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PROSPR Project 1: Identifying and Tracking Personalized CRC Screening Regimens for Patients in Clinical Settings

ABSTRACT: The overall goal of the Parkland-UT Southwestern Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) Center is to optimize colon cancer screening through personalized regimens in the integrated safety-net clinical provider network, which serves a large and diverse population of under- and un-insured patients in Dallas. Together, three research projects will assess clinic, system, and organizational factors associated with over-, under- and guideline-based screening among this important population and will compare benefits, harms, and costs of strategies for facilitating optimized screening regimens. The theme of optimizing colorectal cancer screening in a safety-net clinical provider network brings together several components. Its focus on colorectal cancer (CRC) screening which is important, because CRC is the second cancer killer in the US while being the only major cancer for which optimized screening results in primary prevention. Despite this strong potential benefit, CRC screening remains suboptimal overall, and especially among low-income and minority individuals served by safety-nets. Safety-net networks therefore offer tremendous potential for CRC prevention and control, but numerous factors at the clinics-, system-, and organization-level influence their ability to provide optimized care.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2286810 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the US, though CRC death can be reduced by screening. However, there is uncertainty as to which screening strategy is most clinically and cost-effective from a population perspective where the aim is to optimize completion of the entire screening process continuum. Modeling studies suggest benefits and harms of colonoscopy and stool blood test strategies are similar, but generally assume 100% participation and subsequent clinically appropriate follow up--something never achieved in clinical practice. Comparative effectiveness studies of testing strategies, including comparisons of specific tests and approaches to optimizing effective test use, are necessary. Safety-net health systems care for populations at increased risk for adverse CRC outcomes, such as the uninsured and minorities, and have more limited resources. Therefore, safety-nets must resolve the uncertainty regarding the most effective screening strategy. The investigators will conduct a system-level, randomized comparative effectiveness trial of the benefits, harms, and costs of 3 screening strategies over 3 years, among 6000 patients age 50-64 years, who are not up-to-date with CRC screening, served by a large safety net health system. The three strategies studied will be: 1) Fecal immunochemical testing, with annual mailed invitation outreach (including a test kit), and a centralized process to promote participation and complete clinical follow up (FIT); 2) Colonoscopy, with annual mailed invitation outreach, and a centralized process to promote participation and complete clinical follow up (Colo); 3) Usual Care, with no mailed invitation outreach, and screening offered at primary care visits. The primary measure of benefit will be an outcome measure that summarizes patient-specific effective screening successes. The primary measure of harm will be screening non-participation. The primary measure of cost will be cost per-patient effectively screened. Our specific aims are to: 1) Compare benefits, harms, and costs of a FIT strategy versus a Colo strategy for CRC screening among patients not up-to-date with screening, and 2) Compare benefits, harms, and costs of a) the FIT strategy vs. Usual Care and b) the Colo strategy vs. Usual Care for CRC screening.

Project description:In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh-frozen tissue from 86 CRC patients using Illumina’s Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF), which is a representation of allelic composition. This data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (MSI, histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g., amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From the Therapeutic Target Database we found relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions harboring genes which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high-density SNP arrays for cytogenetic study in CRC and its importance for personalized treatment. DNA was extracted from colon tissue samples provided by 86 CRC patients. Each patient provided paired CRC tumor tissue and adjacent normal colon mucosa samples, which were fresh-frozen after resection. Samples were genotyped using Illumina's Infinium-based 610 Quad and CytoSNP 12 microarray chips. The genotype data from paired tumor and normal samples was used to detect tumor-specific chromosomal instabilities in copy number, including copy-neutral LOH, which cannot be assessed by many other cytogenetic methods. Supplementary file "GSE34678_raw_GPL8887.txt" includes the raw data for Samples using GPL8887 (GSM853162-GSM853239); supplementary file "GSE34678_raw_GPL13829.txt" includes the raw data for Samples using GPL13829 (GSM853240-GSM853363).

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PROSPR Project 1: Identifying and Tracking Personalized CRC Screening Regimens for Patients in Clinical Settings

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