate from colorectal cancer. IMPORTANT FOR YOUR PATIENTS: The Septin 9 blood tests can be performed at any time and can easily be included in a general health checkup. No dietary restrictions are required before performing the test. Both blood sampling and discussion of test result are handeled in the physician s office with an average time for testing of around one week.

4 Study data Epi pro Colon 2.0 CE is a 2 nd generation Septin 9 blood test with substantially increased clinical performance compared to the first generation test. Performance evaluation studies demonstrated > 80 % sensitivity to colorectal cancer with 99 % specificity (Figure 3). The effectiveness of the Septin 9 blood test was determined in numerous studies involving thousands of participants including a prospective evaluation in a screening cohort of 8,000 subjects. 5 7 The first generation Septin 9 blood test, Epi pro Colon, has been available as a CE-marked kit since Oct 2009 in Europe. The Septin 9 blood test therefore offers a well established, safe and patient-friendly option of taking part in colorectal cancer screening that so often saves lives. # Samples 1/149 79/98 18/27 25/29 27/31 9/ % 99 % 81% 67 % 86 % 87 % 82 % 80 % Positivity 60 % 40 % 20 % 0 % CVNs * All CRC ** Stage I Stage II Stage III Stage IV * Colonoscopy verified normals ** Colorectal cancer Figure 3: Detection rates of the Epi procolon 2.0 CE blood-based 2 nd generation Septin 9 blood test by stage from three case-control studies. Comparison of Epi pro Colon 2.0 CE with non-invasive screening tests The most widely used non-invasive CRC screening methods are the guaiac FOBT and variations of the OC-Sensa Micro Test, an immunological FOBT. Compared to those methods the Epi pro Colon 2.0 CE has an unmatched positive predictive value at an equally high negative predictive value. On average one out of two positive tested patients has cancer and the probability of a true negative result is 99.9 %. Epi pro Colon 2.0 CE provides the most accurate option for non-invasive CRC screening combined with the unprecedented convenience of a blood test.

5 METHOD SPECIFICITY SENSITIVITY NEGATIVE PREDICTIVE VALUE POSITIVE PREDICTIVE VALUE 2 nd Generation Septin 9 Test Epi pro Colon % 80.6 % 99.9 % 45.7 % Guiac Fecal-Occult Blood Test % 37.1 % 99.6 % 10.1 % OC-Sensa Micro qfit1x % 69.2 % 99.8 % 7.5 % OC-Sensa Micro qfit3x % 84.6 % 99.9 % 5.6 % CRC with positive test result, healthy with positive test result assuming a prevalence for CRC of 0.7 % Septin 9 performance in polyps Normal epithelium Large adenoma Colon carcinoma SEPTIN 9 POSITIVE FRACTION 10 HEALTHY ADVANCED ADENOMA CANCER Tissue 8 % 100 % 100 % Plasma 15 % 35 % 75 % Figure 4: Detection rates of Septin 9 in plasma from patients suffering from advanced adenomas and cancer. Tissue samples from both adenomas and cancer were 100 % positive. The data were generated by Tóth et al. 10 with a modifi ed Epi procolon 1.0 assay.

6 Simple performance in the medical practice The Septin 9 blood test allows you to offer your patients a new, reliable alternative for early detection of colorectal cancer. No intestinal preparation is required before performing the test. There are no restrictions with regard to food or drug intake. The patient can be tested at any time by a simple blood draw which can easily be included in a general health checkup. Sampling for the test and communication and explaination of the test result is in the hand of the physician (Figure 5). Patient with average risk of colorectal cancer Blood sample Laboratory Test report Physician Figure 5: Schematic of Septin 9 clinical work-up Blood sampling for the test In order to perform the Epi pro Colon 2.0 CE blood test, a blood sample is taken using a 9.5 ml EDTA tube or a 8.5 ml CPDA tube and sent to a diagnostic laboratory which measures and evaluates Septin 9. Within approximately one week the test result is returned to the physician. Who should take the test? The test is suitable for everyone with an average risk of colorectal cancer, who has no symptoms, but wants to take part in colorectal cancer screening. The purpose of the test is not to replace screening colonoscopy. Instead, it is aimed at people looking for a safe alternative that enables them to take part in colorectal cancer screening. Test costs The Septin 9 blood test is a diagnostic method that, at present, may not or only partially be reimbursed in your country. Thus, the patient may have to bear all or part of the test costs. Please contact your local laboratory for the exact price. For a list of laboratories, which perform the test, please contact Epigenomics.

