Limburg, Paul J.

AbstractRecommended colorectal cancer screening modalities vary with respect to safety, efficacy, and cost. Better understanding of the factors that influence patient preference is, therefore, critical for improving population adherence to colorectal cancer screening. To address this knowledge gap, we conducted a panel survey focused on three commonly utilized colorectal cancer screening options [fecal immunochemical test or guaiac-based fecal occult blood test (FIT/gFOBT), multi-target stool DNA (mt-sDNA) test, and colonoscopy] with a national sample of U.S. adults, ages 40–75 years and at average risk of colorectal cancer, in November 2019. Of 5,097 panelists invited to participate, 1,595 completed the survey (completion rate, 31.3%). Our results showed that when presented a choice between two colorectal cancer screening modalities, more respondents preferred mt-sDNA (65.4%) over colonoscopy, FIT/gFOBT (61%) over colonoscopy, and mt-sDNA (66.9%) over FIT/gFOBT. Certain demographic characteristics and awareness of and/or experience with various screening modalities influenced preferences. For example, uninsured people were more likely to prefer stool-based tests over colonoscopy [OR, 2.53; 95% confidence interval (CI), 1.22–5.65 and OR, 2.73; 95% CI, 1.13–7.47]. People who had heard of stool-based screening were more likely to prefer mt-sDNA over FIT/gFOBT (OR, 2.07; 95% CI, 1.26–3.40). People who previously had a stool-based test were more likely to prefer FIT/gFOBT over colonoscopy (OR, 2.75; 95% CI, 1.74–4.41), while people who previously had a colonoscopy were less likely to prefer mt-sDNA or FIT/gFOBT over colonoscopy (OR, 0.39; 95% CI, 0.24–0.63 and OR, 0.40; 95% CI, 0.26–0.62). Our survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal cancer screening recommendations.Prevention Relevance:Our national survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal screening recommendations.

Abstract Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (−2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. Prevention Relevance: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.

27 Background: Colorectal cancer (CRC) is the second most deadly and fourth most frequently diagnosed cancer in the United States. Early detection can improve CRC outcomes, but overall screening rates (62%) remain below the 80% goal set by the National Colorectal Cancer Roundtable. Multiple options are endorsed for average-risk CRC screening, including the multi-target stool DNA (mt-sDNA) test, which includes patient and provider navigation support. Cross-sectional adherence with the mt-sDNA test was previously reported in a large Medicare population (71%). In the current study we investigated cross-sectional adherence with the mt-sDNA test in a broader, national sample of insured patients. Methods: Aggregate data from Exact Sciences Laboratories LLC (ESL; Madison, WI) were retrospectively analyzed in compliance with HIPAA requirements. Study participants included individuals ages 50 years and older who were covered by commercial insurance or Medicare, had a valid mt-sDNA test order placed between January 1–December 31, 2018, and received a test kit shipped from ESL. Cross-sectional adherence, defined as successful completion and return of the test kit within 365 days of the shipment date, was assessed overall and by patient- and provider-level factors. Results: In total, 1,420,460 participants met the study criteria (61.2% women; mean age 65.7 years). Overall cross-sectional adherence was 66.8%. Adherence was 72.1% in participants with Traditional Medicare, 69.1% in participants with Medicare Advantage, and 61.9% in participants with commercial insurance (p<0.001). Adherence increased by participant age (p<0.001): 60.8% for ages 50-64, 71.3% for ages 65-75, and 74.7% for ages 76+ years. For Traditional Medicare patients, ages 65-75, adherence was 73.6%. Participants with mt-sDNA tests ordered placed by gastroenterologists had a higher adherence rate (78.3%) than those with orders placed by primary care clinicians (67.2%) (p<0.001). Adherence rates were highest among patients with ordering providers in the Pacific region (71.4%) and West North Central region (70.1%), and lowest in the Mid-Atlantic region (65.7%), New England (65.2%), West South Central region (64.6%), and Puerto Rico and US territories (60.7%). Conclusions: Novel data from this large, national sample of insured patients demonstrate high cross-sectional adherence with the mt-sDNA test (66.8%), supporting the substantial contribution this guideline-endorsed option plays in average-risk CRC screening. At the patient-level, adherence increased with patient age, and was highest in those covered by Traditional Medicare. Provider-level stratification showed the highest adherence for mt-sDNA tests ordered by gastroenterologists. This study adds to data regarding the impact of accompanying navigation support and at-home convenience of mt-sDNA on screening completion rates.

