Hamilton, Stephanie

4052 Background: 18q LOH may be a useful marker in stage II colon carcinoma to assess who needs adjuvant chemotherapy. The objective of this study was to evaluate the intra- and inter-laboratory reproducibility of an assay for 18q LOH that is similar to the integral assay used in E5202, the current Intergroup phase III stage II colon carcinoma clinical trial. Methods: Specimens from 130 stage II/III colon cancer patients were obtained from the Cooperative Human Tissue Network and evaluated at three different laboratories. Samples were divided into subsamples, coded and distributed. Each laboratory used similar equipment in an established PCR protocol with 5 dinucleotide repeats. Starting materials used both histologic sections and extracted DNA samples of tumor and non-neoplastic tissue obtained only by scalpel microdissection. LOH was defined as tumor/normal peak ratio that was >1.35 or <0.67 without microsatellite instability (MSI). Tumors were categorized as either MSI+, LOH + or -, uninformative/monoallelic, or unevaluable (DNA not amplifiable). Standard tests assessed reproducibility of both the numerical ratios and the tumor 18q LOH status. Results: Sample quality issues prevented analysis of 13 tumors (10%). The frequency of 18q LOH was 64%. The probability of agreement on the same tumor evaluated twice was 92% (Cohen's kappa 0.83). Intra-class correlation coefficients for individual markers were consistently over 0.90. Tissue specimens must have high (>85%) tumor cell content for reproducibility. Differences among patients affected reproducibility much more than effects of laboratory and sample type (DNA vs. histologic section). Conclusions: This study validates reproducibility of the 18q LOH assay for both clinical categorization of status and numerical ratios if samples are high quality and appropriate for scalpel microdissection. [Table: see text]

Abstract Background: Mammography (digital 2D or digital 3D/tomosynthesis) is the cornerstone of current screening strategies for breast cancer, but new approaches are needed to further reduce the proportion of cancers diagnosed at advanced stages and more effectively identify those women in need of additional testing and biopsies. Circulating cell-free nucleic acids (cfNAs) shed from tumors, isolated from peripheral blood, and analyzed with ultra-deep and broad sequencing of cancer-associated genes, have great potential for early cancer detection. The ultimate goal is to develop blood cfNA cancer screening tests for use in conjunction with established risk factors and/or radiographic features for improved cancer detection. Development of these tests requires large, well-annotated cohorts of asymptomatic participants with adequate volumes of prediagnostic blood. The STRIVE Study cohort was recently established to train and validate cfNA-based tests for early detection of breast cancer. Eligibility criteria and trial design: The STRIVE Study is a new prospective, multi-ethnic mammography cohort that will recruit 120,000 subjects from 15+ US breast cancer screening centers (including Mayo Clinic and Sutter Health sites). Eligibility criteria require only that a participant has a scheduled routine screening mammogram at a participating center and has not received a biopsy prior to the research blood draw. Participants are recruited within 28 days of screening mammography (digital or tomosynthesis), consent electronically, provide blood samples, and complete an on-line risk factor questionnaire. Participants will be followed for all cancer diagnoses, cancer recurrences, and death for at least 5 years. Pertinent medical record information, imaging findings (including breast density), and follow-up data will be transferred electronically to a central database throughout the study period. Additional blood samples will be collected from participants with abnormal mammogram results, or who are diagnosed with cancer, to document and better understand the evolution of cfNA signals. Recruitment began in February 2017. Primary Aims: To train and validate a cfNA blood-based test to identify breast cancer overall in a cohort of women undergoing screening mammography. Statistical Methods: The study will be divided into a training phase (1/3 of participants) and an independent clinical validation phase (remaining 2/3 of participants). In the training phase, statistical machine learning techniques will be used to develop algorithms incorporating cfNA signals, clinical characteristics, or radiological features. In the validation phase, the prespecified locked algorithm developed from the training phase will be clinically validated in an independent group of women. Contact information for people with a specific interest in the trial: Additional details regarding the STRIVE Study are available on the ClinicalTrials.gov website (NCT03085888). For site-specific questions, please call 844-366-9738 for the Mayo Clinic and 1-855-578-7483 for Sutter Health. Citation Format: Liu MC, Cummings S, Vachon CM, Kerlikowske K, Couch FJ, Morris EA, Olson JE, Polley EC, Conners AL, Ellis RL, Patel B, Maimone IV S, Zhang N, Hamilton S, Clarke CA, Allen BA, Maddala T, Hartman A-R. Development of cell-free nucleic acid-based tests for early detection of breast cancer: The STRIVE study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-02-01.