7 1. Lofton-Day et al, DNA-Methylation Biomarkers for Blood-Based Colorectal Cancer Screening, Clin. Chem, 2008;54: Grützmann et al, Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay, PLOS One, 2008;3(11):e DeVos T. et al, Circulation methylated SEPT9 DNA in Plasma as a Biomarker for Colorectal Cancer, Clin. Chem, 2009;55:7m Weiss G. and T. Rösch, Potenital of a new blood Test for Colorectal Cancer Screening-the Septin9 Gene Biomarker, European Oncology, Volume 6, Issue 1, (2010) 5. Church et al, Prospective clinical validation of an assay for methylated Septin 9 DNA in human plasma as a colorectal cancer screening tool in average risk men and women 50 years and older, Oral Presentation at DDW, Chicago, IL, m S9 real-time PCR Assay, Gebrauchsanleitung, Abbott Molecular, Rösch et al, Prospective Clinical Validation of a Biomarker, Methylated SEPT 9 DNA, for Colorectal Cancer Detection in Plasma of Average Risk Men and Women Over the Age of 50, Poster Presentation at UEGW, Barcelona, Spain, Heichmann et al, Use of Septin 9 Methylated DNA Biomarker to Detect Cancer in the Blood of Colorectal Cancer Patients Poster Presentation at ASCO-NCI-EORTC Annual Meeting on Molecular Markers, Hollywood, FL, Lofton-Day et al, DNA-Methylation Biomarkers for Blood-Based Colorectal Cancer Screening, Clin. Chem, 2008;54: Grützmann et al, Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay, PLOS One, 2008;3(11):e DeVos T. et al, Circulation methylated SEPT9 DNA in Plasma as a Biomarker for Colorectal Cancer, Clin. Chem, 2009;55:7m Weiss G. and T. Rösch, Potenital of a new blood Test for Colorectal Cancer Screening-the Septin9 Gene Biomarker, European Oncology, Volume 6, Issue 1, (2010) 5. Church et al, Prospective clinical validation of an assay for methylated Septin 9 DNA in human plasma as a colorectal cancer screening tool in average risk men and women 50 years and older, Oral Presentation at DDW, Chicago, IL, m S9 real-time PCR Assay, Gebrauchsanleitung, Abbott Molecular, Rösch et al, Prospective Clinical Validation of a Biomarker, Methylated SEPT 9 DNA, for Colorectal Cancer Detection in Plasma of Average Risk Men and Women Over the Age of 50, Poster Presentation at UEGW, Barcelona, Spain, Heichmann et al, Use of Septin 9 Methylated DNA Biomarker to Detect Cancer in the Blood of Colorectal Cancer Patients Poster Presentation at ASCO-NCI-EORTC Annual Meeting on Molecular Markers, Hollywood, FL, 2010 The test result The Septin 9 blood test result is either negative or positive with respect to the presence of Septin 9 in plasma (Figure 6). A negative test result means that the likelihood of the patient having colorectal cancer is extremely low. For Epi pro Colon 2.0 CE a negative test result indicates a probability of 99.9 % that the patient does not suffer from colorectal cancer (99.9 % negative predictive value). Nevertheless, as colorectal cancer can develop spontaneously over time, the patient should be advised to repeat the test every one or two years similar to conventional stool tests. A positive Septin 9 blood test result means that the likelihood of the patient having colorectal cancer is increased. For Epi pro Colon 2.0 CE a positive test results indicates a probability of 45 % that the patient suffers from cancer (45 % positive predictive value). These patients are strongly advised to undergo colonoscopy for establishing the diagnosis and initialization of treatment. Septin9 Test Result Analysis Report: Septin9 Test Result TEST RESULT: NEGATIVE Test Description: The Septin9 test Epi procolon detects presence of methylated Septin9 DNA ( m SEPT9) in a plasma sample of a patient. Test