Heigh, Russell I.

341 Background: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have historically been underdetected by screening due to their inconspicuous, nonhemorrhagic, and proximal nature. New generation sDNA-MT show high sensitivity for both CRC and advanced adenomas (Gastroenterology 2012;142:248), but screen detection of serrated polyps by this approach requires further validation. Aim: To assess and compare noninvasive detection of sessile serrated polyps >1cm (SSP) by sDNA-MT and a commercial quantitative FIT. Methods: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA-MT in batches using optimized analytical methods (Gastroenterology 2012;142:S770). The sDNA-MT panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab <2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). Results: Age/sex distributions were similar in cases and controls: 40% vs 45% > 65 years and 51% vs 59% women, p=NS respectively. SSP median size was 1.2cm (range 1-3cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among sDNA-MT markers, mBMP3 proved highly discriminant for SSP detection (AUC=0.87, p<0.00001); other DNA markers were less informative and provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC=0.50, p=NS). At matched specificities, SSP detection by stool mBMP3 was significantly greater than by either FIT-50 or FIT-100 (Table). Conclusions: From a screening and surveillance setting, SSP can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection. [Table: see text]

Abstract Background: Studies of colorectal cancer screening by multitarget stool DNA (MT-sDNA) show false-positive (FP) rates of 7% to 13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes. Methods: We compared subsequent clinical events among patients with apparent FP MT-sDNA with those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having nonadvanced or negative baseline colonoscopy findings from a single referral center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis, and onset of alarm symptoms. Results: Of 1,050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years [interquartile range (IQR), 56.8–72.3]; 54% were female. Median follow-up time was 4 years (IQR, 3.5–5.3). Eight aerodigestive (lung and gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol, cutoffs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cutoff method, FP status was not associated with mortality or alarm symptoms. Conclusions: Although FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population. Impact: These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings. Cancer Epidemiol Biomarkers Prev; 26(4); 614–21. ©2016 AACR.

Abstract We have demonstrated that colorectal cancer (CRC) and advanced pre-cancers can be detected non-invasively by a manual multi-target stool DNA-based test (sDNA-MT) comprising exfoliated DNA markers (methylated BMP3 and NDRG4, mutant KRAS (7 mutations, codons 12, 13), plus β-actin) and fecal hemoglobin (Hb) (Lidgard, Gastroenterology 2012;142(5);S-770). We now report the clinical performance of this sDNA-MT test using an optimized automated analytic platform and logistic algorithm. This platform could facilitate the routine performance of sDNA-MT for CRC screening by molecular diagnostics capable clinical laboratories. Method: Stool samples were collected from 1003 subjects at 36 study sites after informed consent and prior to colonoscopy bowel preparation from those presenting for average risk CRC screening (283) or surveillance (176) at 2 sites. From referred subjects with CRC, Advanced Adenoma (AA) or Sessile Serrate Adenoma ≥ 1 cm, (SSA) stool was collected at least 7 days post-colonoscopy and prior to surgery or chemo-radiation (135; 21 sites) and similarly for subjects with no neoplastic findings on colonoscopy (Neg) (409; 13 sites). The study population included: cases (207), 58% male, median age 65 yrs. (38-87), CRC (93), AA (84), SSA ≥ 1 cm (30) and controls (796), 42% male, median age 65 yrs. (50-84), Neg (641) and non-advanced adenomas (NA) (155). Stool sample collection and DNA isolation were previously described. Automated methylation, mutation and actin assays were performed with a Hamilton STARlet fluid handler (Hamilton Robotics, Reno NV), and QuARTS (Quantitative Allele-specific Real-time Target and Signal amplification) run on an ABI 7500 FastDx real time thermal cycler (Applied Biosystems, Foster City, CA). Fecal Hb (ng/ml buffer) analysis was performed by automated sandwich ELISA. A “Positive” or “Negative” result was determined with an algorithm that included the methylation and mutation results and a logistic regression score, which combines DNA marker results with Hb and actin results. Algorithm results exceeding a threshold were called “Positive”. The algorithm provided good discriminative ability, stability, sensitivity and specificity. Robustness was tested with computer simulations and statistical techniques (leave-one-out and 10-fold cross validation). Results: At a 90% nominal specificity, sDNA-MT sensitivity was 98% for CRC (91/93) [Stage: I, 95% (20/21), II, 100% (23/23), III 96% (26/27), IV 100% (7/7) and I-III combined 97% (69/71)], 57% (65/114) for precursors ≥1 cm (AA, SSA), and 86% (12/14) for precursors with high grade dysplasia. CRC patients were typically referred to colonoscopy for symptoms and test sensitivity may be elevated relative to that seen with screening. Conclusion: With this study using a novel automated sDNA-MT analytic platform with logistic algorithm, we corroborate our earlier findings using a manual process and demonstrate a platform that allows testing to be performed routinely by molecular diagnostic capable laboratories. The high sensitivity of sDNA-MT for CRC across all stages and for advanced precursors with high-grade dysplasia could lead to improved non-invasive CRC screening performance with wide accessibility to patients. A large multi-site pivotal CRC screening study (DeeP-C study clinicaltrials.gov, NCT01397747) to support such use is underway. Citation Format: Graham P. Lidgard, Michael J. Domanico, Janelle J. Bruinsma, James Light, Zubin D. Gagrat, Rebecca L. Oldham-Haltom, Keith D. Fourrier, Hatim Allawi, Tracy C. Yab, Julie A. Simonson, Mary Devens, Russell I. Heigh, David A. Ahlquist, Barry M. Berger. An optimized molecular stool test for colorectal cancer screening: Evaluation of an automated analytic platform and logistic algorithm. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B12.

Background and Study Aims. The presence of an implantable electromechanical cardiac device (IED) has long been considered a relative contraindication to the performance of video capsule endoscopy (CE). The primary aim of this study was to evaluate the safety of CE in patients with IEDs. A secondary purpose was to determine whether IEDs have any impact on images captured by CE.Patients and Methods.A retrospective chart review of all patients who had a capsule endoscopy at Mayo Clinic in Scottsdale, AZ, USA, or Rochester, MN, USA, (January 2002 to June 2010) was performed to identify CE studies done on patients with IEDs. One hundred and eighteen capsule studies performed in 108 patients with IEDs were identified and reviewed for demographic data, method of preparation, and study data.Results.The most common indications for CE were obscure gastrointestinal bleeding (77%), anemia (14%), abdominal pain (5%), celiac disease (2%), diarrhea (1%), and Crohn’s disease (1%). Postprocedure assessments did not reveal any detectable alteration on the function of the IED. One patient with an ICD had a 25-minute loss of capsule imaging due to recorder defect. Two patients with LVADs had interference with capsule image acquisition.Conclusions.CE did not interfere with IED function, including PM, ICD, and/or LVAD and thus appears safe. Additionally, PM and ICD do not appear to interfere with image acquisition but LVAD may interfere with capsule images and require that capsule leads be positioned as far away as possible from the IED to assure reliable image acquisition.

Abstract COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported. Cancer Prev Res; 5(12); 1381–93. ©2012 AACR.

Abstract Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5–34) and 8 (0–37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (−69% to 143%), −18.6 (−83% to 160%), −3.6 (−88% to 83%), and −10.0 (−100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12–0.59) nor between-arm (P = 0.30–0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P &gt; 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size. Cancer Prev Res; 4(2); 259–69. ©2011 AACR.