Stool DNA Screening for Colorectal Cancer David Ahlquist, MD Carrol M Gatton Professor of Digestive Science Mayo Clinic, Rochester MN
Disclosures Relationship with Exact Sciences Mayo Clinic Equity investor Licensed technologies Dr. Ahlquist Scientific Advisor Inventor of licensed technology Research collaborator 2
Stool DNA Testing A more thoughtful approach and anyone can do it!
Effective Detection Effective Detection = S x C x A S = sensitivity C = compliance A = access 4
CRC Screening Tool Ideal Features Accurate detection Curable stage CRC Critical precursors (adenoma + serrated) Both R & L sides Noninvasive & safe Simple & convenient No prep or restrictions Affordable Widely distributable S C A 5
Stool DNA Testing High detection rates for CRC & precancer Unaffected by site Noninvasive No cathartic preparation No diet or med restriction Off-site collection Widely accessible Biologically rational Muco-cellular layer * * Ahlquist et al. Hum Pathol 2000 31:51
Optimized Stool DNA Test Simple device for collection & mailing Buffered, stable >2 wks Targets multiple markers Methylated BMP3 & NDRG4 Mutant KRAS β-actin (human DNA) Hemoglobin (FIT) Sensitive multiplex DNA assay (QuARTS) Automated
Automated Stool Assay Developed by Exact Sciences Lidgard et al. CGH-Online 2013
Next Generation Stool DNA Testing for Detection of Colorectal Neoplasia: Early Clinical Evaluation Ahlquist, Zou, Domanico, Mahoney, Yab, Taylor, Thibodeau, Rabeneck, Kinzler, Vogelstein, Bjerregaard, Laurberg, Sørensen, Berger, Lidgard Multicenter casecontrol study N=678 CRC 253 Adv ad 130 Freezer archived specimens Stool DNA test Non-optimized prototype Covariate analyses 2012; 142:248 9
Cancer & Adenoma Detection Effect of Lesion Site 100 80 87 83 Proximal Distal % 60 55 53 40 20 0 Cancer Adenoma 1 cm 10
Sensitivity (%) Adenoma Detection Effect of Size P<0.0001 79 91 64 31 ~ 1 >1 >2 >3 Adenoma Size (cm) 11
Detection of Sessile Serrated Polyps >1cm From Screen Setting: sdna vs FIT Heigh et al. GI Cancer Symposium (San Francisco 1/2013) 12
Factors NOT Affecting DNA Stool Markers Sex, Race, or Geography Smoking Alcohol NSAIDs Personal hx polyps FHx CRN Body mass Ahlquist et al. J Mol Biomark Diagn 2012 13
Optimized & Automated Stool DNA Test Case-Control Study Lidgard et al. CGH-Online 2013 Prospective, blinded, multicenter Cases CRC 93 Adv precancer* 114 Controls Normal colonoscopy 641 * Advanced adenoma + serrated polyp >1cm
Cancer Detection Effect of Stage 95% 100% No stage effect p = NS 97% 96% 100% Overall sensitivity 98% 15
Adenoma Detection Effect of Size Sensitivity for HGD* 83% *94% found In lesions >2cm
Optimized Stool DNA Test Screen Setting Multicenter study completed (Imperiale et al) Cross-sectional, >10,000 Stools prior to screening colonoscopy Stool DNA vs FIT Topline data only Sensitivity CRC 92% Adv precancer* All 42% >2cm 66% (specificity 87%**) Currently under FDA & CMS review in USA * Adv adenoma + serrated polyp >1cm ** Normal includes polyps <1cm Superiority over FIT, all categories
Hypothetical Programmatic Sensitivity of Next Gen Stool DNA Testing Screen Frequency q 3 yr Cumulative Sensitivity, % Lesion Cohort Large Precancer* CRC Screen 1 42-66 92 Screen 2 71-91 (99) Screen 3 90-98 -- * 1-2cm size cutoff, assume volume doubling time 6 yrs 18
Stool DNA Test Is More Accurate Than Plasma Septin 9 Test in Detecting Colorectal Neoplasia DA AHLQUIST, WR TAYLOR, DW MAHONEY, H ZOU, M DOMANICO, SN THIBODEAU, LA. BOARDMAN, BM BERGER, GP LIDGARD CGH 2012;10:272 Cancer Large Adenomas False Positives: sdna 7% pseptin9 27% 19
Plasma Septin9 in Screening Setting The PRESEPT Study Church et al. Gut Online 2/13/2013 7941 asymptomatic persons, >50 yrs, prior to screening colonoscopy Sensitivity @ 91% specificity CRC (53) 48% Stage I 35% Stage II 63% 45% Stage III 46% Stage IV 77% Adv Ad (314) 11% HGD 12%
Conceptual Model Plasma Markers (vascular invasion) Distant metastasis? Stool Markers (exfoliation) Large Pre-cancer I II III IV Cancer 21
Stool Collection Not a barrier to compliance Much easier than bowel prep & completely noninvasive With pt-friendly collection device, return rate >95% Ann Intern Med 1988;108:607 Key determinants of screen test selection* Accuracy/effectiveness Convenience 3 rd party coverage *Mayo patient survey (unpublished) 22
Comparison of Tests FS Colo VC Cap sdna Accurate detection CRC + precursors - + +? + Both R & L sides - +/- +? + Operator-independent - - - - + Noninvasive & safe - - - - + Simple & convenient - - - - + No prep or restricts - - - - + Affordable???? + Widely distributable - - - - + UGI Screen Capacity - - + + ++ 23
Stool DNA Testing The Clear Winner!