Methods: DNA purification from plasma, bisulfate conversion, duplex real-time PCR. Test Result: The blood plasma sample no. was analysed with the Septin9-Test Epi procolon. The analysis was done in replicate. A sample is classified as positive, when at least one of the two measurements was tests positive for m SEPT9. The sample submitted for analysis was classified as: Negative Analysis Report: Test Description: The Septin9 test Epi procolon detects presence of methylated Septin9 DNA ( m SEPT9) in a plasma sample of a patient. Test Methods: DNA purification from plasma, bisulfate conversion, duplex real-time PCR. Test Result: The blood plasma sample no. was analysed with the Septin9-Test Epi procolon. The analysis was done in replicate. A sample is classified as positive, when at least one of the two measurements was tests positive for m SEPT9. The sample submitted for analysis was classified as: Epi procolon 2.0 CE negative patients are correctly classified as healthy with 99.9 % probability. Screening should be done regularly. for the presence of m SEPT9 in blood plasma. Positive Test Analysis: It has been validated in several clinical studies that there is a strong association between detection of m SEPT9 in blood plasma with presence of colorectal cancer. for the presence of m SEPT9 in blood plasma. Comment on positive test result: a positive test result means that there is an increased likelihood for the presence of CRC. Individuals with positive test results are encouraged to undergo a diagnostic colonoscopy. From 20 positive tests, an average of 1 person will be diagnosed with Test Analysis: It has been validated in several clinical studies that there is a strong association CRC and 7 will be diagnosed with polyps. between detection of m SEPT9 in blood plasma with presence of colorectal cancer. Comment on negative test result: a negative test result means that m SEPT9 methylation Comment on positive test result: a positive test result means that there is an increased like- could not be detected, so with this method, there is no indication for increased likelihood for the lihood for the presence of CRC. Individuals with positive test results are encouraged to undergo presence of CRC. Individuals with negative test results are correctly classified as being CRC a diagnostic colonoscopy. From 20 positive tests, an average of 1 person will be diagnosed with negative 99.7 % of the time. CRC and 7 will be diagnosed with polyps. Comment on negative test result: a negative test result means that m SEPT9 methylation could not be detected, so with this method, there is no indication for increased likelihood for the presence of CRC. Individuals with negative test results are correctly classified as being CRC negative 99.7 % of the time. TEST RESULT: POSITIVE An average of one out of two Epi pro Colon 2.0 CE positive patients suffer from colorectal cancer. The probability is 45 %. Figure 6: Example of a laboratory report LITERATURE 1. American Cancer Society, Colorectal Cancer Facts & Figures, Globocan 2008, Cancer Fact Sheet, Telephone survey Colorectal Cancer Alliance. CCA Denver, Zarca et al. Transversales Biarritz, Weiss G. and T. Rösch, European Oncology, Volume 6, Issue 1, Rösch et al. Poster Presentation at UEGW, Barcelona, Spain, Tetzner et al. UEGW, Allison et al. NEJM, Park et al. Am. J. Gastro., Tóth et al. UEGW, 2011.

8 INFORMATION FOR PHYSICIANS You can obtain further information on the Epi pro Colon 2.0 CE test at: Phone: contact@epigenomics.com Epigenomics AG Kleine Praesidentenstr Berlin Germany Not for sale in the United States. MKT0012GB, rev Epigenomics AG