Abstract High-specificity colorectal cancer screening is desirable to triage patients &lt;50 years for colonoscopy; however, most endorsed colorectal cancer screening tests have not been rigorously evaluated in younger populations. This prospective cross-sectional study determined the specificity of the multitarget stool DNA (mt-sDNA) test in an average-risk screening population of 45 to 49 year-olds. Specificity was the primary outcome and was measured in participants without colorectal cancer or advanced precancerous lesions [APL– advanced adenomas (AA), and sessile serrated lesions ≥10 mm], and in the subgroup of participants with negative colonoscopic findings. APL sensitivity was a secondary outcome. The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. Of 983 enrolled participants, 816 formed the evaluable cohort, with a mean age of 47.8 (SD, 1.5) years; 47.7% were women. No participants had colorectal cancer, 49 had APL, 253 had nonadvanced adenomas (NAA), and 514 had negative colonoscopic findings. mt-sDNA test specificity was 95.2% (95% CI, 93.4–96.6) in participants with NAA or negative findings [96.3% (confidence interval (CI), 94.3%–97.8%)] in those with negative findings, and did not differ by sex (P = 0.75) or race (P = 0.36) in participants with NAA or negative findings. Sensitivity for APL was 32.7% (CI, 19.9–47.5%), with most APL (83.7%) measuring 10–19 mm and none having high-grade dysplasia. The area under the ROC curve for discriminating between APL and lesser findings was 0.72 (CI, 0.64–0.81). mt-sDNA's high specificity would help minimize risk from unnecessary diagnostic procedures in this age group. This study shows that mt-sDNA has high specificity among average-risk 45 to 49-year olds, supporting its use as a noninvasive option for colorectal cancer screening. Prevention Relevance: This study shows that mt-sDNA has high specificity among average-risk 45–49 year olds, supporting its use as a non-invasive option for colorectal cancer screening.

We conducted a survey of primary care clinicians and gastroenterologists (n = 938) between 11/06/19–12/06/19 to assess knowledge and attitudes regarding colorectal cancer screening. We assessed clinicians’ attitudes toward lowering the colorectal cancer screening initiation age to 45 years, a topic of current debate. We also evaluated provider and practice characteristics associated with agreement. Only 38.1% of primary care clinicians endorsed colorectal cancer screening initiation at age 45 years, compared to 75.5% of gastroenterologists (p < .0001). Gastroenterologists were over 5 times more likely than primary care clinicians to endorse lowering the screening initiation age (OR = 5.30, 3.54-7.93). Other factors found to be independently associated with agreement with colorectal cancer screening initiation at age 45 years included seeing more than 25 patients per day (vs. fewer) and suburban (vs. urban) location. Results emphasize the need for collaboration between primary care clinicians and gastroenterologists to ensure that patients receive consistent messaging and evidence-based care.

Abstract Background Real‐world data for patients with positive colorectal cancer (CRC) screening stool‐tests demonstrate that adenoma detection rates are lower when endoscopists are blinded to the stool‐test results. This suggests adenoma sensitivity may be lower for screening colonoscopy than for follow‐up to a known positive stool‐based test. Previous CRC microsimulation models assume identical sensitivities between screening and follow‐up colonoscopies after positive stool‐tests. The Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC‐AIM) was used to explore the impact on screening outcomes when assuming different adenoma sensitivity between screening and combined follow‐up/surveillance colonoscopies. Methods Modeled screening strategies included colonoscopy every 10 years, triennial multitarget stool DNA (mt‐sDNA), or annual fecal immunochemical test (FIT) from 50 to 75 years. Outcomes were reported per 1000 individuals without diagnosed CRC at age 40. Base‐case adenoma sensitivity values were identical for screening and follow‐up/surveillance colonoscopies. Ranges of adenoma sensitivity values for colonoscopy performance were developed using different slopes of odds ratio adjustments and were designated as small, medium, or large impact scenarios. Results As the differences in adenoma sensitivity for screening versus follow‐up/surveillance colonoscopies became greater, life‐years gained (LYG) and reductions in CRC‐related incidence and mortality versus no screening increased for mt‐sDNA and FIT and decreased for screening colonoscopy. The LYG relative to screening colonoscopy reached >90% with FIT in the base‐case scenario and with mt‐sDNA in a “medium impact” scenario. Conclusions Assuming identical adenoma sensitivities for screening and follow‐up/surveillance colonoscopies underestimate the potential benefits of stool‐based screening strategies.

AbstractTumor‐infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T‐lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T‐cells in colorectal tumor and histologically normal tissues with CRC‐specific and all‐cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin‐embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55–69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow‐up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC‐specific and all‐cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38–0.89) for CRC‐specific mortality and 0.82 (0.63–1.05) for all‐cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19–1.17) and 0.50 (0.27–0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC‐specific and all‐cause mortality. Although the association between tumor CD3+ score and all‐cause mortality was not significant, both higher CD3+ T‐lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC‐specific and all‐cause mortality.